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And these are the kinds of things that many people experience. These would be things where you were affected in a way that you thought your life was being threatened or you were seriously injured. Let me give you some examples. People may have been in a very serious motor vehicle collision where they or others were injured or even killed. People sometimes have been held up at gunpoint or assaulted badly. And particularly for women, it's important that we ask about experiences of domestic violence, of intimate partner violence. And for both men and women, I'll ask another question and say, you know, what was it like for you growing up? Were you in situations where you felt unsafe? Were there times where you were maltreated as a child, where you were either beaten or punished severely? And then I'll usually ask, you know, was there a time where you might have been sexually assaulted? And so, you know, the whole set of questions asked takes maybe a couple minutes. But I think it's very important to be asking those questions. Maybe not necessarily the first time if you're not a psychiatrist, you're seeing a patient. But certainly, once you get to know them a little bit from the perspective of a psychiatrist, these are things we would be asking in the very first visit. Oh, that's really helpful advice. And I think the more that cardiologists can start to ask patients about these and then capture it in a way that we're documenting it will not only help us take better care of our patients, but will help observational researchers be able to understand these links. I think often even people who have previously diagnosed PTSD don't end up having those diagnoses entered into the medical record. So if you're looking prospectively, you may miss a number of cases. I think it's also important to point out we're just coming out of Mental Health Awareness Month in May. So hopefully we learned some lessons during that month that we can keep with us throughout the year. So let's end this conversation by putting our researcher hats back on. You both have talked about some clear gaps in the evidence and your panel with NHLBI was convened to try to identify research gaps and future needs. Dr. O'Donnell, tell us what the panel thinks in terms of what should we be doing next to help unravel this link and then potentially even start to do something about it. There are a number of recommendations that came through in this excellent exercise of our panel. First would be to any new population studies that would be formed, and that was certainly recommended, would focus heavily on very precise phenotyping of PTSD, capture of all important covariates and risk factors, and also good outcome ascertainment, and ideally prospective longitudinal studies. These can be expensive, but if there were one or two very focused studies on this topic, much could be learned. Second is that it turns out there's not much in the way of great animal or even human tissue models for the study of PTSD. And two mechanisms that were particularly focused on were altered neuronal circuitry, brain circuitry, as well as increased inflammation and altered immune system. And those were highly recommended as the focus of studies, both in animal and human models. Thirdly, that there's an emerging studies of genome-wide association for PTSD that is recommended to be combined with existing and newly accruing studies of genome-wide association for coronary disease, heart failure, and its risk factors. And this provides opportunities for Mendelian randomization studies. And finally, as we move towards the real goal, which is clinical trials that could test the question whether modification of PTSD symptoms could lower risk, to think carefully about the best clinical studies that could be put together now that would lay the groundwork for future trials that could really potentially benefit this important population. Yeah, and just to add what Chris was mentioning about clinical trials, I mean, one of the problems we have on the psychiatry side of the shop is that our clinical trials, a large clinical trial in PTSD might have 200 individuals in it. And they're typically pretty short. A pharmacological treatment trial might be, you know, 12 or 16 weeks. So none of those studies are large enough or long enough for us to actually be able to see whether the effects of the primary PTSD treatments are beneficial or maybe even worsening cardiovascular outcomes. So, you know, putting in a plug for NHLBI and NIMH and BA and DOD to think more about the possibility of tracking PTSD in some of the large cardiovascular outcome studies, but also to be thinking about conducting PTSD studies in a way that they're long enough and large enough that we actually could look at cardiovascular outcomes. I think those are great suggestions, both a call for increased funding for studies specifically looking at this association, but also a reminder that we can probably learn a lot about PTSD and cardiovascular disease in a lot of the other studies that we're doing, but we have to remember to collect that data and ask the patients or people who are enrolling in those studies about their experiences. Just one final question for either of you. The Million Veterans Study is an amazing example of a large cohort study getting really in-depth data on genetics and other phenotypic data on persons at the VA. Should we be looking for more information about this PTSD link either in some of the mechanisms in terms of the genetics through that study? Perhaps, Dr. O'Donnell, do you know anything that we maybe should have our antennas up for? Well, first of all, both Dr. Steen and myself are investigators in that study and have worked really since its inception. It is an amazing cohort that now has over 850,000 enrolled participants and is indeed studying both the genetics and epidemiology of PTSD, as well as cardiovascular disease and its risk factors. And so absolutely, yes, this is an opportunity that I'm pleased to say is already being explored in the Million Veteran Program. We've had several other members of our panel who are very expert in the genetics of PTSD, in addition to Dr. Steen. And so definitely, this is going to be a source of some great findings that could potentially help guide the research directions. Yeah, and as Chris noted, the manuscript itself talks about using some of those large biorepository-based studies to look at associations and using techniques such as Mendelian randomization to be able to address the question of causality. So yes, those are all great ideas. And in fact, they're in process. And I think we all hope to start to see some of those results soon. Dr. Steen, Dr. O'Donnell, thank you so much, both for joining us on the podcast today, but also for your work on this really important manuscript published in JAMA Cardiology. I think we have some great reminders for clinicians listening to remember to ask about mental health and PTSD in particular to identify people who may be at increased risk and a really good call for those of us researchers in cardiovascular epidemiology and clinical trials to think about how we can better unravel the link between PTSD and cardiovascular disease, and perhaps even more importantly, start to identify treatments to mitigate that risk. Finally, thanks to our listeners for joining us today on this podcast. Please visit jamanetworkaudio.com for more from the JAMA Network, Thank you.
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Okay, welcome. This is the 120th episode of the Divine Intervention Podcast. My name is Divine. I am an R01 Reology resident, I guess PGY2. And today I'll be continuing my rapid review series for the USMLE Step 1. And I will be, so this will be series, I mean, sorry, for the USMLE Step 2CK, and this will be series 4, and I'll focus on a broad range of subjects, but again, I will try to hit internal medicine pretty hard. So let's go ahead and begin, right? So what if you get a question about like an 80-year-old person that, you know, is losing their way, like coming back from a store, excuse me, and they forget to turn off the stove and the MMS is like 20 over 30. What are you thinking about? Right. That is clearly Alzheimer's. Right. So those people have Alzheimer's. And remember, in Alzheimer's. Right. What is the neurotransmitter that is classically low? That would be acetylcholine. And unfortunately, your friends at the MBME, they love to test your ability to integrate neurological disease with neuroanatomical relationships. So the thing is, in Alzheimer's, there's low levels of acetylcholine. thing is if that's all you needed to know everyone will crush step two right but unfortunately that's not the case so they kind of take things a step further right so remember that acetylcholine is made in the basal nucleus of mynert right so when a person has this dysfunction of the basal nucleus of mynert they will have symptoms of alzheimer's disease right and another way they also love to test it on exams is remember that the rate limiting enzyme in the synthesis of acetylcholine is an enzyme known as choline acetyltransferase right so if you have dysfunction of that enzyme right you again that will increase a person's risk of like an acetylcholine deficiency and alzheimer's right and then don't forget right that kids with um um kids with down syndrome right they tend to get early onset alzheimer's because they have trisomy 21 so they have too much of the pre-seniline gene if you may right so if you know right off the bat that a deficiency of acetylcholine is kind of like involved in many of the symptoms in Alzheimer's, or at least in the pathophysiology, you then ask yourself, okay, so how do I treat Alzheimer's, right? So obviously, you want to do something that involves bumping up your levels of acetylcholine, right? So you want to do something like an acetylcholinesterase inhibitor. And those acetylcholinesterase inhibitors that I use for Alzheimer's, you do actually need to know them specifically, right? There's three of them, like a DRG, right? So the one is a donepezil, right? And then the next one is galantamine. And then the next one is a rivastigmine. They are all acetylcholinesterase inhibitors that are used in the treatment of Alzheimer's. Okay. Now, what if you get a question about a kid, you know, let's assume it's a kid that, so this will be a PEDS-focused stem, I guess. What if you get a kid that has, the location of this kid has episodes where he cries and he becomes cyanotic. And let's assume they tell you that, oh, when you listen to his heart, you hear like a harsh, hollow, systolic murmur at the left lower sternal border. What am I going after here? Well, I really hope you're thinking about Tetralogy of Fallot, right? Tetralogy of Fallot, remember, it's a common congenital heart disease, and you should hopefully remember the four findings, right? So those people tend to have, and again, when I give an anatomy lecture in the future on congenital heart disease, I will explain the pathophase with a diagram. It's actually something that's pretty easy to understand. Right. But basically, those people, because really all those findings, like I really never try to memorize them. Because if you understand the pathophase behind Tetralogy of Fallot, it makes perfect sense. Right. But those people, right, they have like the pulmonic stenosis. They have the, in in fact maybe let me try to take a small stab at um explaining it right so the thing is when you want to form the um usually usually the thing that happens is that this is again this is a generalized explanation right again i'll go into more detail in a future podcast. But the thing is, the aortic pulmonary septum usually tries to meet up with the muscular interventricular septum, like sort of align nicely with it. So I sort of think of it as you're trying to form a straight line and you want the aortic pulmonary septum to fall right on top of the muscular interventricular septum. Well, if things don't work out so well and the aortic pulmonary septum comes and descends to the right of the muscular interventricular septum, it's like you're not dividing the two sides of the heart very well. It's like one side has a ton of space, and then another side has very little space. And the side that has very little space, guess what, is the right side of the heart, right? So if you sort of understand that basic pathophys, you see that, again, a lot of what you observe makes sense. Because the uricopulmonary septum and a lot of it is coming off to the right, then that means outflow from the right right side of the heart is very restricted. So those people should have pulmonic stenosis, right? And then because they have pulmonic stenosis, the right ventricle have to work real hard to get blood out. So you have a hypertrophied right ventricle. And then because that overriding a order is not meeting nicely in the middle, you'll notice that those people will have a VSD. You'll have a VSD because again, you're literally creating a space because things are not lining up as they should right and then obviously they have an overriding aorta overriding aorta because it's just taking more space than you should ordinarily take because the aortic pulmonary septum is not dividing things as it should remember the aortic pulmonary septum i mean look at the name aortic pulmonary septum it's a septum between the aorta and the pulmonic trunk right so if you are not dividing things equally and you give too little space to the pulmonic trunk, you have pulmonic stenosis and you give too much space to the aorta, you have a right in aorta, right? Those are the four things that work with Tetralogy of Fallot, right? And remember the pathophys behind those Tet spells, right? So remember those Tet spells because the problem with Tetralogy of Fallot is because you have right ventricular hypertrophy, those kids have a right to left shunt. Remember, any shunt that is right to left is cyanotic, but any shunt that is left to right is asyanotic. So that's why they have those tet spells. With those tet spells, those kids, they cry or they squat. And when you squat, right, guess what you're doing? You're compressing on your blood vessels. So you're increasing systemic vascular resistance. When you up that systemic vascular resistance, right, blood will be harder to eject from the left side of the heart. So you basically turn that right to left shunt to a left to right shunt, okay? And you basically reverse the cyanosis, right? So that increase in systemic vascular resistance or afterload promotes a left to right shunt, right? So that's the pathophase behind those tet spells helping under those, oh, I guess those maneuvers helping under those circumstances. And then just again, some key buzz phrases you want to remember for your order cardiac things, right? Or some other, I guess, high-yield cardiac associations. Again, since this is just a rapid review series, remember, right, they love to test this wide fixed split of the S2 heart sound, right? They love to test that in the context of an ASD, right? Remember, if they give you a question about like an old guy having like syncopal episodes, exercise intolerance, adenogena and all that stuff, and then they tell you that his carotid pulse is delayed, right? You should be thinking about aortic stenosis under those circumstances. Remember, it's a systolic murmur, right? Heard best at the right upper sternal border, right? And remember that those people, you have to replace the valve.
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You don't do any of that crap. Replace the valve, okay? And remember that once they start having symptoms, their life expectancy is actually pretty minimal, right? So remember, I think I used this mnemonic, ashnemonic ash to remember like oh in order of like decreasing life expectancy right so if they have like so the a stands for angina the s stands for syncope and then the h stands for heart failure if a person with aortic stenosis has heart failure symptoms their mortality within a year is i think like 50 or some? So that's a high-yield thing to know. And then if you see a person in their 50s with aortic stenosis, right, you want to think about a bicuspid aortic valve, right? That's pretty classic for aortic stenosis there. And remember, people that tend to get bicuspid aortic valve early are people that have, like, Turner's syndrome, right? Like, Turner's syndrome. Remember, Turner's syndrome has some other high-yield associations. In addition to the bicuspid iotic valve, they have like congenital lymphedema, right? So those are cystic hygromas. And then remember that they can also have coarctation of the udder, right? So if they give you a Turner syndrome patient that has hypertension in the upper extremities and hypotension in the lower extremities, think about a coarctation of the udder, right? And then remember those people, they also have like a hypergonadotropic hypogonadism, right? Because they don't have, their gonads basically don't work, right? So their FSHLH levels will be high. So that'll be a cause of hypergonadotropic hypogonadism, right? And then remember that they can also have horseshoe kidney, right? So again, if they describe recurring UTIs in a lady that is like four foot and some inches tall, right? Think about horseshoe kidney, right? Because remember those Turner syndrome kids tend to be pretty tiny, right? They tend to be like short, right? So think about like horseshoe kidney where the inferior poles of the kidney fuse, they're stuck on there, the inferior mesenteric artery, right? Again, these are all integrations you need to, that's the thing, like I tell people this, I tell all the people I tutor this, doing well on these MBME exams is not about how much did you memorize. Of course, like you need to have a good memory to do well on this. To be honest, actually, you don't need a great memory. You just need an okay memory. The thing that is important is being able to, one, be a good test taker, and then two, just be able to integrate concepts amongst multiple fields. That's why I do these rapid review series. It's really like literally from requests like, Devine, how do I put this together? That's why I love to do these kinds of podcasts. Okay, so back to the real world, right? So I just talked about aortic stenosis. Now, if you get a question, right, about a person that has, they have like bounden pulses, they have this diastolic murmur that is heard best at the left lower sternal border and then you notice that their blood pressure is like 150 over 50 right so they have like a super wide pulse pressure what murmur are you thinking about I really hope you're thinking about aortic regurgitation right in fact let me tell you this trick for mbmes if you ever see a wide pulse pressure on an MBME exam, your next thinking step is, am I dealing with a kid or an adult? If it's an adult, it's very likely going to be aortic regurgitation. That's the right answer. If it's a kid, it's very likely going to be patent ductus arteriosus. That is the right answer. The thing is, aortic regurg and patent ductus arteriosus, those things tend to have fairly similar, like, hemodynamic consequences, if you really think about it. Again, that's something for, not something I'm going to be discussing in a rapid review lecture, but it's just one of those things you want to keep at the back of your mind for exams. Again, I promise you, take these MPMEs, take your real exam. You'll see that all these things I'm saying are true, right? And then what is the congenital heart condition that's classically associated with people with Marfan's? Right? So people with Marfan's, they tend to get what? Mitral valve prolapse, right? And I hope you remember the pathophys buzzword for mitral valve prolapse, right? That'll be your myxomatous degeneration, right? Myxomatous degeneration. And then they also can get like aortic dissection, right? And remember, in aortic dissection, the buzz phrase you want to remember is like a cystic medial necrosis, okay? Cystic medial necrosis or cystic medial degeneration. They love to test those for whatever bizarre reason on MBMs, right? So remember Marfan syndrome with those, right? And then also remember like those other connective tissue diseases like Ernest Danlos, right? Those things can be associated with like aortic dissection as well, aortic valve problems. Also, if a person has ankylosing spondylitis, it has an association with aortic problems, right? And then also don't forget, right, if a person has syphilis, remember syphilis loves to torch the vis-a-vis of your aortic arch that can also cause an aortitis, right? And then what if you get a question about a person that has like, you know, they're an immigrant from a developing country and you hear a diastolic murmur with an opening snap at the apex, right? What are you thinking about there? I hope you're thinking about, again, mitral stenosis, right? Mitral stenosis. So why did I mention the term immigrant? Well, I mentioned that term because they likely had an upper respiratory infection that was likely from strep pyogenes, right? So group A strep, and then it was likely not treated, and then they got mitral stenosis from that, right? So remember that their biggest risk factor for mitral stenosis is rheumatic fever, right? That's how you ought to know for exams. And then remember that mitral stenosis itself is the biggest risk factor for AFib. Again, they love to test these risk factors on step 2CK on step 3, right? And then remember that your biggest risk factor, right, for like a myocardial infraction for AAA smoking, right? And then your biggest risk factor for strokes and voyeuric dissection is hypertension, right. These are things you should have on your fingertips as you prepare for these exams. Now, what if you get a question about a patient that has a continuous machine-like murmur? Like they say, oh, you'll hear this murmur throughout the cardiac cycle. What are you thinking about, right? That's pretty easy. That's a patent to Dr. Sartorius. And then remember, people that have a history of like carcinoid syndrome, right? Remember, carcinoid doesn't cause any problems if it's in the bowel, right? Because the liver has the ability to metabolize a carcinoid. But remember, again, carcinoid is a tumor that makes serotonin, right? Pretty much, right? So remember that in carcinoid. But, and remember, again, carcinoid is a tumor that makes serotonin, right, pretty much, right? So, remember that in carcinoid, you need meds to the liver to begin to have, like, systemic problems, right? So, when you have those meds to the liver, the liver, right, will release the serotonin from the carcinoid or tumor, and then that will begin to cause a lot of, like, right-sided heart lesions, right? And the way I remember the right-sided heart problems is, like, with the pneumonic tips, right? So, like, tricuspid insufficiency and pulmonic stenosis, right? So those people have those kinds of symptoms. The reason you don't get left heart problems with carcinoid is, again, the lungs has the ability to metabolize that serotonin, right? Remember, the lungs, in addition to helping with, like, oxygenated function and all that crap, your lungs are actually pretty solid metabolic organs, right?
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It's found in the lungs, right? It's found in the endothelium of the capillaries of the lungs, right? So your lungs have the ability to work on a serotonin. And you do need to remember the right, and again, I apologize if this podcast seems kind of random. I'm literally like about to go to bed. It's almost 1130. I'm literally about to go to bed. I'm literally just sitting on my bed, just saying out Step 2 CK related things before I sign off and go and sleep but basically um um people with carcinoid right so remember one of the breakdown things from uh serotonin is something called 5-hi-a-a right so remember that if a person has carcinoid you screen first by checking levels of, like you observe elevated levels of 5-HIAA in the serum or in the urine. And the thing is, one nifty way your friends at the NBMA actually love to test that 5-HIAA concept is in the context of depression. So we know that people that right? If you remember like the monoamine theory of depression, those people tend to have low levels of serotonin, norepinephrine, and dopamine, right? So the thing is, if a person is depressed, they probably have low levels of serotonin metabolites in their CSF, for example. Like what? 5-HIAA, okay? So that's a very nice way they can test that factoid on MBME exams. Right? So those are, I guess, kind of like the cardiac things I want to... Actually, let me say one more thing about carcinoid syndrome. So the thing is, carcinoid syndrome, right, you're basically making a ton of serotonin. The problem there is serotonin ultimately comes from tryptophan right i mean another name for serotonin is 5-ht 5-hydroxy tryptophan right so if you're burning up all your tryptophan in making serotonin there is some other high yield amino acid you're not making like niacin right, right? If you're not making niacin, that's a problem, right? Because you can get pellagra with that, right? So you get like the four Ds, the dermatitis, the diarrhea, the dementia, and then the bad D that is death, right? So that's one way they can integrate carcinoid syndrome with pellagra, right? With like a niacin. Remember, niacin, if I'm not mistaken, it's vitamin B3. OK, so again, those are all high yield things to know there. OK, so let me maybe talk about one more topic and then integrate a few more things and then I'll sign off for the day. Let's see. What can I talk about? Okay. So what if you get a question about a patient that... Let's see. So what if you get a question about a patient that over the last three months, he has been feeling really tired, like just feeling super fatigued. He has been losing a ton of weight. He has been having like skin hyperpigmentation. And then you get some labs, right? And then you notice, you're like, man, your CBC looks terrible. You're like, man, this person's eosinophil count is like 15%. And then you look at their BMP, you notice their sodium is like 123, their potassium is like 6.5. What are all those things leading you towards? I really, really hope you're saying Addison's disease, right? Addison's disease, disease right so addison's disease another name is a primary adrenal insufficiency right um remember addison's disease it's basically an autoimmune problem where you destroy like the essentially destroy the adrenals right so your adrenal cortex is gone right so your zona glomerulosa will not work so you're no longer making aldosterone your zona fasciculata will not work. So you're no longer making aldosterone. Your zona fasciculata will not work. So you're no longer making cortisol. And your zona reticularis will also not work. So you're no longer making sex steroids. Although that's maybe not the most important consideration in the world. But you won't be making things like GHEAS anymore. So let's sort of revisit that right so the thing is uh addison's disease right so you see all these things i posed in the q stem right they have hyponatremia because remember when you have an aldosterone deficiency remember aldosterone right so if you go way back to step one you remember like the distal nephron that has like the collecting duct with the principal cells? Remember on the urine side of the principal cells, you have this Enec channel that reabsorbs sodium. That's under the activity of aldosterone, right? And then as sodium is being reabsorbed, you create a negative charge on the urine side that draws out potassium through, I believe, a channel known as the Rhum-Key channel, right? And then you waste potassium in the urine. So aldosterone's job is to reabsorb sodium, waste potassium, right? Easy enough, right? So if a person has an aldosterone deficiency, basically they have Addison's disease, they will have hyponatremia because they are not reabsorbing that sodium, and they will have hyperkalemia because they are not wasting potassium. That's one thing. Next thing is those people tend to get a metabolic acidosis, because if you really think about it, aldosterone, if you scale a little further down in the distal nephrine, right, you have those alpha-intercalated cells. Those alpha-intercalated cells, right, on their urine surface, they have a proton pump that literally just dumps protons into the urine. So the problem is, again, if you have an aldosterone deficiency, you will not be able to dump those protons in the urine. And if you don't dump those protons in the urine, you retain them. And the thing is, if you want to sort of take this thought to a logical conclusion, those people, the metabolic acidosis they have is a non-anion gap metabolic acidosis, right? And taking this even a step further, remember, that non-anion gap metabolic acidosis, right? I mean, it's literally arising from a hypoaldosterone state, right? So that's literally a type 4 renal tubular acidosis that you got there, right? So remember, anything that causes a hypoaldosterone state will cause a type 4 RTA, right? So again, that's a high-yield way to sort of put Addison's disease together with your non-anion gap of metabolic acidosis, right? And then remember, right, people with Addison's disease, they have this eosinophilia, right? So remember, you definitely, like, this is one of those things where you'll be doing yourself a huge disservice if you take Step 2CK without knowing this. You absolutely, positively need to know the differential diagnosis for eosinophilia. It just shows up too often on the internal medicine shelf exams, on the surgery shelf exams, on the MBMs for Step 2CK, on the real exam for many people, right? And that differential is something called DN. I kind of borrowed this from many different sources and then I've progressively expanded it as time has gone on. But probably the more complete one is DN quadruple ACP, right? So what does that stand for? The D stands for drugs, right? The N stands for neoplasms. The first A stands for like Addison's disease. The second A stands for acute interstitial nephritis. Remember that with the threat of a fever rush and eosinophilia. The third A stands for allergies, right? The fourth A stands for asthma, right? And then the, so DEN A, C, P. The C stands for collagen vascular disease. So your autoimmune crap like lupus, scleroderma and all that. And then the P for parasites. So the thing is, if people have Addison's disease, maybe like divine, why do they have eosinophilia? Well, here's the thing. The thing is steroids, glucocorticoids, basically, they cause apoptosis of eosinophils, right? So the thing is, if you have glucocorticoid deficiency, because your zona fasciculata is all knocked out with Addison's disease, well, your eosinophils will persist for a longer time in the serum because they're not just going to die. They're not going to like die before their time pretty much, right? So you have an eosinophilia with that, okay? If you ever see a CBC or eosinophilia, that should be a gimme question on an MBME because they're essentially telling you the answer.
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So how do we diagnose Addison's disease, right? Classically on MBMEs, what you will do is you will do something called an ACTH stimulation test, right? Because if you think about it, if you give ACTH, right, if your adrenal glands don't work, right, your cortisol levels will not rise, right? Your cortisol levels will not rise. So failure of your cortisol to elevate with acth administration is pretty good with regards to diagnosing addison's disease and obviously if you want to treat addison's disease you need to replace the mineralocorticoid they are missing with the fludrocortisone and then you need to replace the glucocorticoid they're missing okay again, remember you have sodium and potassium problems when you have primary adrenal insufficiency. If you had secondary adrenal insufficiency, so let's say for example, you have like some reason why you're, I don't know, like Sheehan syndrome or some weird crap where you're not making ECT, so you're not stimulating the adrenal glands. You're not going to have sodium and potassium problems, right? Because remember, your sodium and potassium balance is maintained primarily by aldosterone, right? And aldosterone is under the control of the renin-angiotensin-aldosterone system. So if your adrenal gland itself is not all screwed up, then that's not a problem at all. That is literally not a problem, right? Because reninnal angiotensin system sort of starts, kicks off in the kidneys. The adrenal gland is right there. It's not a huge issue. So you will get like the eosinophilia and all the other weird crap, but you won't have like the, you won't necessarily have the hyponatremia or the hyperkalemia, right? Because again, your aldosterone is alive and well. The reason you get those problems in primary adrenal insufficiency is like literally angiotensin 2 has no sites to act on because the adrenal gland is essentially gone, right? So on this whole topic of primary adrenal insufficiency, right? So why do they have the skin hyperpigmentation, right? Clearly, they have that because remember, there's this agent known as POMC or pro-opio-melanio melanocortin right that is a precursor to ACTH and MSH right and so an MSH right is melanocyte stimulating hormone so if you're making a ton of ACTH because there's no negative feedback from the adrenal gland because you're not making cortisol you'll be making MSH at the same time you. You stimulate your melanocytes. And you get a skin hyperpigmentation. And some other weird high yield things. You want to know there. So remember the term. Pro-opio-melanocortin. That should kind of tell you. What POMC gives rise to. So if by some weird chance. You're step one or you're taking step three in the future and you're listening to this podcast, because believe it or not, on step three and also on step two, CK, to a very large extent, they test these basic science thingies every now and then. So what does pro-opio-melanocortin stand for? So pro, I mean, let's break down the term pro. So precursor, opio, so some kind of opioid-related thingy. Melano, melano, right, something that relates to melanocytes like MSH. Cortin, like cortisol, like atropine for cortisol, like ACTH, right? So the thing is the three derivatives of POMC actually, ACTH, MSH, and also an endogenous opioid known as beta-endorphin. That is one of those weird high-yield things that you probably need to know for step one. But again, it may show up as an incidentaloma on step two CQ or step three. So let's those products a little bit, right? So probably the big one I should focus on is ACTH, right? So ACTH already talked about how you can use it to diagnose primary adrenal insufficiency. But remember, ACTH also has another use in the pediatric population, right? So if they were to give you a question about a patient that has, I don't know, like hypopigmented macules on the skin, intellectual disability, and they have like a renal mass, so like a renal angiomyolipoma, or they have like a cardiac mass, like a cardiac carabinomyoma, I would hope under those circumstances that you're thinking about tuberous sclerosis, right? So remember, kids with tuberous sclerosis, especially if they're less than a year old on MBMEs, they tend to have this seizure syndrome known as infantile spasms. Another name for infantile spasms is West syndrome, right? Remember, that seizure disorder, right, like generalized seizures, classically on an EEG, you'll find like your classic hypsarrhythmia. You actually treat that with ACTH. Okay. So that's kind of like a nice ACTH relationship you want to tie together on, on your exams. Okay. So I think, um, that's all I'm going to say with this podcast. It's already 30 minutes long. That is right around where I want these rapid review series to fall around. And again, as I always do for every podcast, I do offer, I guess at the end of every podcast, I do offer one-on-one tutoring for many exams. So step one, 2CK, 2CS. Step three, internal medicine board exams, internal medicine in Training Exam, right? Your preclinical med school exams, your 30-year shelf exams. And then if you have like a college buddy that needs tutoring like physics, gen chem, O chem, physiology, histology, biochemistry, I do offer tutoring for all those things, right? And if you're a college student applying to med school, so like an AMCA SAP or a med student applying to residency, so like an ERASAP, I do offer one-on-one like advising and consulting for those. Again, I've been on the admissions committee of like a top two med school for like a year. And I've also worked with hundreds of people through the ERAS process. And again, pretty much everyone I've worked with has matched that usually at their first choice. So take that for what you will. So if you need any of these services, reach out to me through the website. Or you can email me personally at divineinterventionpodcasts with an S at the end at gmail.com. Or just email me through the website. So have a wonderful rest of the day. I guess a rest of the night. And I will see you in the next podcast. God bless you. Thank you.
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Welcome back to Run the List, a medical education podcast in partnership with McGraw-Hill Medical. Our hosts are Dr. Naveen Kumar, Dr. Walker Redd, Dr. Emily Gutowski, Dr. Joyce Au, and myself, Blake Smith. As a quick disclaimer the most important areas in the practice of medicine, goals of care conversations. We're really thrilled to have Dr. Andy Lawton as our guest expert to share his wisdom today. He's a palliative care physician at Dana-Farber Cancer Institute, as well as director of communication skills education in their department of psychosocial oncology and palliative care. He's also really involved in medical education within the Brigham and Women's Hospital internal medicine residency. Dr. Lawton, thanks so much for being here with us. Joyce, thanks for having me. I've listened. I've heard so many great things about Run the List. Really glad to be joining you guys today. That's really kind. We're really, really excited to have you. So before we dive into a case, I think it's important in this particular episode that we're all on the same page about some key terms. So when we refer to this idea of goals of care conversations, what do we actually mean? How does it fit into some of these other terms such as advanced care planning, MOLSTs or POLSTs, as well as this idea of determining code statuses? Absolutely. So Joyce, what we mean by a goals of care conversation is really just a conversation that explores patients' values and concerns in order to guide the treatment plan that we're going to make. And so really the intent is to create a plan of care that aligns with those values that we elicit from the patient, what matters most to them. We typically have these conversations with seriously ill patients, and that may occur early in the disease course when the diagnosis is new, when things are stable and we're just thinking about the future together, or later in the disease when things are changing and advancing in some way. We often have goals of care conversations as well when we're facing a treatment decision. And that might be things like whether to pursue more chemotherapy or whether interventions like dialysis make sense for a given patient. And in some cases, though, these conversations can be particularly urgent, especially if the decision we need to make is right in front of us, such as, for example, deciding about intubation for someone who's sick and in the hospital. And I agree with you, Joyce, there's a lot of different terms. Goals of care conversations are really one part of this broader work that we call advanced care planning, which includes actually having the conversations themselves, as well as documenting the patient's wishes on forms like a healthcare proxy form, a MOLST form, as you mentioned, or advanced directives. That's super helpful. Thanks for clarifying. So what it sounds like is that the goals of care conversations are really in its essence about understanding the values of our patients and their wishes and really understanding this idea of what matters most to them, which I love. So with that, let's dive into a case now. So I will tell you about Mr. R, and he is a 44-year-old male with a past medical history that's significant for hypertension and alcohol use disorder. He comes to his primary care physician for a follow-up after a recent hospitalization where he presented with subacute fatigue and abdominal swelling, and he was diagnosed with decompensated alcohol-related cirrhosis. When preparing for this follow-up visit, his primary care physician realizes that he hasn't yet had any conversations with Mr. R about his goals of care, as this was really his first hospitalization in his life. And the primary care physician hopes to get that conversation started today. So Dr. Lawton, let's now step into this primary care physician's shoes. Do you have a general approach to having effective goals of care conversations? And how might it maybe relate to Mr. R's case here? Absolutely. So, you know, first of all, I want to applaud you, Joyce, for suggesting that we have a framework. I think more and more we're trying to think about communication skills and difficult conversations as, in fact, a medical procedure. And just like any other procedure that you and I would do, we want to have an approach. We want to have a framework going in, and that's going to allow us to be more successful. The framework I use to navigate goals of care conversations is called WeMAP. And this is a five-step framework, or what we often call a talking map, for navigating goals of care conversations. And this was developed by the communication experts at Vital Talk. And I'll just kind of overview each of the five steps here, and perhaps we can get into them in a bit more detail. The first step is what we call reframing, which is really just getting everyone involved on the same page about the fact that our patient, their health or this illness that they have has changed in some important way, and we need to talk about it. And reframing the situation involves a couple steps. First, I need to ask the patient and family what they understand about the illness. Asking for understanding is really the key first step to almost any goals of care conversation. So asking their understanding, what have they already heard from other doctors, from other clinicians about this illness? If there's a key piece of information that they don't have, but they need in order for us to have an effective conversation, then I need to tell them that information. The second step in our framework is expecting and responding to emotion. And this is really a key important step throughout a goals of care conversation, but especially after we reframe the situation. Because if patients and families heard and took in what we had to say about the seriousness of the situation, about the things that we're worried about as the clinicians, then we would expect that patients and families would become emotional. And the way we respond to emotion is we use empathy. We use empathic statements to respond and help the patient and family feel heard. What's really important here, and in fact, Joyce, I would say, if folks take away nothing else from our episode today, I hope they take away this idea that expecting and responding empathically to emotion that comes up during a goals of care conversation is probably the most important skill of any that you and I could talk about. Really briefly, I would say the reason this is so important is because if you and I think about when we're emotional, it often kind of overwhelms our ability to think concretely about what to do next. We often say, oh, emotion overwhelms cognition. So if we can make space for the emotion, help patients and families feel heard, and drop the emotional temperature in the room, then not only will patients and families feel aligned with, but we'll actually be in a place where we can move forward together in the conversation. So it's often really helps us kind of unlock the conversation and move forward. Once we've made space for the emotion, then we're going to move on to the third step of our REMAP framework, which is called mapping values. And this is really a key step because what we're going to do here is pause. And before we get into the details about specific treatments, you know, doing option A, option B, chemo, no chemo, dialysis, no dialysis, we're not going to get into that right away. We're going to pause and explore what's important to this patient and family. What concerns do they have? And we're going to map out the values using what we call mapping questions. So as you look forward to the future, what feels important? What do you hope to be able to do? As you think about your health, what worries do you have? And we're going to listen for hopefully a variety of things that are important to the patient family. And we're going to end up using those values to guide the plan that we make. The fourth step is going to be aligning with patients' values, summarizing and reflecting back the things that we heard them say when we were asking about what's important, when we were asking about what they're worried about, and make sure we heard them right. The last step then, Joyce, is going to be making a plan, planning treatments that match those values that we heard. And this is really the skill of making recommendations that incorporate both the values that we heard and the medical reality of the situation we're in now. So five steps, reframing the situation. We got to be on the same page throughout the conversation, expecting and responding to emotion, mapping values before we get into treatments, aligning with those values, and then making a plan, making recommendations that uphold the values that we heard. Great. This is incredible. So I think this REMAP framework can be a really good way to walk into a room or talk to a patient with this approach in mind.
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So he does exactly this. He follows a framework such as REMAP. And he has this conversation during which he's struck by how strongly motivated Mr. R is to stop drinking and how he wants to reset his life so that he can see his two high school children graduate. Mr. R actually completes a MOLST form that documents that he wants to be full code during this conversation, and he leaves the office on both pharmacologic and psychosocial treatment for alcohol use disorder. He's followed up closely by his gastroenterologist. He's put in touch with transplant hepatology, and he does all the medical things that we won't dive into here. So nine months later, Mr. R presents the ED with hematemesis. He's hypotensive. He requires two units of red blood cells, and he undergoes an emergent endoscopic treatment of a variceal bleed. He requires a brief ICU stay and is ultimately transferred to the floor where he stays there because of a tenuous volume status. His wife comes in to visit him and they ask to check in with the team about next steps. So now I want to step back for a second. Without getting too much into, again, the medical details of this case, Mr. R's liver disease has now taken a turn for the worse. So you decide that you want to use this opportunity in the hospital to revisit his goals of care. How can REMAP apply more specifically here in what might be considered to be a later conversation when a patient has become very sick and there may be a change in urgency? Sure, Joyce. So, you know, as you say, Mr. R is certainly sicker now. And I think most of us would call this a late goals of care conversation, meaning that we're having the conversation in the context of the illness progressing as it is sort of more quickly now versus months back when we were in the clinic, the diagnosis was new, things were stable. We often call that an early goals of care conversation. And back then, we might have done the work of moving through those REMAP, the remap steps, over multiple visits, over multiple conversations. But things are different now. They're more urgent now. And we're going to revisit where we're at with the goals of care. And part of the work that we need to do now is really make sure that we're still on the same page with Mr. R and his wife about how things have changed. We want to talk, you know, compassionately and honestly, openly about the fact that the liver disease has worsened and there's a real possibility he could continue to get sicker. Again, the key part there is all going to be in that reframing, that first step of our framework. And doing this important work of reframing how things are different now is going to allow us to revisit his goals and values, really with a shared understanding of the new place that we're in, so that we can make a good plan together about what kinds of treatments are going to be helpful to Mr. R at this point, and what kinds of treatments may not be as helpful at this point. Great. So for me, as well as for our listeners, I think sample language can sometimes be very helpful. I think that actually saying the words can be very challenging. And when we try to have these conversations, we can sometimes just beat around the bush. So can you give us some words of how you can actually go through all of these steps with Mr. R? Absolutely. So I'd start by reframing. That's, again, our first step. I'd probably ask, what have you heard about what's going on here in the hospital? What have you heard or taken away from your conversations with the other doctors? I'm listening for, do they understand what's different now? Do they understand the seriousness of the situation? If there's key information that they don't have, but that they need in order for us to have an effective conversation, I want to tell them that. And I'm going to use that information headline again, that key information that they need to know for us to move forward. So that might be something like, Mr. R, I'm worried that you're getting sicker overall as a result of the liver disease. And I hope we'll see things improve. And also there's a real chance that things could continue to get worse. And I really think we're in a different place now with the liver and your overall health than we were nine months ago. And then we're going to pause and see what reaction he and his wife may have. And again, we're expecting and going to be ready to respond to emotion at that point. This must be overwhelming. I can only imagine how hard this is to hear, naming and acknowledging or understanding the emotion at that point. We might say, I really wish things were different. I really wish this wasn't the situation we were in today, that I wish statement can be so partnering. After we've had time to express that empathy, use those empathic statements and sit with the emotion, then at some point I'd ask Mr. R, you know, given what we've talked about in this new place that we're in, I wonder if we could spend some time thinking about where we go from here. And I'd ask him for permission to kind of move the conversation forward. And we would move into that third step of the REMAP framework, mapping values. And I'd ask him, you know, given what we've discussed, what feels important moving forward? If time were shorter than we hope, what worries might you have? And what else are you hoping for? What else feels important? What else worries you? Joyce, one of the things we often find is that patients and families don't necessarily share with us the more deeply held concerns that they have or the values that they have right away. And we often have to ask several of these mapping questions in order to get a strong sense of what really is important to this patient and family. We might hear things about having meaningful time with loved ones naturally, right? Like that's something a lot of us care about. It might be about being at home. It might be about being outside and being as independent as he can be. Whatever it is, we want to make space for what those important values are. The fourth step then is going to be to align with the values that we heard. And again, that's summarizing and reflecting back. You know, Mr. R, what I hear is that staying active, having time with your family, being as independent as you can be are really some of the most important things. And I also hear that you're worried about your wife and how she might handle all this, how she might handle taking care of you if you really needed extra help. Do I have that right? Checking in, making sure he knows I was listening. He can add other things. And then I would end the conversation by making a plan, making recommendations that pull together what I heard as the important values and what I know about the medical reality of the situation that we're in. That might sound something like, Mr. R, given what you've shared with me and given what I know about this condition, I'd recommend a few things that we focus on medications and treatments for the liver disease that ideally will help you feel as well as you can and have that good time with your family that we want. And I'm hopeful that we can do that. At the same time, if you're getting sicker, I think we should avoid things that aren't likely to get you that good quality time that we're all hoping for. And that would include things like a breathing tube or CPR. I'm really worried that if you were that sick, that those things wouldn't help and might only cause you to struggle. And really, Joyce, we're ending the conversation with recommendations there, starting with the things that we do recommend. And then in this example, following up with things that we don't think would be helpful at this point, including a recommendation about code status. Wonderful. This is super, super helpful. I think the two things that really struck me was one, when you were talking about reframing, I think you said something along the lines of, I hope we see that things improve. And also there's a very real chance that you may continue to get worse, that you use and instead of but. I think this is something that I've noticed that you can have both of them at the same time. And I think the second thing was when you talked about this plan to start with something that we would do before we dive into the things that we recommend not doing. And I think that oftentimes probably leaves patients feeling a little better than talking about all the things we do not recommend. So I want to talk about this idea of prognosis because I think that figures into how we have some of these conversations.
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Absolutely, Joyce. So I think you and I could probably book a whole separate episode just to talk about prognosis. But let me share a few thoughts about that. I often ask patients how much they want to know and what kind of information they want in terms of prognosis before I start giving information. Because people can mean different things when we start to get into the prognosis space. Some people want to know about time in the way that we typically think about prognosis, but other people may want to know about other things. Maybe it's about how they're likely to feel or how functional they're likely to be, what kinds of things they'll still be able to do over time. And maybe other people want to know about, are they going to make it to a certain life event? So I first try to pause and ask, what kind of information would be helpful? And then when we're actually getting into sharing information that I hope and I worry language again can be really helpful. So maybe for Mr. R, it might sound something like, you know, Mr. R, I really hope that we have a long time, even years. And also I worry that some patients with this liver disease can get sicker quickly. And it's possible that time will be shorter than we hope. ethically, giving a general recommendation such as, I think you should continue treatment, I think you should stay full code based on some of your values, which for some people can be seen as very paternalistic, and balance that with giving patients the ability to choose from a menu of options in all these different scenarios, which may foreground patient autonomy over specific choices. How do you balance those two aspects? Joyce, this is such an important question. And I would say a few things. Many of us are taught, I think, in medicine, or it's modeled for us, that we should, as you say, present patients with a variety of options and then allow them to decide what feels right for them. I think many of us have seen clinicians do that. And while that certainly comes from a well-intended place, I think this idea of presenting a menu of options often ends up being pretty challenging for patients and families. Most patients don't have the medical background to weigh the complexities, the nuances of decisions about being in the ICU or dialysis or chemotherapy. And furthermore, we want to remember that we're often talking with patients and families about these decisions during some of the most stressful emotional moments in their lives, which really makes it even harder for folks to weigh these decisions and weigh options. And really, most often patients and families are looking for our guidance. And I see it as my job to give them that guidance wherever possible, to make recommendations to them. This is so, so important. I, of course, want the patients and families input, and I'm going to ask for that. But I give my recommendations first. Making recommendations, Joyce, is just so important. And frankly, it can be really a gift to patients and families. One story comes to mind from my own training. I'll always remember talking to this mother of a patient I was caring for during my residency. And this young gentleman was declining pretty quickly. And as a team, we were worried that he may die even very soon. And after exploring their goals and values, we made a recommendation to this patient's mother against going back to the ICU, against being re-intubated. And she looked at us and she said, thank you. You have no idea what this means to me. And Joyce, I was so struck by that reaction from her. And it's really something that stays with me. And it was clear that what she meant was that she was relieved of the fact that she wouldn't have to carry the weight of having to have made that decision with her forever. She could hold a narrative of, I just followed the doctor's guidance. I just did what the doctors recommended that I do. And that was so powerful. So making recommendations can be so helpful, so valuable to our patients and families. Thanks so much for sharing that story. I think it really strikes a chord with those family members who feel guilt for withdrawing care and having permission from their doctors to do less rather than more can be really liberating sometimes. So I want to turn towards now cases in the ICU, for instance, where patients are really, really sick and their families are seeing them every day and they feel very strongly that the length of time that they live and even hope that the smallest chance is really important. So in cases like these, I think sometimes we consider recommending time-limited trials for intensive or aggressive interventions. Can you define time-limited trials and tell us a little bit more about your thoughts around this? Sure, Joyce. And just to say, I think the example you're giving in the ICU, really sick patient, family that is hoping that what we would consider to be more intensive or aggressive interventions are going to be continued, I think this really gets to the heart of what's challenging about these conversations. Specifically with regard to time-limited trials, I agree. I think this can be a really valuable tool and concept to bring into our practice. So with a time-limited trial, we establish that we're going to try a given intervention for a defined period of time to see if it's helpful. And we set up front how long the trial will be and what improvement would actually look like for us, what parameters we'll use to monitor for improvement. If the patient does improve and is tolerating the treatment, then we would continue it and we'll make that clear to the patient and with the family. And if it's not helping or the patient isn't tolerating the treatment or improving, then we'll discuss stopping it. And so what might recommendation language sound like that incorporates this idea of a time-limited trial? Well, maybe it's something like, you know, it sounds like your dad would do most anything for the sake of more time with his family. I really hear that. Given that, I'd recommend that we try another 48 hours on the breathing machine to see if he might improve. And if he's getting better, that's wonderful. And if he's not improving or if he's getting sicker, we can discuss how we would continue to care for him even if he can't recover. So again, Joyce, that's some of the language I might use. And I really agree with you that that time-limited trial concept can be a really helpful one. I think that's a super helpful final point to be clear about what we're talking about when we talk about timing or timeline, to be very clear that even if things don't go the way that we hope, that we're still going to intervene in ways that are supportive. So the final question that I wanted to ask is about troubleshooting. So I know sometimes conversations can get into a place where we're really kind of feeling stuck. The conversation might be going in circles. We're not moving forward. How do you think about getting stuck? In other words, what's your differential when we're getting stuck during these conversations? Yeah. So I think, Joyce, that high on our differential for why we feel stuck in conversations really has to be the idea of, am I missing emotion? And am I missing an emotional cue in the room from the patient and family? So what's notable here is if we think about places where we feel stuck, many times patients and families may be asking questions or making statements that can sound like their requests for more information when actually they're an expression of emotion. An example might be when a patient or family says, you know, there's got to be another treatment you can try. There's got to be something more you can do. We might think to ourselves, you know, why are they not hearing us? We already talked about the fact that we've tried so many different treatments for this cancer. We don't have another one. But we can also ask ourselves, is this really a cognitive question? Are they really asking for more information about treatments? Or might this be an emotional statement? And what emotions might be at play here? Is it fear? Is it sadness? Is it anger? And so often why we're stuck is because we might not be making the space that we need to for the emotion that's already in the room. And as we've talked about, what we want to do here is be really ready to respond empathically. And when we respond empathically to emotion, we often start to see a shift in the conversation. And it's often what sort of unlocks that stuck point and helps us move forward. Because really, these stuck points are often less about the details of the medical scenario and often more about the experience of being ill, the experience of feeling powerless, the fear of losing a loved one. And what we want to do is really instead lean into that emotion.
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And just to say, Joyce, I think that feeling of being aligned and connected with patients and families, that's the kind of experience that drew many of us into medicine to begin with. And it's the kind of feeling that keeps many of us going in this work as well. I agree. I think some of these conversations can be very, while serious, there's an element of connecting with people in this deep way that can be very meaningful. I want to turn back to Mr. R now. So the inpatient team actually had a series of very productive conversations with Mr. R and his wife, and they decided that they still wanted him to be full code. They really wanted everything done for him. This was in the context of Mr. R feeling like he had started to turn his life around at the face of a potentially very severe condition. Three days later in the hospital, the nurse actually called a code when she found him unresponsive and pulseless with vomited blood on the floor. CPR was performed according to his wishes, but was unsuccessful. While his family was very devastated about his death, his wife later told the team that she was really appreciative that they quote unquote did everything and she was really grateful for their care in the hospital. So unfortunately here, the patient ended up passing away during this stay, but they were able to have some key conversations to make sure they were respecting his choices about how to live when he was very sick. So as we wrap up, I wondered if you had any key takeaways that you wanted our listeners to walk away with from this episode. Sure. Well, I would say a couple things. First is that our REMAP framework can be an incredibly valuable five-step tool for discussing goals of care. And I would encourage folks to read more about this and try it in their own practice. Second is that looking for and responding to emotion is really essential to any effective goals of care conversation. And it's often the key to getting unstuck in these conversations as well. And lastly, Joyce, I would say that whenever possible, we want to provide patients and families with recommendations, again, that are informed by their values that we've elicited and our knowledge and expertise about the medical situation. Wonderful. This was super, super helpful for me. I hope that this was helpful for our listeners as well. So thank you so much for your time, for sharing with us how to have effective goals of care conversations. Thanks so much for having me.
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Well, on that Indian note, welcome to the 13th episode of the Divine Intervention Podcast. My name is Divine. I am a fourth year medical student. Some friends of mine, I have an appreciation for Indian music and I've been trying to learn one song. So I was discussing with some friends of mine yesterday about trying to learn this specific song. That was just a teaser release for my new album. I'm just kidding. But hopefully I can learn that song at some point in the future. Okay, so today we're going to be talking about metabolism. I'm going to break this up in parts. Metabolism is something that's probably a little too big to discuss in one podcast. So I'll discuss it over a series of podcasts. And by the end, hopefully you should have a very good review going into step one. So let's go ahead and jump right in. So the big things I'm going to say I'm going to talk about today, I'll talk about nucleoside synthesis. And I will also talk about some problems with proteins and drawing a lot of like pharmacology and other biochemistry and pathology and all that crap. So let's go ahead and start. So summary of nucleotide synthesis. Remember that nucleotides include DNA and RNA. So to make DNA and RNA, you do in fact need nucleotides. And nucleotides basically contain a sugar, a nitrogen base, and a phosphate group. Okay, a sugar, nitrogen base, and a phosphate group. So that nucleotide, the precursor to a nucleotide is a nucleoside. A nucleoside is just the sugar and the nitrogen base. You haven't added a phosphate group just yet. Okay, but those nucleosides need to come from a nitrogen base. And those nitrogen bases can be one of two kinds. It can be a purine or it can be a pyrimidine. So you start with the nitrogen base. If you add a sugar, you form a nucleoside. If you form a phosphate, you form a nucleotide. And those nitrogen bases, like I said, they can be one of they can be a two ringed nitrogen base they are called the purine nitrogen bases those include adenine and guanine okay and the way you differentiate between adenine and guanine is adenine has an amino group at a like the top most position like the 12 o'clock position guanine has a ketone right so it has like a carbonyl group carbon double bonded to an oxygen the pyrimidine nitrogen basis they're one base they're one ring uh nitrogen basis okay and there's three kinds there is cytosine there's uracil and there's thymine uh there's a classic mnemonic, cut the pie, that can help you remember those three. And one nice thing about them that I think is actually kind of helpful is that order also shows you how those nitrogen bases are made, right? So cytosine, if you deaminate cytosine with cytosine deaminase, you make uracil. You'll see a pharmacology time with that in a bit. And if you methylate uracil, you actually form thymine. So you'll see a pharmacology time with the first step shortly. And this sugar that joins up with a nitrogen base to form a nucleoside, where does this sugar come from? The thing is the sugar actually comes from the hexose monophosphate shunt, which is also known as the pentose phosphate pathway. So that pathway makes ribose 5-phosphate. That ribose 5-phosphate can join up with a pyrophosphate group from ATP, right? So two phosphates to make something called phosphoribosyl pyrophosphate. And the enzyme that makes that happen is PRPP synthetase, okay? So that's a summary of nucleotide synthesis. So now we know how to actually synthesize nucleotides. Let's then go into a little bit more detail. But first, let's talk about pyrimidines. As you can see on the second slide, I say that pyrimidines, to make them, you make the nitrogen base first and then you add the sugar. But for the purines, you make the sugar first and then you add the nitrogenous base. So let's talk about pyrimidines. Let's make the nitrogen base first and then we add the sugar. So to make the base first, all of this actually happens in the cytosol or nucleotide synthesis in general happens in the cytosol. So the first thing that happens is that you condense glutamine and carbon dioxide with some other stuff. And you make something called carbamoyl phosphate and the enzyme that makes this happen is cps2 carbamoyl phosphate synthetase 2 okay and again this is a cytosolic enzyme uh there's a cps2 you should probably know that there's a cps1 okay remember the one in cps1 as being like an eye to help you remember that cps1 works in the mitochondria okay works in the mitochondria of the urea cycle we'll talk about that in a later slide okay so you make carbamoyl phosphate and then that carbamoyl phosphate is then made into erotic acid by some magic that we don't are not really interested in for the purposes of board exams and then that erotic acid is the nitrogen base. So we've accomplished our first objective. Okay. Now we want to make a nucleotide. Okay. So we are adding a sugar and we're adding phosphate, right? And that's done by an enzyme known as UMP synthase. UMP synthase takes that phosphoribosyl pyrophosphate I talked about on the previous slide. Okay. and helps us make uridine monophosphate. I'll talk about pathology associated with that in a bit. And then that UMP is made into UDP. Don't care much about that. But that UDP is a ribonucleotide, okay? UDP is a ribonucleotide. The thing is, we have RNA and DNA. If you want to go down the DNA pathway, you need to convert your ribonucleotides to a deoxyribonucleotide the thing is we have rna and dna if you want to go down the dna pathway you need to convert your ribonucleotides to a deoxyribonucleotide ribonucleotides in general have hydroxy groups at the two prime and the three prime uh carbons of the sugar structure okay but a deoxyribonucleotide does not have that two prime hydroxy group it only has that three prime hydroxy group that it uses to form those phosphodiester bonds with a 5' phosphate. So to remove that 2' hydroxy group, we need an enzyme known as ribonucleotide reductase. I'll talk about some pathologies related to that. So that UMP, DUDP, you can clip off a phosphate, make DUNP, and then that DUNP can then be be converted to D-TMP and if you remember I said that the difference between uracil and thymine is a methyl group okay so this reaction clearly needs a methyl donor okay and one high yield methyl donor that exists in the body is the methylated form of tetrahydrofolate the methylated form of tetrahydrofolate can give a methyl group to D-UMP, and then we make deoxythymidine monophosphate from that. And then that cycle needs to keep going, and I'll talk about some pathologies relating to that shortly. So, what are those pathologies? If you go to the very top of the slide, top right, I guess, I talk about how having a UMP synthase deficiency is associated with erotic aciduria. The thing is, if you have a deficiency of the enzyme that metabolizes erotic acid, obviously your levels of erotic acid in the serum will go up. You'll see how this is related to another disorder that I'll talk about in a later slide. Now, ribonucleotide reductase helps you go from RNA land to DNA land. The thing is, you can actually inhibit that enzyme with an anti-cancer drug known as hydroxyurea. Hydroxyurea, yes, it's an anti-cancer drug, and it is in fact used for some hematologic malignancies. But the thing is, hydroxyurea is primarily used in the real world for the treatment of sickle cell disease, okay? Because by some unknown mechanism, it increases the synthesis of hemoglobin F, which is alpha 2 gamma 2. Now, if you then jump down to thymidylate synthase, thymidylate synthase, which helps us go from DUNP to DTNP, that enzyme can be inhibited by a drug known as 5-fluorouracil. Okay, 5-fluorouracil.
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The thing is, if you look further upstream, there is an arrow going from 5FC to 5FU. The 5FC actually stands for 5-fluorocytosine. If you remember, this is an antifungal that is used to treat cryptococcal, neoformance, meningitis in AIDS patients. The way 5-flu-cytosine actually works is that it is deaminated by cytosine deaminase. Remember that principle I talked about on the preceding slide. Cytosine deaminase converts the 5-flu-cytosine to 5-fluorouracil. That 5-fluorouracil inhibits thymidylate synthase. You make less thymidine monophosphate, and then you basically treat the cryptococcal meningitis. So that's a very nice tie-in there. Now, I also said that for thymidylate synthase to work, you need a methyl group coming from methylene tetrahydrofolate. So when methylene tetrahydrofolate gives that methyl group to thymidylate synthase to make DTMP, dihydrofolate is made as a byproduct of that reaction. If you want to keep thymidylate synthase doing its job, that dihydrofolate has to be reconverted back to tetrahydrofolate by an enzyme known as dihydrofolate reductase. This enzyme is inhibited by methotrexate, trimethoprim, and pyrimethamine. Methotrexate, remember, it causes pulmonary fibrosis as a side effect, and it can also cause a liver dysfunction. And remember that methotrexate can be used to treat hydratidiform moles, right? So like molar pregnancies. Remember the snowstorm appearance on ultrasound of the pelvis. Trimethoprim, it's usually combined with SMX, right? So trimethoprim sulfamethoxazole to treat the pneumocystis gyrvetsi pneumonia. You can also use it to prophylax against the PCP when the CD4 count drops below 200. And remember that trimethoprim TMP-SMX by TrimRite can also be used to treat UTIs. It can also be used to treat the nocardia. Okay, remember as a review from a previous podcast, remember that nocardia is an aerobic organism. It's a gram-positive branching filamentous rod, and it's also weakly acid-fast, right? So stains positive with a zeonilcine stain. And then pyrimethamine combined with sulfur diazine can actually be used to treat the toxoplasmosis, right? So classically, if you think about an AIDS patient that has ring-enhancing lesions on an MR, on a MR magnetic resonance imaging, you think about toxoplasmosis. Okay, so that's what I'm going to say about this slide. So let's jump on to the next one. So an interesting comparison of two cycles, right? So these two cycles, they are not just, I mean, intellectually, it's stimulating to compare these two cycles, but these two cycles actually are USMLE relevant. Okay, so these two cycles include the urea cycle and the synthesis of pyrimidines. I just said that to make pyrimidines, you do that in the cytosol. But the thing is, the urea cycle actually operates in two spots in the body. I mean, in the cell. The first two steps actually work in the mitochondria, and then the final steps work in the cytosol. Okay, you may ask yourself, Devine, this is too low-yield to know. Well, think again. It's actually high-yield to know these double localization details for step one. So, in the urea cycle, stuff, including ammonia, is acted on by carbamoyl phosphate synthetase 1 to make carbamoyl phosphate okay that's the first step of that cycle and then that carbamoyl phosphate can be converted to citrulline by an enzyme known as onythine transcarbamylase okay so onythine transcarbamylase converts carbamoyl phosphate to citrulline okay and that citrulline can then go into the cytosol to complete the remaining steps of the urea cycle right so it condenses with aspartate and all that fun stuff now um so that is the urea cycle okay but the thing is uh if you contrast that with pyrimidine synthesis pyrimidine synthesis i said that instead of using cps1 you actually use cps2 okay cps2 carbamoyl phosphate synthetase 2, works in the cytosol, okay? It converts glutamine and CO2 with some other stuff to carbamoyl phosphate, and then that carbamoyl phosphate, by some magic, becomes erotic acid, and then that erotic acid, okay, is converted to uridine monophosphate by an enzyme known as uridine monophosphate synthase, or UMP synthase, okay? So So if you notice, I put two red star Xs in those two pathways. So first we've contrasted those pathways by location. So like mitochondria for the first two steps of the urea cycle, cytosol for all the steps of pyrimidine synthesis. But the thing is you can have two enzyme deficiencies in both pathways that can create an erotic acidemia, if you may. OK, that erotic acidemia. Right. It's like similar phenotype, but they're different. There are some extra findings that can tell you that, oh, it's this enzyme deficiency that's in operation versus this other enzyme deficiency. Right. So if you have an OTC deficiency and only think trans-cabamylase deficiency, you will have a very big buildup of carbamoyl phosphate, okay? And if you're thinking with regards to Loschuttle's principle from college chemistry, as carbamoyl phosphate builds up, okay, it can spill into the cytosol, okay? It can spill into the cytosol. That's one fate. Another thing that can happen is as carbamoyl phosphate builds up, the upstream contributor to the synthesis of carbamoyl phosphate in the mitochondria also builds up. Okay. So ammonia in this case, so you can get a hyperammonemia with OTC deficiency. But this carbamoyl phosphate that spills in from the mitochondria into the cytosol, it can actually just basically join into the pyrimidine synthesis game. That carbamoyl phosphate can be converted to uric acid and you can get an uric acidemia under those circumstances. Now, if we go to the pyrimidine synthesis side of things, if we have a UMP synthase deficiency, we have a disease known as erotic aciduria. So if you have a deficiency of UMP synthase, erotic acid builds up. But because this is part of the pyrimidine synthesis pathway and not the urea cycle, you don't have any elevations in your ammonia. So that is how you tell the urea cycle deficit, only thing transcarbamolase deficiency apart from the pyrimidine synthesis deficit, UMP synthase deficiency. And then in the middle, I put as an aside, if they wanted to make this a more nifty step one question, they could talk about, oh, a person has hyperhormonemia, sorry, they have like the encephalopathy you get with too much ammonia dancing around in your blood. But these people have no erotic aciduria. OK, you may be like, hmm, how did that happen? Right. So that's one very nice way you can test your knowledge of the urea cycle. OK, if you have a CPS1 deficiency, your ammonia will build up. But because carbamoyl phosphate is downstream of that, you have decreased levels or normal levels of carbamoyl phosphate. So that's how you can compare these three enzyme deficiencies. In fact, I try to do that on the next slide. If you have a CPS deficiency, it's a urethyl cycle problem. So your ammonia levels are up, but your carbamoyl phosphate and uric acid levels are down. If you have another uric cycle deficiency that's a little more downstream, onythin transcarbamolase deficiency, your ammonia levels go up because again, it's a uric cycle problem. Your carbamole phosphate levels also go up because onythin transcarbamolase converts carbamole phosphate to citrulline. And then your uric acid levels also go up because that carbamoyl phosphate spills into the circulation, I mean, spills into the cytosol, and that joins in pyrimidine synthesis, so you make more uric acid, okay?
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And really the way you treat UMP Synthase Deficiency is just to give back what is deficient. You give back uridine in the diet and you can largely relieve the sequelae of UMP Synthase Deficiency. But if you have a CPS CPS1 or OTC deficiency, it's really bad because that ammonia can build up in the brain and cause a lot of problems for the infant. So those kids usually don't live super long, unfortunately. So next slide. So we've talked about pyrimidines. Now let's talk about purines. So let's talk about how you make purines and let's talk about how you break purines. So to make purines, we said that you start with the sugar first and then you add the nitrogenous base. So we make the sugar first. I've talked about how the sugar is made with PRPP synthetase in a previous slide. So you make PRPP and then you make something known as 5-phosphoribosylamine with an enzyme known as PRPP amidotransferase. The reason I'm mentioning PRPP amidotransferase is that it's actually the root-limiting enzyme of purine synthesis. So you definitely want to know that for step one. So you make 5-phosphoribosylamine, and then you have some magic happen, and then you make inosine monophosphate. Now, the inosine monophosphate can either be converted to adenosine monophosphate or guanosine monophosphate. And the enzyme that helps you go from inosine monophosphate to adenosine monophosphate is inosine monophosphate dehydrogenase. Now, why do I mention this enzyme? I mention this enzyme because it's inhibited by certain drugs, okay? So, one drug that inhibits this enzyme is mycophenolate morphotil, okay? It's an immunosuppressant. It's used after transplants, okay? Ribavirin, which is used to treat the RSV and also like hep C under certain circumstances, also works by inhibiting inosine monophosphate dehydrogenase. And the rate-limiting enzyme PRPP amido transferase, if you notice, I put like five red thins by PRPP amido transferase. I put AMP, GMP, IMP to help you remember the regulation of PRPP amido transferase, those products of that enzyme go back and feedback inhibit the enzyme. And then allopurinol and 6-mecaptopurine actually go back and also inhibit PRPP amide transferase. So you may be like, hmm, divine. How is that relevant to our discussion? You'll see why when we're done talking about purine breakdown. I'll talk about some integration with that. So let's break down our purines. Right. So, again, remember, nucleotide, nucleoside, nitrogen base. OK, so the nucleotide, AMPG, AMP, you pull out a phosphate, you make the nucleoside, you pull out the sugar, you make the nitrogenous base. The nitrogenous basis, hypoxanthine or guanine. And then those nitrogenous bases, they can be converted by xanthine oxidase in two sequential steps to uric acid. And then that uric acid is actually poorly soluble. So if you have too much uric acid in your blood, you could get gout or you could get nephrolithiasis from uric acid stones. Remember, uric acid stones are radiolucent, so you don't see them on an x-ray, but you can see them on a CT scan. And then in birds, the uric acid could actually be converted by an enzyme known as uricase to allantoin. Allantoin is water-soluble. It's much more soluble than uric acid. So now that we understand this, we can then begin to bring in some integration. And then I'll go back to that PRPP amidotransfer story that I was fleshing out a few minutes ago. So one thing we could do is if a person has gout, right, or they have tumor lysis syndrome, where they have some kind of hematologic malignancy and the person's white cells or whatever are dying, and they're dumping a lot of purines into the serum and making a lot of uric acid that's clogging up the kidneys and also causing gout. You could try to solubilize that uric acid by giving a pharmacological agent that replicates the activity of uricase. That's where drugs like piglotticase and rasburicase come in. Piglotticase and rasburicase, they are uricase analogs that help you dissolve uric acid nicely by converting it to something that's a little more water soluble. Now, another thing you could do to prevent tumor lysis syndrome, right, is to say, okay, you know what, let me go ahead and inhibit the enzyme that helps us make uric acid in the first place, xanthine oxidase, right? So that's how drugs like allopurinol and feboxostat work, okay? They inhibit xanthine oxidase so you don't make uric acid. Now, the thing is, xanthine oxidase, in addition to helping us make uric acid, it actually has another high-yield USMLE role. One thing it does is that it breaks down 6-mecaptopurine to inactive metabolites. So if you think about it, if you give a xanthine oxidase inhibitor like allopurinone of a boxostat, you decrease the breakdown of 6-mecaptopurine. And that can do one of two things. One is that it could do a bad thing to you. It could increase the toxicity of 6-meca purine alternatively if you're a wise uh pharmacologist or physician you can actually give allopurinol with uh as part of the drug cocktail for a person that's being treated with chemotherapy that includes six make up the purine to decrease the dose of six make up the purine that you have to administer okay so that's a very nice time there now the thing is um if you have to administer. So that's a very nice tie-in there. Now, the thing is, if you want to take this nitrogenous base that you got from breaking down the purine and remaking, if you wanted to say, okay, you know what, why don't I conserve my purines instead of wasting them in the urine? Why don't I conserve them by converting the nitrogen base back to a nucleotide uh you do that in a pathway known as the purine salvage pathway okay and the one big enzyme you need to know for that pathway is hgprt okay uh hgprt stands for hypoxanthine guanine phosphorybosotransferase okay it's the enzyme that takes hypoxanthin and guanine and adds a sugar and a phosphate back. So phosphoribosyltransferase, it transfers a sugar and a phosphate back to hypoxanthin and guanine and remakes the nucleotide. So why is it important to know this enzyme? It's important for certain reasons. One is that you have, one is that it's the enzyme that helps us in the purine salvage pathway. The other thing is, this is the enzyme that's deficient in Lesch-Nyhan syndrome. Okay. Lesch-Nyhan syndrome, it was actually discovered at my, at my med school by a med student, go figure, and some physician. You can look that up in your free time so lesh-nyhan syndrome it's a hgprt deficiency and the thing is if you think about it if hgprt is deficient you basically kill the pathway that helps us deal with a nitrogen basis okay because these nitrogen bases we can deal with them in one of two ways at least on this slide you can deal can deal with them with HGPRT, which is what happens more than 85% of the time, or you can deal with them with xanthine oxidase, okay? So if the 85 percentile plus pathway is gone, then this other pathway then becomes the 100% pathway, okay? So make a ton of uric acid. So gout is a classic finding in Lesch-Nyhan syndrome, although you also tend to get self-mutilation and all that stuff in Lesch-Nyhan syndrome. So one treatment for Lesch-Nyhan syndrome is that you can give a xanthine oxidase inhibitor to sort of prevent the gouty sequelae that you get with the disease. Although the self-mutilation and the neurological problems, those are unfortunately not very treatable. Now, the thing is, if you notice, another rate I put by HGPRT is isothioprine.
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So the way ezathioprine works is that it's converted to a purine analog by the action of HGPRT. HGPRT helps us activate ezathioprine, helps us convert it to 6-mecaptopurine. 6-mecaptopurine has purine in the name. That should help you remember that it's a purine analog. So 6-mecaptopurine goes and inhibits PRPP amidotransferase. And by inhibiting PRPP amidotransferase, you basically shut down the synthesis of purines. It also so happens that 6-mecaptopurine can also inhibit HGPRT. So overall, you decrease purine synthesis, and that's how isothioprine slash 6-MP work as anti-cancer agents. So that's what I'm going to say on this slide. And let me just talk about one last offshoot of the purine salvage pathway. So again, you start with a nucleotide, you break it it down to a nucleoside and then that nucleoside is broken down to a nitrogenous base okay so amp is a nucleotide it's broken down to adenosine okay that's a nucleoside and then you pull off the sugar with uh actually you don't uh you actually don't pull off a sugar just yet you deaminate the adenosine to make another nucleoside known as inosine. And the enzyme that makes that happen is adenosine deaminase. And then you make inosine. Inosine, you then pull off the sugar. And then you're left with a nitrogenous-based hypoxanthin. So the thing is, if you notice, I put ADA, adenosine deaminase, between adenosine and inosine. The thing is, if you have a deficiency of adenosine deaminase, it's an autosomal recessive disease, you have a buildup of adenosine. And again, if you're walking backwards with the Lushatli principle, as your adenosine levels go up, your AMP levels go up. If your AMP levels go up, your deoxy ATP levels go up. And that your higher levels of ATP, that ATP can combine with methionine to make SAM. We'll talk about SAM in a different podcast. As you'll come to know, SAM is a very good methyl carrier in the body. It works like in the adrenaline dollar, for example, to help you convert norepinephrine to epinephrine. But that's a different story for another podcast. So Sam, if you pull off a methyl group from Sam, you can actually make something called S-adenosyl homocysteine. The thing is S-adenosyl homocysteine is actually toxic to B and T lymphoblasts, okay? So if you kill your B and T lymphoblasts, you do not make B or T cells. So you get something called a severe combined immunodeficiency, okay? So that's the pathophysiology behind adenosine deaminase deficiency being one cause of autosomal recessive SCID. Now, another thing that could also happen is that AMP that's building up, right, because it's not being, because of a buildup of adenosine, that AMP that builds up, okay, remember, if you remember your negative feedback, that inhibits PRPP amido transferase, which, as we said, is the rate-limiting enzyme of purine synthesis, okay? So you also have decreased purine synthesis under those conditions. That's why you can get into a lot of trouble with adenosine deaminase deficiency. So next slide. So protein metabolism. Protein metabolism, basically, for the rest of this podcast, I'm just going to talk about how you deal with proteins. So let's assume you eat some protein-containing dish like meat or chicken or turkey, whatever. So you guzzle it down your throat. And as it goes down your esophagus, it gets to the stomach. The stomach, remember, there's parietal cells that make acid through a hydrogen potassium antipoder. It's an antipod, it's an ATPase. So you make a ton of acid, that acid denatures the protein. And then that protein, pepsin, in the stomach begins to digest the protein. Remember, pepsin is the active form of pepsinogen. Pepsin actually comes from chief cells okay chief cells another cell type you find in the stomach uh to actually go from pepsinogen to pepsin you actually need the acidity of the stomach to make that happen as well so that's a nice gi tie in there okay now that protein then makes its way to the uh to the small intestine okay and the pancreas releases certain like trypsin, chemotrypsin, carboxypeptidase, whatever. They also help with digesting the protein. Although remember that enterokinase is what kickstarts this process, right? So enterokinase converts trypsinogen to trypsin, and then trypsin can then go and break down the zymogen forms of chemotrypsin and carboxypeptidase to the more active forms, okay? So you break down those proteins to amino acids, okay? Amino acids are like the monomers that build up proteins. But another thing that could happen is instead of breaking the protein down completely to an amino acid, you can break it down to like a dipeptide or a tripeptide, okay? And then the dipeptide or tripeptide or monopeptide, which is an amino acid, they can all go, they can be pumped into an enterocyte in the small intestine by sodium glucose linked transporter, okay? Sorry, not sodium glucose, sodium amino acid linked transporter. Okay. So remember, sodium is primarily an extracellular ion because of the activity of the sodium potassium ATPase pump. So as that sodium goes down its gradient into the enterocyte, you have the active transport, I guess not pumping, active transport of amino acids, okay, or dipeptides or tripeptides. And if you notice in the slide, I see that O versus glucose. I just want to remind you that you cannot transport disaccharides or trisaccharides across an enterocyte membrane with sodium-linked transportation, okay? Contrast that with your amino acids where, oh, you could take like a diamino acid, okay,-peptide or a tri-peptide, and bring it into the enterocyte with a sodium-linked transporter, okay? Now, if you have a problem, some kind of mutation in those transporters for amino acids, you can have two high-yield diseases for step one, okay? You can have something known as heart knob disease, or you can have something known as a cystinuria. Okay. And the thing is these transporters, they do not just work in the, in the small intestine. They actually also work in the proximal convoluted tubule. Okay. They actually work in the kidney as well. In fact, I'll just tell you this as a general principle. Most transporters you'll find in the small intestine are also found in the proximal tubule. Why does that make any sense? The thing is, both parts of the body, okay, are involved in reabsorption, right? So if they are both involved in reabsorption, it should make sense that they have similar transporters. If you even wanted a very nice tie-in here, if you remember like the sodium glucose linked transporter, right? So we have SGLT transporters in the kidney, like SGLT2, but in the enterocyte, in the small intestine, we actually have SGLT1, right? So remember your SGLT2 inhibitors like canagliflozin and dapagliflozin that basically help you pee out sugar in your urine. So these are sodium amino acid link transporters. You find them in the GI tract, in the small intestine, and also in the proximal tubule. In fact, if you also think about both parts of the body being involved in reabsorption, you can see why there's microvilli in the small intestine and there's also microvilli in the proximal convoluted tubule. So just some nice tie-ins between those two parts of the body. So Hartnett disease is basically a problem with neutral amino acid transporter. And again, this transporter is found in the small intestine and the kidneys, right? So if you have a mutation in this transporter, you do not reabsorb. You do not reabsorb a neutral amino acids, either in the gut or in the urinary tract. And if you have that, you won't reabsorb tryptophan. Tryptophan is a high yield neutral amino acid.
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Serotonin is 5-HT, 5-hydroxy tryptophan. But tryptophan can also be converted to niacin, okay? So if you have a tryptophan deficiency, you can also get a niacin deficiency, okay, with heart and heart disease. A niacin deficiency, remember the four Ds so like dermatitis uh dementia diarrhea okay and death death is the fourth d i guess that's not very ideal okay so you can get the pellagra presentation if you have a heart knob disease now cystinuria is a mutation in another amino acid transporter but But this transporter, it's classically known as the cola transporter because it transports cysteine, ornithine, lysine, and arginine, okay? Which are all basic amino acids, okay? So the thing is, again, if you have a mutation in this transporter, and like I said, that this transporter operates in the GI tract and in the urinary tract, cysteine can begin to show up in your urine, okay? And the thing is, the cysteine can pair up with a body, another cysteine body, and you make a cysteine, and that cysteine can form kidney stones, okay? Because it's not very soluble in the urine, okay? So it can form kidney stones. Remember, those cysteine stones are like 16 stones. Right. So they're shaped like hexagons, like benzene rings. So that can cause nephrolithiasis. Okay. So that can be a presentation of cysteine urea. Okay. And the thing is, those cysteine stones, you can actually solubilize them under basic conditions. Okay. So you can actually give acetazolamide as treatment for cy treatment for cystinuria it helps you solubilize the cysteine stones now the thing is we like protein right but the thing is protein actually does some bad things to the body okay i mean it's not necessarily bad if you have a good organ to deal with it in this case the liver and your kidneys to a limited extent okay So the thing is, to deal with our protein problem, we also need to deal with the ammonia that we get from proteins. So to deal with that ammonia, we have something known as the urea cycle. But before I can talk about the urea cycle, let me just give some preamble relating to amino acids now the thing is amino acids they have two lives okay so one life is as being an alpha keto assets the second life is as being amino acids okay now the thing is to basically interconvert between alpha keto acid and amino acid you either lose an amino group or gain an amino group if If you lose an amino group, you go from an amino acid to an alpha-keto acid. If you gain an amino group, you go from an alpha-keto acid to an amino acid, okay? So, to make those interconversions, you need enzymes known as aminotransferases, okay? Aminotransferases, you could also know them as transaminases, just one and the same name for the same kind of enzyme. OK, and these enzymes, they all use vitamin B6 as a cofactor. OK, pyridoxal phosphate. Hopefully you remember your B vitamins. Right. So vitamin B1. Right. That's thiamine. OK. Vitamin B2 is riboflavin. B3 is niacin. There's no B4. B5 is biotin. Okay. B6 is pyridoxal phosphate. Hang on. Vitamin B5, B5, B5. Wait. B1 is thiamine. B2 is riboflavin. B3 is niacin. Vitamin B5. Wow. I'm actually ashamed I forgot this. I actually kind of like biocap. Vitamin B5. What is B5? Panthothenic acid. Oops, sorry. So it's panthothenic acid. B6 is pyridoxal phosphate. B7 is biotin. B9 is folic acid. B12 is cobalamin. So vitamin B12. So just a quick review there. And we'll talk about what you use those different vitamins for in a later podcast. So back to this. So B6 is a cofactor for the aminotransferases. It also so happens that B6 is a cofactor for ALA synthase, which is the rate-limiting enzyme of heme synthesis. And B6 is also a cofactor for glutamate decarboxylase, which helps us convert glutamate to GABA. So hopefully with these other reactions I mentioned, you can see why a person taking isoniazid can get a sideroblastic anemia because they can, I remember INH depletes vitamin B6. So by having a B6 deficiency, ALA synthase doesn't work. So you can get a sideroblastic anemia because you're not making him. Alternatively, if you have a B6 deficiency, you have a buildup of glutamate and a downregulation of GABA synthesis. Okay, remember, glutamate is an excitatory neurotransmitter, so you can get seizures with that. So, this alpha-ketoacid-aminoacid pairing, there are some that I will say are relatively high yield to know for step one. That's, for example, like pyruvate and alanine or alpha-ketoglutarate and glutamate or oxaloacetate and aspartate. Pyruvate, for example, is the alpha-ketoacetate of alanine. So to deal with our protein problem, we need to also deal with the ammonia that comes as a byproduct of proteins, right? So the thing is, one way we can deal with this ammonia problem is to simply just pair it up with a hydrogen ion, okay? You make ammonium and then you pee out ammonium in the kidney, okay? This is the primary way the kidney deals with ammonia problems for us. But that's a very minor pathway. It doesn't do much, Okay. To really, really get rid of ammonia, you want to condense it with a carbonyl group and another ammonia. Okay. Into something known as urea. Okay. So you make urea and then urea can travel in the blood nicely. It doesn't cause any problems. Doesn't change the pH of the blood. Doesn't need any kind of carrier in the blood. So it moves safely in the blood and then we just pee it out in the urea. So urea is a great molecule. We actually have to make that urea. And it so happens that that urea is made in the liver. That's why if you have liver problems, you can get a hyperammonemia because your urea cycle doesn't work anymore. So the urea cycle is a very complex cycle, but to be honest, there's not much you really need to know for step one. There are just very few things that you sort of need to take away. Okay. So the thing is, um, urea contains two amino groups. Okay. And those two amino groups come from glutamate and aspartate. Okay. Glutamate and aspartate. So the glutamate and aspartate take ammonia. Because remember, glutamate is an amino acid. Aspartate is an amino acid as well. So it should stand to reason that these two amino acids were previously alpha-keto acids at some point in the distant past. So those alpha-keto acid forms of glutamate and aspartate receive ammonia. Okay. And they are made into glutamate and aspartate, which then donate the amino groups to the urea cycle to help us make urea. Okay. And the thing is for those, because I mean, think about it. Ammonia is not made only in the liver. Ammonia is made in many different parts of the body. So the thing is, ammonia itself should probably not be traveling in blood right because it's a basic molecule it will raise the blood ph and you could like die okay so the body uh puts that ammonia with in an amino acid format and then those amino acids they travel safely in the blood get to the uh get to the liver and in the liver they dump those amino groups into oxaloacetate to make aspartate and into alpha-ketoglutarate to make glutamate and then you're good to go. And those are ammonia carriers in the blood. There's glutamine and there's alanine.
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Let's take the muscle breakdown ammonia, pair it up with pyruvate, you make alanine. That alanine makes its way to the liver. And then in the liver, that alanine dumps the amino group with alpha-ketoglutarate to make glutamate or with oxaloacetate to make aspartate. And then you reform pyruvate. And then that pyruvate can be acted on by pyruvate carboxylase to make oxaloacetate. That oxaloacetate can then be acted on by phosphoenolpyruvate carboxykinase to make phosphoenolpyruvate. And then you work your way up and remake glucose that can then be shipped right back to skeletal muscle, okay? Basically, all I described right now is the alanine cycle, okay? So that's why it makes sense that alanine comes from muscle, okay? Because again, if you think about it, the alanine brings, break down ammonia from muscles, but it also brings carbon, which can be used as feedstock in gluconeogenesis so that the liver can replenish muscle glucose stores. Okay. So, uh, the uro cycle, again, it's a cycle that helps us deal with ammonia. Okay. So the thing is that ammonia is usually packaged like in glutamate, for example. Okay. And that glutamate is condensed with carbon dioxide and some other stuff by an enzyme known as CPS1, which I already talked about before, to make carbamoyl phosphate. And then carbamoyl phosphate is converted to citrulline with an enzyme known as onythine transcarbamylase. And the thing is, it's literally those two enzymes you need to know from the urethral cycle, CPS1 and onythine transcarbamylase, okay? And the thing is, it's literally those two enzymes you need to know from the urea cycle, CPS1 and onythine transcarbamylase, okay? And remember that these two enzymes work just in the mitochondria, okay? And the rate-limiting enzyme of the urea cycle is actually CPS1, okay? And the regulation is actually pretty easy, okay? You have a substance known as N-acetyl glutamate. It's an obligate activator of CPS1. And when it activates CPS1, you have more flux through the urea cycle. Okay. And you may ask yourself, Devine, this is kind of like out of thin air. How does N-acetyl glutamate make any sense, right? Well, if you think about it, N-acetyl glutamate, glutamate is an amino acid, okay? You get amino acids from protein, okay? So it should make sense that if you're consuming a ton of protein, right, you're about to build up this nasty ammonia problem for your body, okay? So a high-protein meal should logically, right, increase the production of N-acetyl glutamate, which logically should activate CPS1, which logically should help you deal with that incoming ammonia load, okay? Now, so the uricycle, it's a high-yield pathway, helps us make urea. But in the uricycle, one thing I just want to throw in here is that as an offshoot, you make arginine. Arginine is kind of important. You can use it to make histones. Remember, histones, right? They have positively charged or basic amino acids in them like lysine or arginine. And remember that arginine is also used for nitric oxide synthesis. Remember, nitric oxide is a vasodilator. And if you're really thinking about this, you may be like, hmm, arginine, positively charged, binds DNA, negatively charged, basic amino acids. Again, if you have a cola transporter deficit, so cysteine urea, remember, it's a deficit of a basic amino acid transporter? So cysteine, arginine, lysine, and arginine, okay? Lysine and arginine are not made, okay? So you could potentially imagine that, oh, your step one exam could word a question that says, oh, this person may potentially have problems with like DNA expression, for example, because they have an arginine deficit, if you may. And if you have that arginine deficit, because they're not reabsorbing it from the diet or from the urinary tract, okay, you could imagine that you have decreased histone synthesis. Although as far as I know, that having an arginine deficit does not really cause many problems for humans. Okay, and if a person has hepatic encephalopathy, I just put that as an aside. In general, you give lactulose for that. So remember, lactulose is converted to lactic acid that can acidify ammonia. Convert it to ammonium. Ammonium is not very absorbable, so you basically poop it out. So that's where I'm going gonna stop today and um i will pick up from here in a different podcast i just want to make sure you guys have a solid grounding for metabolism so we'll just keep going with this and other topics if you have any questions or you spot any errors uh feel free to post a comment or send me an email okay divine intervention podcastsinterventionpodcasts at gmail.com. I wish you a wonderful day and God bless. Thank you.
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From the JAMA Network, this is Conversations with Dr. Bauchner, interviews featuring researchers and thinkers in healthcare about their publications in the latest issue of JAMA. Hello and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, Editor-in-Chief of JAMA. And I'm delighted today to be joined by I.K. Jang, who's the Allen and Gil Gray Professor of Medicine in the field of cardiology at Mass General Hospital, where he's a professor of medicine. Welcome, I.K. Thank you, Howard. We're going to talk about a fascinating viewpoint. It's a bit unusual for JAMA, but we decided to go forward with it because we thought it was so unique. The title of the viewpoint is New Insights into Plaque Erosion as a Mechanism of Acute Coronary Syndromes. I.K., before we start, could you just say a little bit about your two co-authors? Absolutely. Dabal Kolti is a colleague of mine, interventional cardiology at Mass General. And Peter Levy, as everybody knows well, is a cardiologist, basic scientist at Brigham and Women's Hospital, now we call MGB, Mass General Brigham. Peter has been working on plaque erosion for the past 10 years, and our group has also been working on plaque erosion past 10 years, but we have been working independently until a few years ago. And at one of the conferences we met together, that's when we started our collaboration. So IK, I think you're going to have to take some time to walk people through the process of acute coronary syndromes before we get to what you're trying to describe in the viewpoint. Firstly, how large a problem is acute coronary syndrome? So in the United States, there are more than 1 million hospitalizations due to acute coronary syndrome. Actually, we should say acute coronary syndromes, plural, which consists of STEMI, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina pectoris. So those are the three that contribute to the broad definition of acute coronary syndromes? Exactly. In the viewpoint, you're trying to articulate new concepts that you and Peter have developed over almost a decade. And that notion is plaque rupture and then superficial plaque erosion. Can you talk about the mechanisms, the diagnosis, and the prevalence of plaque erosion? Plaque rupture has been known for a long time. It is a local plaque destabilization of panvascular inflammation. Compared to plaque rupture, not much has been known in plaque erosion. And the third category is calcified plaque, people call also calcified nodule, which is really in a minority of patients, 5 to 7%. Plaque rupture is responsible for roughly 60 to 70% of acute coronary syndromes, and plagg erosion is responsible for somewhere around 25 to 40%. Unlike plagg rupture, which is associated with panvascular inflammation, plagg vulnerability, the underlying mechanism of plagg erosion has not been well investigated. That's what Peter Levy has been doing over the past 10 years. And he came up with this two-hit hypothesis. And first hit is due to local flow perturbation, toll-like receptor 2 gets upregulated, activated, and then leading to endothelial denudation. And second step is formation of NETS, N-E-T-S, neutrophil extracellular trap, which will attract platelets, fibrin, and form an occlusive thrombus. So those are the hypothesis, but there are still a lot more to be done. Obviously, you may diagnose acute coronary syndrome with ST elevation or not with ST elevation. At that point, without any other tests, would you have any hint about whether or not this was erosion or rupture? If you look at the coronary arteries at the culprit's side, there are three characteristics of plaque erosion as compared to plaque rupture. Number one is vascular structure. Vascular integrity is much better preserved. And number two is, in general, residual lumen. The opening inside the vessel is larger. And number three is platelets. So those are three characteristics. And as I said, vascular structure is preserved. So when you see a patient at the emergency department with acute coronary syndrome, and we have found there are five predictors. Number one is, in general, patients with plaque erosion are younger, and our cutoff age was 68 or younger, and absence of diabetes and normal renal function. And typically, people with plaque erosion, they have anterior ischemia and higher hemoglobin level, higher than 15 grams per deciliter. So if you look at those first three parameters, young, no diabetes, normal renal function, those are the parameters associated with less vascular inflammation. Anterior ischemia, typically left anterior descending coronary artery. So left anterior descending coronary artery compared to left circumflex artery or right coronary artery has a lot of side branches. So side branch is the point of flow perturbation, changes of endothelial shear stress. And then high hemoglobin is also associated with high endothelial shear stress. So what Peter Levy proposed is local flow perturbation are related to this anterior ischemia and high hemoglobin level, higher endothelial shear stress, and also endothelial shear stress gradient. And the other three parameters are associated with less vascular inflammation. When someone comes to the emergency department with ACS, when one has all these five predictors, the probability of plaque erosion is 73%. You're an interventional cardiologist. What imaging would you do to define plaque erosion versus plaque rupture? What approach technique would you use and what would you see? Right now, the hallmark of plaque erosion in pathology is absence of endothelial monolayer. There is something called OCT, optical coherence tomography, which is an intravascular imaging modality with very high resolution, somewhere between 5 and 15 micrometers, as opposed to, for example, intravascular ultrasound, which is very widely used in the cath lab, has resolution somewhere around 100, 150 microns. So with this high resolution, right now, OCT is the only modality which can make a diagnosis of plague erosion. So in other words, patient has to come to the cath lab. We can make a diagnosis, definitive or probable diagnosis of plaque erosion only in the cath lab. You've defined through a number of epidemiologic studies that those patients tend to be younger. You've said no diabetes and no evidence of any renal compromise. Do you have information yet, and I know this is still evolving, do you have any information yet about whether or not this portends a different prognosis? We'll get to therapy later, but a different prognosis. People with plaque rupture are known to have poor prognosis compared to those with plaque erosion and total or peak CPK cardiac enzyme or cardiac markers, including troponin, is in general higher in those people with plaque rupture compared to plaque erosion. Obviously, since those with erosion tend to be younger and have no diabetes, they automatically would have a better prognosis. But if you had patients who had rupture by that test that you mentioned, and they were younger and no diabetes, would they still have a worse prognosis even though they were younger than the standard individual who would have rupture? I'm trying to sort out whether or not it's independent of the notion of age and lack of diabetes. Excellent question. Plague erosion is relatively new, as I mentioned, can be diagnosed only using intracoronary imaging modality. So total number of patients with plaque erosion is still small. So we really don't know, but on the basis of CK or troponin release, in general, people with plaque erosion has a smaller myocardial necrosis. You've worked on it for almost a decade with Peter separately and now together. Do you think ultimately, IK, this will have therapeutic implications? Yes. As I mentioned earlier, there are three characteristics, larger lumen, preserved vascular integrity, and platelets. So if you can somehow identify patients with plaque erosion, at least theoretically, you should be able to manage these patients without stenting. At the present time, interventional cardiologists, anybody with acute coronary syndrome, we don't think about underlying mechanism, underlying pathology. We treat them universally with intraconar stenting. So we don't pay any attention to the underlying mechanism. Once in a great while, even patients with ST elevation MI after antithrombotic therapy or thrombolysis, we bring them to the cath lab and we had a hard time to find the corporate lesion. There is minimal lesion. In those cases, we don't stent, but vast majority of people with ACS, they are universally treated with stenting. Based on those three characteristics of plaque erosion, we performed a prospective proof of concept study, whether we can manage those patients conservatively with antithrombotic therapy without stenting. We decided to call the erosion study.
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The primary endpoint was more than 50% reduction in thrombus volume at one month. And surprisingly, close to 80% of patients met the primary endpoint. About 50% had zero, no residual thrombus at one month. And we followed all those patients up to one year. And there was further improvement of lumen size without clinical event. In the era of precision medicine or individualized medicine, I think this is something we should seriously consider. When you think about your research portfolio, you've done obviously lab-based studies, and now you've done clinical epidemiologic studies, and now you've done this prospective cohort study to try to understand what it would truly mean. Do you think ultimately you need to do a clinical trial? Absolutely. We need a prospective randomized trial to show in a subset of patients with the ACS caused by plaque erosion, this conservative management would be equivalent or superior to invasive coronary stent management. You may have less friends in the interventional cardiology world, though. I'm a little worried about that, IK. That's absolutely correct. So you do have to do a prospective cohort study. What's the benefit of avoiding stenting? So stent is, as you know, very widely used with extremely high success rate. However, it is not without risk. There are two potential problems. One is, as everybody knows, restenosis. With the introduction of drug-eluting stent, restenosis rate is low, but it still happens. Other complication is catastrophe in stent thrombosis. It can happen acute, subacute, or there is what we call very late stent thrombosis after one year. Now with the OCT, we now understand the underlying mechanism of very late stent thrombosis called neo-atherosclerosis. Inside the stent, in neo-intima, new atherosclerosis occurs, which can rupture, cause acute coronary syndrome. So when that happens, 70% of people will develop heart attack with a very high mortality. What I'm saying is stent is not without risk. If we can avoid stent, we don't have to worry about risk stenosis, certainly not stent thrombosis. IK, the test OCT, I think is what you called it. How readily available is it and how long does it take? Actually, our group performed first in-man study in 2000. So last year was 20th anniversary. It is widely available. And it is soft. The imaging acquisition takes just a few seconds, but including catheter placement, everything, I would say, depending on the lab, not more than 10, 15 minutes. To me, it seems like you'd establish your eligibility criteria. It may not be everyone. There may be some exclusions. But people with ACS would come in, then they'd undergo OCT. And it's at that point, if they look like they had evidence of erosion versus rupture, it's at that point that they would be randomized to either a stent or to what I think most people would call more conservative treatment. Is that how you would imagine a randomized trial playing out, IK? That's certainly one study that we have to do. One step further, what I would eventually like to do is you identify patients with ACS caused by plaque erosion at the emergency department. So using these five predictors, hopefully novel biomarkers specific for plague erosion and non-invasive imaging studies such as CTA. We are trying to figure out CTA characteristics of plague erosion. So you have a patient with ACS at the emergency department. You subulize them with antithrombotic therapy and confirm plague erosion with biomarker and non-invasive imaging. So if you are convinced or if the probability of plague erosion is high, patient has been subulized, you may not have to bring those patients to the cath lab. So forget even invasive procedure. That's my ultimate goal. IK, cardiologists like intensive care physicians, critical care medicine, have really held on to so-called hard outcomes, generally MACE, as well as death. Critical care medicine has done a spectacular job. I mean, they really look at 28-day, 30-day, 60-day mortality. This is in contrast to oncology, where they have now gone from five-year survival, three-year survival, to progression-free survival. It's so different. It's interesting to see the different disciplines. In a clinical trial, how long do you think you'd need to follow the patients to make sure that it appears as though the outcomes are equivalent? In retrospect, we have MGH OCT registry. So we follow these patients up to four years. Minimum, I think we need to follow two years. Really key question is, you know, what is the primary endpoint? Everybody loves to have a hard endpoint. With contemporary medical therapy in acute coronary syndrome area, it is extremely hard to have only heart endpoint, which is cardiac death and MI. That's why everybody is using composite endpoint, but only heart endpoint, it will be hard to design a study. You will need a huge number of patients. That's what's been so striking. The success in cardiovascular medicine has been so stunning over the last two decades. You've made doing research with hard outcomes more difficult. You've so reduced morbidity and mortality. Now you need studies of 2,000, 3,000, 4,000 long-term follow-up to find a 1% or 2% difference. And I think people begin to say, is that study really worth it? Very good point. How long do you anticipate, IK, until you'll have answers to some of the questions we've discussed? The immediate answer, biomarker non-invasive imaging, I hope within one to two years. The ultimate outcome data, I am a bit skeptical, using primary, hard primary endpoint. When you present this theory to other cardiologists, do they agree or do they snicker a little bit? They do agree in general concept, whether they are ready to readily accept this in their practice, it varies. And another thing that I have seen many occasions is people think it's erosion and for the lesions that should be stented, they didn't stand. So in other words, the diagnosis of erosion is not all that simple. You have to have a little bit of experience. So we are trying to develop an objective diagnosis of plaque erosion so that less experienced interventional cardiologists can easily get the answer. Yeah, it seems like you need to start with a definitive diagnosis to the extent that's possible because otherwise you'll misclassify individuals and they could end up with the wrong treatment. I would imagine those characteristics that get you to 73%, you'd really like to try to see your diagnostic accuracy, I'm assuming, above 90%. Exactly. This is Howard Bauchner, Editor-in-Chief of JAMA, and I've been talking with I.K. Jang, who's the Allen and Gil Gray Professor of Medicine in the field of cardiology at Mass General, where he's a professor of medicine. And along with his two co-authors, Dave Colte and Peter Libby, has written a viewpoint for JAMA entitled, New Insights into Plaque Erosion as a Mechanism of Acute Coronary Syndromes. IK, thanks for joining me today. Thank you for sending us the viewpoint. As I said, we don't publish that many like this. And I think Phil Fontana-Rosa, the executive editor, myself, Eric Peterson, who's on the editorial board, Greg Kirkman, Phil Greenland, all thought it was really an intriguing concept that we wanted more and more people to know about. Thank you very much. For more of our podcasts, please visit us at jamanetworkaudio.com. You can listen and subscribe on your favorite podcast app.
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Welcome, this is the New England Journal of Medicine. I'm Dr. Lisa Johnson. This week, December 27, 2018, we feature articles on maintenance olaparib in ovarian cancer with mutant BRCA, antipsychotics for ICU delirium, ibrutinib in chronic lymphocytic leukemia, nosocomial transmission of sphingomonas, and tofacitinib and RNA sequencing of cutaneous sarcoidosis, a review article on glucocorticoid-induced osteoporosis, a case report of a woman with recurrent sinusitis, cough, and bronchiectasis, and perspective articles on opioid use disorder in survivors of cancer, on a 24-7-365 option for combating the opioid crisis, on ramping up the response to Ebola, and on pregnant women and the Ebola crisis. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer by Kathleen Moore from the Stevenson Cancer Center at the University of Oklahoma, Oklahoma City. Thank you. The benefit of the oral PARP inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain. This Phase III trial evaluated the efficacy of olaparib as maintenance therapy in 391 patients with newly diagnosed advanced ovarian cancer, with a germline or somatic mutation in BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with Olaparib than with placebo, 60% versus 27%. Adverse events were consistent with the known toxic effects of Olaparib. The use of maintenance therapy with Olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1-2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo. In an editorial, David Spriggs from Harvard Medical School, Boston, writes that the article by Moore and colleagues is the culmination of a long march for olaparib in the treatment of BRCA-mutated high-grade serous ovarian cancer, one that began with its discovery by means of synthetic lethality screening, followed by years of clinical trials to define its activity and refine its uses, and finally led to its implementation in a population of women with potentially curable ovarian cancer. Nearly all the patients in this trial had a germline mutation in BRCA1 or BRCA2, and the results may not be generalizable to patients with either somatic BRCA mutations or wild-type BRCA genes. Implicit in the successful trial is an unresolved problem in precision oncology. The patients who were enrolled in the trial had a deleterious or suspected deleterious germline or somatic BRCA1-2 mutation. Thus, the generalizability of the results of this trial to other populations depends on the definition of deleterious mutation. It is likely that only a few patients with controversial variants were included in this trial and that the effect of these variants did not alter the reliability of the results. Given that the knowledge of genetic variants is dynamic, and additional specific adverse variants will certainly be discovered, full transparency by reporting to ClinGen or similar sources would be a helpful requirement in the future, so that patients with BRCA1-2 mutations can fully benefit from the sacrifices of the participants in the trial. Haloperidol and Ziprozidone for Treatment of Delirium in Critical Illness by Timothy Gerard from the University of Pittsburgh School of Medicine. There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit. In this randomized trial, 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium were assigned to receive intravenous boluses of haloperidol, zeprazidone, or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium. The median duration of exposure to a trial drug or placebo was 4 days. The median number of days alive without delirium or coma was 8.5 in the placebo group, 7.9 in the haloperidol group, and 8.7 in the zeprozidone group. The use of haloperidol or zeprozidone as compared with placebo had no significant effect on the primary endpoint of the number of days alive without delirium or coma during the 14-day intervention period. There were no significant between-group differences with respect to the secondary endpoints of 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge, or the frequency of extrapyramidal symptoms. The use of haloperidol or zeprazidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. Thomas Bleck from Rush Medical College, Chicago, writes in an editorial that perhaps the most vexing problem in a patient in an ICU is an unexpected change in mental status. The two dopamine D2 antagonists, haloperidol and zeprazidone, used in this study are commonly used in patients who exhibit agitated and potentially injurious behavior in the ICU, such as intentionally or inadvertently removing endotracheal and gastric tubes, or who exhibit agitation that impedes mechanical ventilation. Intensivists have used these classes of drugs, often combined with sedatives, for decades and have considered them helpful in the treatment of patients with delirium. In the study by Gerard and colleagues, the primary result was that neither drug was better than placebo in the management of acute hypoactive or hyperactive delirium. The editorialist would still consider using dopamine antagonists in patients at imminent risk of injurious behaviors, but he would have less confidence in their benefits than he had in the past. Why did the trial fail to show benefit? It is likely that our concept of delirium is flawed. The neurochemistry of sudden alteration in mentation is complex and involves several neurotransmitters, as well as structural, immunologic, and network alterations, and possible brain infection that is not clinically evident. The investigators deserve credit for conducting a difficult trial, but it would have been astounding if there were a single magic bullet for the restitution of normal brain function in ICU patients with delirium. Ibrutinib Regimens vs. Chemoimmunotherapy in Older Patients with Untreated CLL by Jennifer Wyack from the Ohio State University Comprehensive Cancer Center, Columbus. Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia, CLL, since 2016, but has not been compared with chemoimmunotherapy. In this Phase III trial, 547 patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone, 87%, and with ibrutinib plus rituximab, 88%. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab, 61%, than with ibrutinib or ibrutinib plus rituximab, 41% and 39%, respectively. Whereas the rate of grade 3, 4, or 5 non-hematologic adverse events was lower with bendamustine plus rituximab, 63%, than with the ibrutinib-containing regimens, 74% with each regimen. Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. Investigation of a Cluster of Sphingomonas Coriensis Infections by Ryan Johnson from the National Human Genome Research Institute, Bethesda, Maryland. In 2016, a cluster of sphingomonas infections sparked an epidemiologic investigation that identified 12 patients over 11 years who had been infected with genetically similar strains of sphingomonas coriensis, a rarely reported pathogen. Sink faucets and water from numerous patient rooms were positive for S. coriensis, which implicated hospital plumbing infrastructure as a possible reservoir.
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Whole genome sequencing of 68 escorriensis isolates from the NIH Clinical Center obtained from patients and the plumbing system revealed a genetically diverse population. Hospital remediation strategies were guided by results of microbiologic culturing and fine-scale genomic analyses. This genomic and epidemiologic investigation suggests that S. coriensis is an opportunistic human pathogen that both persisted in the NIH Clinical Center infrastructure across time and space and caused healthcare-associated infections. Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis by William Damski from Yale School of Medicine, New Haven, Connecticut. There is evidence that Janus kinase, JAK signal transducer and activator of transcription, STAT signaling, plays a role in the pathogenesis of sarcoidosis. These authors treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib. The patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. Glucocorticoid-induced osteoporosis, a clinical practice article by Lenore Buckley from Yale School of Medicine, New Haven. Approximately 1% of all adults and 3% of adults older than 50 years of age receive glucocorticoids for allergies, inflammatory conditions, or cancer. Fracture is the most common, serious, and preventable adverse event associated with these agents. Risk factors for glucocorticoid-induced fractures include age, greater than 55 years, female sex, white race, and long-term use of prednisone at a dose of more than 7.5 mg per day. Screening for fracture risk should be performed soon after the initiation of glucocorticoid treatment. The risk of fracture among patients who are 40 years of age or older can be estimated with the use of bone mineral density testing and the Fracture Risk Assessment Tool, FRAX tool, the risk of major osteoporotic fracture is 20% or higher, or the risk of hip fracture is at least 3%. Among patients who are receiving glucocorticoids and have a bone mineral density T-score of minus 2.5 or less, indicating osteoporosis, at either the spine or the femoral neck, pharmacologic treatment is also recommended for men who are 50 years of age or older and for postmenopausal women. Bisphosphonates are recommended as first-line treatment because of their low cost and safety. The risk of fracture decreases rapidly when glucocorticoids are discontinued. Exposure to glucocorticoids should be minimized as much as possible. A 47-year-old woman with recurrent sinusitis, cough, and bronchiectasis. A case record of the Massachusetts General Hospital by James Mojica and colleagues. A 47-year-old woman was evaluated at the outpatient pulmonary clinic because of recurrent sinusitis with progressive cough and bronchiectasis. Since her mid-20s, the patient had had recurrent episodes of sinus congestion with two or three sinus infections annually, which had prompted treatment with multiple courses of antibiotics. When she was approximately 30 years of age, skin testing revealed environmental allergies, and blood testing revealed allergies to multiple foods, including milk, yeast, wheat, gluten, rye, and egg white. Elimination of milk, grains, and eggs from her diet resulted in a reduction in sinus symptoms for approximately five years. However, sinus congestion and sinus infections recurred in subsequent years. Three years before the current evaluation, a persistent cough developed. Approximately six months before the current evaluation, the patient noted the onset of daily production of yellowish-white sputum. The amount of sputum increased, and the sputum occasionally appeared green. Examination of a sputum specimen was notable for the presence of 3-plus to 4-plus acid-fast bacilli. CT of the chest revealed bronchiectasis that involved all lobes of the lung but was most severe in the right upper lobe. In this case, the differential diagnosis was narrowed to disorders that cause impaired airway clearance. Given the presence of chronic rhinosinusitis perspective article by Allison Wakehoff-Loren from the University of Pennsylvania, Philadelphia. Ms. M was a 24-year-old with chronic myeloid leukemia in blast phase who received an allogeneic hematopoietic cell transplant from an unrelated donor. She developed acute graft-versus-host disease of the gastrointestinal tract that evolved into overlap syndrome with severe chronic GVHD of the skin, connective tissues, and joints. Her pain was debilitating and led to prescriptions for first morphine and oxycodone and ultimately hydromorphone. Ill-equipped to manage her increasingly complex pain syndrome and low mood, Dr. Wakehoff-Lawren referred her to psychiatry and pain management. But at their weekly visits, Ms. M began mentioning pruritus, constipation, and sleepiness. When her boyfriend expressed concern about her hydromorphone use, she admitted that she had been receiving hydromorphone prescriptions from her internist as well as from Dr. Wakeoff-Lawren. She was taking it every hour or two. Trouble continued to simmer. Her pain was mitigated by immunosuppression, yet she insisted she could not tolerate lower opioid doses. Dr. Wakeoff-Laworen agonized about renewing her hydromorphone. Ms. M finally admitted that she had a substance use disorder and acquiesced to residential treatment. Woven into our language about the opioid epidemic is an implication that oncologists can hand out opioids as if there were no tomorrow. But for many people with cancer, there is now indeed a tomorrow, one that should be free of opioid addiction. Emergency Departments, a 24-7, 365 option for combating the opioid crisis. A perspective article by Gail D'Onofrio from Yale University School of Medicine, New Haven, Connecticut. Emergency departments, EDs, administer life-saving interventions all day, every day, and all night, every night. In addition to rapidly resuscitating and stabilizing patients with acute illness and injury, emergency physicians are charged with identifying the appropriate level and type of care within the health care system, from intensive care to treatment in an outpatient clinic, for patients who are seen in the ED. When it comes to opioid use disorder, however, there has been reluctance among emergency physicians to initiate treatment with buprenorphine, despite the preponderance of evidence from well-designed clinical trials supporting opioid agonist treatment. Most recently, a randomized trial conducted by Yale School of Medicine investigators demonstrated the feasibility and efficacy of ED-initiated buprenorphine treatment. ED-initiated buprenorphine was also found to be cost-effective. Even with decades of research demonstrating the effectiveness of opioid agonist treatment, a minority of patients are benefiting from these medications. Engaging patients with opioid use disorder in opioid agonist treatment, a minority of patients are benefiting from these medications. Engaging patients with opioid use disorder in opioid agonist treatment with either buprenorphine or methadone is essential to addressing the opioid epidemic. For patients who present with opioid overdose, an ED visit represents a critical, time-sensitive point at which initiating life-saving treatment is possible. Ramping up the response to Ebola. A perspective article by Jennifer Nuzzo from Johns Hopkins Bloomberg School of Public Health, Baltimore. Before 2014, it seemed unimaginable to many experts that Ebola would rip through dense urban areas, ultimately sickening nearly 30,000 people and killing more than 13,000. Four years later, Ebola is again spreading in urban areas, this time in the Democratic Republic of Congo, DRC. Since September, the incidence of Ebola has more than doubled, according to WHO situation reports. The virus has spread to 11 DRC health zones, and the WHO has deemed the risk of further regional spread to be very high. Containment is not possible without bolstering efforts to detect all cases, conduct thorough case investigations, monitor case contacts, and rapidly isolate anyone with symptoms. At this point, intensified efforts, as requested by the WHO Emergency Committee, will require additional seasoned responders with cultural competency, including local language skills, technical expertise, and experience in managing complex outbreaks. Given the highly dynamic nature of this outbreak, additional experienced personnel are needed in the field to lead response operations and develop and implement strategies as dictated by changing information. However, CDC staff were recently pulled from the field in the DRC owing to U.S. government concerns about security. These concerns need to be addressed so that CDC staff can return. Security arrangements should be made to ensure that any deployed teams could operate safely in affected areas. Pregnant Women and the Ebola Crisis A perspective article by Lisa Haddad from Emory University School of Medicine, Atlanta.
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As of November 13, there were 341 cases and 215 deaths, making this the world's third-largest Ebola outbreak to date. The public health community learned several lessons when West Africa experienced the largest-ever Ebola outbreak beginning in 2014. Current prevention and control measures have benefited from these lessons and are directed toward a coordinated response, including improvements in cross-border surveillance, laboratory capacity, case management, infection control at health facilities, culturally sensitive safe burials, and psychosocial care, as well as inclusion of vaccination as a control measure. However, according to available documents, issues related to pregnant women have been largely ignored in these efforts. Though data are limited, the available information regarding pregnancy during Ebola outbreaks provides a reason for concern. Women appear to have higher Ebola infection rates than men. Ebola infection during pregnancy threatens the fetus. In nearly all cases, Ebola in pregnant women has resulted in miscarriage, stillbirth, or neonatal death. Obstetrical units may also amplify the spread of Ebola. Given the hazards for pregnant women and obstetrical health care workers, we need protocols to reduce the transmission risk and to improve maternal and fetal outcomes. Our images in clinical medicine features an 84-year-old man who presented to the primary care clinic with fever, malaise, and discoloration and pain in the fingers and toes that had progressed over a two-week period. The patient had a body temperature of 37.8 degrees Celsius. A physical examination was notable for blue-black discoloration of the distal second through fifth fingers of the left hand, dusky discoloration of several fingers of the right hand, purpuric lesions on both hands, and similar discoloration on the toes of both feet. There was associated edema but no sclerodactyly or telangiectasias. Radial, posterior tibial, and dorsalis pedis pulses were palpable on both sides. Laboratory tests revealed normal renal and liver function and an elevated C-reactive protein level of 12.29 mg per deciliter. Necrosis of the fingers and toes has a broad differential diagnosis, including vasculitis, infection, arterial embolism, and thrombophilia. Given the clinical concern about vasculitis, treatment with glucocorticoids was initiated, and a biopsy of the lesions on a finger and toe was performed. The biopsy specimens showed fibrinoid necrosis, inflammation, and medial thickening in a medium-sized artery, findings that are consistent with a diagnosis of polyarteritis nodosa, a medium vessel vasculitis. The symptoms of fever and malaise diminished with treatment, which included the addition of azathioprine and the level of C-reactive protein normalized. The necrotic areas of the fingers were amputated, and the remaining fingers and toes recovered completely. A 24-year-old man presented to the neurology clinic with a one-year history of progressive dysphagia, dysarthria, and weakness in his arms and legs. Three months before the onset of these symptoms, he had received an electric shock while repairing an electric fan. The contact point was the right hand, which had touched an uninsulated wire. The physical examination was notable for clonus of the jaw, brisk deep tendon reflexes in the arms and legs, and fasciculations of the tongue and of the muscles in the arms and legs. See the video at NEJM.org. Nerve conduction studies of the median ulnar, tibial, and common perineal nerves on both sides of the body showed diminished amplitude of compound muscle action potentials. Electromyography revealed neurogenic motor unit action potentials with fasciculation potentials in the tongue and in all limbs. These findings were consistent with chronic motor denervation and reinervation. MRI of the brain and spinal cord revealed no abnormalities. Given the presence of both upper and lower motor neuron signs with sparing of the sensory pathways, a diagnosis of amyotrophic lateral sclerosis was made. Jaw clonus typically indicates damage to the upper motor neurons in the corticopontine tracts. At follow-up, six months after the diagnosis was made, the patient had worsening limb and bulbar muscle weakness and atrophy. This concludes our summary. Let us know what you think about our audio summaries. Any comments or suggestions may be sent to audio at NEJM.org. Thank you for listening.
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Hello and welcome to the Lancet podcast. I'm Richard Lane on Friday, March the 21st. In a moment, encouraging results from two Phase 3 trials for the treatment of rheumatoid arthritis. Before that, some other highlights from this week's issue dated March the 22nd to the 28th. In research, strong evidence that chemotherapy given before and after surgery is more effective than surgery alone for removing secondary liver tumours associated with colorectal cancer. Our lead editorial discusses geriatric medicine, a very important but unfashionable discipline that needs reinvigorating, especially as the elderly population is rapidly expanding in most parts of the world. Emerging technologies suggest that drugs targeting the genetic defects of leukemic cells could revolutionize the treatment of acute lymphoblastic leukemia, and the development of new drugs has helped treat chronic lymphoblastic leukemia. The bottom line of two leukemia seminars in this week's issue. But back to our main feature this week, a potentially new approach for treating rheumatoid arthritis by blocking interleukin-6. Earlier I spoke to Professor Joseph Smolin from the Medical University of Vienna in Austria and I began by asking him to outline the main biological mechanisms that lie behind rheumatoid arthritis. There are several factors that contribute to rheumatoid arthritis. Number one, there is a predisposition of individuals, a genetic predisposition. Number two, there is a so-called autoimmune component. In other words, the body's defense system reacts against its own structures. That's why this disease is also characterized by the presence of so-called autoantibodies, such as rheumatoid factor, which is one of those autoantibodies. Three, we know that the number of cells of the defense system of the immune system are activated. In the final pathways to the disease, secret messenger molecules, so-called cytokines, such as tumor necrosis factor or interleukin-6. It is all these parts of the evolution of the disease that we aim to target with current therapies. We have therapies that target the activation of lymphocytes, so-called T-lymphocytes. We have agents that target the B-lymphocyte, which is the cell population that produces the autoantibodies. And we have agents that target these messenger molecules that I was speaking about, primarily TNF, as we now show also interleukin-6. Can you just explain in a little bit more detail what exactly interleukin-6 is? From my lay perspective, I see this as like a pro-inflammatory cytokine, which is involved in this process behind rheumatoid arthritis. Interleukin-6 is a pro-inflammatory cytokine. It has originally been described many decades ago as a B-lymphocyte growth factor, but it turned out that it has many, many activities. Among these activities are activation of liver cells, hepatocytes, and these liver cells then secrete so-called acute phase proteins, such as C-reactive protein, which we measure in serum to have a surrogate of the inflammatory response of the body. The cytokine also can contribute to the activation of so-called osteoclasts, those cells that destroy bone and rheumatoid arthritis has one major characteristic and that is joint damage, cartilage and bone destruction. So IL-6 also contributes to that and it has many many other activities in the context of the inflammatory system. So by targeting interleukin-6, we can target all these activities we see as one of the effects of reduction in C-reactive protein, but we would also expect a reduction in signs and symptoms of an inflammatory disease, in this case rheumatoid arthritis, and also a reduction in the propensity to destroy the joint. Moving on to the current study, Dr. Smolin, can you just comment on the methodology here? I'm particularly interested, obviously, in the way patients were recruited. This is an international study crossing many medical centers in many countries. What treatments or existing treatments were allowed to be continued as well as the study treatment in this case? Can you just comment on that? We took adult patients with moderate to severe rheumatoid arthritis diagnosed according to specific criteria. These individuals had to have rheumatoid arthritis for at least six months duration. They were to have an inadequate response to the major synthetic disease modifying anti-rheatic drug, methotrexate. What we mean by inadequate response is that they would have active disease, six or more swollen and eight or more tender joints, despite therapy with methotrexate. The patients were allowed to continue the pre-study dose of methotrexate and received either placebo infusions on top of it or tocilizumab at 8 mg per kg or 4 mg per kg as infusion every four weeks, six times. And four weeks after the last infusion, at week 24, we evaluated the primary endpoint. Can you just describe the intervention therapy here, tocilizumab? What kind of intervention is it? Tocilizumab is a monoclonal antibody to the receptor for IL-6. The IL-6 receptor can occur in a soluble form as well as in a membrane-bound form. And it's interesting that in contrast to several other cytokines or most other cytokines, the receptor that binds the cytokine, in this case IL-6, does not transduce signaling itself. It needs an additional molecule, GP130, and it can activate that molecule either after engagement of IL-6 with the membrane-bound IL-6 receptor, or even only after engagement of IL-6 with the soluble IL-6 receptor, because that soluble IL-6 receptor complex can also bind to GP130 and activate the cell system. Tocilizumab reacts with both the membrane bound as well as the soluble IL-6 receptor and thus interferes with the activation of any cell that carries GP130 and inhibits the inflammatory effects that occur in the context of such activation. And in terms of the results of the study, some interesting results here, can you just briefly summarize these? And I'm also interested in terms of how it is possible to measure, if you like, improvements in rheumatoid arthritis symptoms, the various scales that are used to do that. Rheumatoid arthritis has many signs and symptoms. Patients suffer from pain. Pat suffer from joint swelling, patients suffer from joint tenderness, patients suffer from disability. All these signs and symptoms of the disease can be measured in one way or another. Several of them, such as pain, for example, is measured by so-called visual analog scales, where you have a 100 millimeter line to the left. There is no pain at all. To the right is the worst pain that one can imagine, excruciating pain, and the patient then indicates with a line where the pain level is today. The same can be done for the global assessment of the disease activity by the patient or by the physician. One of those ways to measure improvement is the so-called ACR response. And we know from previous studies, the 20% improvement, according to these ACR criteria, differentiates an active medication from placebo best. That score is assessed by evaluating swollen and tender joint counts. You need to have 20%, at least, at least 20% improvement of tender and swollen joints, and then 20% improvement in three out of the other so-called CORE set variables, which are pain by VAS, as mentioned before, patient and physician global, which is a CRP or ESR level, so a laboratory indicator of inflammation, and physical disability, which can also be measured by the so-called health assessment questionnaire. So if the first two items and three of the next five items improve by 20% or more, one is an ACR20 responder. There is also other composite scores, such as the disease activity score. We also use that. That gives you a formula and gives you a very general indication of disease activity, whereas the ACR response always starts with the baseline because you need an improvement from baseline. The disease activity score gives you a very general level of disease activity, which you can compare between and within patients between groups and so on. So the ACR20 response as the primary endpoint was achieved by 59% of the patients in the 8 mg per kg group compared to 26% of the patients on placebo. Everything with continuing methotrexate. The lower dose of tocilizumab gave 48% ACR20 responses. One can then go on and say, what about an ACR50, a 50% and more response or a 70% and more response? And the 50% response was attained by 44% of the patients in the tocilizumab 8 mg per kg group compared to 11% on placebo. And when we go to the very profound ACR 70% response, then it was achieved by 22% of the patients in the 8 mg per kg group, 12% in the 4 mg per kg group, but only 2% in the placebo group.
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The results are very clear, but it begs an obvious question. Given that this is a Phase 3 trial, these are the results of an international Phase 3 trial, what happens now? Is there a change in clinical practice now, or do these results need further follow-up? These results need further follow-up for a number of reasons. Number one, it is the first of several phase three clinical trials. Usually one needs several clinical trials in phase three to be absolutely sure. Now, given the phase two data, this is reassuring because it confirms the phase two data. More patients need to be treated in such clinical trials. Number two, we also want to know the effect of docilizumab on radiographic progression in a phase 3 trial, and that is pending. And number three, we need additional observation, longer-term observational data with respect to the safety. Having said that, that study had obviously an extension phase. It is possible that the compound, if it passes through all regulatory authority queries, may become available in Europe somewhere early next year. That then will give rheumatologists and patients with rheumatoid arthritis a new option to treat the disease. Dr Smolin on the line from Austria, many thanks for talking to The Lancet. Thank you very much. Also this week we publish a smaller phase 3 trial from Japan showing how tocilizumab could be effective in children and young adults and look out for the link comment which discusses the implications of these two important trials. Well that concludes this week's podcast for the issue of The Lancet dated March 22nd to the 28th. Many thanks for listening. See you next week.
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Okay, welcome. My name is Devine. I am a PGY1 resident. Welcome to the 42nd episode of the Devine Intervention Podcast. It's been a while. It's probably been about two weeks since I made a podcast, which is kind of unfortunate. It's just that residency gets a little on the busy side, but I'm glad to be back again. And over the next few days, hopefully I should put out a couple of podcasts. So let's begin. In today's podcast, really, I'm just going to talk about the pharmacology of the eye. It's going to be a short podcast, but I'm just going to also try to integrate a few things from renal and from some other body systems. But I want to basically use this podcast to round up our discussion of neuropharmacology so that we know we're done with that permanently so the eye um really the drugs that work on the eye there's not many of them just a few high yield things you want to know here and there but i feel like this is something that occasionally like annoys people so i'll try to make it as logical as possible so that it's very easy to remember. Really, eye pharmacology is not terrible. You just learn it in a logical fashion and it just sticks to your brain really well. So what if you got an exam question about a 70-year-old male that is losing central vision? What are you thinking about? Well, I hope you're thinking about macular degeneration. Remember, in macular degeneration, you lose the central vision first, and then you lose the peripheral vision later, okay? Versus glaucoma, where you lose peripheral vision first, and then lose central vision later, okay? And there are two types of macular degeneration, right? So there's the dry kind and the wet kind. The dry kind, basically, the pathophysiology involves the deposition of something known as drusen okay it's like a yellowish kind of extracellular material and for the most part you really cannot treat dry armd um i mean there are some things you can give in the literature like you can give like vitamin e you can give like antioxidants you can give You can give zinc. But for the most part, it's not very treatable. Now, the wet kind of ARMD, this one is more dangerous, but it's actually treatable, right? So the thing that happens is that the thing that sort of destroys the eye is that you form all these new blood vessels, right? So the boss phrase you're looking for in tests is a neovascularization and those blood vessels are kind of fragile right so they they bleed and as they keep bleeding into the into the macula you begin to run into trouble so um the thing is there is this enzyme that makes new blood vessels it's known as vegf vascular endothelial growth factor okay it helps you make new blood vessels so if you know that vegf helps you make new blood vessels and it's these new blood vessels that are causing all these problems in wet armd if you then make sense that you should try to inhibit vegf right so you can give a patient monoclonal antibodies against vegEGF like Bevacizumab and Ranibizumab. Usually those drugs are given as intraocular formulations. So you literally inject it directly into the patient's eye. Now, the next topic I'll talk about is glaucoma. So in glaucoma, again, like I said earlier, you lose peripheral vision first and then you lose central vision. And remember, it's associated with an increased uptake cup to disc ratio, right? So classically, it's more than 50% on exams. And if you do some kind of tonometry, you note increased intraocular pressures, right? And don't forget some other high-yield associations with glaucoma, especially this one, right? So steroids, actually, if you take steroids chronically, it actually does increase your risk of glaucoma remember steroids do many bad things to you they can cause like osteonecrosis of the hip they can cause osteoporosis right so steroids can actually cause compression fractures of the vertebrae and remember steroids can cause um can cause peptic ulcer disease right that's why if a patient needs patient needs to be placed on a steroid for more than three months, usually you place them on a PPI, okay? So just, and the osteoporosis link, that's why you have to place patients taking steroids chronically on bisphosphonates, right? As again, osteoporosis or prophylaxis. So steroids can also cause glaucoma. That's why I'm mentioning them mentioning them in this context now before we talk about the pharmacology of glaucoma i need to talk about some quick eye anatomy right so the thing is the eye has two big sections okay there's a posterior segment and there's an anterior segment okay the posterior the thing that uh the divisor between the posterior segment of the eye and the anterior segment of the eye is the lens. Okay. The posterior segment of the eye lies behind the lens. The anterior segment lies in front of the lens. Okay. And in the posterior segment, that's where you make vitreous humor. Now, in the anterior segment, there are two sub compartments. Okay. So again, I said there's a posterior segment, there's an anterior segment. The anterior segment has two compartments. It has a posterior chamber and an anterior chamber. I know it's annoying, but it's something that's high-yield to know. So posterior segment, anterior segment, anterior segment has a posterior chamber and an anterior chamber now um the thing that divides the anterior and posterior sub components of the anterior segment is the iris so the iris the posterior chamber of the anterior segment is behind the iris the anterior chamber of the anterior segment is in front of the iris now there's a special population of cells known as the ciliary body uh they rest in the posterior chamber of the anterior segment the ciliary body makes aqueous humor okay and it makes it through an enzyme known as carbonic anhydrase okay now carbonic anhydrase hopefully you remember that it's one of those high yield enzymes that operates at the proximal convoluted tubule of the nephron. OK, remember, that's what's inhibited by carbonic anhydrase inhibitors like acetazolamide and dorzolamide. And remember, those are all sulfur drugs. Right. And don't forget osteopetrosis. Right. It's associated. It's like an osteoclast defect is associated with a mutation in carbonic anhydrase 2. That's the disease you treat with interferon gamma. Okay, so carbonic anhydrase is one of the big enzymes you need to make aqueous humor from the ciliary body, which is part of the posterior chamber of the anterior segment. And this production is actually stimulated by the activation of beta-2 receptors. Remember, those are adrenergic receptors. Now, when you make the aqueous humor in the posterior chamber of the eye, okay, it flows around past the iris, okay, and it then drains through the canal of Schlemm. The thing is, the canal of Schlemm is a blood vessel. Okay, so because it's a blood vessel, it can be acted upon by vasoactive agents. You'll see what I mean as we proceed further. Now, one of the things you want to know is that the ciliary body, when it, I mean, for the pupil, whenever you have constriction of the pupil, you actually draw the iris away from the cornea and that actually promotes drainage through the canal of slim so that is that the angle that they refer to when they are talking about glaucoma is the angle between the cornea and the lens okay that angle you can decrease that angle and decrease drainage of the canal of Schlemm by causing mydriasis, pupillary dilation. But if you had pupillary constriction, aka meiosis, and you made the pupae smaller, that would increase the angle and that will increase drainage through the canal of schlimp so in open angle glaucoma right so this is classically in another person um african americans they actually have a pretty high risk and the pathogenesis really of open angle glaucoma is you're either making too much aqueous humor or you're having too little drainage of aqueous humor right right? So think of it as either a production problem, you're making too much, or a drainage problem, right? So the works have been clogged up, so you're not draining things as well. So now let's talk about glaucoma drugs.
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So I already said that receptors right when you activate them uh the beta 2 receptors on the ciliary epithelium you begin to make a ton of aqueous humor so if you wanted to treat glaucoma you would want to go ahead and block those beta 2 receptors right now you can use drugs like timolol and needle okay those are non-selective beta blockers okay but they can also act on beta-2 receptors so by blocking those beta-2 receptors they decrease the production of aqueous humor now some other drugs that also use that are beta blockers are a cebutolol and pindolol but hopefully you've not forgotten from the adrenergic pharmacology podcasts that um i mean autonomic pharmacology podcasts that these drugs actually partial beta ag Okay? So the thing is, in the presence of norepinephrine, it's like we are stealing norepinephrine's thunder, if you may. Because if you have norepinephrine around, it will exert the full, or I guess, epinephrine, since we're talking about beta-2 receptors. Because norepinephrine really has no effects on beta-2 receptors. So, if you have full epinephrine around, it activates those beta-2 receptors, you get full epinephrine effect. But if these guys like asabidolol and pindolol are hanging out on the beta-2 receptor, you're getting a partial effect, you're not getting the full effect. So it's like you're having a reversal, if you may, like a functional reversal of the effects of epinephrine. So that is a blockade. Relatively. Okay. So these partial beta 2 agonists are actually pretty good beta blockers. And again, they are used for glaucoma. So drugs like asabutilol and pindolol. Now, alpha 2 agonists can actually be used to treat glaucoma as well. So you may say, come on, Devine, this doesn't make any sense. Alpha-2 agonists, is that not an adrenergic receptor? Is that not an activating business? Well, if you step back to the Autonomic Pharmacology podcast, you may remember that I said that alpha-2 receptors are GI coupled, okay? So it's an inhibitory G protein that's coupled to the receptor so if you activate that alpha-2 receptor okay you actually cause an inhibition of adenylate cyclates okay and by inhibiting adenylate cyclates you actually have less release of norepinephrine at the adrenergic synapse so think about it if you are releasing less catecholamine at the adrenergic synapse, you can already begin to imagine that you have less of an agonist available for the activation of beta-2 receptors. And really, I think for this, I would say that beta-2 receptors... In fact, let me call back something I've said. So, if you notice, I've been saying that for the ciliary epithelium, you have beta-2 receptors. If I'm not mistaken, so I'll have to look this up, so I may correct this in a later podcast, I believe there's actually beta-1 receptors as well on the surfaces, on the cell membranes of the ciliary epithelium. So don't think just beta 2 receptors. Also think of beta 1 receptors. I'll check on that and get back to you. To whoever is listening to this. In a later podcast. But I'm almost certain that's the case. So if you activate alpha 2 receptors. You decrease less norepinephrine. Remember those alpha 2 receptors are a negative feedback system. For the sympathetic nervous system. So you activate those. You release less norepinephrine. Remember, those alpha-2 receptors are a negative feedback system for the sympathetic nervous system, okay? So you activate those, you release less norepinephrine, so you have less activation of the beta receptors on the slurry epithelium. If you have less activation, you produce less aqueous humor. So that's how drugs like apriclonidine and brimonidine work. And if you really sound out the names of these drugs, if you notice, they all end in D, just like clonidine, right? Clonidine is a blood pressure med that works by activating alpha-2 receptors because it causes a decreased release of norepinephrine. Now, the next set of drugs I want to talk about are the carbonic and hydrate inhibitors. The big one I want to mention here is acetazolamide, okay? Acetazolamide is a ubiquitous drug. It can work for many, many, many things. One thing you can use acetazolamide for is for the treatment of glaucoma. I'm talking about glaucoma now, so that should make sense. And again, by inhibiting carbonic anhydrase, you're inhibiting one of the enzymes necessary for the production of aqueous humor. So you have a decreased production of aqueous humor now some other high yield things here um acetazolamide is actually used also to treat idiopathic intracranial hypertension okay also known as pseudotumor cerebrum right so remember if a patient has iih they have like too much csf basically in their ventricular systems right and it can cause trouble right so um classically on exams they'll tell you about like a young female like 20s 30s or early 40s that has a high bmi so like 35 and they could tell you that oh she takes vitamin a or she's being treated for acne with like a vitamin A derivative. And she has like eye pain. She has like headaches, like chronic headaches. And they tell you, oh, you do a physical fundoscopic exam and you observe papilledema. Right. So that's pretty classic for idiopathic intracranial hypertension. So if you know that too much CSF and elevated CSF pressures are implicated in the pathophysiology of this disorder, you can try to kill an enzyme that is necessary for the production of CSF, like carbonic anhydrase. Another thing you could also do for these patients is to do like a large, like to do like a lumbar, like serial lumbar punctures to just drain off some of that fluid. Now, another thing you can use acetazolamide for is altitude sickness, right? So let's think about some physiology here. If you go to higher elevations, right, what happens to your O2 tension, your oxygen tension? It should decrease, right? Because yes, your FiO2 is not going down. It's still like 21%, but remember, the higher you go, the less the atmospheric pressure, right? So, as you go higher in the atmosphere, atmospheric pressures go down. So, if you're taking 21% of like 700 as against 21% of 760, you can already begin to see that you have a decreased oxygen tension as you go higher, right? So, because the oxygen tension in the atmosphere decreases as you go higher, right, toations, you begin to get hypoxic. And the way your body tries to respond to that is by encouraging hyperventilation. Now, if you hyperventilate, you're blowing off a ton of CO2, so that causes a respiratory alkalosis okay causes a respiratory alkalosis now the thing is your body will take a few days to try to compensate for that respiratory alkalosis remember your body will compensate for that respiratory alkalosis with a metabolic acidosis you can speed that compensatory process along by giving acetazolamide remember by inhibiting carbonic anhydrase at the level of the proximal convoluted tubule, you do not reclaim bicarb at the PCT. So that bicarb is dumped in the urine. When you dump it in the urine, you actually create metabolic acidosis as a side effect. In fact, remember that acetazolamide is one of the few diuretic. In fact, it's probably like the only high yield diuretic that causes a metabolic acidosis as a side effect with a concomitant hypokalemia. That is very rare, right? Because most of the other diuretics cause metabolic alkalosis and hypokalemia. So you use the metabolic acidosis side effects of acetazolamide to make that compensation by the kidneys faster. Okay. So that you can create that metabolic acis to compensate from for the respiratory alkalosis that you get from hyperventilating to bring in as much oxygen as possible now um remember again uh they could make this like a nifty question on the test right so acetazolamide basically by virtue of its mechanism of action causes a type 2 renal tubularidosis. Because again, it's acting at the level of the proximal convoluted tubule.
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Now, one other high-yield thing you probably want to know about acetazolamide. Actually, a few more high-yield things you want to know about acetazolamide. One is that it can actually be used to treat central sleep apnea. So the thing is, I always wondered, like, why is that the case? The thing is, I really have not found any convincing explanations online, but, or like in papers or whatever, but there is something that makes teleologic sense to me. So I'm going to try to explain it in that context. So I already said that acetazolamide inhibits carbonic anhydrase, right? So if you inhibit a carbonic anhydrase, I already told you that you'll get a metabolic acidosis because you are dumping a lot of bicarb in the urine. Now, think about it. When you get a metabolic acidosis, how does your body try to compensate? Well, I hope you're thinking that it compensates with a respiratory alkalosis. And to achieve that respiratory alkalosis, what do you need to do? You need to hyperventilate, right? So if a patient has a central sleep apnea where they have like a decreased respiratory drive, you could try with acidozolamide to essentially create an acid-base deficit that will force the body to hyperventilate as a compensatory response. So that's my teleologic means of understanding why acetazolamide could potentially be used for the treatment of central sleep apnea. Now, other high-health things with acetazolamide, right? So you probably know about cystinuria, okay? It's like a defect in colar transporters at the level of the nephra, the level of the proximal convoluted tubule, right? So you probably know about cystinuria, okay? It's like a defect in cola transporters at the level of the nephron, the level of the proximal convoluted tubule, right? So remember, colas, the C stands for cysteine, the O stands for ornithine, okay? The L stands for lysine, and the A stands for arginine. Remember, arginine is used to make nitric oxide. Now, those things, because that transporter doesn't work, they all show up in the urine okay now the thing is cysteine can form kidney stones okay remember it's the it's the kidney stone that looks like a benzene ring it's a six membered ring in fact there's this fancy mnemonic you've probably heard of as you're studying that cysteine sounds like six team okay to help you remember that cysteine stones are shaped like a benzene ring. Now, so they are hexagonal crystals. So the thing is, these cysteine stones, you can actually increase, like you could actually like dissolve them in the urine and sort of like prevent a kidney stone, you may by alkalinizing the urine now by virtue of acerazolamide's mechanism of action right you can alkalinize the urine when you alkalinize that urine you um you basically increase the ph of urine and by doing that you can dissolve those 16 stones now also don't forget that acetazolamide is a sulfur drug right so if a patient has a sulfur allergy no acetazolamide the high yield diuretic you probably want to know about that is not a sulfur drug is the loop diuretic uh ethocranic acid okay it's just it's not used very commonly because it's odotoxic now uh also don't forget that if a patient has like a Proteus Mirabilis UTI, for example, remember Proteus is a urase positive bug. Acetazolamide could technically worsen that, right? Because again, it raises the urine pH by dumping more bicarb in the urine because it's inhibiting carbonic anhydrase. Now, the last set of drugs I'm going to talk about are the prostaglandin analogs, okay? So, these drugs all end in prost, right? So, like latanoprost, travoprost, bimatoprost. They are all used for the treatment of glaucoma. The thing is, again, I mentioned earlier that the canal of Schlemm is a blood vessel, okay? So, if you give a prostaglandin analog, remember prostaglandins cause vasodilation, you can dilate that that canal of shlem and promote the drainage of aqueous humor. The big side effects you want to know with these drugs are that they can cause a discoloration of the eyelids. They can cause a discoloration or they can cause thickening of the eyelashes. So just sort of keep that thing in mind. Now, whoops, I made a mistake. So just some real quick things. I guess I'll go ahead and talk about like closed angle glaucoma. Right. So closed angle glaucoma. Basically, if you have anything that suddenly dilates your pupil. OK, say, for example, you go to the movies and in the movies. Right. Because the uh let's say you step out into the light right uh i mean sorry that for example right so um if you're in if light is shown in your eye right you have like pupillary constriction right and then let's say you then go into darkness and then you open that darkness you're getting into causes pupillary dilation that can acutely narrow the angle between the iris and the cornea okay and that can trigger a closed angle glaucoma classically on exams it's in young asians okay so um so for closed angle glaucoma what could you do right so you could give acetylzolamide, although that's probably not first line, but there are other things you could do, right? Classically on exams, you do like a laser iridotomy. So you basically use like lasers to burst holes in the iris so that you can promote drainage of that aqueous tumor. But another thing you can do is you can actually give muscarinic agonists, right? Because muscarinic agonists, they cause pupillary meiosis. So pupillary constriction. So that increases that angle. Between the iris and the cornea. So that you have better drainage through the canal of Schlepp. And don't forget that closed angle glaucoma. Classically shows up as a rock hard eye. In a patient with nausea and vomiting. On tests. So that is where I am going to end today. Thank you for listening. I will hopefully make a 43rd podcast soon. I wish you all the best. Have a wonderful month and God bless. Thank you.
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From the JAMA Network, this is the JAMA Editor's Summary, a review of important research, viewpoints, and review articles appearing in the latest JAMA issue. I'm Dr. Kirsten Bibbins-Domingo, Editor-in-Chief of JAMA, and I hope you find this week's issue beneficial. Here's your host, Dr. Kristen Walter. Hello, and welcome to this edition of the JAMA Editorial Summary Podcast for the January 23, 2024 issue of JAMA. I'm your host, Dr. Kristen Walter, Deputy Editor of JAMA. Let's begin with the original investigations. This week's issue includes three research articles and two research letters. The first research article by Dr. Thornburg and colleagues is titled Anxiety and Depression Symptoms After the Dobbs Abortion Decision. This retrospective analysis examined changes in symptoms of anxiety and depression following the June 2022 U.S. Supreme Court ruling in the Dobbs v. Jackson Women's Health Organization that abolished the federal right to abortion and triggered abortion bans in some U.S. states. Using data from a nationally representative survey, investigators compared anxiety and depression symptoms in residents of 13 states with trigger laws to ban abortions versus the 37 states without trigger laws. Among the 718,753 survey respondents after Dobbs, residents of trigger states had a small but statistically greater increase in anxiety and depression, particularly in females of reproductive age, and suggests these findings should inform the U.S. Supreme Court as it hears other cases about abortion law. In an accompanying JAMA author interview podcast, JAMA Associate Editor Dr. Donald Goff discusses this topic further with editorial author Dr. Julia Steinberg from the University of Maryland. The second research article by Dr. Al Alamoy and colleagues is titled Functional Outcomes After Localized Prostate Cancer Treatment. This observational study of U.S. registry data compared rates of adverse functional outcomes between specific treatments for localized prostate cancer. Among 2,445 people treated for localized prostate cancer, patients with a favorable prognosis were treated Thank you. radical prostatectomy, or external beam radiotherapy with androgen deprivation therapy. Rates of patient-reported adverse sexual, urinary, bowel, and hormone outcomes were measured with a 26-item expanded prostate cancer index composite score. A 10-years follow-up among 1,877 patients who had a favorable prognosis, treatment with radical prostatectomy compared with active surveillance was associated with worse urinary incontinence but not worse sexual function. Among 568 patients who had an unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function when compared with external beam radiotherapy with androgen deprivation therapy. However, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel function and hormone function. The third research article by Dr. Wang and colleagues is titled Cancer Diagnosis After Recent Weight Loss. This prospective cohort study examined the one-year risk of cancer diagnosis in health professionals who experienced weight loss during the prior two years. The more than 157,000 participants included males and females aged 40 and older from the Nurses' Health Study and the Health Professionals' Follow-Up Study. At an average of 28 years of follow-up, recent weight loss of greater than 10% of body weight was associated with significantly higher rate of cancer during the next 12 months compared with those without recent weight loss. The between-group difference was 493 cases per 100,000 person years. Cancer of the upper GI tract, including esophagus, stomach, liver, biliary tract, or pancreas, was particularly common among participants with recent weight loss. The first research letter by Dr. Siebert and Ioannidis is titled Lifting of Embargoes to Data Sharing in Clinical Trials Published in Top Medical Journals. Using data from a previous study that examined 487 randomized trials in JAMA, Lancet, and the New England Journal of Medicine between July 1, 2018 and April 4, 2020. This study focused on 158 trials that had originally had an embargo for data sharing and found that within three to five years of publication, two-thirds of these trials had lifted their embargoes on data sharing. The second research letter by Doctors Tu and colleagues is titled Biologic Patent Thickets and Terminal Disclaimers. This study found that among 271 biologic patents involved in litigation from 2010 to 2023, 48% had a terminal disclaimer, which is a tool that allows drug manufacturers to quickly obtain new patents that offer trivial changes over existing innovations. Terminal disclaimers spiked 12 years after product approval, coinciding with the end of their statutory exclusivity periods. The authors state that Congress could reduce barriers to biosimilar entry by capping the number of patents that brand name manufacturers can assert against biosimilar drugs. Let's turn to the two viewpoints in this week's issue of JAMA. The first viewpoint by Drs. Peter Mark and Robert Califf from the U.S. Food and Drug Administration is titled, Is Vaccination Approaching a Dangerous Tipping Point? This viewpoint points out that the number of people declining vaccinations in the U.S. is increasing. For example, the uptake of the updated COVID-19 vaccine XBB1.5 monovalent in the U.S. is only about 35% in those older than age 65, which is approximately half the rate of this age group in the United Kingdom. This viewpoint explains that vaccination saves lives, citing a study that found the risk of death was 2.46-fold higher in 11.7 million unvaccinated individuals versus 9.9 million individuals who had received at least one dose of a COVID vaccine. The authors urged the clinical and biomedical community to redouble its efforts to provide accurate, plain-language information to patients about the individual and collective benefits and risk of vaccination so they can make well-informed choices based on accurate scientific evidence. The second viewpoint by Drs. Miguel Hernan and Sander Greenland is titled Why Stating Hypotheses in Grant Applications is Unnecessary. This viewpoint argues against the hypothesis-centric approach of research and proposes that grant applications should instead be evaluated by their relevance and methodological quality rather than by qualitative assertions about explicitly stated hypothesis before the study has been conducted. This week's clinical review and education section includes the 2023 U.S. Preventive Services Task Force Recommendation Statement on Screening for Speech and Language Delay in Children. This was informed by the systematic review of published evidence by Dr. Feltner and colleagues. The task force concluded that the current evidence was insufficient to assess the balance of benefits and harms of screening for speech and language delay in disorders in children five years or younger without signs or symptoms of language delay. In an accompanying JAMA Clinical Reviews podcast, JAMA Editor-in-Chief Dr. Kirsten Bivens-Domingo discusses this recommendation statement with Task Force member and co-author Dr. Toumani Rukerkoker from the University of Washington School of Medicine. Dr. Spites and colleagues have an accompanying editorial to the U.S. Preventive Service Task Force recommendation titled, Recommendations for Speech and Language Screenings. Lack of Evidence Should Not Endorse Lack of Action. This editorial points out that the USPSTF recommendation does not apply to children whose parents or primary care clinicians are concerned about a child's speech and language development. The authors also highlight the urgent need for more research on the benefits and harms of universal speech and language screening and encourages pediatricians to ask parents about their child's speech and language development and to refer children for evaluation if parents express concern. This week's JAMA patient page also covers the topic of screening for speech and language problems in young children and describes the USPSTF recommendation about the pros and cons of screening for speech and language problems in children age 5 or younger. Dr. Altenberg and colleagues have a JAMA clinical guideline synopsis that summarizes the 2022 American College of Cardiology and American Heart Association guideline for the diagnosis and management of aortic disease. This synopsis mainly focuses on recommendations for aneurysms that involve the aortic root and or the ascending aorta. This week's issue features two medical news articles. The first news article by Melissa Saran and Yulin Sun is titled How to Navigate the Pitfalls of AI Hype in Healthcare. In this interview, JAMA editor-in-chief Dr. Kirsten Bibbins-Domingo and Dr. Arvind Narayanan, professor of computer science at Princeton University, discuss the potential benefits and risks of using artificial intelligence in research and Clinical Settings. The full interview is available in podcast and video formats. The second medical news article in this issue is by Howard Larkin and is titled, What to Know About PREVENT, the AHA's New Cardiovascular Disease Risk Calculator. This article discusses the American Heart Association's new cardiovascular risk calculator called PRE January 23, 2024 issue of JAMA. This is JAMA Deputy Editor, Dr. Kristen Welcher. For more podcasts, visit jamanetworkaudio.com. You can also listen and follow wherever you get your podcasts. This episode was produced by Shelley Steffens.
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The Curbside Ridge Podcast is for entertainment, education, and information purposes only, and the topics discussed should not be used solely to diagnose, treat, cure, or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the host and should not be interpreted to reflect the official policy or position of any entity, aside from possibly cash 154,000 members. For a limited time, post-training docs save $100 on their first year membership dues. Visit acponline.org forward slash join and use the code curb100 to get your discount. What was that code again? That's C-U-R-B 100. Are there any spaces in that? No spaces. Hey, Paul, we're back. Did you actually interrupt yourself? No, I think I was just speaking. So, Paul, this is the Curbsiders, and you're going to tell people what we do. Tonight, it's just me and you and our wonderful guest. Stuart couldn't make it tonight. He is on a busy inpatient service, but he's with us in spirit, Paul. Always. I carry Stuart in my heart. So we are the Internal Medicine Podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And we also like to talk to our guests at the very beginning just to learn about them, what makes them tick and how they relax. I think no chiding this time around. And you already hopefully know our guest this time around. He's been on one of our earlier Peabody Awarding episodes. So this part will be a little bit shorter, but if you want to skip past it, just look to the show notes for your timestamps. In this episode, you'll hear all about the cirrhotic patient with decompensated cirrhosis, or is it acute on chronic liver failure? We'll talk about some of that terminology. We'll talk about variceal bleeding, hepatic encephalopathy. We talk about coagulopathy in cirrhosis and spontaneous bacterial peritonitis. Just a ton of really interesting physiology stuff. Lots of pearls from Dr. Matherly walking us through how he interprets labs. I mean, this episode just has so much great stuff in it. And to remind you, our wonderful guest, Dr. Scott Matherly, he is an assistant professor in the Department of Medicine at VCU in Richmond, Virginia. He is a board-certified internist and boarded in gastroenterology and transplant hepatology. He completed medical school at the University of South Carolina, residency at Johns Hopkins, and completed his fellowship training in GI and transplant hepatology at VCU. As a member of the faculty at VCU, he has been recognized no fewer than five times as VCU School of Medicine's best teacher. In addition to his teaching responsibilities, Dr. Matherly is a co-director of the Multidisciplinary Hepatocellular Cancer Clinic in the Hume-Lee Transplant Center. And I can't wait for everyone to hear this wonderful discussion. And pun. Scott, we are thrilled to have you back. This is a huge topic, one that terrified me during training and, to be honest, still terrifies me more than it should. Well, actually, I think it's a terrifying condition, so we're going to ask you for a lot of advice. I hope you're ready. I'm ready. I'm ready. Looking forward to it. Yeah. You're going to live up to your Twitter handle tonight, which is at liverprof for those of you at home. Can you give us a one-liner, Scott, to just kind of remind the audience who you are? Yeah, I'm a 44-year-old father of two. I have an eight-year-old son and a five-year-old daughter. I also have a rescue pup. I'm a single dad. I'm dating a beautiful physical therapist. I'm a keto practitioner and a novice weightlifter, but I'm also a transplant hepatologist on the side as well. Good. It's important to have hobbies. There's so many follow-up questions. Wait, I don't think you told us you were a keto practitioner last time. Yeah, yeah. I'm a lot skinnier than I was last time I saw you guys. Tell us about the keto thing. Like, is it a, yeah, like, is this good for the liver? Maybe we'll just start there. Well, my expert opinion would be, yes, it is good for the liver. Weight loss is good for the liver. Sure. You know, I think when it comes to dietary science, it's remarkably difficult to figure out what the right thing to do is. So I always advocate for folks to do what works for them. And so far, the keto diet has worked for me. I'm enjoying it. I enjoy being on it. And I've lost a boatload of weight. So I'm sticking with it. Oh, congrats. That's great. If an audience member wanted to get on the keto diet, is there like a particular resource that they could use to learn about it the way that you did? You know, I really learned about it through a physician at work who has a weight loss clinic. And I didn't necessarily go to the weight loss clinic, but we sit in clinic together every Wednesday and talked about it sort of a lot. There's tons of stuff out there these days. It's an extremely popular diet. Yeah. Fairly simple overall, really. Just a low-carb, high-fat sort of diet. Sounds a little crazy on on the face to be honest with you, but it actually works fairly well. It's good for my irritable bowel syndrome too. For anybody out there with the, with the irritable bowels. And how, how OCD are you? But now I know we're going on the rabbit hole with this. Sorry, Wado, but like, are you to the point, like I know that some of it is actually monitoring whether or not you're generating ketones. Like have you gone that far into it or is it just a matter of eating the foods that are sort of part of the diet? No, I'm a very OCD kind of guy, but I refuse to make it that complicated. From the very beginning, I set some guidelines about things that I shouldn't be eating. I don't weigh things. I don't measure things. And to be honest with you, I don't worry about it if I eat too many carbs in one day. I just stay away from stuff. But I'm not dipsticking my urine looking for ketones. Forget it. I guess that was the question I was dancing around for whatever reason. No. Yeah. later in 2019. He's an expert on the keto diet. He lived on it for several years. He's a physician and he's also knows all about like intermittent fasting, time-restricted feeding. I'm really interested in this stuff. So look out for that later in 2019. Yeah, it would be a great episode. It's very hot right now. All right. So, Paul, speaking of hot right now, why don't you give one of your famous hot takes on a pick of the week? I'm excited for this one. Because usually, you know, I do a pretentious movie that no one actually enjoys. Side note, one of my colleagues actually followed one of my movie recommendations and made a point to seek me out to tell me he hated the movie. So it's always nice to hear from our fans. So it's usually a high-flote movie or book. This time around, I'm going to recommend the History Channel program, Truck Night in America, which is one of my all-time favorite shows. Do you have any idea about this, Matt? No, no. Scott, have you heard of this? Truck Night in America. It sounds amazing. It is fabulous. It starts out with four contestants who basically soup up their trucks. They bring them in from home, and they're all jacked up in these gigantic tires, and they're a bazillion horsepower. And they're put through this insane obstacle course in the competition to eliminate them until the last driver goes through this thing called the Green Hell, which is like this insane mountain of mud and rickety roller coaster type things. The whole thing is just an excuse to just beat these trucks to death. And half the time they're exploding and stuff. And it's, it's just almost Zen, like how much I enjoy it. I just sit and watch people beat up their trucks for an hour and it is fantastic.
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Truck night in America. Got it. I, uh, I can't, I cannot say that I've seen that before. Okay. The History Channel is killing it because they do the Forged in Fire too, like the blacksmithing competition where they have to make these blades and then prove how actually sharp they are. There's all kinds of amazing game shows, for lack of a better term, on the History Channel. So if you have some time to kill and you're tired of netflix documentaries head on over take a look i'm gonna give i'm gonna give that actually a tv show recommendation paul i was texting you about this the other night i really i'm a huge fan of like time travel groundhog's day happy death day uh this this is this new netflix show russian doll it came out february 1st and it's a really cool show like the soundtrack i like the main character natasha leone it's just a it's a it's a great show and so i would recommend it it's eight episodes there are only like 25 minutes which kind of checks off my you can't ruin too much of your time with it uh or waste too much with it. And hopefully it'll be back for some other seasons. Scott, did you have any sort of pick of the week? You know, guys, I live a very sheltered life. I just work and read. But no, the thing that I'm really enjoying right now, and this may sound incredibly stupid, is weightlifting. Okay. You know, I've always hated exercise. I've always been a chubby boy my whole life, and I always hated cardio and always find reasons not to do it. But I decided to start trying lifting weights, and I have this simple little app on my phone called the StrongLifts 5x5 app. And I have absolutely loved it, and it's really changed me a lot. I go to the gym three times a week. I'm happy as a peach lifting weights, getting me some muscles, which I never had before. So maybe if you have trouble with your fitness, just try a different way. But that's my hot pick for the week. I like it. So this app that you're mentioning, the five, are they kind of Olympic lifts, like deadlift, squat, like those sort of? It's very simple. That's the other thing I like is basically three exercises that you do alternating. So you always do squats every time. And then you alternate deadlift and overhead press, bench press, and barbell row. And so it's very simple. Three exercises each time. You do five reps, five sets, and that's it. Simple. That sounds great. My brother-in-law is a strength and training coach, and he talks about that. I think this would meet his approval. He talks about basically those exercises, a push, a pull, a hinge at the hips, and squats. Yeah, it's great. Yeah, these are all compound, hit all the major motions. Yeah. You would not know that we were going to talk about cirrhosis based on the last 10 minutes of conversation, which I have thoroughly enjoyed. But at this point, I'm going to ask Paul if he would be so kind as to start us off with a case from Cashlack and throw you the first question. I'd be happy to. So let's talk about Mr. Keith. Mr. Keith is a 45-year-old male. He's got a past history of alcoholic cirrhosis, also past history of hepatitis C, former cigarette smoker, 40 pack years total, who presents to Cashlack, brought in by his family with concerns for altered mental status, everyone's favorite diagnosis. He also vomited blood this morning and was found confused in his bathroom. His wife reports that his stools have been dark for the past couple of days. For an examination, he's tachycardic. His heart rate is 115, blood pressure 92 over 55, setting 92% on room air, and his temperature is 97.6 degrees. His wife says he may have had fevers or chills yesterday, but who can tell? And we didn't actually check his temperature. And then the initial ER labs that we get back is a hemoglobin of 9, platelet counts that's still cooking, which is always a great sign, white count of 13.5, creatinine of 1, BUN of 42, potassium of 3. He's hyponatremic with a sodium of 127, bicarb of 17, chloride of 97, albumin of 2.5, total bilia of 5.6, and an INR of 1.7. And this is already a boatload of information for you. Like a really scary board question. Yeah, right, absolutely. Where you just hope or fur is actually one of the options. Where is this one going? But for you, you have this patient who comes in with altered sensorium and this history of already known liver disease. So can you just talk us through your initial approach for the patient, starting maybe even with the history? Yeah, that's a great question. With this kind of patient, it's a little overwhelming due to the very significant possibilities of badness going on with him, right? So with him, I'd want to figure out some things fairly quickly from hopefully his family members since he's altered. You know, things like, is he on blood thinners? What NSAIDs? You know, something like that. Has he been taking medicines that would alter his sensorium like benzodiazepine or narcotics? Has he had any recent alcohol or substance abuse? And has he fallen? So when somebody comes in altered with assumed encephalopathy, oftentimes, especially with alcoholism as their underlying liver disease, you have to worry about falls and subarachnoid hemorrhages and subdural hemorrhages and stuff like that. So those are sort of some quick things that I would want to try to figure out while I'm trying to figure out what to do with this guy. What do you think of his labs? Well, I think his labs are very concerning. The few things that immediately pop out to my mind, I, as a hepatologist, as is albumin, is very low, suggesting fairly advanced liver disease. He's quite jaundiced, and I don't know what his baseline is. His sodium being low is a big red flag for me. This often portends hepatorenal-type physiology going on with these people, and he would be fairly high risk for going into renal failure. And he's obviously anemic and altered. The other thing that kind of jumps out is his BUN being elevated. That often makes me think that, you know, maybe he's ingested a blood meal, if you will, and may have an upper GI bleed, but you've kind of gotten from your history anyway. And exam-wise, anything specific that you pay attention to in this guy? Like you spend a lot of time looking for asterixis, things like that? No, I don't really. I mean, from my standpoint, this guy is critically ill. And as a hepatologist, I'd be worrying about what can I do to keep this guy from dying, right? So really, it's very, very back to basics, which is the ABCs, airway, breathing, circulation. This guy's airway is a big concern to me, and it should be when any time cirrhotic comes in altered. Because aspiration is going to equal death for these people. So you have to be very careful if they're obtunded, if they're vomiting. I have a very low threshold to get ICU team down here and get this guy intubated. He's vitals, is he stable or unstable? This guy does not look stable to me. He's tachycardic. He's hypotensive. And that, I mean, that suggests a significant blood loss somewhere in 15 to 40% if this is bleeding. Or this could be septic shock. That's another thing that he needs resuscitation fairly aggressively. As for physical exam, I'm not going to spend a whole lot of time looking for asterixis in this guy. Pretty obviously, probably encephalopathic, but I am going to be looking for things like, does he have ascites? Does he not have ascites? Are there any signs of infection? Does he have, you know, are his lungs clear? Those sort of things. In the acute setting like this, I don't spend a lot of time, you know, worrying about whether they have spider angiomas or not.
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Is there a whole lot of utility in fussing around with that stuff, or is it more just a matter of making sure the patient's stable is kind of what I'm hearing? Yeah, in this setting, I think it's much more important to make sure the patient is stable. Really with the encephalopathy, your decision tree here is does this patient need to be intubated or is this somebody that we can try to wake up on a step-down unit or something like that? Before we kind of go into the acute management of this patient and any further kind of workup we're going to send, can you talk to us a little bit about this terminology of decompensated cirrhosis, acute on chronic liver failure? How should we talk about this among colleagues and when we're communicating with you as a hepatologist? Yeah, so that's a great question. And there was actually a whole conference on this back in 2015 called the Bovino Conference, where we really wanted, we endeavored to adequately define cirrhosis and its stages. And they came up with several different terminologies, okay? And one is compensated cirrhosis. So this is your cirrhotic patient who doesn't have ascites, encephalopathy, variceal bleeding. You would otherwise not even know that they had cirrhosis potentially. They're doing well. These people can live 10 to 20 years with their cirrhosis as their lifespan, and they're broken down based on this criteria into those with portal hypertension that's mild or those that have clinically significant portal hypertension, and those people are broken down into those who have varices or don't have varices. That's not too terribly important for non-hepatologists, but the bottom line is that compensated cirrhosis is that's your patient who maybe has cirrhosis and is showing up with a diabetic foot ulcer or something like that in the emergency room. Decompensated cirrhosis is somebody that has now developed one of the big complications of cirrhosis, and that's ascites, hepatic encephalopathy, or a variceal bleed. And this is a big inflection point, right? So if they go from compensated cirrhotic to uncompensated or decompensated cirrhotic, that's a big prognostic milestone because their survival is automatically going to be much, much shorter than a compensated cirrhotic, somewhere in the neighborhood of one to two years instead of 10 to 20 years. And this is the point where you really need to start wondering if this person is going to need a liver transplant, or is there anything else we can do to abort this kind of process before it advances? But even further beyond that, they have what they term the late decompensated cirrhotic. So this is really where our patient would be described as a late decompensated cirrhotic. These are people with recurrent variceal bleeds, refractory ascites, hepato-renal syndrome, recurrent encephalopathy, or jaundice. And these people have very high levels of mortality and really need consideration for transplant. But even then, our patient was a decompensated cirrhotic probably at baseline, even though we don't really know. But what he really has right now is acute on chronic liver failure. And this is an important concept, an important terminology that even in my short period of time as a hepatologist has been argued about. And quite honestly, every society on earth has its own separate definition of this entity. But basically what this is, is this is a syndrome of acute decompensation of a patient with prior underlying liver disease characterized by the development of liver failure plus one or more extra hepatic organ failures. So the way I think about this is you got somebody with some kind of underlying liver disease and it doesn't have to be cirrhosis. I mean, this could happen in a patient with chronic hepatitis C, somebody with alcoholic fatty liver disease. It doesn't matter. But something happens to them, and their liver goes from being okay to failing. And the way we characterize by failing is that they become jaundiced. Their INR elongates. They develop an elevated INR way above their baseline significantly. So if their normal bilirubin is 1.3 and they come in at 5.6, that's a significant increase in their bilirubin suggesting liver failure. And if you add on to that another organ failure, so with our patient, the hepatic encephalopathy would be considered CNS failure. The hypotension is cardiovascular failure. The AKI would be renal failure. So these additional organ failures would suggest this patient has now acute on chronic liver failure. And the significance of that is that mortality is very significant even in hospital. So about 50% of people with acute on chronic liver failure will die in the hospital before they leave. So you got about a half a penny, a coin flips chance of getting out of the hospital when you come in with acute on chronic liver failure. It only accounts for about 5% of admissions with cirrhosis. So if you just get admitted with ascites or you just get admitted with SBP, that doesn't mean you have acute on chronic liver failure. Acute on chronic liver failure, you have to have jaundice, worsened INR, plus some other organ going down as a result of the liver failure. And I think our patient meets that criteria. It is an important distinction between that and just decompensated cirrhosis. Okay. And are any of these definitions fluid? So can you walk back? So if someone comes in as maybe not late decompensated, but just decompensated, and you sort of fix the underlying derangement, can you move backwards to compensated or are you sort of almost like healing pressure ulcers where once you're a stage four, you're always a stage four? Traditionally, we don't think so. I mean, if somebody became, you know, a decompensated cirrhotic with ascites, we would just consider them a decompensated cirrhotic forever. And if you look at our notes, that's what we'll say forever, decompensated cirrhotic. But you can do certain things to these people that can dramatically improve their liver function. If they're an alcoholic and their alcohol is what's really driving their liver disease and they stop drinking, we can see dramatic improvements, even in short periods of time. People can go from being jaundiced and bellies full of fluid to having no ascites, no jaundice. And then three years later, you're still going to call them a decompensated cirrhotic when they have normal albumins or everything else is fine. No, at some point, they probably become a compensated cirrhotic again. Same thing with hep C treatment. We see this time and time again. People with, even on transplant lists, get treated with hepatitis C and their liver function improvement over the years after that is dramatic sometimes. And do they become compensated yet? I guess they do. I don't know exactly when you start calling them compensated again, probably when you realize that, hey, it's been three years since they had ascites or something like that. I want to move forward with the case. Let's say that we start doing some basic things for Mr. Keith. He gets two large-bore IVs. We give him a little bit of fluid and maybe you can comment on, on what, what fluid you might give for the hypotension and how much. And he starts bleeding again, right in the ER. So we, we call you Scott and you're going to take this guy for EGD. You see that he's got some large bleeding varices, so you ban them. So what else, you know, as that all is happening, what other treatments might we be giving him in the ER to stabilize him as he's on his way to the endoscopy suite or the ICU for you to do at bedside, wherever it's going to be done? Well, a couple of things I would say when we're still doing our workup lab-wise that I would advocate for, and that's really looking for infection in these people is very important. And we will talk about SBP probably in a little while. But, you know, my old saying with cirrhotics is that any cirrhotic admitted with any complaint who has ascites has SBP until you prove that they don't. I think that's wise words to live by because SBP kills and it's hard to diagnose sometimes. Very protean manifestations when they're admitted. ABGs, blood cultures, urine cultures, chest x-ray, make sure you're not missing an infection on these people. And I would kind of advocate against a couple of tests. And I think that's important too.
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Not important. Hemocult is a screening test for colorectal cancer. And in this setting, I think we can assume that he's having a GI bleed. And then ammonia levels. And this is a pet peeve of mine. Whenever I'm rounding and a medical student or resident tells me that the ammonia level is X on said cirrhotic patient, I hiss at them like a cat. And I keep making hissing noises whenever they mention ammonia. Because it's really not a test that is indicated or useful. I actually tweeted about this today. If you guys see me on Twitter, especially in this setting right here, when you have a cirrhotic who's severely decompensated and obviously encephalopathic, sending an ammonia level adds zero to that conversation. Encephalopathy is a clinical diagnosis, not a lab diagnosis. And the reason I'm so grumpy about this is because I see it lead to harm of patients. And this is what bothers me, is I see people drawing ammonia levels every week on their patient and making them take insane amounts of lactulose and having tremendous diarrhea just because their ammonia level is 64 that day, rather than looking at the patient and seeing that they're not confused or whatever. There are a couple of clinical situations where the ammonia level is useful. And I will say in adults, you know, I don't deal with kids, but urea cycle disorders in kids, it can be useful, but I don't see those. But in adults, if you have somebody who doesn't have cirrhosis, who has encephalopathy, who's altered and you don't know why, an ammonia level in that setting can be useful because there are certain things, certain drugs that can cause elevated ammonia levels which can lead to encephalopathy. So it's worth investigating then. If you have a patient with acute liver failure, say somebody comes in with a Tylenol overdose or something like that, the ammonia level is beneficial there because it can tell you the risk of brainstem herniation. So it has some prognostic abilities in that setting. But in a cirrhotic patient, it's never useful. And I never want it drawn, ever. So I went on a tangent there. It's a pet peeve. What can I say? All right. So you were asking me what else should we do, right, with regards to fluid and everything. I would say resuscitation is very important here. Before you call in the cavalry to come in with our endoscopes and throw some rubber bands on this gentleman, we need him resuscitated a little bit. We don't want anybody to die because of conscious sedation for an upper endoscopy that makes us twitchy, and there's a lot of paperwork involved. So getting the patient resuscitated with fluids and blood is important. Now, what kind of fluids to use? I don't know that there's a right answer for that. I would probably just advocate for plain old crystalloid. Now is not the time to worry about, are they going to third space that into ascites? Sure, they might later on. You can deal with that later on. You need to get their blood pressure up. I don't think giving them 25% albumin right now is going to effectively get his blood pressure up. So I would bolus him with crystalloid and blood. So the blood transfusions, there is some science to this with regards to variceal bleeding in general. And you don't want to just hammer them with tons of blood and get his hemoglobin up from 9 to 13 or something like that because that's been shown to increase the risk of recurrent bleeding and death. So the sweet spot for blood transfusions in a cirrhotic patient is 7 to 9. And that's where we want their hemoglobin to be and not much above that. So you have to gingerly transfuse blood in these folks. But mechanistically, why is their mortality higher if you push the blood? Is it just the usual complications of transfusion, or is there another reason that it seems to? I think just the increased blood volume leads to increased portal pressures and probably increases their risk of bleeding is probably the pathogenesis of that. For this patient, would you be starting them on octreotide? How important is that in the acute setting, or can that wait until after we give the blood, the fluids, and we get this person banded? No, octreotide is very important in this situation, and it's probably your number one priority. And I'm saying octreotide, I'm being very USA-centric here, because this is another situation where in the rest of the world, a different agent is used, and that's terlopressin. So octreotide is obviously a somatostatin analog. It's given as a bolus followed by a continuous infusion, And we typically keep it going for three to five days in variceal bleeds. This can acutely decrease portal pressures and stop the bleeding by itself. So this is very important and probably the number one priority of an agent to hang on these folks, right? So we always want to get the vasoactive substances, either octreotide or terlopressin and other parts of the world going as soon as possible. The second thing to give them obvious is it seems a little unusual as an antibiotic. And in particular, we usually recommend third generation cephalosporins or higher. So if the patient is super sick and you want to do, you know, antibiotics, that's fine and that'll probably work. If not, then we usually give something along the lines of ceftriaxone. And you want to give that soon because giving the antibiotics during a variceal bleed has been shown to decrease mortality, decrease infections, and it's just a very important part of that. So for me, it's octreotide number one, number two is ceftriaxone. And then obviously the endoscopy within 12 hours to get some rubber bands on those veins. You notice I haven't said PPI, and I'm sure you're going to ask me about that. But proton pump inhibitors don't really have a role in variceal bleeding in particular. If you look at the variceal guidelines, there's no mention of PPIs. And that's because giving acid suppression is not going to prevent them from bleeding to death from a varix. That being said, most of these folks come in with an upper GI bleed. And you don't know that they're a variceal bleed until we actually do the endoscopy. And many upper GI bleeds do respond to PPIs. And so giving them on a PPI is pretty standard, and we always do it. But it's not necessarily for the varices itself, and it's not necessarily your number one priority. I would say if you're choosing the, do I give them the octreotide or the proton pump inhibitor? I would go with the octreotide first. Octreotide will actually decrease bleeding from other GI bleeding sources like ulcers and stuff like that as well. So it's just a good, a good first choice. PPIs can also benefit you after we band, you know, we put these rubber bands down in the lower esophagus and they only stay on there for a day or two usually. And then they, they necrosis and fall off and they leave behind them a giant ulcer in the lower esophagus and they only stay on there for a day or two usually and then they necrosis and fall off and they leave behind them a giant ulcer in the lower esophagus and those ulcers if you ever go down there like a week afterwards they're quite impressive sometimes these big giant ulcers and if you think thinking about they're sitting on these bed of high pressure blood vessels it's kind of terrifying to think about but how did I not know this yeah you, you don't want to know. You don't want to know some of this stuff. But anyway, there is something called a post-banding ulcer bleed, and this can commonly happen within the first week or so after a banding procedure, and the PPIs actually decrease the incidence of that. So, PPI will be given, but it's not my number one priority in this situation. I wanted to ask you if you could talk a little bit about the octreotide mechanism of action and how, if at all, that differs from terlopressin. I was hoping you weren't going to ask me that, Dr. Watto. I thought you loved talking about that. What do I look like, some kind of physiologist? Yes. I'm not sure. Somatostatin works by causing vasoconstriction in the mesenteric vasculature, which decreases portal flow, which decreases portal pressure.
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Turlepressin is a vasopressin analog. It does that more directly by causing, directly causing vasoconstriction of the mesenteric vasculature. The nice thing about turlepressin is that it also kind of boosts your blood pressure. So you get kind of an increased blood pressure with turle usually when it's given IV. So that's basically how they both work by decreasing portal inflow and decreasing portal pressure as a result. I think that's plenty. I don't think we need to go to the molecular level. That was a great explanation. All right. All right. So let's kind of recap. So basically, we've pan-cultured this person. We've given them crystalloid. We're giving them blood. We got them octreotide and antibiotic, a third generation cephalosporin or more. So we're sort of stabilizing the patient. They've got good IV access. You ban them and create a giant ulcer in their lower esophagus. What's next for this person? Anything else? We just kind of cross our fingers and hope that they're stabilized, the next thing you really need to worry about is how to prevent this from happening again. And there's a couple of ways that you can prevent this from happening again. One is you can do a TIPS procedure on the patient, right? And so this is kind of a hot topic. And there's been a lot of research about doing what is called an early TIPS after a variceal bleeding. You know, TIPS, for those that don't know, is a transjugular intrapatic portosystemic shunt. It is basically an interventional radiology procedure where they artificially connect the portal vein to the hepatic vein, allowing blood to shunt from the portal vein straight into the vena cava and to the heart without having to go through the knotted up, scarred up liver. And the immediate result of a TIPS procedure is that decreases portal pressures dramatically, maybe not to normal, but certainly to a level where you don't have variceal bleeding. Another upshot of these is they typically get rid of ascites or make ascites much more manageable. So TIPS is fun. They're great, but there are a couple of downsides to a TIPS. Number one is if you're too sick, if your liver is too sick, you can cause your liver to fail by shunting the blood away from the liver and you die. So that's bad. If you have pulmonary hypertension, they can kill you from the increased preload. So you have to be kind of cognizant of that. And then afterwards, about 30 to 40 percent of people will develop encephalopathy afterwards. And encephalopathy, which I'm sure we'll talk about later, is much more of a shunting phenomenon than people realize. So if you shunt a significant amount of blood around the liver, people tend to become encephalopathic. So whether or not to do a TIPS is something you really need a hepatologist to kind of help you with. They've been shown to be really helpful in patients who have very high hepatic venous pressure gradients, very high portal hypertension, greater than 20 millimeters of mercury. And that's typically going to be your child's C-cirrhotic or a child's B-cirrhotic who is still bleeding even after you've banded them. These are the people we typically think about doing a TIPS right away. Just roll them down to IR and get the TIPS done, okay, because they might bleed. That being said, this isn't universally done and is somewhat controversial, so I won't necessarily advocate that that be done on everybody. It really needs to be a case-by-case basis. But assuming that we're not going to do a tip spoon on the patient, then the next step and the most important thing to keep them from bleeding again is to start them on a beta blocker at some point. And this is a non-selective beta blocker? Yeah, absolutely. You have a favorite? Well, there's two major ones that we use in the United States, and that's propranolol and natolol. Propranolol is twice a day, and natolol is once a day. So we like natolol because it's once a day, and we probably think compliance is better. But really, between the two, it doesn't really matter. Carbetolol is also used for varices, and you'll certainly see patients on Carvetolol for primary prophylaxis of varices. But as it stands right now, Carvetolol is not recommended as a secondary prophylaxis beta blocker. And so at this point, we typically are just going to use propranolol or natolol. When to start these guys is always a hot question because these people are coming out of the ICU. They're pretty sick and hypertensive. Obviously, you need them to be kind of stabilized from a cardiovascular standpoint before you go putting them on a non-selective beta blocker. Okay, and I usually, usually around the time that they come out of the ICU is when we want to start them on. We start them on a low dose, so maybe 10 milligrams twice a day of propranolol or something like that. And we just work it up as tolerated. Your goal is not to get their blood pressure down. Your goal is to get their pulse down. And we really want their pulses to be in the 50 to 60 range or a 25% reduction in their basal heart rate. Beta blockers also have some potential downsides in cirrhotics in people with refractory ascites. And for the most part, we don't recommend their use if their systolic blood pressures are 90 or less. Okay. And there's probably a thousand internists out there going, duh. But, you know, cirrhotic patients, you know, 95 systolic blood pressure is not unusual for these folks. This might be just where they live. And so having them on a little bit of beta blocker because their systolic blood pressure is 98 is okay. But if that systolic blood pressure is 88, you probably don't want them on a beta blocker. And the bottom line is if they can't tolerate a beta blocker because this is so important for keeping them from bleeding again, then this is somebody that should be considered for a TIPS. I had read that once someone has SBP, beta blockers are no longer an option, that there's increased mortality. Is that true? Is that a sort of time to stop them? No, no, not necessarily. There's conflicting data on that. And I don't think that question has been adequately answered at this point. And Scott, I want to ask, you had mentioned actually a child score, which reminded me of a question I wanted to ask you way, way earlier, is when these patients initially present, you often hear either a child score reported or a MELD score. And I was just wondering if you wouldn't mind speaking a little bit to the prognostication that's done when someone sort of comes in acutely sick with a liver complication. Yeah know, that's a good question. We have a variety of scoring mechanisms out there to kind of give us a sense for whether patients will survive. The thing to kind of remember is that none of these have been created for the acute cirrhotic patient entering the emergency room with a variceal bleed, okay? From my standpoint, I don't spend a lot of time in the emergency room wondering what their MELD score is and whether I should be doing this, that, or another. This is more of an acute thing. When we were first looking at how to tell whether a cirrhotic is going to live or die, the first thing that came out was the child Turcotte-Pugh score, and this was way back. And this utilizes several parameters, plus the presence and absence of ascites and hepatic encephalopathy to give you a score as an A, B, or C. Now, roughly a child's C cirrhotic is a significantly decompensated cirrhotic, and a child's A cirrhotic is a compensated cirrhotic. Child's score has kind of fallen by the wayside as a usefulness. It used to be used to kind of prognosticate who's going to live or die with abdominal surgeries and this sort of thing. But at this point, it's mostly used as sort of a functional status type thing. The MELD score has really become the dominant way of predicting prognosis in cirrhotic patients. And the MELD score, MELD stands for Model for End-Stage Liver Disease.
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It utilizes the INR, the creatinine, and the bilirubin to spit out a number somewhere between 7 and 40, and 7 being normal, 40 being sort of death store liver failure. And the MELD score has been shown to be useful across a broad domain of liver diseases for prognostication, but mostly for prognosticating who's going to be alive or dead in 90 days, okay? And not necessarily who's going to be alive or dead in seven days, all right? So the MELD score isn't really fantastic in a short interval type patient like this. There is a scoring system that can be useful in the acute setting. And that goes back to that definition of acute on chronic liver failure. And there is a score called the ACLF CLIF score, a CLIF score that was developed out of the CLIF consortium in Europe. This is a modified SOFA score, which is sequential organ failure assessment score, that can be utilized to predict mortality in patients who have acute on chronic liver failure. And I frequently use this in like the ICU setting when we're thinking about, is this somebody we're going to keep moving forward trying to do this, that, or the other? Or is this someone that's not going to survive no matter what we do? But really, for the day-to-day cirrhotic who rolls in with some complication in the emergency room, I don't spend a lot of time doing scoring things, trying to figure out whether they're going to live or die. Paul, why don't you move us on through the case? Because I want to make sure we have time to get to all these various segments that we have planned. We have a lot to go. Yeah, and I love this one. So we're going to change the case up a little bit. So happily, Mr. Keith isn't bleeding. So all we talked about is completely moot. Put it out of your mind now. Instead, he's admitted with abdominal pain and encephalopathy. His blood pressure is low, but stable. His heart rate's in the 90s. He's not been febrile. His exam shows bilateral or extremely edema and tensusitis with a thin-walled umbilical hernia. It takes several tries to engage him, but eventually he follows the exam and mumbles some short answers that are sometimes relevant. He does have asterixis. And so your intern is writing admission orders and asks if the patient needs DVT prophylaxis. Of note, the patient's lab shown INR of 2.1 without the benefit of any medications to get it there. So I guess what we're asking and trying to set you up for is can you talk just a little bit about the bleeding or thrombotic risks in patients with cirrhosis and how should we sort of manage venous thrombotic prophylaxis in the inpatient setting and how should we sort of think about this problem more broadly? Well, you guys are hitting me with the easy questions tonight, right? Just explain coagulopathy of cirrhosis. All right. Yes, right. So, is the patient at risk for clotting? Is the patient at risk for bleeding? The answer is that they're at risk for both, okay? This is part of the fun of cirrhosis. They get it bad on both ends. Do cirrhotics bleed? Yeah. I think we just saw them earlier in the case bleeding, right? From varices, they bleed from portal hypertensive gastropathy. They tend to bleed, but their bleeds tend to be more pressure phenomenon, right? I mean, this is from portal pressures being really high and blood vessels literally bursting from pressure. That's what a variceal bleed is. Variceal bleeds are not coagulopathy issues. They're not bleeding because they're over anticoagulated. They're bleeding because that blood vessel literally burst as a result of increased pressures. But cirrhotics also clot. There's some data that cirrhotics get DVTs at higher rates than average patients in the hospital. But that data has been somewhat, I don't know what the word I'm looking for. It's controversial, right? Some of the data says they do. Some of the data doesn't say they do. But what we do know that they get very frequently is portal vein thrombosis, okay? So these people get, they get clots in the portal vein. About 10 to 25% of cirrhotics will end up with a portal vein thrombosis. So we know that they clot there fairly frequently. So should I prophylax them for DVTs? My answer to that is probably yes. I would say that this is just expert opinion. But in our hospital, we put our patients on anoxaparin or heparin DVT prophylaxis unless they have some reason not to, like their platelet count is just simply too low to do that, okay? Because they can very easily get a DVT. They can very easily get portal vein thrombus, and portal vein thrombus is a potentially devastating complication in a sick cirrhotic. A nice illustration of this and an illustration of whether they can be anticoagulated or not was a very, one of my favorite studies of all time in hepatology was in hepatology in 2011 by Villa and colleagues in Europe. Basically, they put cirrhotic patients on anoxaparin prophylaxis so that they didn't develop portal vein thrombosis. This was a randomized control trial. So half the folks got the anoxaparin, half the patients got placebo. But what they found is there's no chance, no difference in the bleeding between the two groups. The anoxaparin group didn't bleed more than the non-anoxaparin group. And there was no portal vein thrombosis development in the anoxaparin group. So it worked. It worked great. But what they didn't expect and what was really amazing was that the inoxaparin group had less episodes of decompensation and they had increased survival compared to the patients that did not get inoxaparin. And so I suggest that, you know, anticoagulation in a cirrhotic may even be beneficial in some ways. And so, this is why I don't hesitate to put people on DVT prophylaxis if they have cirrhosis, unless there's a big reason not to. Wow. Do you have a platelet threshold that makes you nervous? We've been focusing kind of on the INR, but thrombocytopenia being part of it, too. Is there a level where you start to get a little bit squirrely about starting? Yeah, for me, the platelet thing, the platelet level that gets me start squirrely is 50 to 60. If they're much below that, then that's when their bleeding risk increases. And we can talk about that a little bit more when we get more into the meat of the coagulopathy here. But yeah, the platelets I do worry about if they get much lower than 50. I've seen IR, interventional radiology, they'll do a paracentesis even on someone with an INR around, if it's two plus or minus a couple points, they might, like 2.1, they would do it. I don't see them reversing. Do you have any sort of threshold for that sort of procedures if someone's going for surgery? is that this is a complicated problem. So the liver makes all of your blood's clotting factors, right? Except for factor VIII. Factor VIII is made mostly by the endothelial cells, but the liver makes them all, all the other ones come from the liver. So they all tend to be low in chronic liver disease. But what people don't kind of think about is the liver also makes most of your blood's anticoagulation factors as well, right? So it makes protein C, it makes protein S, it makes antithrombin. And the end result of this is that you have an overall balance. You have low clotting factors, but you also have low anticoagulant factors. And they're pretty balanced, so they're not clotting or they're not bleeding. But because it's a tenuous balance with low factors on both sides, they can easily tip in one direction or another. So they can easily be tipped, maybe an infection or something like that may make them bleed. Whereas maybe some slow blood flow in the portal vein will make them clot. It's a very tenuous balance one way or another. So how do we figure out, you know, are they a bleeder? Are they a clotter? It's difficult.
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The INR is the most sensitive test for liver function that we have and has the most power in the MELD score. It tells us if the liver is working or not, but it doesn't tell us if they're going to bleed or not. And basically, that's because it measures the clotting factor deficiencies in the coagulation cascade, but it doesn't measure the anticoagulant deficiencies because it doesn't have thrombomodulin in the assay, so protein C activity cannot be measured by the INR. As a result, you're only measuring one side. So you're only seeing the bleedy side, but not the anti-bleedy side. Okay. And, and so the INR, we, we just can't really use, um, I think of the INR as basically showing you their relative factor seven deficiency and, and factor seven is the one that tends to get the lowest because it has the shortest half-life of all the factors. And, you know, you can give recombinant factor seven to these folks and completely reverse their INR very, very quickly. Okay. And so does that help? And there's actually been a couple of good studies on this where in one variceal bleeding study, they gave patients recombinant factor VII to reverse their INR. And there was no difference between the people who had their INRs reversed with recombinant VII with regards to bleeding, mortality, anything. They also gave recombinant factor 7 to people going into liver transplant. And guess what? There's no difference between the people that got recombinant 7 or the people that did not get their coagulopathy reversed before transplant when it came to bleeding, blood products, anything like that. So it doesn't work. Making the INR better doesn't fix anything with regards to bleeding. So that's why we don't do it. So to get to your initial question, do I look at the INR before I do a paracentesis or simple procedure? And the answer is no. I don't even pay it any attention. I don't care if the INR is 6 or 1.6. It doesn't make a hill of beans difference to me. That being said, I do paracentesis on fully anticoagulated patients. So I don't really consider paracentesis to be a terribly bleeding procedure to begin with. But it's really, you can't use the INR as your thing to worry about. And fixing it does absolutely nothing for you. So there was this question from social media. They said, what is the utility of a TEG, a T-E-G, TEG scan? Is that, I don't even know what that is. Do you guys know what that is? I know what it is. You do, okay. I don't know what that is. Bombo elastocramp. Thank God we have an expert on here. Okay, and then the other. You know what's funny is a TEG is a really, really old test. And this is a test from like the early days of hospital medicine. I mean, literally, they would just put the blood in a cup, and you put a little electrode in the middle, and it measures how long a clot takes to form and then how strong of a clot forms. So it's really a very old test that's sort of become sexy again in hepatology circles these days. Do we get them? Yeah, we get tags frequently, but I've become kind of cynical about tags because if you do enough tags on cirrhotic patients, you will see something funny. And that is that they're all the same. Okay. And, and what the, what the thromboelastogram is going to end up showing you in most cirrhotics is that they're going to have a short, what's called our time and our time on the thromboelastogram is basically the time that it takes to form a clot. So, cirrhotics have short R times. So, guess what that means? They clot quickly. They clot quicker than the average Joe. But then there's basically what you're going to see when they do form the clot, that it's going to be kind of a low amplitude on the curves that you get with a thromboelastogram. And that tells you that they don't form very strong clots. They form weak clots. And that is very, very much correlated with their platelet level. So the lower the platelets, the lower the amplitude, the higher the platelets, the higher the amplitude, the stronger the clot that they form. And so that's why I don't put too much stock in tags, to be honest with you, because they just really show the same sort of pattern over and over and over again, that cirrhotics form clots quickly. They just form kind of wimpy clots. And I don't know how you utilize that to fix underlying bleeding problem. What else? Well, the other part of the question they had was, and I think you kind of already answered this with the recombinant factor 7, but FFP or vitamin K, is there any role for that? Are you using any of that? Are we just kind of treating the numbers, making ourselves feel better? You know, we use FFP a lot when people are going for invasive procedures and stuff like that because, you know, people just can't get over the fact that fixing the INR doesn't solve any problems. So they just feel like they need that number. If the patient's going to have their gallbladder out, they want their INR less than two. And because they're doing the operation, they're doing the procedure or whatever, and they're taking that risk, you have to go with that. But the bottom line is that, do I advocate for giving FFP to improve INRs? No. Do I advocate for prothrombin complex concentrate to reverse INRs? No. Do I recommend factor VII? No. And the problem is that when you give folks FFP, you give folks PCC that have cirrhosis, they can and do form clots when you do this. If you shift that tenuous balance towards the clotting side, they will form clots. They will clot off their portal vein. They will clot off their mesentery venous system. And then you've done them a big disservice. And, you know, I've seen people go in the trolley after FFP. I mean, so these things do have potential downsides that you have to be cognizant of. Now, vitamin K. Vitamin K is obviously a little bit more innocuous. And whether or not giving them vitamin K will work, who knows? In your garden variety cirrhotic, I don't typically do it because it doesn't seem to really do anything. If you have some reason to believe that they might be vitamin K deficient for some reason, like say they've been taking Coumadin or maybe they have chronic cholestasis, fat-soluble vitamin malabsorption for whatever reason, maybe they have cystic fibrosis, maybe they've been on chronic antibiotics, you know, some reason that they might have vitamin K deficiency, then yeah, I give them vitamin K. Why not? I give them some oral vitamin K, about 10 milligrams daily for about three days to see if there's any improvement. But if they don't have any reason to be vitamin K deficient, giving us a cirrhotic or decompensated cirrhotic with a prolonged INR vitamin K is not going to do anything because it's not a vitamin K issue. It's a liver synthetic function issue. Paul, you want to move us along in the case? Yeah, probably we should. So this is the big ticket stuff. I mean, this is all spectacular. But our patient with the tensisitis, what we'll recall, has popped out his umbilical wall hernia. So we've decided as a team to perform paracentesis. And I think probably the first question to even ask is just how much should we take off? Well, thank God we're finally doing a paracentesis. We should have done it in the emergency room, Paul. No. So if you're concerned about infection in the patient, just do a diagnostic paracentesis to start with. And, you know, you can remove up to five liters of fluid and without causing too much catastrophe with regards to post paracentesis circulatory dysfunction. But really your number one priority is to get enough in your syringe to make sure the patient doesn't have SBP. My sort of philosophy when it comes to large volume paracentesis is that this is a palliative procedure, okay? This is a comfort procedure.
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So the large volume paracentesis are there to make people feel better. And if you can take two or three liters off of them in the emergency room and make sure that they don't have SBP and they're not going into renal failure, and maybe two days later do a large volume paracentesis and remove the other eight liters of fluid from their belly, I think that that's probably a wise way of approaching this. Because, you know, if somebody's got SBP and their kidneys are on the brink, do you really want to remove 15 liters of fluid right up front? I probably wouldn't. I think that's playing with fire a little bit. We remove the fluid. So we remove two or three liters. We send it. Any words of wisdom there for what fluid studies you send and how you interpret those? Yeah, absolutely. And this is very important. So the first time that you do a paracentesis on somebody, you should be sending the SAG labs, if you will. So SAG stands for serum to ascites albumin gradient. Okay. It's one of these weird concepts that if you ever really figure it out, it just makes everything make sense with regards to ascites and portal hypertension. But basically if the SAG is greater than 1.1, so in other words, you draw the fluid out of their belly, you send the albumin from the fluid, and you also send a serum albumin at the same time and you subtract the two. That's the complicated math involved, right? And if that number is over 1.1, what that tells you is that the fluid in their belly is very albumin poor. There's just not much albumin in there compared to the albumin in their blood. And that should tell you immediately, that tells you from a physiologic standpoint, that that fluid is being produced in the liver at the level of the hepatic sinusoid. This is hepatic lymph is the way to think about ascites. It's being pushed out of that hepatic sinusoid in volumes that is too high for the liver and in liver lymphatics to handle. And as a result, the liver just begins weeping this fluid into the abdominal peritoneal cavity, okay, through the capsule, everything. That's what ascites is. And that high sag tells you that that is coming from that. And why does it tell you that? Because the liver sinusoid, which is the liver's capillary, is built, is evolutionarily created to keep albumin in the blood vessel, okay? And so even when you're pushing fluid out in the sinusoid, that albumin is going to stay in the blood vessel. It's not going to get pushed out into the, into the, the intracellular spaces in the liver, because that sinusoid is built for that not to happen. And that's a healthy sinusoid. If you take that sinusoid and you now make it capillarized, so it's lost its fenestration, you surround it with fibrosis, then albumin is even less likely to make it into that fluid. And in fact, even small proteins can't make it into that fluid. And as a result, that fluid becomes increasingly protein poor. And so ascites from a cirrhotic patient is very protein poor, very albumin poor, and that's why they have a high sag. And so the corollary to that is that you can also send a protein on the fluid. And that can be helpful in figuring out where the fluid is coming from as well. Because we know that SAG is greater than 1.1. That tells us the patient has portal hypertension and the ascites is coming from the liver. But you can have portal hypertension without having liver disease necessarily. Okay. So if you have post, what we call post-hepatic portal hypertension, say right heart failure, pulmonary hypertension, Bud Chiari syndrome, something along those lines, you're going to have really high pressures in the sinusoids. It's going to push out hepatic lymph, but it's going to be pushing it through fairly normal sinusoids that are still fenestrated and are not surrounded by fibrosis. And as a result, you're not going to have much albumin because albumin can't get out of the hepatic sinusoids, but you will have a lot of protein in there. And so if that protein is a high SAG and low protein, that is the classic picture of cirrhotic ascites. Okay, it has just got no protein in it. If it's high SAG and it has high protein, in other words, that protein level is over two and a half, then that suggests that maybe this is a post-hepatic portal hypertension and this might be coming from, maybe you should start concentrating on the heart a little bit, getting an echocardiogram, getting a Doppler to make sure their outflow vasculature is appropriate. So the SAG is very important. The SAG and the protein for characterizing the ascites right off the bat is very important. Now, anytime you do a paracentesis on a patient, unless they're on hospice or something, you should be sending a cell count with differential, okay? Every time, maybe you do the SAG the first time you ever do a tap just so you can characterize it, but every time you do a parasynthesis, you should be doing a cell count with differential, okay? And the reason is this, this is how we're going to look for spontaneous bacterial peritonitis or SBP. Spontaneous bacterial peritonitis is a situation, it's a failure of the innate immunity in a cirrhotic patient that basically allows bacteria to translocate, get into the bloodstream and ultimately seed the peritoneal fluid or the ascites. That acidic fluid in a cirrhotic patient, because it is so protein poor and so albumin poor, they can't do anything with bacteria that translocates into that fluid. It's basically just sugar water. It's just an inoculant waiting for an infection, right? There's no immunoglobulins in there. There's no complement in there. There's nothing to opsonize the bacteria. There's no nothing. The bacteria can just go wild in there. So that's why these folks are at such high risk of SBP. If the cell count shows more than 250 PMNs, neutrophils, that is the diagnosis of SBP. So they can have 400 nucleated cells and only 10% are PMNs. That's not SBP. That's 40. They could be all monocytes and all kinds of things. That is not indicative of an infection. But if the PMNs are over 250, then that is SBP. Unless you have some obvious reason that they don't have, that this wouldn't be SBP, like say a bullet wound in their abdomen. You know, some reason they might have a perforated viscous. They have a surgical abdomen. You know, if they have peritonitis, peritonitis for some reason, then yeah, they're going to have elevated neutrophils in their fluid as well. But if you don't have any suggestion that they have some kind of perforated viscous or intra-abdominal infection and they have PMNs greater than 250, that's SPP. Oftentimes when you do the fluid, you'll notice it'll be very cloudy rather than a kind of mountain dew or urine appearance of typical ascites. It'll be cloudy, very, very milky looking fluid. So one of the important things, if you're worried about SBP, and this is one of the take-home points for your audience, is if you're worried about SBP and you're doing a diagnostic parasynthesis and you're going to send a culture, you're going to inoculate a blood culture vial at bedside, okay? This is how you do it. You don't put it in one of those little urine cups and send to the lab. Don't put it in some other culturette sort of thing and send it to the lab later on. You're going to inoculate a blood culture vial at the bedside. And the reason that we do that is that it increases the yield for positive cultures by almost 30% over sending cultures in little jars or whatever at later times. So those are the basics of fluid analysis of acidic fluid. In this guy, you want to get it, send the SAG, but send the cell count, inoculate yourself a blood culture vial right there beside it and send it off for culture. That's what you want to do right off the bat. Scott, I just, I wanted to check one thing.
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High. High sag as well. Okay. Because even in that situation, the ascites is being produced in the liver. It's being produced in the sinusoid. The sinusoids are producing it because they're congested with blood that can't get out and there's high pressure there. You know, I always think of ascites as just thinking back to your old Starling forces or whatever from medical school about why, you know, we produce lymph at every capillary in our body. We have the whole lymphatic system that sucks that back up and sends it out. It's the balance between hydrostatic forces, oncotic pressures, and stuff like that. And a cirrhotic patient or a patient with heart failure, they have increased hydrostatic pressure in their capillary, so they're going to push more fluid out. They also have low oncotic pressure because they don't have a lot of albumin floating around, so their net movement of fluid is going to be out of that capillary system. So that's just basically how ascites is produced. So you may ask me, what does a low sag mean? So if the sag is less than 1.1, what does that mean? Well, that means that your ascites in your fluid is nearly the same as the, I mean, sorry, the albumin in your fluid is nearly the same as the albumin in your serum. And that equals not the liver. So that ascites is not being produced in the liver. That ascites is being produced somewhere else. And that's why low sag ascites is stuff like infections, malignancy, peritoneal carcinomatosis, renal failure, pancreatitis. you know, that fluid is coming from somewhere inside the abdomen, but it's not coming from the liver. So that's why the SAG is so important in just telling you where that fluid is coming from. Fantastic. I love it. So let's say we do our due diligence. We send off our fluid studies, including the critical cell count with differential and the SAG, and we do determine that we think this is SBP. So I guess a good place to start is what should we be doing to treat this, I feel like is a reasonable question to ask ourselves. So what antibiotics do you choose? How long do you treat for? And then what other considerations are there? Yeah, so that's a great question. With SBP in general, you need to start treating this as soon as possible. And typically the treatment is with a third-generation cephalosporin. Again, that's a classic treatment, though some people are arguing in this day and age of multidrug-resistant organisms that we may be needing to do more aggressive antibiotics. But at this point, I would say that third-generation cephalosporins are the first choice for this to this point. The treatment duration is typically about five days of IV antibiotics. People always want to switch to oral antibiotics, and you can switch to oral fluoroquinolones at some point, but I typically like to give a good five days of IV ceftriaxone before I do that. The other treatment point that's fairly important with regards to SVP is albumin. And one of the seminal studies in hepatology was the SORT paper from 1999 in the New England Journal of Medicine, where they gave albumin at 1.5 grams per kilogram on day one of SBP diagnosis. And they gave it again, gave one gram per kilogram on day three. And the difference between those groups was fairly dramatic. Mortality was decreased from 29% in the patients who did not get albumin to 10% in the patients that did get albumin. So getting albumin on day one and three with SBP is very, very important. There has been some studies suggesting you don't need to do it unless their creatinine is greater than one or their bilis greater than four. But I don't like to play with that sort of fire. I typically just, if they have SBP, they get albumin. They have looked at albumin and other infections and cirrhosis like pneumonia, urinary tract infections, and it doesn't seem to work. It seems to be, it seems to only decrease mortality in SBP for whatever reason. And that likely is very related to the development of hepatorenal syndrome, which is oftentimes how people with SBP die. So hepatorenal syndrome is a very complicated topic physiologically. The way I think about this is that basically having cirrhosis leads to very disordered cardiovascular blood flow. And cirrhotic patients tend to have a lot of blood pooled in their mesentery. And when I say the mesentery, I mean their superior mesenteric artery and vein, the inferior mesenteric artery and vein, all the gut blood vessels are overly and inappropriately dilated in serotic patients. As a result, a lot of their blood volume is inappropriately hanging out in their gut, and their systemic blood volume is low, and their arterial blood, systemic arterial blood pressure tends to get low as a result. Now, the body tends to, the reason for this is very complicated, and it has to do with nitric oxide and bad humors. But basically what the result is, is because you have low circulating blood volume and low arterial blood pressure, your kidney doesn't like that. It senses that. Your brain senses that. And they start releasing hormones and other vasoactive substances in an effort to try to get your systemic arterial blood pressure up. But you can't get your systemic arterial blood pressure up because the liver is going to keep everything pulled in the gut. And it leads to this vicious cycle of worsening vasoconstriction in the periphery from renin, angiotensin, aldosterone, vasopressin, adrenergic outflow, you name it. And the bottom line is that the kidneys basically squeeze themselves off and start to become dysfunctional. They basically kill themselves trying to get your blood pressure to go up. And now, you'll hear me say hepatorenal physiology. And I'll tell you that I believe that everyone with portal hypertension has hepatorenal physiology. They exist on a spectrum somewhere in hepatorenal physiology, whether it's fairly mild and you can't really detect it, all the way up to their kidneys no longer work, and if they don't get transplanted, they'll die. So type 1 hepatorenal syndrome is when you go from being normal kidney function to dead aneuric kidneys in just a matter of a few days. And if you don't transplant those folks, they die. And that's how SBP tends to kill people. It triggers this catastrophic cycle of hepatorenal physiology that leads to the kidneys failing, the liver failing, everything fails, and people tend to die. But you can also have type 2 hepatorenal physiology, and that's a slower process. Those are the people that exist on that continuum somewhere where they do have this dysfunctional circulation of hepatorenal physiology, but they don't necessarily have kidney failure. These people will manifest not so much as elevated creatinines, because you know your creatinine is not going to go up until you've lost at least 40% of your renal function. So MDRD and whatever are going to not adequately describe this situation. But what you will see with these people is you're unable to get them on diuretics. You can't control their ascites with diuretics. They get hyponatremic. Hyponatremia for me is a sign of this hepatorenal physiology. This is your kidneys becoming dysfunctional. This is too much antidiuretic hormone flooding out of the brain trying to fix this problem. And you end up with this global hyponatremia. Every time you touch them with Lasix, their sodium drops like a bomb. This is hepatorenal at its worst. And this is why hyponatremia is such a negative prognostic sign in cirrhotics. And this is why sodium was added to the MELD score as a prognostic indicator. So now we deal with MELD sodium only with people on a transplant list because we know that low sodium, that's a sign of very bad circulatory dysfunction in the cirrhotic patient that is only at some point in the very near future going to dive off the hepatorenal cliff into full-blown renal failure. I forgot what I was talking about, but there you go. All right, so, and this is important with regards to paracentesis in general, why we should be giving folks albumin, okay?
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So if you remove more than five liters of fluid of paracentesis, you've got to give 25% albumin. And there are, you can do six to eight grams per liter if you're a calculator. But for me, if I remove more than five liters, I give them 50 grams of albumin. If I get close to 10, I give them another 25 grams of albumin. If I get close to 15, I give them another 25. I usually max out at 100 grams. I don't usually give much more than that. But that's just an effort to keep their blood where it's supposed to be and keep them from entering this horrific cycle that leads to death. Scott, I wanted to just ask a follow-up about the antibiotic thing. I was reading that you should see a dramatic improvement in their symptoms once you have them on antibiotics. And if at five days, they're still not looking right, they're still having a lot of pain or fevers or whatever, you should repeat the para and then based on the PMNs in the fluid, you kind of make your decision. Is that actually done in practice? I haven't seen that done before, but it's something I read about. Absolutely, no. I think you should have a very low threshold to repeat the paracentesis at the end of the five days and make sure they've cleared the infection. The thing to remember about SBP is that this is a silent infection. They don't necessarily have symptoms. They don't necessarily have fever or abdominal pain. Their first presentation might be aneuric renal failure from hepatorenal syndrome, or their first presentation might be encephalopathy. Their first presentation might be a variceal bleed. You don't know if this infection is gone until you've sampled the fluid and made sure that the infection is gone. So I don't always do it. If the patient's clearly clinically getting much better, I don't necessarily repeat the paracentesis at day five. But if I have any doubt or if the infection was very severe to begin with, a really high PMN count, or they were really, really sick, then yeah, absolutely. I would repeat it five days and see if I don't need to give this person antibiotics for a longer period of time. And you also got to remember that once somebody gets this, they are on antibiotics for life after this. And that's what you have to remember, that you have to have this person on secondary prophylaxis for the rest of their life. And that's typically with ciprofloxacin, 250 or 500 milligrams a day, depending on which guidelines you believe. But they have to be on that for life after the SBP. That's mandatory. They're poor. They're poor tendons. Yeah. I'm sorry, Achilles. You're a goner. Someone from social media was asking about draining all the fluid, tap them till they're dry. I think you sort of answered that. You said that basically you got to be careful. Initially do the diagnostic, maybe a smaller volume, and then if you can't get the fluid off or if you need to get more fluid off, you can do that later once they're more stabilized. I will tell you that hepatologists and nephrologists have very different opinions on this question about how much fluid we should be removing. Hepatologists, you know, we run around with our personal best, you know, like mine is is 18.5 liters. Oh, my gosh. One of my colleagues is 23 liters. So we have our personal records. And a lot of the hepatologists I know, we don't worry about how much volume we remove. Now, like I said, in an acute setting where you think they're infected, it's probably not wise to do a huge volume of parasitesis. But if you're just bringing a patient in for a random routine parasitesis, I tap them until they're dry and just give them albumin. But some nephrologists would argue that we shouldn't be doing that, but I don't know that the data is clear on that. And once you, if their blood pressure can tolerate, then these people are going on. We talked about this on the last episode. I think this was our 100th episode that we had you on, maybe the 101st one where we actually talked about diuretics, but you would put them on the diuretics at that point if they're not diuretic refractory. Yeah, absolutely. actually are quite non-compliant with a low-sodium diet. So the first step in you kind of a patient coming in the hospital, let's say he was encephalopathic, not to the point where he had to be intubated, but his mental status was terrible. Other than treating the SBP, what else should we be doing in the hospital for that? And is there any interesting physiology to talk about, you know, in what's causing this? What, the encephalopathy? Yeah, do we know what's causing it yet? Yeah, well, encephalopathy, there's a couple of things to realize about encephalopathy. Number one is that this, encephalopathy tends to be a shunt phenomenon. I mentioned this a little bit earlier in the podcast. Encephalopathy is a complex condition that results from shunting of blood around the liver, as well as complex interactions with the brain and ammonia and other mediators. But if I put a shunt in you, Dr. Watto, I mean, there would be a chance that you would become encephalopathic. You can become encephalopathic with a shunt, whether you have cirrhosis or not. The decreased function of a cirrhotic liver does make it worse. It makes it more likely to develop encephalopathy. But I don't think of encephalopathy as a phenomenon of liver failure in a cirrhotic patient. I think it's more of a shunting phenomenon. These people are shunting blood around their liver, and as a result, they become encephalopathic. You see this when we give somebody a TIPS, right? You get a TIPS, they get encephalopathic afterwards because they're shunting blood. Now, how should we approach encephalopathy? Well, the way you should approach encephalopathy is that hepatic encephalopathy is a sign of another problem that you have not diagnosed yet. Hepatic encephalopathy is not your major concern. Your major concern should be what the heck is causing this encephalopathy? What is precipitating this encephalopathy? Because the things that precipitate encephalopathy are deadly if not diagnosed. Okay. Number one on your to-do list should be ruling out infection. And, you know, we've talked about SBP ad nauseum, but other infections, even the most minor of infections can trigger encephalopathy. Urinary tract infections are notorious for doing it. Skin infections, you name it. Any kind of little infection can trigger encephalopathy. Bleeding is your next thing. You know, a big gut meal full of blood will trigger encephalopathy fairly frequently. So what you got to figure out is this person variceal bleeding and I don't know it. Then you start thinking about over medications. Are they on benzodiazepines or narcotics? All of these things are very much so will trigger encephalopathy. More than one time I've had patient, you know, who they're well-meaning primary care doctor put them on Ambien or Lunesta or something to help them sleep because all of my patients have insomnia. And then they come in densely encephalopathic as a result. They can't handle anything that's gabinergic. Under medication is also on your differential, so non-adherence to their medicine. So lactulose sucks. No one likes taking lactulose and it's gross and it makes you poop a lot. So people not taking their medicine is very common. You have to think about electrolyte issues like hypokalemia in particular. Hypokalemia has an actual physiologic effect in the kidney that leads to increased ammonia production, and so hypokalemia has to be fixed. Volume depletion is very common in our patients if they're over-diuresed or having too many bowel movements from their lactulose. But you also have to think about, is there something causing increasing shunting? Do they have a new portal vein thrombosis? Do they have a liver cancer? Something like that. So getting something like a liver Doppler just to make sure.
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Wow. It's just a lot. It's a lot. Well, that's why I'm here, Dr. Watto. I can always take the load off your back. Okay. Any other tips that you have for hepatic encephalopathy? And I apologize for the pun. That was not meant to be a pun. I'm just asking, is there any more advice that you have? It's a bad pun because TIPS is an awful treatment. It's the absolute worst. And also there are no good puns. So really just by definition. No, there are a couple of good treatment nuggets for encephalopathy. So encephalopathy really, when a patient comes in with an encephalopathy and you've already done your differential and made sure they're not going to die of something else, when you're concentrating on treating the encephalopathy, catharsis is what you're looking for here. We've got to make them poop and poop a lot to start with on day one. And what you don't want to do is bring them in and put them on their home dose of lactulose and just expect that to work, okay? Lactulose is still, in my opinion, the absolute front-line therapy for this. You want to give them a lot of lactulose fairly frequently until they are having regular bowel movements. You can titrate it on day two and three when they're waking up to the normal three to four bowel movements a day that we're looking for. But on day one, you want them pooping and pooping a lot. Now, there was a study that came out, what, a year ago where they looked at using PEG or, you know, a liter of Golightly. This was in 2014 in JAMA. They gave folks four liters of polyethylene glycol up front to get them pooping. And guess what? They actually got better from the encephalopathy standpoint faster than the people that were given lactulose standard way. So everybody's like, oh, we should be giving Golightly. The problem is if you look at the study, 84% of the folks that got PEG got lactulose before they started getting the PEG. And so we currently think, you know, if you want to give PEG as your way of catharsis on day one, that's great. Just give them some lactulose too. So, so lactulose plus PEG or lactulose, you just want them pooping very aggressively on day one. How do you give them the lactulose? How do you give them the PEG? This is important because then we're hearkening back to the very beginning of the podcast where I told you, you have to pay attention to their mental status and you have to worry about their airway. You have to worry about aspiration. You don't want to be adding an infection to this picture. So if a person is obtunded and gargling and can't even say their name, you don't want to be trying to feed them oral lactulose. The nice thing is that lactulose works very nicely as an enema. It has the same effect as taking it orally. And that is my preferred go-to method for giving them when they're really, really obtunded. I usually give them PR lactulose until they can more adequately wake up. You could, in theory, put down an NG tube, but I think if you look at NG tubes, the data on them and preventing aspiration, you'll find that people aspirate quite nicely with NG tubes when when you're putting stuff down into their stomach. So I typically prefer PR lactulose to PO when they're really significantly encephalopathic. The nurses hate it. Yeah, I was going to say, do the nurses hate it? And how does the patient hold the enema if they're kind of out of it? It's just sort of... I don't know that you necessarily need them to hold it for too long. You just got to squirt some up in there. So basically, lactulose really works by, you know, kind of out of it is just sort of. I don't know that you necessarily need them to hold it for too long. You just got to squirt some up in there. So basically, basically lactulose really works by, you know, acidifying the lumen of the colon. And that's been shown in some early studies. You know, just to give props to one of my colleagues, Elliot Tapper, who's a hepatologist in Michigan, has quite a Twitter following and is very active on Twitter. And he did a tutorial on hepatic encephalopathy back in September of last year that was just absolutely fantastic. I retweeted it on my Twitter feed. It was just a very impressively done tutorial about how to attack and deal with encephalopathy on your inpatient patients. So I would definitely recommend that your listeners check that out and check him out in general. He just does really good liver type tweets. We can definitely put that in the show notes. I feel like I did see that when it was out there. Paul, any other questions that we should ask? Or you think we're at a point to get take-home points and we'll just have to do a part three? No, I think we solved cirrhosis. I feel pretty good about it. So, strong work team. Certainly feel better than I did before. Yeah, well, we didn't talk about rifaximin, so I'll just add a little blibbit there because that was on the questions. Rifaximin is your second-line therapy for encephalopathy. This is a non-absorbable antibiotic. Hepatologists absolutely love rifaximin. I just want you to know it's our favorite drug. It has great benefits for our patients. It's good for encephalopathy. I typically use it with lactulose or in a patient that simply cannot tolerate any non-absorbable disaccharides for their encephalopathy. The thing to know about Rifaximin is it is vastly expensive, in the neighborhood of $2,000 a month. So just think about that when you're putting your patient on it. This should not be a first-line, first-time-they-ever-have-encephalopathy-type medication. This is for a patient that's failed lactulose alone. Wow. $2,000 a month. Hopefully, is that going to be generic anytime soon? I guess that doesn't even matter these days. Generic drugs sometimes are not even that. It's one of those, I think, that's been bought up by one of these hedge fund type things. Because it didn't used to be $2,000. It used to be $1,600, but it got more expensive recently. It should be generic. It's been out for more than seven years. The culture scene story. Yep. Let's get some take-home points, Scott, so we can let you... I mean, we can't thank you enough for all this teaching, but at some point, we have to let you go. And we'll just have to build up some more questions about the liver for you. All right. So my main take-home points for you, number one, is any cirrhotic with any complaint with ascites is SBP until proven otherwise. Just drill that into your head. It's just sort of like the same thing with, you know, any female between the ages of 12 and 60 that comes in the hospital with any complaint is pregnant until proven otherwise. It's a very similar kind of rule. If you're going to rule out SBP, make sure you're doing your cultures in a blood culture vial at bedside while you're doing the tap. That makes a significant difference when it comes to yield of the culture. Understand the concept of acute on chronic liver failure and how this differs from decompensated cirrhosis. And then basically stop checking the ammonia levels, people, please. I'm begging you. I think we could do that. I think our audience, you know, they'll just, just picture Scott hissing at you like a cat, which is, I've actually, since we talked the first time, that came up as well. And I say that to my team whenever I'm like, if I were Dr. Matherly, I would be hissing at you like a cat right now. Right. And I think they get it. Yes. Okay. Well, that's all I got, guys. I'm out of knowledge for you for the evening. We got to let you get back to whatever else you have planned.
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So thank you so much. Well, thanks for having me, guys. I've really enjoyed it. I love talking about the liver and I appreciate you giving me this platform. and sign up for our mailing list at thecurbsiders.com forward.com. A special thanks goes to our writers and producers for this episode, Justin Lee Burke and Nora Toronto, and to our social media team, Hannah R. Abrams on Twitter, Beth Garbs Garbatelli on Instagram, and Chris the Chew Man Chew on Facebook. Until next time, I've been Dr. Matthew Frank Watto. And I remain Dr. Paul Nelson-Williams, and goodbye. And I think what I really like about him is he talks about them. He describes them as tenuous as they actually are. Like, you need to do this or they're going to die. Their mortality is very high. If you don't do this, you'll kill them. Like, it's very, he reinforces how sick these patients are, which is one. And then talks about the pathophys. Like, he's such a great guest.
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From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Hello, and welcome to this JAMA Clinical Reviews podcast. I'm your host, Dr. Revital Marcus, JAMA Fishbein Fellow and neurologist. Today I will be speaking with Dr. Ingo Mellinghoff. Dr. Ingo Mellinghoff is a neuro-oncologist at Memorial Sloan Kettering Cancer Center in New York City, where he is the chair of the Department of Neurology. As a clinician-scientist, he has participated in and led numerous clinical trials. His research laboratory focuses on molecular and genetic changes in brain tumors and the development of new treatments for these tumors. We will be discussing the review article written by Dr. Mellinghoff and co-author Dr. Lauren Schaff on glioblastoma and other primary brain malignancies in adults, published in the February 21, 2023 issue. Dr. Mellinghoff, thank you for joining us on the podcast today. It's my pleasure to join. Thank you for having me. In your review, you note that the annual incidence of primary malignant brain tumors is about 7 per 100,000 people per year, with nearly half of these from glioblastoma. Roughly speaking, how common are primary malignant brain tumors in comparison with metastatic brain tumors and benign tumors? So there are approximately 85,000 individuals in the United States who are diagnosed with a primary brain tumor every year. And about one-third of those primary brain tumors are malignant. And within that group of malignant brain tumors, around 80 or 85% are gliomas. And those are the tumors which diffusely infiltrate the brain parenchyma in adults. And they are subdivided into many other subgroups, which we will talk about, I'm sure, a little bit later. The main cancer type that comes, I think, to everyone's mind is a glioblastoma. That is the most common malignant primary brain tumor in adults. And that is a tumor that increases after the age of 40 in incidence and peaks in adults around 75 to 85. And that is in contrast to lower grade diffuse gliomas, which usually afflict patients under the age of 50. And then there are less common malignant brain tumors. And in that group, there is primary CNS lymphoma. That is a rare variant of non-Hodgkin's lymphoma that only presents in the brain and does not occur outside of the brain. Occasionally, meningiomas that can turn more malignant, even though the vast majority of meningiomas in adults are not malignant, they're benign. And then the most sort of diverse and increasingly better understood subgroup of malignant brain tumors are ependymomas. These can arise in the supratentorial brain, also in the posterior fossa and spine. And they are more common actually in children. In a general medical practice, you will see many more patients with metastatic brain tumors, tumors that originate in other sites, particular, for example, lung cancer, and then metastasize to the brain. So these malignant metastatic brain tumors are the bulk of what you'll encounter in a general practice. Thank you so much for going through that. In follow-up, I wanted to get a sense if there's a useful way to conceptually organize these various types of primary malignant brain tumors. What's a good way to think about these? Should we think about them as age of onset, anatomical location, or is it really molecular classification? Let me start with the gliomas. So the diffuse gliomas, as I mentioned earlier, really are the most common molecular primary brain tumors in adults. And for those types of tumors, we classify them now primarily based on their molecular features and age. For example, there is one genetic alteration. The name of the gene is isocitrate dehydrogenase, also abbreviated as IDH. And this status of that gene really stratifies all the adult diffuse gliomas into two groups, the tumors that have an IDH mutation and the tumors that do not have an IDH mutation. That is sort of the first dichotomy within the adult diffuse gliomas. And within the tumors that do have an IDH mutation in adults, there is a second marker, and that is a co-deletion of 1p and 19q. So that's a chromosomal alteration that further divides them into tumors that do or do not have the second genetic alteration. So as a first approximation, you can think of the adult diffuse gliomas as three groups. One is the tumors that do not have an IDH mutation. We call them IDH wild-type gliomas. And then the other group is the tumors that have an IDH mutation and a 1p19q co-deletion. We call them oligodendrogliomas now. And the third group that have IDH mutation but do not have a 1p19q co-deletion, those are astrocytic tumors. So that is a very useful framework now for the classification of what used to be a very heterogeneous group of tumors. It has clear implications on prognosis and treatment. Another consideration, I think, for a general practitioner is the age of the patient. Just to back up, because it is such an important question, I would like to emphasize that these brain tumors are classified according to the WHO classification of tumors of the central nervous system. And that classification has been updated twice in the last 10 years, in 2016 and again in 2021. And the main change really has been the appreciation of the importance of molecular alterations in the classification of these tumors. So historically, the primary brain tumors were classified based on their histological appearance. Over the last 10 years, this framework has been supplemented and almost replaced by an increasing number of molecular alterations. This is what we now call an integrated reporting framework, where we have the first layer is the histological classification, and the second layer is the molecular classification. And together, you arrive at what is an integrated diagnosis that considers both the histological as well as the molecular properties of the tumor. That was an excellent review, extremely helpful, and also interesting to learn the evolution likely to come to medical attention more immediately, like a new onset seizure, but other symptoms may appear more commonplace initially. Can you give us a few examples of what you would consider common presentations and then maybe more challenging nebulous symptoms that come to medical attention? Absolutely. So headaches are common and found in about 50% of patients with newly diagnosed brain tumors. And almost everyone with a headache does not have a brain tumor. So the question always is, what type of headache should you be worried about? And generally, headaches that are associated with sort of red flag symptoms, they include acute severe headaches, which really are different from any prior headache pattern, new headaches in older adults or children, headaches that are positional or worsen with exertion and headaches associated, and that's probably the most distinctive feature with any new neurologic symptom. And when the pressure in the brain is increased, they can also be accompanied with nausea or vomiting and fatigue. And in extreme cases, when there is very high intracranial pressure, patients even can have episodic loss of consciousness, so-called plateau waves. And that might be mistaken for seizures. I have certainly witnessed those. A little bit harder to sort out are these focal neurologic deficits that relate to the location of the tumor. And then, of course, as you mentioned, seizures are common, like headaches, very common, up to 70% in patients with lower-grade gliomas. So it's a mixture, I would say, of common symptoms such as headaches and seizures, depending on the tumor type. And then, you know, a long list of location related symptoms that tend to be a little more subtle and difficult to pinpoint and often missed and only really elicited during a detailed conversation in the practice, you know, in the office. When you really probe for these symptoms, it becomes obvious often to the patient and their caregivers. Yes, that is very challenging. So there is, of course, much to consider with regards to the diagnostic process. Once you suspect a tumor on brain imaging and get a tissue diagnosis, when do you need to do a systemic workup and what might that entail? Generally speaking, the most common primary brain tumors, they do not need an extensive systemic workup. The exception to that are CNS lymphoma, where we do need a systemic workup to exclude the possibility that this is actually a lymphoma originating from a different site. For the most common and the most problematic brain tumor, it's really all about the brain MRI scan. And once that the brain MRI scan shows certain abnormalities and you need to establish a diagnosis, there is no other way to get to that point other than a biopsy of the tumor. I see. Thank you for clarifying that.
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Can you please bring us up to date on the current best practices and treatment? and if there's anything new in the pipeline, particularly for glioblastoma, since we know it has such a poor prognosis and short life expectancy? Sure. So the first step in the treatment of these tumors is a good tumor surgery. That is very important. We call it safe maximal resection, which means that we go out of our way to try to resect as much tumor as possible without compromising in any way the neurological function. So the preservation of neurological function is a top priority before and during surgery because these tumors cannot be cured by surgery. For malignant gliomas, both glioblastoma and astrocytomas and oligodendrogliomas, sort of the three main groups that I mentioned earlier, it is a combination of radiation and chemotherapy. For glioblastoma, which is the single most common malignant brain tumor in adults, the treatment is post-operative radiation. And the radiation is given in combination with an oral chemotherapy called temozolomide. It's an alkylating agent. There are a number of slight modifications to this. One has to do with the general performance status of the patient and the age of the patient. And then another consideration has to do with a marker. So there is a repair enzyme in the tumor cells that that repair enzyme actually counteracts the activity of temozolomide. So we do not like this repair enzyme because it really gets in the way of temozolomide being an effective treatment. And so we measure whether or not this enzyme is active in these tumors. The name of the enzyme is MGMT. So it turns out that MGMT methylation status has become one of the most useful predictive markers in terms of the likelihood that standard therapy will be able to contain this disease. More recently, there has been the FDA approval of tumor treating fields. That is, it's a low frequency electromagnetic field. So there's really an urgent need to develop new therapies for glioblastoma. Most patients with newly diagnosed glioblastoma, you know, on average live less than two years. So that is really an unacceptable state of the field. And there are many, many attempts to improve upon that. And the types of therapies that are being investigated, you know, they run the gamut from targeted therapies targeting specific genetic alterations in these tumors, such as V600EB-RAF is one of the more promising targets, but unfortunately very rare in this tumor type. But there are many other potential opportunities for targeted therapies. There has also been a great interest in immune checkpoint inhibitors, with inhibitors, antibodies that target the PD-1, PD-L1 signaling axis. Those drugs have been very successfully used in many cancer types, including CNS metastasis for certain cancers, but they really unfortunately have not been shown to be helpful in glioblastoma so far. So they're negative phase three studies in newly diagnosed and recurrent GBM. There has been a substantial interest in more recent years in oncolytic viruses. So there's a series of different viruses that are modified, you know, engineered to promote sort of inflammation and an influx of immune cells into the tumor and perhaps also directly kill tumor cells through infection. It is too early to really comment whether they are effective. It would be wonderful if something came through. It is hopefully promising. I also enjoyed the emphasis on the surgical preservation of neurological function, how important that is, and also how treatment is adjusted depending on patient's age and functional status. Can you please discuss if there have been any changes in prognosis over the years in some of the primary brain malignancies? Yeah, one of the more recent findings is a long-term follow-up of trials that were actually initiated 10 or 15 years ago. And two clinical trials kind of stand out. And one is for astrocytic tumors are the long-term results of the Ketnon study, which really have established the value of adding temozolomide to radiation for patients with anaplastic astrocytomas. And that really is very important that these studies now have matured. We do have long-term follow-up and we have good confidence that there's real value in adding chemotherapy to radiation for those patients. And that's really important when you deal with a rare cancer type and you feel like you're the only one with this disease. And there's hardly any studies that definitively show benefits for any of the treatments you're getting. So that is really for us, for a neuro-oncologist has been sort of a gratifying experience in the last year or two is that some of these trials that were initiated a long time ago now have matured and show clearly for astrocytomas the benefit of temozolomide chemotherapy. And also even more exciting is the sort of for oligodendroglial tumors. These are the tumors with IDH mutation and 1p19q deletion that the treatment of these tumors, these are grade 2 anaplastic oligodendrogliomas. These trials were initiated 20 years ago and have now matured and have shown that really long-term survival with this treatment is possible where many patients have lived 20 years or more. And I think that's an important message to remember that, you know, you can actually achieve long-term disease control with the available treatment even in the appropriate subset of brain tumor. So what that means is we should always make an effort to really make an accurate diagnosis of the subtype of brain tumor you have, and then initiate the treatment that can result in really long-term overall survival. And that has been gratifying, I think, to see that in the last few years, both the accuracy of the molecular classification of the tumors, and then the connection to a therapy that can have clear activity, even long-term activity. That is very encouraging for neuro-oncologists and, of course, patients and their family members. Dr. Mellinghoff, thank you for all you do to advance the treatment of patients with these conditions. And thank you again for joining us today to discuss this important topic. Thank you very much for having me. And thank you to all our listeners for listening to this JAMA Clinical Reviews podcast. I want to remind the listeners that further details may be found in the review article written by Drs. Mellinghoff and Schaaf on glioblastoma and other primary brain malignancies in adults, published in the February 21, 2023 issue of JAMA. A link to the paper can be found in the show notes. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. This episode was produced by Daniel Morrow at the JAMA Network. The audio team also includes Mary Lynn Ferkaluk, Audrey Foreman, Lisa Harden, Hannah Park, Shelley Steffens, and Dr. Linda Brubaker, Senior Editor, Multimedia. Thanks for listening.
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Hello, welcome to another special episode of The Lancet Voice. I'm Gavin Cleaver. And I'm Jessamy Baganal. So we're talking today about something that's got a lot of media attention recently, and that's presentation of Kawasaki-like syndrome in children. Jessamy, tell us a little bit really about what this Kawasaki-like syndrome is. So Kawasaki disease is a relatively new concept that was first seen in 1961 and then a case of 50 were reported by Mr. Dr. Kawasaki in 1967. It's something that we don't really understand quite why it happens. It's an immune response to infections. And patients typically present with quite striking features. So they have a kind of strawberry tongue, a redness of their hands and feet become a bit swollen and they get rashes on them. It's a vasculitis. So it means that there's some inflammation in the body in some of the blood vessels. How badly does it affect children generally when they do get this disease? In general it's a self-limiting disease and what we mean by that is that you know we believe that it's sort of immune mediated so it's the body's immune response kind of going in overdrive almost producing a set of symptoms and signs that can make you quite unwell or make these children quite unwell. But at the end, it's self-resolving. And it seems to be if we are able to treat it effectively in hospital, either with something called IV immunoglobulins or other medications that are able to sort of alter and change the immune response a little bit, then patients generally recover and do quite well. It can cause problems with the heart and some of those complications can be long term. It just depends on what the course is for those specific children really. Yeah, so we talked with Dr. Lorenzo Dantiga, who's the director of General Paediatrics at a hospital in Bergamo in Italy. He's one of the authors of a new paper in The Lancet. And of course, he's been working at a hospital in one of the worst affected regions of Italy. Okay, so Lorenzo, it's great to have you with us today. Perhaps you could tell us a little bit about who you are, what your role is and where you work. Yes, my name is Lorenzo Dantiga. I'm the director of the paediatric unit and child health at the Papa Giovanni XXIII Hospital in Italy. That is a big hospital in Lombardy, northern Italy. And well, the hospital is dedicated to the care of patients and children. And we have a big pediatric unit. We look after patients with any disease. And we are also a referral center for pediatric transplantation. And in this case, we are obviously concentrated in COVID-19 pandemic. And you've published this great series with us about 10 children who presented with this sort of Kawasaki-like presentation over the period of the COVID-19 outbreak. Could you tell us a little bit about what Kawasaki disease is? Yes, well Kawasaki disease is classified as vasculitis of the medium caliber arteries. It involves very often the heart arteries, so the coronaries, but it presents typically with high temperature for more than five days and a rash and some other abnormalities that are quite easily visible. For instance, abnormalities of the hands and feet, such as erythema or swelling, and also what we call mucositis. For instance, the conjunctiva is inflamed and also the mucosa of the oral cavity is inflamed. So that's the typical presentation. And it has been described in Japan in 1967. I guess from a medical school point of view, we always learn about the sort of strawberry tongue picture. Yeah, well, that's quite nice to see. Yes, there is also the strawberry tongue, which is not typical only of Kefersackie disease, but that's, yeah, that's a sign. And as you say, it's a relatively kind of new disease in terms of our knowledge about it and understanding. First described in 1967. How did that come about, that sort of first description? Well, you know, this disease for some reason is more common in the Far East. So it was firstly seen, actually seen in 1967, but described later. And then there were a few outbreaks in those regions. They were recorded in Japan in 1979, 1982 and 1986. But very soon, all pediatricians realized that this disease is diagnosed, should be diagnosed because it's present worldwide. And this sort of vasculitis, that's an inflammation essentially of the sort of veins and arteries. It tends to be self-resolving, is that correct? Yes, it does. Although if you don't manage, if you don't treat these patients appropriately, it can have more complications. It is self-resolving. But if it is treated, it has less complications. And the most important complication is the dilatation of the coronary arteries, which we call aneurysmatic dilatations that can persist into the adult age. And that type of lesion can be actually a problem in adulthood. And is there a relationship then between when you treat Kawasaki's disease and whether you get these long-term complications from the disease? Yes, to some extent, yes. And the main treatment is quite well standardized. We actually use the American Heart Association guidelines, and these involve the use of an infusion of antibodies that we call immunoglobulins, and the aspirin infusion at anti-inflammatory dosage and in some cases also steroids. So maybe we could just talk a little bit about the case series. How did it come about? When did you first start realising that something unusual was happening? Unfortunately, the Bergamo province has been affected by this virus very early on. It was actually the first area affected by this novel coronavirus in Western countries. So actually, we represent a particular observatory to see the manifestations of this disease. At the beginning, we were concerned about the respiratory aspects because we knew that in adults, the respiratory disease was quite tough, quite dangerous. And we were also concerned about the immunosuppressed patients because, as I was saying, we have many children who are transplanted or on oncology treatments. But we soon realized that all these aspects were actually not very relevant. And at some point, a little bit later, I should say, about a month after the first cases showed up, we started to see a few cases of Kawasaki disease. And Dr. Verdoni, who is my colleague looking after patients with this disease and with their rheumatology disorders told me, well, we're seeing two or three days, you know, one after the other with Kawasaki disease. So we started focusing on that. And actually in 20 days, we saw 10 patients. We described those 10, but I can tell you that by now they are already 20. How interesting. And this is a sort of, well, in your manuscript, you say a kind of 30-fold increase on what it has been over the last five years. That's right. And in terms of our sort of understanding about what's going on here, obviously it's very much an evolving field, and so we don't have all the answers. But from your own sort of perspective and the sort of perspectives of your unit, which has now had quite a large experience of this, what do you think is happening? As you can imagine, we reviewed all the past literature, both on the coronavirus family and Kawasaki disease to see whether there was anything about this association in the past. So it is quite obvious to us that there is an association in these cases. But we want you also to understand whether there was anything suggesting that in the past. We want to understand more on that. Actually, we saw that in the past, the family of coronaviruses, that is a very, very special family of viruses because they don't act directly, but they act actually triggering a very severe immune response in the host. Actually, they were involved in this disease, but some authors, some colleagues have been looking for the virus itself in patients with Kawasaki, and very often the virus is already gone when you look for it. If you look at serology, meaning the antibodies against the virus, that's probably the way to connect the disease with the virus. And actually, in 2014, a group from Japan did that and looked at serology and found that a strain of coronavirus was actually apparently involved in some cases of Kawasaki disease because many of the children with that disease were positive to the antibodies. So we believe this is a very tough strain of coronavirus, but we also want to test the hypothesis that the family of coronaviruses have been involved even in the past in this disease. Perhaps you could summarise the main findings of the study. I think we should say that we have recorded a large number of patients presenting with the features of Kawasaki disease.
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These patients are a little bit different or quite different from the classical type of Kawasaki disease because despite they fulfilled the criteria, they have a more severe disease, definitely. Some will be brought directly to intensive care units or to the cardiology unit because they have a very severe cardiovascular involvement. So actually, these patients can also be misdiagnosed because an intensivist focusing on the cardiac and cardiovascular aspects might not look at other aspects that at that point are less important. And in fact, three or four of our patients actually came directly to our intensive care. But when we discussed those, it was clear that there were very severe cases. So I would say these are cases of severe Kawasaki disease requiring aggressive treatment. And I would say most of them require adjunctive steroid treatment that occurred clearly in association with an epidemic of the novel coronavirus. And just going a bit more into the sort of presenting symptoms, there are much more sort of gastrointestinal symptoms for these patients. I know that, you know, this is something that we're seeing in other countries now. And certainly within the NHS, there was this NHS alert put out because there was concern that some patients were presenting with, you know, sore tummies and being misdiagnosed, you know, potentially worked up for appendicitis when in fact, you know, this was a cow satellite presentation. Yes, in fact, even in our series, six of 10 patients had some gastrointestinal signs. The coronavirus does involve the gastrointestinal tract since the receptor, the ACE2 receptor is also present in the gastrointestinal tract since the receptor, the ACE2 receptor, is also present in the gastrointestinal tract and also in the biliary tract. So the virus has been shown to also to be present and infect the gastrointestinal tract. So it is quite likely that the virus itself in these patients is causing also some gastrointestinal problems. And that is probably the reason why we see these symptoms quite often in these patients. Whereas in Kawasaki, the classical Kawasaki disease, they're not very common. And this differs slightly from a letter that we published yesterday, which was Tuesday the 6th of May, that showed a group of patients in South London who were asymptomatic and didn't have any symptoms of a kind of current infection. What was the sort of profile of the patients in this case series? Well, you know, I think we have seen all the wider, the entire spectrum of manifestations of this coronavirus in our unit because, unfortunately, as I was saying, our province has been widely infected by this. So, for sure, there are patients that are completely asymptomatic. And actually, we decided early on to test all patients admitted to our unit, even if they were admitted for other reasons. And we found quite, I would say, 10% of the patients were positive at the nasopharyngeal swab. So there are definitely asymptomatic patients. There are patients with some mild respiratory disease. There are newborns and infants with a more severe picture, sort of a viral sepsis, but they also respond very well. And now we know that there are patients presented with this Kawasaki-like disease. But I mean, particularly these Kawasaki patients, their sort of profile is not one of children with a huge amount of sort of comorbidities or immunosuppressants. They are fairly sort of average children and it's unclear why this presentation has occurred in them. In general, patients having Kawasaki disease are actually normal children, very healthy children. So there is obviously some susceptibility in these patients. We don't know anything about that. But we do know that just some of children that are infected by this virus, for instance, develop Kawasaki disease. For instance, we worked out that probably in our province, in our experience, in about a thousand children infected, probably just one developed Kawasaki disease. So there was some predisposition, but at the moment we don't know much about it. But it is not new because even before we were seeing Kaphasakian disease in very healthy children. And two of the patients tested negative for SARS-CoV-2 serology. What's your explanation for that? Well two of ten of these patients tested negative. They were both tested after immunoglobulin infusion and one was tested the day after immunoglobulin infusion. That might be one reason, a good reason probably. One patient might also be not related to this infection. Your kind of baseline presentation of Kawasaki disease that you mentioned. Yeah, it might be because usually we have one or two in this period. So we cannot exclude that one patient was a classical Kawasaki related to some other condition, maybe some other infection. But one particularly, I'm pretty convinced that we should have tested this patient before immunoglobulins. But you have to consider that the serology testing have become available a little bit late after the emergence of the epidemic. So we actually tested everybody at the same time once we had a test available. What do you see as the kind of implications for our understanding of the sort of immunological processes that are going on with SARS-CoV-2? What insights can be gained from this case series? I think this case series confirms that SARS-CoV-2 is a virus not damaging directly, but triggering a very severe immune response in the host. That's true even in lung disease and COVID-19 disease. We have clearly seen that injury is mediated by the host immune response. So actually the best treatment is with immunomodulators. And that's also why probably immunosuppressed patients, for other reasons, are not affected. They actually might be protected. We also published something on that because we have many patients. So this manifestation, which is clearly an immunomediated manifestation, confirms that these are very special viruses that we have to concentrate on their ability to trigger a cytokine storm, what we call also a macrophage activation syndrome in the host. And what are the sort of next steps for research? What is it that we need to see next to broaden out and fill out our understanding of what's going on here? In my view, if you want to understand more on the etiology of Kawasaki disease, we have to start looking at immune response against viruses. Because as I was saying, most likely this disease is due to an immune response to a virus, but we should look at serology, not to, for instance, PCR, looking directly to the virus. So if you want to understand about the etiology, I think that's the way forward. In terms of the epidemic, I think there are important issues here because once we are ending the lockdown period and we have to allow persons, including the children, to go back, for instance, back to school, we have to consider the implications of this. Of course, this remains a rare disease, but we have to be aware that it will present more commonly. Another issue is that it relates to the immunity to the virus and the vaccine in the future. So if we can develop a vaccine, probably if this is the main cause and will remain the main cause, probably we can also prevent the development of Kawasaki related to the coronavirus. That's great Lorenzo. And I guess we should just finish by saying that in fact all the outcomes of all of these children were good and they were all discharged from hospital and to be doing well. This is an important message I would like to give because although correctly there have been warnings around, I think it is important to say that this remains a rare disease. So as I was saying, probably it affects just one in a thousand children that got infected by the virus. And secondly, although some require intensive treatment, they respond very quickly. I think it is important to consider to use steroids at the very beginning. And in a few days, these patients will respond to the blood pressure, would get back to normal. And at the end, all these patients, at least in our experience, went back home and they're very well. They went back to being fit and very well. That's great, Lorenzo. Thank you so much. Thank you. So as we always try and stress, our understanding of COVID-19 is very limited. And just as we're talking about a disease, Kawasaki syndrome, that we really know very little about being caused by a disease that we really know very little about. It's kind of, we're really in a kind of mystery zone here in terms of the causes of this particular disease. Yeah, exactly. And I think the important things to stress here is that it's still very rare for children to be affected by SARS-CoV-2 or to get any kind of severe response to COVID-19. You know, this is something that is an emerging problem. We didn't really get much information from this from China. And there might be several reasons why that is. This seems to be the sort of first case series and we're looking for more information.
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It's particularly interesting, I think, especially with all the talk about reopening schools, of course, which is something that's happening in phased terms in Europe at the moment. You know, it's important for us to be aware of complications like this that seem to arise from COVID-19 in children. But like you said, it's really important to stress how incredibly rare this disease is, as well as children being affected really by symptoms of COVID-19. Exactly. So I think the message still is that, you know, we should be reassured that children, for the most part, don't get severe disease. All of the children in this particular case series survived and had good outcomes. But there is obviously some potential link between having the virus and later having some kind of immune-mediated, quite severe response to it in children. And that needs a lot more untangling and a lot more information for us to really understand what's going on there. And I think that's something that we're seeing. We've just published a correspondence letter from a group about a small series of children in South London who have presenting symptoms that are similar to this sort of Kawasaki-like presentation. And so what we're seeing are clinicians across the world becoming alive to this situation and we'll be, I'm sure, seeing many more cases and many more pieces of sort of the puzzle as we move forward. Yeah, absolutely. Very interesting piece of research. Thanks for listening to this episode of The Lancet Voice. We'll have more episodes coming soon and you can find our whole archive, which since the outbreak of COVID-19 has covered lots of topics to do with COVID, including advice for asthmatics, for pregnant women, for the elderly, other topics including misinformation. And you can find this archive wherever you usually get your podcasts. Thanks for listening again and see you next time. Yeah, see you next time. Thank you. Bye.
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Welcome. My name is Devine. I am a fourth year medical student. In today's episode of the Devine Intervention Podcast, we'll be talking about bacteria, primarily gram-negative organisms. So let's jump right in. So the first question says to compare and contrast the two nyserial species, to discuss the general gram-staining characteristics, talk about having a capsule or not. Talk about having a vaccine or not. What kinds of infections do these bugs cause? You see some question marks with glucose and maltose and growth media. And then we'll see some things about how Neisseria meningitidis is detected. So let's begin. So the thing is, the two Neisseria species you want to be concerned about for exams, Neisseria meningitidis and Neisseria gonorrhea, right? Both organisms, two certain things they have in common is that they are gram-negative, okay, and they are gram-negative diplococci, okay? Remember your gram-negative cocci, that's where you have your Neisseria species and your Moraxella species. So the two Neisseria species, they are gram-negative, they are diplococci, and they are actually oxidase-positive. They are oxidase-positive. So if you see diplococci on your exam, don't always jump to strep pneumo. Strep pneumo is a gram-posococcus nyserium species are gram negative diplococci now if you're looking at the capsule business nyserium meningitis does in fact have a capsule so that's a high yield virulence factor nyserium gonorrhea does not okay if you're looking in terms of vaccination right we know i mean before you start in general before you at least middle school, you get your Neisseria meningitis vaccine. But there is no such vaccine against Neisseria gonorrhea. And in general, Neisseria meningitis tends to cause respiratory infections. Neisseria gonorrhea tends to cause sexual infections, so like genital infections. Although one thing you should keep in mind is if a person, for example, gives oral sex to a person that has Neisseria gonorrhea urethritis, they can get a pharyngeal infection from that. Both organisms do, in fact, ferment glucose. So Neisseria meningitidis and Neisseria gonorrhea, but it is only Neisseria meningitidis that has the ability to ferment maltose. So remember the M in meningitidis for the M in maltose. And with regards to growth media, the big thing you want to remember is the Theomartin agar, okay? Both organisms grow on Theomartin agar and you can actually use PCR to detect Neisseria gonorrhea. Okay. You can use PCR to detect Neisseria gonorrhea. So next question. So a 17-year-old college student presents with a 13-hour history of fever and severe headache. Physical exam is notable for a petechial rash on the left upper extremity and nuchal rigidity. What's your diagnosis? What's the bug? What's the demographic? How's this transmitted? What's the relationship to mucosal immunology, if you may? Okay, and then I'll say some things in relation to eculizumab. And then the final part of this question says, what's the diagnosis? If this patient loses consciousness, has a blood pressure of 50 over 30, potassium of 6.1, that's super high, and glucose of 45, that is super low. Now, what's the treatment? How do you treat this bug? How do you prophylax against this? So let's talk about this. So hopefully with all this information I've given you, so local rigidity, headache college student i hope you're thinking about nyserium meningitidis okay so nyserium meningitidis again it's a gram-negative diplococcus okay it grows on theomartin agar okay um theomartin agar is actually chocolate agar but you actually add some antibiotics so that normal flora does not grow so you're selecting for nyserial species like nyserial meningitides okay now uh the classic demographic are military recruits or like college students right so people in dorms so if you see mention of like college students military recruits dorms think about nyserial meningitides um with regards to the method of transmission, this is actually transmitted by respiratory droplets. And one high-yield relationship to mucosal immunology is that Neisseria meningitidis actually expresses IgA protease. Remember, IgA is a dimer. It's a dimer immunoglobulin that protects the mucosal surfaces. So if you want to be any kind of pathogen that wrecks havoc on mucosal surfaces like nyserial species, you want to have IgA protease to help with that. So you cleave IgA, so it's ineffective. Now, the eculizumab connection I'm talking about here is that if they describe a person that tends to get recurring nyserial infections, I really hope you are thinking of a C5 through 9 deficiency. Remember, if you have a C5 through 9 deficiency, you have an increased risk of recurring nyserial infections. Remember that those are the constituents of the membrane attack complex. And the relationship to eculizumab. Remember, eculizumab is used to treat paroxysmal nocturnal hemoglobinuria. That's where you have like a P-gauge mutation. So you basically don't have GPI anchors like CD55 and CD59. I mean, GPI anchored proteins like CD55 and CD59 on the surfaces of your red cells, right? So complement comes and explodes your red cells. So the drug of choice in the treatment of that disorder is eculizumab, which is a monoclonal antibody against C5. So the thing is, by giving eculizumab, you're inducing a pharmacological C5 deficiency. So those patients should actually be placed on my serial vaccines. Now, the diagnosis. So what's the diagnosis? So notice this patient loses consciousness, is profoundly hypotensive, has hyperkalemia, and has hypoglycemia. If I add in this extra information that this patient is bleeding from every side, what do you think about? Well, I hope you're thinking about Waterhouse-Friedrichsen syndrome, okay? This is bilateral adrenal hemorrhage that you get with severe Neisseria meningitis infection. It's usually like a disseminated infection. And the reason this patient has hyperkalemia is because the adrenal gland is basically gone. If the adrenal gland doesn't work, aldosterone is not released. And remember that aldosterone helps you dump potassium into the urine at the level of the principal cell okay so if you have like an aldosterone deficiency if you may with waterhouse-fredrickson syndrome you get a hyperkalemia and also remember that cortisol is a diabetogenic hormone okay that comes from the zona fasciculata of the adrenal cortex okay so if your adrenal gland again is not working you're not making cortisol so you're not increasing blood glucose levels because remember cortisol is a pro basically cortisol basically increases your blood glucose levels right under uh situations of stress so you can deal with that stress better let's say you need to run or work harder for that uh for that stress to pass away right increase your amount of glucose in the serum. So this patient basically has findings consistent with adrenaline insufficiency, okay? From Waterhouse-Friedrichsen syndrome. So that's one thing you certainly want to keep in mind. And in general, if a kid, if a very little kid like a neonate has my serum meningitis, you want to give a third generation cephalosporin like cephotaxim okay in adults usually jump to ceftriaxone okay the reason you avoid uh ceftriaxone in neonates right so like the first 20 days of life is that ceftriaxone can cause a cholestasis which can precipitate uh like some liver problems in neonates okay so you generally go to cephotaximeral they are both third generation cephalosporins now for prophylaxis so close contact right of a person that has Neisseria meningitidis generally you use rifampin for that okay but you could also use cipro which is a fluoroquinolone or ceftriaxone so just something something high yield to keep in mind with that. Okay, so let's go to the next slide. Now, 22-year-old sexually active. Ding, ding, ding.
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So if I'm saying compare with chlamydia, that means the answer to this question should not be chlamydia, right? And then let's talk about how this bug is treated, right? So obviously, you know, I'm talking about Neisseria gonorrhea. Now, Neisseria gonorrhea, classically, diagnostic testing, you can take like a swab of like the purulent discharge that this patient has. You do a smear, you do a gram stain, and you'll see gram-negative diplocoxide. Okay? Gram-negative diplocoxide. But another thing you can do is PCR. In fact, PCR is probably one of the more common things that are done right now to detect my serum gonorrhea okay and one thing that my serum gonorrhea has going for it that makes it possible to attach to the urinary tract is that it has p-line okay it has p-line don't forget another high yield thing if you're sort of drawing a correlation here is that e-coli the reason e-coli causes a lot of utis is that it has a fimbria that enables it to attach to urinary epithelium. Now, the common presentations of Neisseria gonorrhea in women, right, it can present as an infection of the cervix, so like cervicitis. It can present with PID. It can present as PID, so pelvic inflammatory disease. That's an infection, a nyserial infection of the liver capsule, okay? It's not only nyseria that can cause that kind of infection. Any bug that causes PID can also cause that kind of infection, okay? But a can also cause that kind of infection okay but a liver capsule infection right upper quadrant pain sexually active person think about fisiocarditis syndrome okay and it can be a sequelae of neisseria meningitis i mean neisseria gonorrhea now with regards to neonatal ophthalmology right so if a lady has gonorrhea and the kid passes through the birth canal, those neisseria bugs can cause conjunctivitis in the neonate. And it's usually super, super, super purulent. So that's why in general, most kids that are born in the US, they get prophylactic erythromycin ointment to prevent ophthalmia neonaturum that you could get with Neisseria gonorrhea from passing through the birth canal. And in general, if you're comparing Neisseria gonorrhea with chlamydia, the discharge you get from the vagina or the penis in chlamydial infection, it tends to be not as purulent as what you get with Neisseria gonorrhea. It's not usually purulent. It's more watery and it's more clear. Okay. So that's another high yield thing you want to know. And if you do a Gramstein, in general, you don't see anything with chlamydia. And I will just tell you this, that chlamydia is actually a much more common STI than Neisseria gonorrhea. Okay. So just something to keep in mind. If they give you a very non-specific question where you're just supposed to make a diagnostic prognostication with regards to STIs, think more about chlamydia. It's a lot more common than nyserogonorrhea. And in general, nyserogonorrhea, you typically treat with ceftriaxone. Remember, ceftriaxone is a third-generation cephalosporin that covers nyserial species really well. So you give ceftriaxone, but you also give azithromycin. by giving azithromycin you can cover concomitant chlamydial infection although there are actually some nyserogonorrheal species that are resistant to ceftriaxone monotherapy so adding azithromycin actually decreases that resistance okay so that's just another thing to keep in mind another cocktail you could use is ceftriaxone plus doxycycline. Remember doxy is a tetracycline. So 30S inhibitor that is bacteriostatic also covers chlamydia. So just something else to keep in mind there. So I hope with this question, you sort of see how Neisseria gonorrhea presents. I think you should be able to answer any Neisseria gonorrhea question after this. So let's go to the next one. A three-year-old male is brought to the pediatrician by his concerned mom. He has been tugging his ear and wincing in pain for the past two days. Otoscopic exam is notable for erythema and decreased mobility of the tympanic membrane, right? So this kid obviously has otitis media. A gram stain of purulent material around the eardrum reveals gram-negative circular organisms, okay? What's the bug and what are your treatment strategies, okay? So this kid clearly has otitis media, okay? And there are certain bugs that commonly cause otitis media right so like strep pneumo commonly causes otitis media viruses are probably one of the most common overall causes of otitis media um uh moraxella catarales also causes otitis media okay remember that's a gram-negative caucus. And non-typeable H flu also causes otitis media. In fact, the most common cause, very high yield to know this, the most common cause of otitis media, the most common bacterial cause of otitis media is non-typeable Haemophilus influenzae. Now, this question says you do a gram stain and you see gram-negative circular organisms, right? So gram-negative cocci, okay? If you see gram-negative cocci, that should help you rule out strep pneumo, and that should also help you rule out H-flu. H-flu is not a caucus, okay? So this leaves us with Moraxella cataralis, okay? Moraxella cataralis is actually a fairly common cause of otitis media and the way you treat this infection is with the same drug you use to treat most kinds of otitis media okay use a combination of amoxicillin and a beta lactamase inhibitor like clavulanic acid okay so amoxicillin and clavulanic acid right you are augmenting the activity of amoxicillin with clavulanic acid. That's why the drug is called augmented. I'm just making that up. But amoxicillin and clavulanic acid is actually, in fact, augmented. So short question there. So let's jump up to the next one. Question five. A 23-year-old cystic fibrosis patient is brought to the ED by his mom. His temperature is 105. That's super high. He has had significant respiratory difficulty for the past three days. That is worse than his normal baseline. What's the bug? What are its special characteristics? So let's just sort of take this step by step. So this bug obviously is pseudomonas okay so cystic fibrosis cystic fibrosis patient with pneumonia one big thing you definitely want to think about on your exam is pseudomonas okay and in general on exams the most common cause of pneumonia in a cf patient that is less than 21 years old is staph aureus but when that cf patient becomes greater than 21 years old then you're thinking about pseudomonas. And when the CF patient is about to die, like when they infect, like their disease is terminal, you also want to begin to think about some exotic organisms like Bocoderia sapicia. Now, so this patient has Pseudomonas aeruginosa infection. A few characteristics with Pseudomonas is it's a gram-negative rod. It's oxidase positive. And it's actually catalase positive as well. So if a person has chronic retinomatous right? So NADPH oxidase deficiency, they can get recurring pseudomonal infections, right? Because again, pseudomonas is a catalysis positive organism, right? That's what the last part of this question is talking about, where I say, why would a patient with a negative NBT test get recurring pseudomonal infections, okay? Now, other virulence factors that pseudomonas has going for it is that it is an encapsulated organism. So if a person has a splenia, so like a sickle cell patient, again, they can have life-threatening pseudomonas infections. In addition, pseudomonas has an exotoxin. It's called exotoxin A. Exotoxin A actually ADP ribosilates elongation factor 2, okay? So that decreases protein synthesis, right? So hopefully you can make the correlation between the exotoxin A of Pseudomonas and your protein synthesis inhibitors, right?
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So you decrease protein synthesis with the exotoxin A that comes from Pseudomonas. Now, other high-yield things with Pseudomonas you want to know is that it produces certain pigments. The most commonly tested one on exams is piocyanin okay it's a blue it gives it a blue green color okay in fact that's why if you see like burn patients and you see like pus from their wounds and it has like this bluish green color uh you really want to think about pseudomonas right pseudomonas is a fairly common infection in burn patients and uh uh pseudomonas usually smells like grapes right so if they describe a burn patient and they say like oh this patient person has like cellulitis or whatever and the pulse or whatever like has like this grip like smell or they describe a hospital like a burn unit in a hospital that has like a grip-like smell, you want to think about pseudomonal infections. Pseudomonas, the classic demographics, right? So it has an association with water, okay? So it can cause hot tub folliculitis, right? So if they describe a skin infection in a person that is an avid swimmer, think about hot tub folliculitis with pseudomonas. Although the most common cause of folliculitis, I would say like in a non-swimmer, you probably want to think more about staph aureus with that. And please do not confuse hot tub folliculitis with hot tub lung. Hot tub lung is a very severe respiratory slash lung infection that's associated with mycobacterium avium intracellulare right so remember that bug that is supposed to prophylax with azithromycin in a HIV patient when the acidity count drops below 50. Now another classic demographic for pseudomonas is in a burn again a burn patient in fact one classic presentation on exams could be a burn patient having like a necrotic ulcer on the skin that's something known as eczema gangrenosa it's a very high yield association for exams with Pseudomonas okay so you can present as a black escar okay so a black escar is not something that is only specific to bacillus anthracis. Okay, a black escar is also a finding you could get with cutaneous pseudomonal infections. Now, pseudomonas, right, if they describe a person that has like bone pain or osteomyelitis from having stepped on a nail that went through like sneakers or like workout gear, again, also think about pseudomonas. Okay, pseudomonas lives in, there's a lot of pseudomonas in shoes and in sneakers. Now, again, also think about your cystic fibrosis patients with pseudomonas. That's another thing you want to think about. And I will say in general, those are the people that classically get Pseudomonas on exams. Although also don't forget your CGD relationship with the NADPH oxidase deficiency. Okay. The classic drugs you want to be aware of for exams include drugs like piperacillin and tezobactam okay remember pip tezo that's like what's called zosyn in hospitals or vitamin z if you may pip tezo tezobactam is a beta lactamase inhibitor piperacillin is a kind of penicillin okay it's an anti-sodomono penicillin your amino glycosidescosides, right? So like drugs like gentamicin, neomycin, amikacin, streptomycin. And if you're talking about like the cystic fibrosis patients, inhaletobramicin. Those drugs all cover pseudomonas. Your fluoroquinolones like ciprofloxacin, levofloxacin, moxifloxacin, gadifloxacin, they all cover pseudomonas. And then certain cephalosporins also cover pseudomonas. I'll say like the third generation cephalosporin, ceftazidine, does cover pseudomonas. And then the fourth generation cephalosporin, like cefepine, also covers pseudomonas. So those are high-yield things you want to know in relation to pseudomonas. So let's go on to the next question. So a 59-year-old smoker presents to the ED with a 3D history of diarrhea and shortness of breath. Temperature is 101. That's high. He recently visited a resort in the Bahamas that had an artificial waterfall. Ding, ding, ding. So what's the bug? What are the special characteristics or means of transmission? What's the classic presentation? And what's the classic exam symptomatology, if you may? How do you diagnose this infection and how do you treat this bug? OK, so if you see a waterfall, you see pneumonia. And for example, let's assume they give you a chest x-ray where you see interstitial infiltrates You really want to think about legionella nomophylla. Okay legionella nomophylla So this is legionnaires disease. Okay. So what are some special characteristics of legionella? Okay legionella It's a gram-negative organism Although it doesn'tstain very well because it has like some branching fatty acids in its cell wall. Legionella does actually stain pretty well with silver. So while we're on the topic of silver stains, please don't forget that pneumocystis gerovetsi and H. pylori also stain pretty well with silver. And Legionella, the thing is, it's an intracellular pathogen in general, and it grows very well on chocolate yeast, like, sorry, charcoal yeast extract that you enrich with iron and cysteine. So that's another thing you want to know. And here's one way they'll try to trip you up on exams with regards to the means of transmission. Legionella is not transmitted through person-to-person contact. Even if it's a respiratory infection, right? It is actually not transmitted through person-to-person contact. It's actually transmitted through inhalation of aerosolized fluids. That's why it has an association like air conditioning or with waterfalls or with like mist. OK, so those are high yield things you want to think about with with Legionella. Now, the classic presentation. OK, I think of Legionella as being pneumonia plus. OK, so the person will present with like high fevers, walking pneumonia. You get a chest x-ray, you see like intestinal infiltrates. And these patients tend to have diarrhea. And they also classically have the BMP anomaly of hyponatremia. So if you see a person that has pneumonia, was recently exposed to air conditioning or a business conference or a waterfall, and they have hyponatremia, and they have respiratory problems, and you see like intestinal infiltrates on a chest x-ray, think about Legionella pneumophila, okay? Think about Legionella pneumophila. And the way the diagnosis is made is with a urinary antigen assay, okay. And treatment of Legionella, like all other causes of atypical pneumonia, is with a macrolate, like erythromycin, clarithromycin, ezithromycin, if you may. Now, I guess with that, we can jump up to the next question. So a med student presents to the ED with a temperature of 104 and a painful ulcerating lesion on the left upper extremity. Physical exam is notable for significant left axillary lymphadenopathy. He took a year off to study targeted therapy in rabbit models of the brain malignancy glioblastoma multiforme. So let's assume this is a metastatic that wants to match into neurology or neurosurgery or ENT or whatever. So studying targeted therapy in rabbit models of GBM. So rabbits. So what's the bug? What are the special characteristics or means of transmission of this buck? And what's the classic presentation? Okay. So if you see rabbits on your exam, okay, you want to think about Francisella. Okay. Francisella tularensis. Okay. Causes tularemia. It's a gram-negative rod. Okay. And it's actually a zoonotic infection. Now, there are certain ways you can get Francisella on exams. One way you could get Francisella is to just to inhale like the aerosolized secretions of rabbits. Or let's assume you directly come into contact with secretions of a rabbit. You could get tularemia with that. Alternatively, a tick that bites a rabbit, like a dermacentral tick, for example, that bites a rabbit and then goes on to bite a human being could also transmit tularemia that way. So very high yield to remember that.
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And the classic presentation is the part of your skin that is inoculated with, that's like bitten by the tick or comes in contact with,, let's say like your skin is abrased by like the, I don't know, by like, I don't know, the fingers or nails of the rabbit or whatever. That site of inoculation, you tend to get an ulcer, okay, at that site. And then you also get lymphadenopathy, right? So the lymph nodes that that drain that ulcer you tend to get lymphadenopathy with that okay but the big thing you want to keep in mind is that they will give you a person that they will give you like if you see rabbits in an mbme question and the person has fever and there's an ulcer okay like on the skin and you see like lymphopathy. That's very proximal to the ulcer. Think about tularemia, okay, from Francisella to larynx. Francisella is actually a gram-negative rod. So that's all you need to know with that bug. So next question. A four-year-old female in California is rushed to the ED by her concerned parents. Okay. She has had a severe cough for the past seven days. These episodes have occasionally been associated with vomiting. That's a very high-yield association to know. A fundoscopic exam is positive for a subconjunctival hemorrhage. That's another high-yield association to know. The white count is 60,000 with a lymphocytic predominance. That's another super high yield association to know. Basically, with this clinical presentation, I've given you the details that will almost certainly make its way to any exam question you'll see that tests this bug. Now, what's the bug? What's the diagnosis? What are the stages of disease? What are the virulence factors? Any special characteristics or growth media for this bug? How do you prevent this bug? How do you treat and how do you prophylax? OK, so with all these questions you're seeing, you can probably tell that this is something how you want to know for tests. OK, so this patient clearly has whooping cough. OK, whooping cough. OK, remember, whooping cough is caused by bernatella pertussis uh this is actually a vaccine preventable illness okay so you could get the toxoid vaccine the tdap vaccine or you could get the d-tab vaccine okay although you generally get boosters of those vaccines because immunity wanes after like eight to ten years uh if you're receiving your initial vaccine so it actually preventable. And I'll just talk about the treatment right now so I don't forget. You generally treat bordetella pertussis with a macrolate like erythromycin. And it's also good to know that because that's also the way you treat close contacts, right? That's prophylaxis, so that they don't get the infection. Now, certain high-yield things you want to know about a teloprotosis is that it's a bacterial infection. Unlike most bacterial infections where you get a predominance of neutrophils as a reaction to that infection, you actually get a predominance of lymphocytes. So if you see bacterial infection with a lymphocytic pleocytosis, think about Bortetella on exams. That's one thing. Second thing is that these patients tend to get a very nasty cough and that cough is classically associated either with on exams either with vomiting or difficulty breathing or a subconjunctival hemorrhage those are like three very classic exam presentations like they say oh this person coughs and they're out of breath i will encourage you to look up a youtube video or something of whooping cough. It's actually pretty striking. Now, another thing you want to know with Bordetella pertussis is that it's a gram-negative rod. And one high-yield virulence factor would be pertussis, is the pertussis toxin. That's a very imaginative name. The thing is the toxin has a relatively high-yield mechanism of action because it's unusual. So the way the toxin works is that it inactivates GI, so an inhibitory G- coupled receptor. And when you inhibit GI, you actually increase the activity of adenylate cyclase. And if adenylate cyclase activity is increased, you have an increase in cyclic AMP. That's why you get many problems with bordetella pertussis. Another virulence factor is a protein that it expresses, hemagglutinin. Hemagglutinin, you may remember that I talked about this with influenza virus. But the thing is, the hemagglutinin that's expressed by bordetella pertussis actually binds to the cilia that you find on the pseudostratified columnar epithelium of the respiratory tract. And when it binds, it basically grinds those cilia to a halt. And remember that cilia are necessary for the clearance of respiratory pathogens and mucus. So if those cilia are non-functional, you then basically open up your respiratory tract for infection. That's one. And two, because you cannot whip away noxious substances your airways become hypersensitive to anything you inhale okay that's why you again you get a lot of whooping cough with bordetella pertussis and while we're on the topic of cilia please do not forget cartagena syndrome. Okay. Primary, it's another buzzword name is primary ciliary dyskinesia. Okay. Remember, these people tend to get like recurring respiratory infections. Basically, anywhere you have cilia in the body, they will get problems in that system. Right. So like the respiratory tract, remember the pseudostratified columnar epithelium that has cilia. So they tend to get recurrent respiratory infections. They get infertility because remember the fallopian tubes have cilia. They tend to get hearing loss because remember you have a cilia as part of your hearing apparatus. So don't forget that cilia association. I just decided to talk about that here since one of the virulence factors, hemagglutinin with portotellar pertussis, basically grinds the cilia just in your respiratory tract. So the cilia in your respiratory tract to a halt. And the way you actually acquire portotellar pertussis is through respiratory droplets. So just something to keep in mind there. Okay, now the stages of disease with bordetella pertussis. I remember that with the mnemonic CPC. So the first C stands for the cataral phase, where you basically just feel like crap. You have like runny nose, you have like mild fevers. And then there's the paroxysmal stage where, again, you get the nasty cough. It's usually worse at night with inspiratory whoops. Okay, so like, right? And again, if they describe a kid that has like really nasty cough for like weeks and weeks on end, where the kid has a subconjunctival hemorrhage or vomiting or is out of breath at the end of each coughing episode, think about bordetella pertussis. And bordetella pertussis, so you have the cataract phase, the paroxysmal phase, and then you have the convalescent phase where you're recovering. And if you want to isolate b-pertussis, you can use the Bordetella Jinju or you can use the Regan-Lew media. Those are two things that are definitely exam testable. And treatment is with a macrolate like erythromycin. With a macrolate like erythromycin. Although, don't be an anti-vaxxer. Vaccinate your kids so they don't run into these kinds of problems. Okay, next question, second to the last. So a Kentucky family that resides on a goat breeding farm brings their six-year-old daughter to the ED with complaints of high fevers for the past seven days. Okay. These fevers, right? So goat breeding, that's one key buzzword. High fevers, that's another key buzzword. These fevers are worse at night. that's another key buzzword. So, imagine that these fevers are better during the day. So, it's like a waxing and waning fever. Now, the child's clothes are drenched from profuse sweating, even with outside temperatures of 50. Okay, that's another key buzzword. So, what's the bug? Okay, what are its special characteristics? And what is the classic association? What are the classic associations slash presentation with this book? OK, so if you ever see farming, right, like exposure to like sheep or cattle or goats, and then they describe a person that has fevers that wax and wane.
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So like picket fence fevers, if you may, okay? Ondolent fevers, if you may. I really hope you're thinking about brucellosis, okay? Brucella from a brucellus species, okay? So this is brucellus. Brucellus is a gram-negative rod. It's a zoonotic infection, okay? It's zoonotic because, again, you classically get it from cattle or from sheep or from pigs or from goats okay so if they give you an exam question that describes a person that works in a slaughterhouse or a person that lives on a farm or a person that consumes unpasteurized goat milk okay and then they present with like fevers and very severe sweating that's's a high-yield association. And they say that, oh, this person has fevers that are worse at night and better during the day, right? So, undulant fevers. Think about brucellosis, okay? Think about brucellosis. And the last part of this question that says megaloblastic anemia in an infant with a strict goat milk diet. This is one of those questions for, it's more step two like, but it's one of those things that could potentially show up on step one and most people will get wrong. Okay. So hopefully you won't get it wrong because you listen to this podcast. But the thing is, infants that take a strict goat milk diet actually tend to get folate deficiency, which can present, again, as a megaloblastic anemia where the MCV is greater than 100. You see hypersegmental neutrophils on a blood smear. So just something high you have to keep in mind there. Okay, so again, brucellosis, profuse sweating, undulant fevers, exposure to cattle, sheep, goats, pigs, slaughterhouse, unpasteurized goat meal consumption, things like that. That should tip you towards the diagnosis. Okay, so next and the last question. A 26-year-old female is intubated in the ICU three days after presenting with bilateral low extremity weakness. She had a four-day episode of bloody diarrhea that resolved without treatment two weeks ago. Lumbar puncture is notable for a marked increase in CSF protein. White cell count is within normal limits, right? So hopefully you're already making a link here. Increase in CSF protein, but a normal white cell count, okay? That is a finding known as albuminocytologic dissociation, okay? So what's the bug? What are the special characteristics of this bug, okay? What's the means of transmission? What's the classic presentation? And how is this infection treated? Okay, so this patient clearly has Guillain-Barre syndrome. Okay, remember Guillain-Barre syndrome, you do a CSF study on exams, you see an increase in protein, CSF protein, but no increase in cells. Okay, that's known as albuminocytologic dissociation. There is a dissociation between the protein count, that's the albuminocytologic part, and your white cell count. Because classically, if you have a high white count, you have a high protein count. So having a high protein amount in your CSF with a normal white cell count, that's discordant. That's what's known as albuminocytologic dissociation. So this person has GuillBarre syndrome. Okay, and they tell you that, oh, two weeks ago, this person had a bloody diarrhea that resolved without treatment. Okay, so hopefully you're thinking about Campylobacter jejuni. Okay, C. jejuni. It's a gram-negative organism. It's a gram-negative curved rod. It's oxidase positive, and it actually grows at 42 degrees Celsius, okay? Because at 37, many things grow, but at 42, many things do not grow. I can imagine as a human being yourself, you will feel extremely uncomfortable at 42 degrees Celsius, okay? But Campylobacter Jejuni. In fact, it's probably the most common cause, very high yield to know this, it's probably the most common cause of bacterial bloody diarrhea in the United States, okay? So that's something you definitely want to keep in mind. Now, why do you get Guillain-Barre syndrome with campylobacterial infection? I mean, it's not everyone that gets C. jejuni infection that gets Guillain-Barre syndrome. But it's a principle that they occasionally test on exams. It's the principle of molecular mimicry. The thing that happens here is that the antibodies that your body makes against C. jejuni cross-react with proteins and myelin. Okay. If they want to mess with your head on exams, instead of putting GBS or Guillain-Barré syndrome, they can put acute inflammatory demyelinating polyneuropathy as the answer choice. AIDP. That's just a code word for GBS on exams. So just another thing to keep in mind there. And the way you treat GBS, I mean the way you treat CJ29 is with a fluoroquinolone, like like Cipro or levofloxacin or with a macrolide like erythromycin, okay? So I think with this, we are done for today. I would have a dedicated podcast where I just go through trigger lists that are very useful for microbiology. I'll talk about like, basically, it would just be where I give you like a one-liner and you supply the name of a bug. And the one-liners, I'll group them by disease condition like diarrhea, for example, or pneumonia or STI or drugs and stuff like that. And I think there'll be a very good global micro review down the line. So I wish you all the best. If you have any questions or you spot any errors, please don't forget to send a comment. And if you have any questions, just shoot me a message at divineinterventionpodcasts at gmail.com, or you can use the contact button in the website. I mean the contact page in the website to send me a message. I'll be sure to get back to you as quickly as possible. Have a wonderful week ahead and remain blessed. Thank you.
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This is exactly right. or a thrill seeker. You'll find what you came for here and more. So ask yourself, what is it you want? months of Paramount Plus Essential Plan on us. Mintmobile.com slash switch. Upfront payment of $45 equivalent to $15 per month. Unlimited over 40 gigabytes per month. Face lower speeds. Videos at 480p. Active Mint customers by 531.24 get six months of Paramount Plus Essential Plan. Auto renews after six months. Offer ends May 31st, 2024. Separate Paramount Plus registration required. Terms and conditions apply if rated PG. Hi, I'm Erin Welsh, and this is This Podcast Will Kill You. You are listening to the latest Book Club episode of the season, a series where we get to interview authors about their books covering fascinating and important topics in science and medicine. If this is your first time tuning in this season, welcome, thanks for joining us, and also be prepared to make room on your bookshelf and to read list. Last time we did this series, we just sort of released the episodes without giving you an opportunity to read beforehand, and this season we decided, in the spirit of real-life book clubs, to give those of you who want it a sneak peek of the books that we'll be chatting about this season. So, if you are one of those wanting to read along with us, head over to our website, thispodcastwillkillyou.com, where you can find a link under Extras to our bookshop.org affiliate page, which has our reading lists, including our book club list, featuring all of the books we covered last season, as well as the ones we'll be covering this season. It's a pretty incredible list, if I do say so myself, and I really can't wait to share all of these interviews with you all. I'm especially thrilled for today's conversation with Dr. Sara Manning-Peskin, who is an assistant professor of clinical neurology at the University of Pennsylvania and author of A Molecule Away from Madness, Tales of the Hijacked Brain. In this captivating and heart-rending book, Dr. Peskin takes readers through stories of the brain gone awry, exploring the histories behind some of these neurological illnesses, and deftly explaining some incredibly complex concepts that frame our limited understanding of how the brain actually works. I want to ask you all to take a second to consider the human brain. What are you doing in this very moment, besides listening to the podcast? Maybe you're cooking dinner, maybe you're out walking your dog, maybe you're crocheting, maybe you're driving home from work, or maybe you're just chilling on the couch. What did you do today? Took a shower and got ready for work? Scrolled through Instagram memes for probably longer than you should have? Guilty. Wrote endless emails? Watched some reality TV? also guilty. How do you feel? Exhausted, content, anxious, excited, curious, depressed. We are capable of doing so much and doing it all at the same time, of feeling so much, of creating and imagining, of thinking and overthinking, of holding a million different emotions and to-do lists and memories inside of ourselves all while doing something as mundane as cooking dinner. And it's our brains, of course, that allow us to do this miraculous multitasking. I think it's easy for many of us to take our brains for granted, And maybe some of that comes from the expectation that every morning when we wake up, we assume our brains will be there just as they were yesterday. Maybe a bit groggy, maybe in need of some caffeine, but ready to help us take on the day. But what happens when our brains don't function in the capacity we expect them to? What happens when our brains betray us? I don't think we always appreciate just how close our brains are to the edge, how something so small and seemingly insignificant as a stray protein, for instance, can profoundly disrupt everything about how our brain works. In A Molecule Away from Madness, Dr. Peskin shares stories that reveal the vulnerabilities in our brains, using each story to teach readers what we know about the inner workings of our brains, to remind us how many mysteries remain, and to convey that with every story told, with every molecule or protein examined, people remain at the center. I really loved A Molecule Away from Madness, not just for the fascinating histories or thoughtful examinations of complex neurological concepts, but also for the way that Dr. Peskin centers patients in the narratives of these illnesses, bringing so much compassion and empathy to a field where it can be too easy to lose sight of the whole person when your focus is on an individual protein. I am really excited to share my conversation with Dr. Peskin with you all, so let's just get right into it. Sarah, thank you so very much for joining me today. I absolutely loved your book, A Molecule Away from Madness, Tales from the Hijacked Brain. And I thought you beautifully blended clear and accessible medical information with such a strong sense of humanity and empathy. And it was such a great piece of scientific storytelling. And I know that you've often been compared to Oliver Sacks, but hopefully you won't mind hearing that comparison one more time. Because I really, yeah, I just, I thought it was so amazing. And I've been telling everyone I know about it. Oh, thank you so much. I was so excited to be on. So I wanted to start with, you know, asking you how you got this idea to write this book. When did you decide, I want to write a book? And when did you decide, I want to write this book? And what was your process like? So I started, I came to writing pretty late. Initially, I was going to become a scientist and I wanted to like have a lab. And then I actually, I started an MD- combined program. I did like a year and a half of the PhD and was like, oh no, this is not right. This isn't the right fit. And so I quit the PhD program and I finished medical school and I was an intern and we had to do two months of night shift. And there were some nights that were wild and some nights where it's like nothing much happens and it's a little bit lonely. And so I started writing some memoir stuff. And then I essentially realized like, my life is not that interesting. No one really wants to read about my life that much. And, um, but my work is fascinating and, uh, and the patients I see are amazing. And the family dynamics that you witness are, um, incredibly intricate and emotionally moving. And that stuff is interesting. And so then I sort of started to think about, you know, what are the most interesting stories and the way that someone actually put it to me in terms of how you think about what you want to do in medicine is when you open the clinic door, like who do you want to see on the exam table? And that's how I sort of started to shape the book itself. And I initially wrote, initially the idea was to do sort of the traditional thing of like, oh, this patient shows up and they have these curious symptoms. And then, aha, this is the diagnosis and here's how the disease works. And, you know, that's your package. But the more I wrote about it, I realized that actually the more important thing is actually the history of the disease. Because it's learning about a disease itself and the mechanics is so dry, but learning about how we discovered the disease and what kinds of sort of wacky and outlandish characters were involved, that's actually exciting. The narrative part is what's exciting. Oh, yeah, absolutely. I mean, that's our bread and butter here on the podcast. Mine especially. I love medical history and sort of getting into that step one. Step two, how do all the pieces fit together? So of course, that's another reason why I loved your book. So who did you want to see on the exam table? Like, how did you end up choosing neurology as your specialty? I ended up realizing that I thought the most interesting diseases were ones that change people's identities. And I think, like, we all sort of think about, like, look, if I broke my leg, I would still be the same person. Or, you know, I may go through this bad relationship, but I'll come out and, you know, I'm still me and I'm learning things and I'm evolving. And yet there are these select diseases where there's a, you know, there's a molecular problem and it actually sort of overhauls your identity. And it actually, you know, makes you realize that the essence of what you think is yourself is actually not as protected as you think.
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Head to lomi.com slash this podcast and use the promo code this podcast to get $50 off your Lomi. That's $50 off when you go to lomi.com slash this podcast and use promo code this podcast at checkout. Thank you get into a lot of this in your book, right? And there are so many different ways that the brain can change suddenly and change who you are, or there can be just like the tiniest little switch that flips. And so how did you decide which diseases and also which personal stories that you wanted to include in your book? I tried to think of a structure of like, what are the types of diseases that actually cause this type of thing? And there's not that many different categories. I basically described, just sort of divided it into mutants, which are DNA mutations or DNA changes, rebels, which are problems with proteins. So if you think about DNA is like the biggest molecule that we have in our body, proteins are pretty big and proteins basically carry out, they're kind of the workhorses. That's what really keeps ourselves alive. The DNA is really, for the most part, just a sort of instruction book. It's proteins that really do the work. And then there are small molecules. So there's things that are smaller than DNA, smaller than proteins, and they either cause a problem by being present, I call those invaders, or they cause a problem by being absent or not being there in enough quantities. And I call those evaders. And a lot of the diseases that have a single molecular problem, most of them fit into one of those categories. In terms of the personal stories, are these all patients that you personally have treated? Or how did that aspect come into play? So only two of the patients are people that I treated. And when I interviewed them, they weren't under my care anymore, which also makes it easier to think about being confident that asking them if I can interview them isn't causing them to worry that their care might suffer if they say no. But no, I essentially wrote down the different diseases. And then I reached out to specialists at different fields and said, do you happen to have patients who you think might be interested? And it actually turned out when I went to interview patients, it was, I think it's actually more meaningful for people to be interviewed than I realized. Because you, when we develop diseases, you know, you go to a doctor and you say, like, look, I've been feeling X, Y, Z. And the doctor says, why don't we get some tests? And then you come back and you get a little more information and then maybe your symptoms change or you get more tests. And there's sort of an evolution of getting a diagnosis and then the disease itself can evolve over time. And it's really uncommon for people to be able to sit down and say, you know, what has this entire road been like? You know, what's the last six years of my life been like from the beginning changes to where I am now? And it's actually fulfilling for people to be able to actually walk through that with someone in sort of in slow motion. And so I was actually sort of surprised that after interviews, people be like, oh, that was actually, that was a really wonderful experience. And I was sort of thinking, oh my gosh, thank you so much for giving me so many hours of your time. But actually, it was nice. It was sort of a mutually beneficial thing. Yeah, I can imagine it would be really sort of like cathartic and difficult. But also, I think that the personal stories just add so much because it kind of places it in a human context. It grounds these diseases, these things, and you're like, these are people who are experiencing them. This is their story. It's not just lab charts. It's not just these results. It's not just this list of symptoms. And so, yeah, I felt like that was really impactful. Were there any stories that you didn't end up including or any diseases that you initially thought that you were going to include as part of the book but didn't end up making the final cut? There were some that got cut. I wanted to include a chapter on manganese poisoning because it can cause Parkinsonism. So it can cause people to have movement changes, but it turned out it's really mired in legal issues because a lot of it was workplace exposure. And so I ended up, I was like reaching out to lawyers saying like, are your clients interested in talking? And then it was sort of like, I think I'm entering into a realm that I shouldn't go into. And so, so that one got, even though it's a fascinating story. And, and then there were some people, there was two people who I interviewed who were, you know, wonderful people and wonderful stories. And ultimately when I finished with the structure of the book, they sort of felt kind of extraneous in terms of the stories themselves. But, but the people were, were wonderful. And so in the back of my head, I'm always like, oh, well, I hope sometime I have to write up those stories. Yeah, next book. So when you're not writing, what are you doing on the day-to-day? I mean, I know you're probably still writing, but yeah, what do you do besides being an author? Yes, so I mean, I watch TV. I do the normal things. But, you know, I'm a cognitive neurologist. So two days a week, I see patients and it's mostly patients who are coming in and saying, you know, do I have dementia? What's going to happen in the future? And most of what we see is sort of atypical cases. So often it's people who are younger or people who have unusual symptoms. So someone who comes in and says, you know, look, I've been seeing people at the end of my bed and I know they're not there, but they really look clear to me. Or, you know, things like we had said before, you know, my partner is acting strangely. He's totally apathetic and he used to be so warm and he went out and bought a sports car and didn't tell me. Or, you know, people who say, you know, look, I'm having trouble using the right side of my body and it's gotten worse and worse over time. So these sort of really atypical cases where people have language problems. So they come in and they say, you know, I used to be a big gardener and, you know, someone mentioned the word mulch before and I couldn't really figure out what it meant.
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And so a lot of what we do is sort of seeing those cases and saying, you know, if you're not alone, this is a real disease. It's sort of in your head, but not in your head. And so that's what I do, you know, much of the involves this instance of Alzheimer himself standing up and presenting what he found at a scientific meeting where he was met with like absolute silence. So can you place his findings in the context of dementia research at that time and maybe kind of speculate on why no one really seemed to care all that much about or recognize immediately the importance of his presentation. Yeah, so the story is sort of fascinating. So Alzheimer was this, he was sort of a very social guy, very smart. He'd gone to this top school and then he did a PhD on the cellular life of earwax and he'd gotten like a citation for disturbing the peace. So he was sort of a work hard, play hard kind of guy. And he goes into work one morning at the asylum for the insane and epileptic, it was called in Frankfurt. And he meets this woman, August Dieter, who was a housewife. And she's in her early 50s. She was 51 when he met her, but in her forties, even she started having difficulty. She would forget things in recipes. She was getting confused where she was going around the house. She became very suspicious that her husband was having an affair with a neighbor, even though there was no evidence. And her husband had taken her to the doctor and the doctor basically said, pack her clothes and drop her off at the asylum. And so's what he did and she never got out um but uh but he saw her the next day and he very quickly realized her case was unusual um and what he realized is that she was had a you know a very a horrible short-term memory so he would come and he would show her a bunch of objects and she could name them she could do math she could describe things like the color of soot. But as soon as he would take the objects away, she would have no idea that he had ever shown them to her. Or if he asked her to write her name, she would write, she wrote Mrs. And then she couldn't write the rest of her name. She sort of forgot the task or forgot how to do it. And he realizes the case is unusual. And so he treats her for a little over a year. And then he actually, Alzheimer's own wife actually dies very young and he's left with three kids and he ends up moving to another city, but he basically calls dibs on her brain, which was something you could do in that time. And so everyone knows that this asylum that when, you know, when this woman dies, it's going to, her brain's going to go to Alzheimer. And sure enough, a few years later, she passes away And an intern from the hospital in Frankfurt calls him up and is like, do you want the brain still? And he's like, send it over. And so they fix the brain in formaldehyde. And they send the whole brain and her entire medical record to Alzheimer's at this other hospital. There's no consenting. It's a totally different time. And he looks at her brain under a microscope and he sees buildup of these two structures. One is what we call plaques, which basically look like a spot of spray paint in the brain that obviously is microscopic. And then the other is called, we call them tangles now. And they basically look like spaghetti inside of neurons. And people had seen the structures before, but they had seen it essentially in older people where they thought the structures didn't really mean anything. And Alzheimer's big contribution was finding this woman and realizing she had a enormous, enormous burden of these plaques and tangles. And so what he did that was so sort of, partly he was so good at microscopy and he was such an expert in the field, but also he was very quick to say, is this a different disease? And that was the key. It's that he said, you know, have I actually discovered something new? And so he goes to this conference and he presents his data. And just as you said, so he basically talks about the case, he shows pictures and slides. And at the end, there's like total silence. The moderator basically says, well, it seems there's no desire for discussion and please take a seat. And then, and later in the day, actually the talk that garnered the most interest is the talk about excessive masturbation. That was the highlight of the meeting. Of course. So there's thousands of case reports that come out every day, and it's hard to sift through which ones are actually meaningful. And you can sort of think about, what about the index case of COVID? People probably didn't realize that that was anything unusual. It's only when it becomes more widespread that you realize, oh, in retrospect, that was a big deal. And so I think part of that was that it's a single case. And part of it is also that in that time, it's harder to disseminate scientific information. So you can imagine anyone who's not at that meeting is not going to hear that. So it's not the same as today where you publish a paper and then with a click of a button, the entire world has access to it. So I think that's another part of it. And part of it also is that he wasn't as far in his career as he eventually would get. So the way that Alzheimer's disease, the way the term eventually gets coined is his mentor actually publishes a revision of a textbook and mentions the case and mentions Alzheimer's disease. And so it basically is a little bit of who you know. So that, I think, those are sort of, I think think some of the main reasons why I didn't really get recognition at the beginning. Let, but none of them are easy to complete without the help of a professional. Don't let a project like that ruin your day or your relationship. Let 3 Day Blinds help. You can call or book an appointment online, and once you have your consultation, you'll receive a free no-obligation quote the very same day. And don't let the name fool you. 3 Day Blinds also carries and installs shutters, shades, drapes, and curtains. And if you choose to work with 3 Day Blinds, they'll design, measure, and install everything Bye. off deal on custom blinds, shades, shutters, and drapery. For a free, no charge, and no obligation consultation, just head to 3dayblinds.com slash this podcast. That's buy one, get one 50% off when you head to 3dayblinds.com slash this podcast. It's such a good deal, I don't want you to miss it. One last time, it's the number three, D-A-Y blinds.com slash this podcast. Facebook Reels. I make it super fun and easy and accessible within a 30 to 60 second video. Reels is the cheat code. Thanks, Chris. See you next time her book, A Molecule Away from Madness. Let's get into some more questions. It's such a fascinating story, and another one that I found so interesting and I had no idea about was Abraham Lincoln and how he maybe was taking this medication that possibly was altering his personality. Can you share a bit about how, first of all, how you came across that story and then what that story is? Yeah. So I was looking sort of at, I wanted to do at least one chapter about, you know, toxins. And people have written books about toxins. So I sort of thought, you know, how do you choose which one to write about? Either it's a really, really unusual toxin or it's a sort of unusually salient case. And I figured, you know, everyone's heard of Abraham Lincoln. It's an interesting case. And also sort of the idea of, you know, how do you speculate on the medical issues of historical figures who have died where you can never really prove it? So it brings up all sorts of questions. And the guy who sort of, a nurse, who sort of created the theory is a fascinating guy. He's an infectious disease doctor who actually essentially pioneered oral rehydration therapy. So he's credited with saving thousands and thousands of people. But he's also a medical historian on the side. And he was reading Gore Vidal's book, Lincoln, and he saw that it mentioned something about Lincoln taking a substance called blue mass. And so he went back to the primary literature and realized there's all these references. Lincoln, there's no quote from Lincoln himself, but there are quotes from his, you know, closest confidants basically saying Lincoln used to take Blue Mass.
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And so he stopped taking it. And it's kind of amazing to think about these incredible political figures having medication side effects and sort of thinking about what if he hadn't realized, you know, what would have happened then? And then sort of the guy who created the theory, Norbert Hirscher, he essentially went back and said, you know, look, there are actually these cases of Lincoln being really sort of actually sort of unhinged and not that, you know, we think of Lincoln as basically his emotions are basically like the statue. He's sort of sitting and thinking. And like we think of it, that's what he was always like. He was calm and measured. And yet there are these cases of him attacking a judge in the middle of a court case. In one of the Lincoln-Douglas debates, he almost strangled a guy on stage. And so the question is, you know, were those medication side effects? And the bottom line is, we'll never be able to prove it. The thought is, if he stopped using blue mass, which contains mercury, I should have said that that was the main toxic component. But if he stopped using, you know, mercury right after he got elected, by the time he was assassinated, there wouldn't be any traces of it in his body. So there's no way to figure it out. On the podcast, we are pretty used to dealing with the gross and the gory and the weird, but even I was taken aback by the filth parties, the quote unquote filth parties held by Joseph Goldberger. So what was the deal with these parties? Yeah, so it was from a time when it was very common to test things on yourself. And that's how scientists did their work. So there was this disease called pellagra, which caused diarrhea. It caused people to have a rash in sun-exposed areas. So your face, your hands, the top of your neck. And it caused a dementia and cognitive symptoms. And for a long time, people thought it just didn't exist in America. And then in the early 1900s, it started cropping up in the Southeast. And it basically became this epidemic. It became enormously common. People became extremely scared of it. It was often deadly. And it was affecting primarily impoverished people. So it was affecting orphans. It was affecting prisoners. It was affecting poor farmers. And so at the beginning, it didn't get that much attention, but then it started spreading. And essentially, you started getting national headlines saying that people are scared of this disease. People are scared of this killer. And so the predominant theory at the time was that either it was caused by a toxin in spoiled corn, or the theory that gained traction was that it was caused by an infection transmitted by flies. And the reason why that gained traction, there was literally zero evidence. So there's zero evidence to show the guy who thought of the theory eventually went on to argue that cancer was caused by cockroaches. So there's zero proof that this is correct, but everyone wants to believe it because then you can basically say, you know, look, the disease is, it's their fault. It's the people who suffer from it. They're not clean and that's why they get this disease. And so we don't have any responsibility. And so even though, so that theory starts, you know, taking hold, but there's no proof and the disease is spreading. So people are scared. And so the surgeon general calls on this guy, Joseph Goldberger. And Goldberger was a public health officer who was no stranger to contracting the disease as he was studying. So he'd gotten typhus, he'd gotten typhoid, and he'd actually exposed himself to scabies to prove about, to try to like track that a, a yeah, epidemic was coming through mattresses. Um, so he like very much of his sort of, uh, roll your hands up and get it, roll your sleeves up and get into it kind of guy. And he very quickly realized like, look, this is not caused by an infection. It's caused by something in the diet. Um, but nobody would believe him because the optics are totally different now. If it's a, it's a, um, and he actually realized it's a dietary deficiency. It's not a toxin in the diet. It's that the diets of these people are missing a nutrient. And that's very problematic because now instead of saying, you know, like these people are dirty and it's their fault, you're actually saying our country is literally starving its own people and now they're dying because of it. So the optics are totally different. And it's also more expensive to fix because now suddenly the solution is now you have to feed people. And so nobody really wants to believe him. And so he basically says, you know, I'm going to prove to you that this is not an infectious disease. And so he starts off with him and a colleague and they take a sample of blood from a patient with pellagra and they inject it into their own shoulders. And he talks about how, you know, like we had some sore shoulders, but other than that, it was okay. And then he has more colleagues who are confident in him. And so they start getting a little bit more gruesome with the experiment. So they scrape the scales off of patients' rashes and they mix it in with their stool and their urine, they actually swallow the pills. And actually even his wife wants to participate. They've had this sort of fraught marriage because he's always running off to these different states and other countries to expose himself to these deadly diseases. And she's sort of like stuck at home managing all the children. But she decides she wants to participate. So she goes down to see him and he doesn't let her eat stool or the urine, but he does the blood one. And he makes sure to take it from a female patient. So unless he should take blood from a male patient and give it to his wife. But so she does participate also where they take an injection from a, they take blood from a woman with pellagra and he injects it into his wife's abdomen. And at the end of it, they wait six months and he writes up this paper that basically says, you know, considering the amount of filth that we took in, it's pretty amazing that none of us got pellagra. And that's sort of the punchline. We tried as hard as we could to get the disease and we still couldn't catch it. And eventually he goes on actually to do this incredible work when he actually gets so close to getting to the answer of what nutrient is missing in pellagra and he figures out it's a B vitamin and then he dies pretty quickly. And he was nominated for a Nobel prize multiple times, but he dies before he ever gets one. And, and then other researchers sort of finish it and end up figuring out that it's a deficiency in niacin, which actually was available on the shelf the whole time in the office of the guy who coined the term vitamin, but he just didn't realize that that was the solution. So it actually was an incredibly cheap disease to treat. They just didn't know. So all these people, thousands and thousands of people died in the meantime. One of the themes that we frequently run into on the podcast is the shift that occurred in the late 1800s when medicine starts to become less personalized, focusing more on the disease, treating the disease rather than treating the patient. And it seems like that was largely due to things like, you know, germ theory being like, well, we can solve it this way, or it's this that's making you sick. The problem is external, not internal, as well as technological advancements in like medical measuring devices where we can translate your disease, your symptoms into numbers, essentially. But it seems like these close personal relationships between August and Alzheimer and Anna and Pick that you talk about in your book kind of escaped that depersonalization. Do you think that they were unique at the time, or did neurology as a field kind of overall escape the depersonalization that was happening so broadly in most of medicine? So I don't think they were that unique at the time. I think, so August Dieter was that sort of the first case of Alzheimer's disease that he witnessed. And then Anna Ziernik was this case that Arnold Pick, who was another researcher at the time and kind of a nemesis of Alzheimer's, but that was a case that he wrote about. And they each wrote really extensively about these single patients. But I think the reason it's like that is just because they were the index patients of these new diseases.
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We don't, you know, include some of the offhand comments that people used years ago. But the index cases, I think, are always, they're always still individual cases. And if anything, you know, as you said, it's a little bit funny now that so many of the biggest papers, it's like written by people who have never met people with the disease that they're studying, and they make these incredible contributions to the field, but there's actually no account of anyone with the disease. It's basically, it starts off saying, this is a meta-analysis of X number of papers and X number of patients, and this disease is characterized by blah, and here's the statistics. And you could get through the entire paper, you could learn groundbreaking material, but literally have no idea what it's like to live with the disease. Yeah, I think that it's an interesting disconnect. And do you feel like that's something that in medical school or medical training today kind of is a field that could be improved upon? Or like, how do you integrate witnessing these firsthand experiences of what the disease is like? Is there a gap there that you think could or should be addressed? So there's a sort of emerging field of narrative medicine that's trying to address basically exactly that. If you look at most papers, it's all passive. It's sort of all passive language. It's essentially like you basically remove yourself from the experience. But the place where it's been sort of preserved or ideally is the first line place to preserve that sort of close, intimate narrative relationship is actually in the patient interaction. Because really what you're doing when you sit down with a patient, what you're doing is actually you're trying to get a sense of their narrative. And when you write your note, what you're trying to do is basically say, look, here's their story. Here's how things evolved over time. Here's how they feel. Here's what it's like to be them. And when you're telling your attending or whoever else about the story, you're trying to lead them to a conclusion. So you actually do need a narrative arc. So it actually is a very useful tool in medicine. And so part of what narrative medicine is trying to do is to say, you know, can we treat these patient interviews as intimate personal experiences where you actually extract not, you know, numbers like lab results, but actually you're extracting an experience. And then you're trying to encapsulate that experience for someone else. You're actually using narrative to formulate, you know, what you've heard and to try to communicate to someone else, what is this patient's life actually like? And that also allows you to create a more holistic plan. So for us, it may be, you know, look, we'd like to start this medication, but also, you know, they're bored during the day and they're not engaged. And how can we find a way for them to be active during the day? So it allows you to think a lot more about a person's quality of life than just about whatever numbers get thrown up on the board. Several of the conditions that you discuss in your book, like Huntington's disease or Alzheimer's disease, for instance, are heritable, at least in part. For the children of those diagnosed with these potentially heritable dementias, I feel like that can be doubly traumatic, right? Where you're watching your parent lose themselves or your grandparent lose themselves and knowing that this likely awaits you. Can you talk about this experience and the complex ways that you've seen people deal with it? Yeah, so this is a big part of what we do, partly because we see a lot of these atypical cases. So the woman who essentially pioneered the research that led to finding the gene that causes Huntington's disease, she was a woman who was highly educated. She'd done a Fulbright scholarship. And then her dad called her home and said, your mom has Huntington's disease and you have a 50% chance of getting the disease. And she basically overhauls her career and focusing. She had taken, I think, either zero or one biology classes in her entire life. And she basically starts focusing on trying to find a cure. And in order to find a cure, you have to find the cause. And so eventually she actually pioneers this work that leads to our current ability to test people for the gene that causes Huntington's disease. So you can now tell people who are totally asymptomatic that, look, you have this gene or abnormality that will likely cause Huntington's disease if you live long enough. And even though they have no symptoms, she actually never took the test. She basically said, you know, look, I have a lot more to lose by taking the test than I have to gain. She never took the test. She eventually developed symptoms of the disease and now has sort of come out in public saying that she's developed the disease and her sister didn't. And it's sort of this fascinating story. And so much of what I deal with at work actually is diseases where you find out there's actually a single gene mutation or a single gene change that's causing the disease. And you sort of think it's a little bit strange. You know, you've had this DNA your whole life and why is it suddenly causing you a problem in your 60s, even your 70s? And some of these diseases, you know, you can have the same gene change in one person and multiple family members, and sometimes they all get the disease at the same time. And sometimes they get it at vastly different ages, or it doesn't even always cause the disease. And so the issues that arise are incredibly emotionally complex. So the biggest thing that people think of is, you know, do you want to know? You know, do you want to know if you have a mutation that causes a neurodegenerative, a deadly progressive disease that we have no cure for? And we couldn't tell you exactly when you'll get it. We can tell you the chances of getting it, but we can't tell you exactly when or that you'll definitely get it. And do you want to know? And there's a few things to think about. So one is, you know, maybe you want to know because you want to enroll in a research study. And maybe they'll be, you know, you'll get a treatment. You'll never develop the disease. One of the big things is, you know, do you want to know so you can plan? You know, so if you knew that you were going to get a neurodegenerative disease and someone said, you know, look, it's probably going to, it often starts in your 50s or 60s. Would you change your career? Would you change your, you know, decisions about having kids? Would you change how much you travel? Would you change how much you spend? The other really sort of most, you know, the thing that I find most interesting is you also can have kids that don't have the mutation. So if you carry a mutation and you, you know you want to have biological children that don't have it, you can do IVF. So essentially they take egg and sperm, they mix it together in a lab, and then they take the cells sort of grow and divide and grow and divide. And after a certain amount of time, they take away one cell, or I think it's more like four or five cells. So they take away a few cells and they look at the gene in those cells and they can say, okay, this is a normal version or not a normal version. And then they basically only use the embryos that have normal versions. They put it back in the uterus, you grow a kid and the kid does not have the disease. So it's actually, we have the technology to literally root out the mutations from family lineages, but only if you know to look. So it's really such a complex issue. And ultimately, there are normal people who decide to find out, and there are normal people who decide not to find out. And even within families, there'll be some siblings who do testing and some who don't. And it's one of the most fascinating issues that we deal with. The other big issue that comes up is basically if a grandparent had the disease, a parent decides not to find out, but their child decides to get tested. If the child has the mutation, then the parent now knows. So it actually, your people's decisions affect other people in the family. So it's just this, it's sort of scientifically fascinating and emotionally so fraught, but also actionable. Like with so much else in the history of medicine, broad categories of diseases end up being broken down into smaller clinical units as we grow to understand more and more about their pathologies. You know, like fever became many different things.
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And dementia in some ways was split similarly. In what ways do you think that the diseases that you talk about in your book or that you encounter in your work are still undergoing this type of revision? So the diseases, I mean, one of the big diseases that I see is frontotemporal dementia. And even the name for that is like, you're a little over 20 years old. So it's very much still an active field. And that area in particular, so that's the disease where it's a few different variants. It's been in the press a lot because Bruce Willis has now come out saying that he has, or his family's come out saying that he has frontotemporal dementia. So it's had a lot of coverage lately. And essentially some of it, sometimes it can cause people to have these sort of really sort of antisocial behaviors, going up to strangers, saying inappropriate things, hypersexuality, eating non-food things. Sometimes it can cause people to have language problems where they lose the connection between words and objects. So, you know, you were taught when you were a kid that an apple is, you know, a green or red thing that's crunchy in the middle, but there's nothing inherent about an apple that sounds like apple. It's just that sound was attached to the word, and you lose that connection. Or some people start having trouble with the motor programming of speech. So when you want to say a word, your mouth and your tongue has to move in a certain way to say it. And that's a message that goes from your brain to the muscles in your mouth. And that connection gets lost. So in that disease, it essentially had like 10 different names, each of which had like the names themselves were like six different words put together. And people thought it was like multiple diseases. And then they finally figured out actually it's the same disease. And it's sort of this aha moment. And then actually they go on and they realize when you look at people's brains under a microscope, it's actually not the same disease. So it sort of had this full evolution of like, is this one disease? Is it multiple diseases? And ultimately we're not very good at, for Alzheimer's disease, we actually have tests that we can do in living people. And we can say, you know, look, we're essentially almost sure that that's what it is. With frontotemporal dementia, you know, you can have two people who have exactly the same symptoms, their imaging looks similar. And yet under a microscope, their brains look completely different. It's caused by a totally different protein in one person compared to another. And so a lot of these fields are still very much evolving. And part of the issue is that difficulty in making the link between symptoms and imaging and testing and what's going on under a microscope because you can't access the brain. It's not like the lungs where you can take a piece out and look at the molecules. The brain, it's like we're using all these proxies. And that's the big barrier. Speaking of frontotemporal dementia, in your chapter where you focus on that particular condition, you talk about the stigma. And you mentioned some of these symptoms that are commonly seen with frontotemporal dementia and how they're maybe not what we typically think of when we think of dementia. And maybe that's because that's the way that dementia is portrayed in popular media. So there can be more of like a stigma maybe with these, you know, atypical symptoms or symptoms that we perceive to be atypical, even though they're not. So can you talk a little bit about this, this problem between the disconnect and how dementia is portrayed versus the actual like wide variety of ways that it can actually look in reality? Yeah. So I actually, this was probably maybe two years ago, I actually gave a class about dementia in the media and there's some fascinating stuff out there. And it's also really a big topic of debate because one question is, you know, should you basically, if you were writing a movie about someone with dementia, should your goal be to write about the typical cases so that people could learn about the disease and see what it usually looks like? Or is your goal to write about whatever case is most interesting, whether it's rare or not? So if you think about the example of Still Alice, and she has, it's a young, it's a woman with Alzheimer's disease. So it's a very common disease, but it's young onset. And I think it turns out to be a genetic cause. So it's really atypical. Those are like less than, you know, 1% of cases. And so one question is, is that a really useful movie? Because, you know, it was a big movie, it got lots of attention. So it got a lot of sort of light onto Alzheimer's disease. Is that really helpful? Or is it actually like you're making people think that it's all caused by a single gene when actually that was a really unusual case? Or if you're portraying, you know, people with dementia getting diagnoses, should you portray a compassionate doctor? Or should you portray what often gets portrayed, which is neurologists as being sort of aloof and sort of not emotionally engaged? And, you know, how do you portray that interaction? And I think the bottom line is that it's complex. And the most important thing from my perspective is really just portraying the humanity of the people with the diseases. The key is not talking about them when they're in the room. So portray them as, you know, real people. And then you can drop clues in of like, you know, this, you know, this is unusual. So, you know, this is an atypical case or something like that. So you can get around that stuff. But the key really is to try to portray some sort of semblance of real life experience with these diseases. I want to take that class. That sounds really interesting. In your book, you also tell the story of a young woman who was diagnosed with NMDA receptor encephalitis. And I love how her mom was so integral in like pushing for, no, I think it's this. And, you know, just advocating, advocating, advocating and how frustrating, but also inspiring that part was. But one of the things that you point out is how different this person's experience might have been if she had gotten sick just a couple of decades ago when the disease was largely unknown or completely unknown. And I know there's been some speculation of like historical cases, might the people accused of witchcraft actually had NMDA receptor encephalitis. So do you feel like there might be other fields in medicine or other conditions in medicine that might undergo a similar revolution in the future? NMDA receptor encephalitis is a wild disease that essentially works like PCP and now has been getting increasing attention, but it's still rare. And so the hope is that, you know, can we get there with the more common things like Alzheimer's disease? And so that's the goal. And then the other question, which is, to be honest, beyond my field of expertise is, you know, all these psychiatric diseases that we think of, you know, there's this schism in the late 1800s and, you know, psychiatry and neurology suddenly split. And dementia is kind of at the seams because it's, you know, there may be a molecular cause, but a lot of the symptoms are sort of psychiatric in nature. And it's sort of gone along, it's gone along at the seams of psychiatry and neurology. And one question is, you know, are we going to move that over more to psychiatry? So things like schizophrenia and other conditions that we think of as being really purely psychiatric, are those also going to end up having molecular causes over time. But I don't know. Even though dementia has been now sort of broken down into many different types where you can specify this versus that, and maybe the medications might be different, but is non-pharmaceutical therapy or just care, are there similarities in the way that all of these different types of dementias are treated? Yeah, so there's a lot of similarities and that sort of becomes of importance because in some cases we say, you know, look, I could put you through this invasive test to try to figure out what's actually going on in your, you know, in a molecular level in your brain, but it's not worth it because we're going to treat it the same. So that really comes to, it's actually a clinically relevant question. And the bottom line is there's a few rules of thumb that really are very helpful. Things like, you know, people come in all the time and say, you know, when someone makes a mistake, should I correct them or should I not correct them?
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And that, you know, having dementia, oftentimes people are not aware of it, or if they're aware of it, it's painful for them to, to, to think about. And so the general approach really is if it's not unsafe, you know, if they want to, you know, if they think that their dead father is coming for dinner, then by all means, let them set the table. That's okay. And it's not going to hurt if they are wearing their clothes inside out, who cares? And, and in the same way, you know, in public, one thing that we sort of talked to caregivers about is, you know, if you're worried about them doing something socially inappropriate, you know, carry on business cards that just say, you know, look, my loved one has this condition. Thanks for your understanding. And you just pass it to someone after it happens. And that way you're not having to like yell at your loved one in public. You're not having to explain it to someone else. And it actually spreads awareness and people realize that, you know, there's more than what meets the eye. Um, so there's all sorts of things like that and things like, um, we talk a lot about sort of empathic lying, um, and basically, you know, not, um, if you need something to get done, um, trying to frame it in a way that has nothing to do with the person's cognitive status. Um, so. So, you know, if you need someone to move to a facility, how do you figure out some explanation for that that doesn't completely involve their cognitive status? Because if you can imagine, oftentimes the example we give is like, you know, tell the normal, cognitively normal care partner, like if I was going to try to convince you to move to a nursing home, what would I have to say? And it's tough to think about because with all these conditions, you're dealing with people who live in a different world in some ways. And so the tools, regardless of the type of dementia, a lot of the tools are the same from that perspective. Has the process of writing this book changed the way you practice medicine or the way that you interact with your patients? It has. I didn't expect it to. I think I thought of it initially as like two separate things. But now when I get, I mean, a lot of what I do is give diagnoses of untreatable neurodegenerative progressive diseases. And I talk now a lot in the diagnoses, I talk a lot about the history of the diseases because it made me realize like we all carry around these diagnoses and we have no clue where they came from. It's sort of as if like they were always around, but none of these diseases were known from the beginning of time. And talking to people about how these diseases were discovered actually, first of all, allows you to go back to the basics. So it allows you to communicate at a level that's actually more scientifically clear. And also it gives people a sense of, you know, look, this is an evolving field and our hope is to find cures for these things. And not that this is a static, you know, it's not that Alzheimer's disease has always been around and we've never made any progress. It was discovered at a certain time and we've actually made a lot of progress. And there is a lot of hope hope, even though it's true we haven't found a cure. And so I try to couch the diagnoses and the history of the diseases now. And I haven't gotten any negative feedback, so hopefully it works okay. No, I love that. You cover so many different diseases in your book, and they range from ones that are fairly well-known, like Alzheimer's, to those that may not be on most people's radar, like an MDA receptor encephalitis, even though it has gotten more press recently. Do you find yourself more intrigued by one than the other, or do you find them all equally interesting, or are there aspects of these conditions that you find the most compelling? I think the cases that move me most are the ones where people have these atypical symptoms and they're walking around thinking that they're crazy. So people who have, you know, speech problems, they say, you know, look, for the past two years, I feel like people think I'm drunk every time I open my mouth because my words don't come out clearly. And it's very emotionally fulfilling to be able to say, you know, look, actually, there's a name for this disease and you're not crazy. And this is what's going on. And, you know, if I had to put money down, this is the molecule that I think is going, you know, haywire in your brain. And this is where we are in terms of trying to find treatments and here are research opportunities. That's sort of the most fulfilling is these atypical cases where they've gone years without a diagnosis and you can say, you know, look, this is what's going on. I mean, the typical ones are also interesting because, you know, even typical cases bring up interesting family dynamics. But for me, it's sort of the, I think it's one of the atypical ones that are the most fulfilling in clinic. What is something you wish you had known before starting on your career journey? I guess this is part of what I learned in the book, I guess. I think the biggest thing was that I wish I knew more about communicating with patients. There's so much of medical school is like trying to cram an enormous amount of information in your brain, much of which, if you become a specialist or a subspecialist, you're literally never going to use. And so much of it is just this academic exercise. And there's not as much emphasis on like, how do you explain a disease to a patient who has no medical background and variable health literacy? And that's, I think, in writing a book for the lay public, I was in a writing group with lots of people, none of whom had any sort of medical background. And they were all very educated. And I was shocked. There were words that I would use, and they would say, that doesn't make sense to me. I don't understand that explanation. And I realized it was not them. It was my failing. And I think I wish I was emphasized in medical school more. I mean, there's so much to learn and there's like, you know, there's more to learn every day. So you only have four years and how are you going to learn all this material? So I know that it's sort of tight to fit in new stuff. But it's really something that's not covered much in medicine. What a fascinating conversation. I had such a great time chatting with you, Dr. Peskin. Thanks so much for taking the time and for writing such a wonderful book. If you all enjoyed this as much as I did and want to learn more, check out our website, thispodcastwillkillyou.com, where I'll post a link to where you can find A Molecule Away From Madness, as well as a link to Dr. Peskin's website. And don't forget, you can check out our website for all sorts of other cool things, including, but not limited to transcripts, quarantini and placebo reader recipes, show notes and references for all of our episodes, links to merch, our bookshop.org affiliate account, our Goodreads list, a firsthand account form, and music by Bloodmobile. Speaking of which, thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Liana Squalacci and Tom Breyfogle for our audio mixing. And thanks to you listeners for listening. I hope you liked this bonus episode and are loving being part of the TPWKY Book Club. And a special thank you, as always, to our fantastic, generous patrons. We appreciate your support so very much. Well, until next time, keep washing those hands. you
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Hello and welcome to the March 5th, 2019 Annals of Internal Medicine podcast. I'm Dr. Christine Lane, Annals Editor-in-Chief, and I'm here to let you know about recently published material in Annals. Let's start with articles published online first on February 25th. The first article found that fecal immunochemical tests, or FIT tests, are effective for screening for colorectal cancer in average-risk adults when used annually. Because these at-home tests are easy to use, non-invasive, and inexpensive, adopting their use could improve lagging colorectal cancer screening rates, especially among vulnerable populations. The U.S. Preventive Services Task Force currently recommends colorectal cancer screening for adults aged 50 to 75 years without preferentially recommending one specific screening test over another. Colonoscopy is considered to be the gold standard in the U.S., but several other countries use annual or biennial stool tests. Despite colonoscopy's effectiveness and cost effectiveness, only about 65% of eligible U.S. adults get tested. Adopting a screening strategy based on FIT could increase screening rates, but more information is needed about FIT performance. Researchers from the Regan-Street Institute and Indiana University School of Medicine reviewed 31 studies involving 120,255 patients to summarize FIT performance for colorectal cancer, quantify FIT performance characteristics for polyps, and to identify factors affecting those characteristics. They found that single application FITs have moderate to high sensitivity and specificity for colorectal cancer, depending on the threshold used to define a positive result. At a high specificity, FIT tests are moderately sensitive for colorectal cancer, but much less sensitive for advanced adenomas. But these lesions rarely transition to cancer, suggesting an opportunity to detect this lesion with programmatic screening before they become cancer. James Allison from the University of California, San Francisco in Kaiser Permanente, Northern California laments the designation of colonoscopy as the best gold standard screening test in the U.S. when there exists a paucity of research supporting that assertion or comparing colonoscopy to less invasive, cheaper tests. He notes that some U.S. primary care physicians and many of their patients may be unaware that FIT tests are non-invasive, easy to prepare, and inexpensive, and have effectiveness similar to that of colonoscopy when used in a consistent, programmatic fashion to screen for colorectal cancer. This is because the media and health systems continue to promote colonoscopy as the best test for colorectal cancer screening, according to Dr. Allison, even though U.S. colorectal cancer screening guidelines no longer promote colonoscopy as the single best screening strategy. Dr. Allison suggests that physicians in the U.S. be educated about the advantages of fecal immunochemical tests, a screening test for colorectal cancer, and educate and advocate to increase screening rates. The next article reports a study that found that cognitive behavioral therapy and drug treatment with sertraline were both found to be effective for treating depression in patients undergoing dialysis for end-stage renal disease. At 12 weeks, depression scores were slightly better with sertraline, but patients also experienced more side effects. Thank you. depression have difficulty adhering to diet, medications, and treatment schedules, and in navigating care transitions, and they have greater healthcare use and mortality rates. Both cognitive behavioral therapy and medications are proven effective for treating depression, but data on patients' acceptance of treatment and on the comparative efficacy of various therapies for this population are limited. Researchers from University of Washington, University of New Mexico, and University of Texas Southwestern tested two hypotheses among patients receiving maintenance dialysis who had major depressive disorder or dyspnea. In phase one of the study, the investigators sought to determine if an engagement interview with a therapist would increase the frequency of depression treatment. In phase two, the researchers compared the efficacy of cognitive behavioral therapy with that of Sertraline over 12 weeks among 184 kidney failure patients at 41 dialysis facilities in three U.S. metropolitan areas. First, they found that an engagement interview did not increase willingness to undergo therapy. Second, the researchers found that sertraline was slightly more effective than cognitive behavioral therapy, but both treatments seemed to benefit patients. The researchers suggest that physicians should select the treatment that is available and acceptable to the patient, recognizing that each comes with its own burdens. Many prognostic models for cardiovascular risk can be used to estimate aspirin's absolute benefits, but few bleeding risk models are available to estimate its likely harms. An accurate risk prediction tool is needed. In the next article, researchers from the University of Auckland, New Zealand sought to develop a prognostic bleeding risk model for persons in whom aspirin might be considered for the primary prevention of cardiovascular disease. The 385,191 participants were automatically recruited into the cohort after their first cardiovascular disease risk assessment and their data was entered into PREDICT, a web-based decision support program integrated with New Zealand's electronic health records. The sex-specific model showed that established risk factors for bleeding were associated with an increased risk for bleeding in men and women. Although older age, smoking, and diabetes were associated with an increased bleeding risk in both sexes, no association was observed between bleeding risk and other established cardiovascular risk factors. According to the researchers, these models could help identify people for whom the benefits of aspirin are likely to outweigh its harms in primary prevention. A tool using the prognostic bleeding risk models described by the authors will identify such people and is currently under development. The next article reports an interesting case of severe hypertriglyceridemia. Clinicians from University Hospital of Cologne saw a 39-year-old man with nausea, vomiting, malaise, headache, and slowly deteriorating alertness. He had very high levels of triglycerides and cholesterol, as well as an elevated hemoglobin A1c. The researchers hypothesized that the patient's extreme hypertriglyceridemia with hyperviscosity syndrome was caused by a combination of insulin resistance, obesity, inappropriate diet, and insufficiently treated diabetes. They gave the patient intravenous fluids and vasopressors for hypovolemic shock. The patient was then admitted to the intensive care unit with severe ketoacidosis and treated with insulin therapy combined with fibrate and omega-3 fatty acids. Because the hypertriglyceridemia was still present and severe, the clinicians employed bloodletting to prevent pancreatitis. The patient's serum levels of triglycerides and neurological function improved. According to the authors, theirs is the first report to describe using bloodletting to treat severe hypertriglyceridemia. Also published online first on February 25th is a commentary by Dr. Nariv Shah of Stanford University. Shah poses the question, will Google algorithms and other forms of artificial intelligence replace doctors? Go to the article on annals.org for the answer. Now let's move to articles published online first on March 5th. A nationwide cohort study of all children born in Denmark to Danish-born mothers between 1999 through 2010 concluded that mumps, measles, and rubella vaccine, MMR vaccine, does not increase the risk of autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases following vaccination. You're probably saying, didn't we already know this? The evidence is there, but unfortunately, many refuse to believe it. The hypothesized link between MMR vaccine and autism raised by a 1998 study published in The Lancet that was later found to be fraudulent and retracted, continues to cause concern and challenge vaccine uptake. Currently, there is a concerning increase in measles cases in Europe and in the U.S., and the World Health Organization has declared vaccine hesitancy as one of the top 10 threats to global health. Researchers from Copenhagen, Denmark used a Danish population registry to evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, or time periods after vaccination. Of the 657,461 children included in the analysis over a decade of follow-up, 6,517 were diagnosed with autism. Comparing MMR vaccinated with MMR unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93. Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors, or other childhood vaccinations, or during specified time periods following vaccination. According to the researchers, this study adds to previous studies through significant additional statistical power and addresses questions about susceptible subgroups and autism clustering. In an accompanying editorial, Drs. Omer and Yildirim from Emory University write, quote, generating evidence on MMR vaccine safety may be useful, but is certainly not sufficient. It has been said that we now live in a fact-resistant world where data have limited value, end quote. They offer strategies for how to talk to people who are skeptical about vaccine safety. Recent studies suggest that aspirin use might improve survival in patients with prostate cancer, but studies have been inconsistent. The next article addresses this uncertainty.
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Their analysis did not find convincing evidence of an overall protective effect of low-dose aspirin for men with prostate cancer. However, they did find a reduced risk for prostate cancer mortality with low-dose aspirin use among patients with low Gleason scores, meaning that their prostate cancer was unlikely to progress, and among those who took low-dose aspirin for an extended period of time. The authors of an accompanying editorial from Tampere University in Finland speculate that improved prostate cancer-specific survival among aspirin users with low Gleason scores might be explained by inaccurate tumor grading occurring less frequently in aspirin users than non-users. Aspirin is an anti-inflammatory drug that lowers serum prostate-specific antigen levels. However, whether that leads to accurate determination of tumor aggressiveness in aspirin users remains to be determined in further studies. The editorial suggests that future research evaluate aspirin exposures longer than those studied to date and investigate the effects of aspirin exposure on disease classification. Next is a fascinating case report that alerts clinicians to be aware that methanol toxicity can be a rare consequence of occupational exposure. of household products such as solvents, antifreeze, or fuel. It may cause mild symptoms such as drowsiness and headaches, but could develop into significant illness that includes vision changes, blindness, coma, convulsions, and respiratory arrest. Researchers from Genesis Regional Medical Center in Grand Blanc, Michigan, report the case of a 42-year-old man who came to the emergency department complaining of flank pain and headache. He described one day of nausea, multiple episodes of emesis, and blurred vision, leading to bilateral vision loss. While taking a detailed history, the clinicians learned that the patient had taken a new job as a materials handler at a propane company six weeks earlier, where his job was to inspect, fill, and load propane cylinders. Two weeks after starting the new job, he had begun having lapses in memory and atypical behaviors, such as leaving his car running or the lawn sprinklers on overnight. Since methanol is routinely added to propane to prevent valve freezing, the clinicians deduced that the patient had occupational exposure to a mixture of salt intake in cardiovascular disease in a population of prisoners. Most of the articles in the March 5th print issue were initially published online first and covered in prior podcasts. New material with the issue includes a very practical in-the-clinic review on obesity, several poems, two on being a doctor essays, and the latest installment of our Annals graphic medicine feature, Dr. Mom. Finally, a new episode of the Annals on Call podcast discusses non-alcoholic fatty liver disease. Thank you. org and click on the CME MOC link at the top of the homepage to learn more. Thanks for listening and I hope you'll return in two weeks for the next Annals Highlights podcast. Thanks to Beth Jenkinson and Andrew Langman for their technical support.
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From the JAMA Network, this is the JAMA Network Open Editor Summary, a discussion of the most important articles published in the latest issue of JAMA Network Open. Here are your hosts, Fred Rivara and Steve Finn. Hello, thanks for listening to our podcast here today from JAMA Network Open. This is Fred Rivara, Editor-in-Chief of JAMA Network Open, and I have with me my friend and colleague and Deputy Editor, Steve Finn. We are doing this in the midst of the pandemic from our homes and hope that you are all well and safe. We have two, I think, pretty interesting papers today, quite different, but I think that have a lot of practical significance. Steve, do you want to go first? Yeah, sure, Fred. Hello to everyone. I hope everyone is remaining safe and healthy. So I just, before, this is a paper that comes out of a prominent Eastern medical school from a nephrologist. It's looking at a very common procedure that is the examination of urine by nephrologists and something we take for granted. And I think by way of history, it would be just fun to sort of review that it was almost 1969, so 50 years ago, that radiologists who were examining screening chest x-rays in the days when tuberculosis was still prevalent in the United States. And the radiologists got these small little x-rays and they'd look at hundreds of them. And the question was, how accurate were the radiologists? And one way they tried to discern that was to see when radiologists agreed. And so they looked at, you know, the overall percent of times that the radiologists agreed on the x-rays. And it was actually over 99 percent. And everyone thought this is, you know, a great system. But it turned out when they looked at that 1% of x-rays that the radiologists disagreed with, they were actually the different ones. And when they looked at the abnormal films, the radiologists rarely agreed on which films were abnormal. And so it was almost as if there was some, a great deal, it was as if there was a great deal of randomness in which x-rays, which radiologists were calling positive. A little discouraging. Very discouraging. And a very thoughtful radiologist named Yerol Shomit described that 50 years ago. And every time in almost every setting in medicine since then, when it's been examined, what is the reliability of, you know, two, three, four physicians in reading a certain test or performing a certain procedure, whether there's a high degree of reliability. And remarkably and consistently, reliability is rarely better than 70 or 80%. And that's reading a stress echocardiogram, it's reading a cardiac cath, it's CT scans. And I think the importance here is that whenever we get a diagnostic test back, we never ask the question, is it right? Is it wrong? Is it reliable? You know, we take the result as what the test result says it is. And surprisingly, there's still not very much research on looking at the reliability. And that means, you know, how often is somebody reading something? Will that get read by another person the same way? We call that inter-observer reliability. And in this study, the nephrologists actually made images of a variety of urine specimens and sent them out to 21 nephrologists around the country, most of whom said they regularly looked at urine and they felt very confident and asked them specifically, they even put arrows on certain parts of the urinalysis and asked them, you know, what's this? And they asked them what the diagnosis of the urinalysis was. And it turns out that there was a great deal of variation in how much they agreed. So on some simple things like whether there were epithelial cells in the urine, there was a really high degree of agreement. And they used a statistic called kappa, lysis kappa, which goes from zero, which means there's zero agreement. Really, that's 100% disagreement. They disagree every percent of the time to one, which is perfect agreement, absolutely perfect. A hundred percent of the time they agree. It's said that, you know, 60 to 80 percent is pretty good agreement, you know, over, you know, that's thought around 50 percent is moderate. But I've always thought that's kind of like flipping a coin that, you know, about half the time they're going to agree. So they looked at it and on some of the findings in the urine, and particularly important ones like cellular casts that you would use to diagnose glomerulonephritis, the kappa statistic was 0.2. They didn't agree really at all. Now, most of the time they did agree with what the biopsies ultimately showed, but it just was another example of a test we take for granted. And I know for those of us who work in the hospital, nephrologists come by, they get the early morning urine, they march down to the lab, they look under the microscope and come back and pronounce what's wrong. It just should give us all a little pause, not only about the nephrologist, but about each one of us, about how reliable we are in interpreting things we do every day, including physical exams and diagnosis, et cetera. This is interesting. And I guess I have a couple of questions. One thing that would have been nice is having to test the lab techs who do this more than the urologist. I mean, urologists probably look at urine some, but not really that much, I suspect, anymore. But lab techs do it all day long. And I wonder how much better the lab techs are. I mean, probably they're the gold standard, I would imagine. Yeah, they didn't test it. They do use these too. You know, a lot of this is automated these days. And the machines are wrong a lot of the time too, particularly in the identification of these different types of cellular casts and renal tubular epithelial cells. And so I think you're right. You know, who are the experts here? Right. So you think we should stop berating the interns and medical students on rounds because they haven't gone and looked at the urine themselves? I think it's good for them to go look at it and understand. So when it comes back from the lab, they should understand what it is they're hearing about. It's like looking at a chest x-ray. But for heaven's sakes, let's not trust them to make any life and death decisions based upon those findings. I suspect that many don't do that anymore. They took the microscopes off the wards for just that reason. That's right. Because they were unreliable. Yeah. I suspect that there's not a whole lot of people that do that anymore. Well, that was a good paper. You should run this study by your son, who for the audience, Fred's son is a nephrologist. At our hospital. Well, this other one, I think, has a lot of implications for what's going on right now in the world, particularly the United States. And this is a study from Denmark titled Association of Neighborhood Deprivation with Cardiovascular Risk Factors and Events Among Refugees to Denmark. So, you know, obviously, the whole issue of refugees is, unfortunately, a very political topic here in the United States, and it is to some degree across the world. And in the introduction to this paper, the authors point out that there were something like 20 million refugees in 2019. And refugees are people seeking political asylum. What happened in Denmark was that there was kind of a natural experiment. In Denmark, between 1986 and 1998, what the Danish government did with the incoming refugees was that they actually semi-randomly dispersed these refugees across the country. So they didn't have them all live in one particular locale. They scattered them all around the country. And in these different neighborhoods that the refugees were assigned to, there were obviously different levels of socioeconomic deprivation, socioeconomic resources there. So these researchers had the brilliant idea of taking advantage of that natural experiment to see how this affected cardiovascular disease risk factors, myocardial infarction, and stroke among these resettled refugees. And they followed up these individuals on the order of about 10 years or so. And they looked at the socioeconomic deprivation of the neighborhoods in which these refugees were assigned, which was based upon median income, family poverty level, amount of income inequality, unemployment rate, crime rate, welfare participation, and education. And the outcomes that they examined were hypertension, hyperlipidemia, type 2 diabetes, myocardial infarction, and stroke using their wonderful medical record systems that they have there nationwide in Denmark.
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And in the paper, they divided these up into sort of low deprivation areas and high socioeconomic deprivation areas. And what they found in the paper is kind of what you would expect to see in the United States, but maybe a little surprising to see this in a place like Denmark, in that the refugees assigned to more deprived neighborhoods had a somewhat increased risk of hypertension, increased risk of hyperlipidemia, of diabetes and myocardial infarction, although there was no increased risk of stroke. And the amount of risk was really pretty small, on the order of a half to one percentage point more risk. But nevertheless, it was there. And it, in fact, was even greater in refugees who arrived in Denmark before the age of 35. So I think it's really an experiment to show that even in a place like Denmark, where there's free healthcare, where there is a high level of social support resources of a fairly hefty safety network there, safety net, that even in those situations, the kind of neighborhood you live in makes a big difference. And so I think that this really, you know, we're talking a lot now about systemic racism in the United States, and part of systemic racism is the kind of neighborhoods that Blacks, Hispanics, people of color live in. And it clearly has an effect both in the United States, but also in places like Denmark. Steve, what do you think? Well, you know, the methods were complicated and there are a lot of assumptions. Obviously, this is very complex research to do, but, you know, I was impressed. And although you make the point that it was just sort of a small number, you know, per this deprivation index that they developed, you know. The actual prevalence of diabetes, for example, in the native-born Danes was 7% versus 16% in the refugees. So it was more than twice as high. I mean, that's a stunningly large effect. And so I think it just, again, is a very sort of, I don't know that we can call it elegant because it is so complicated, but it's another sort of brick in the structure that shows us again how important neighborhood is. Right. And I think when we're really struggling to understand the effects of systemic racism and then secondarily trying to figure out how to change both systemic racism as well as to ameliorate the effects of it, this kind of a study is clearly very important. We're seeing it certainly now with COVID and the increased risk of immigrant and refugee families, people living in poor neighborhoods, people of color, and people with comorbidities. And so, you know, given these people have increased risk of diabetes and heart disease, they're also going to be at increased risk of COVID as well. So I listen to these and other podcasts put on by the Gemma Network. And remember that since Gemma Network Open is an open access journal, you have full access to all the content. It's free to everyone in the world. Thanks for listening and please keep safe.
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Welcome back to the Curbsiders. This, of course, is an episode where we're going to quickly recap lots of things, Paul. We're going to talk about hand pain, wrist pain, foot and ankle pain, and of course, myopathy and myositis. How are those things related? Well, it should be self-explanatory. I'm Dr. Matthew Otto here with my great friend, Dr. Paul Nelson-Williams. Paul, how are you doing tonight? Matt, I am as good as can be expected. Thank you for asking. How are you doing? I'm doing well. You were just telling me how you are falling apart. And so on air, we'll say we're both doing great. No, I mean, it's that the Rona finally caught up with me. It was a good three-year run, but now I'm recovering nicely, but not fully recovered. So if I don't sound like my usual bright-eyed, bushy-tailed self, we can blame that. Well, Paul, remind people, what is it that we do on this podcast? Happy to. Usually we are the, well, we're always the internal medicine podcast, Matt, but typically we use expert interviews to give you clinical pearls and practice changing knowledge. This time around, we're going to recap episodes, as you alluded to earlier, and talk about ourselves talking about episodes or something like that. So we'll recap some of our favorite pearls from a couple of episodes and condense down into a high-yield format that you can take away and be better people from. Well, first up, number 339, hand and wrist pain with our favorite orthopedic surgeon, Dr. Ted Parks, with production and graphics by the great Dr. Paul Nelson-Williams. And Paul, the first question I had for you is, how can I differentiate between de Quervain's tenosynovitis and CMC joint arthritis of that first CMC joint? You know, the patient vaguely just presents and says, it hurts here on my thumb, my wrist area. But that, I mean, that's not vague at all. I mean, I feel like you're halfway there if that's what they're telling you. So I think, as you mentioned, sort of very common. I think we all see wrist pain in the office a lot. And the big two diagnoses for pain, especially at the base of the thumb when we're talking about wrist pain here, so we can actually see it on camera, is, as you mentioned, decorvainous tenosynovitis versus CMC arthritis. And so a lot of the times for musculoskeletal stuff, I feel like physical examination is kind of helpful, but not super helpful. This is one where the physical exam is actually really, really helpful. So Dr. Parks talked us through the Finkelstein maneuver, and there are other epitomes that go along with this, but basically the long and the short of it is you have the patient take, sorry, this is right in your face, folks, take your thumb, wrap your fingers around it, and then the examiner will then just sort of point down almost like the patient's sort of trying to stab you with a knife. And if you reproduce pain that way, that is a positive Finkelstein test. And that is, um, they will tell you the patient probably has a flexor tendis and a vitis. The other test, if you're looking for CMC arthritis, uh, is the CMC compression test where basically avoiding the microphone he talks about taking the thumb like a joystick pushing down and just kind of moving it around like a mortar and pestle and seeing if it reduced the pain that way and if you do congratulations you've um you've diagnosed them with cmc arthritis which is one of the more common spots of arthritis because the way the hand is constructed most most the movement is fairly linear flexion extension the lot of range of motion. So unfortunately, because of that, that's the cost of probably an increased risk for arthritis and other joint dysfunction. Yeah, I find people either complain that like all their fingers hurt, you know, the typical like osteoarthritis, or they just complain of just like one thumb, whatever their dominant hand is, is a common complaint. Treatment for this, Paul, everyone's favorite, the thumb spica splint, Paul. And Paul, I should just keep people in that forever, no? Apparently not in perpetuity. There's a lot of me self-disclosing the episode that I don't do a good job of counseling around bracing and splinting and that kind of stuff. But a couple of weeks to allow time for the inflammation to kind of calm down is probably a good place to start. You don't want to do it forever because you can lose mobility if you keep something immobile for a long period of time. So the point being is you don't say, see you in three months and forget to tell them to take the splint off. That's bad form. And like most of the stuff we'll talk about on this episode, steroid injection can help here. You can, of course, try either topical or oral NSAIDs. As we mentioned on some recent shows, Paul, I wish I had better luck with the topical NSAIDs. I know they're kind of upfront in the guidelines now. Maybe it's the patients aren't using them often enough, or maybe it's they just don't work. I don't know, Paul, but I haven't had a ton of luck. But I do try to get them covered by insurance, at least with the plans that I'm used to dealing with. And then they are not inexpensive for patients. So it's a hard sell if they're not going to give you substantial relief and you're paying out of pocket for them. So it can be tough sometimes. All right. Next up, Paul, the trigger finger. And Paul, this is a whole hand cast is how you treat this one? The arm, yeah, from the shoulder down, just immobilize the entire thing. No, it's the pathology of this is super neat. Like he talks sort of about these pulleys, which are not really pulleys, but sort of these rings that the thick and tending can can kind of get stuck on so this idea of triggering is that the finger comes down and then you actually have to kind of physically unstick your finger if you can sometimes even feel this palpable clunk and that's triggering it's very satisfying diagnosis to make in the office um but you you don't have to brace the everything you can actually you can just actually keep the very distal joint immobile and there's there's specialized plinths for that i't have access to those, unfortunately. But if you're lucky enough to be able to get them, that's typically all you need. And again, sort of the same principles apply. It's not in perpetuity. It is for a couple of weeks, and that should be enough for things to calm down. If not, then you might need to escalate their care. What I do in the office is I just pull up on a Google search, Google image search, splint, trigger finger, and then they have multiple splints that they'll prevent like these joints from bending. So they'll just go over the finger there. So that way the finger can't flex. And it kind of rests this spot here where people tend to get that that first pulley goes across here. And then there's a tendon nodule that goes up through that and gets stuck. And if you prevent them from flexing that digit, it'll prevent the triggering from happening and can rest the area. Like most other things in the hand, this responds well to a steroid injection and that may even cure it. I've had a lot of patients who had a trigger finger, got a steroid injection and just went away. Sometimes it comes back and there is a surgery to cut that annular pulley, which then it tends to just go away and cure it. He said it doesn't recur if that's done. So that was pretty easy to treat, but patients do seem quite bothered by it. It's a very common complaint in my office. I love that, you know, not that I'll be doing any of the surgeries, but the fact that the common themes seem to be you don't go after the tendons themselves. Like, you actually just make space for them to kind of move and actually kind of calm down. So there's a lot of sort of snipping the supporting structures and not trying to carve away the lump, which is the thing that makes intuitive sense. So I thought that was an interesting sort of theme. Now, Paul, on to carpal tunnel syndrome. And this one, I think the pathophysiology, Paul, is a good place to start. You want to talk a little bit about that?
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Yeah. So Dr. Parks or Ted talks about how nerves are extraordinarily susceptible to ischemia. They require a lot of energy to do their jobs. The ATPase pumps are sort of constantly going. And so any reduction in the oxygen supply to them can cause pretty quick pathology, as opposed to things like tendons, which are sort of avascular and can tolerate compression. Nerves just don't do as well with that kind of stuff. So it's just by dint of what it is, it's going to be more prone to sort of compressive ischemic symptoms and sort of pathology that way, if I understand things correctly. He talks about the carpal tunnel, which we all kind of know there's the retinaculum, which is sort of the fiber span that goes around and then the sort of bony tunnel that actually kind of makes the whole thing. And then so the treatment, if we're going right into surgery, sort of addresses the pathophysiology. Actually, why don't we take a step back, Matt? So talk me through the progression of how you would actually treat carpal tunnel after you're diagnosed. So you don't go right is when people tend to sleep with their wrist bent for whatever reason, so they can get a lot of symptoms there. So if they wear the brace at nighttime, that can help. And then just having the patient be mindful about the posture of their wrist, if you will, keeping that wrist in a neutral position, that can offload it. And that helps. So that's one of the treatments. And then of course, a steroid injection, he mentioned can be both diagnostic and therapeutic because if the patient doesn't respond to the steroid injection at all, it probably means either you have the wrong diagnosis or you have to look for things like thanar wasting because if you see that, maybe the patient has just progressed too far where they're just not going to respond. This has been present for too long. Anything to add to the treatment part of this? No, and I appreciate the point that the treatment itself can also be diagnostic to some extent, too. So the point being is that our physical examination maneuvers for carpal tunnel specifically are notoriously horrible. So things like phalans and tunnels, well, are satisfying to do, don't have a lot of evidence behind them. We talked about even sort of doing the phalans test, which is sort of that reverse prayer. You're supposed to have the patient hold it there for like a minute, which feels like an eternity, especially if it's not a particularly good test. So it's the treatment itself with a steroid injection. If they have significant relief, then you know you're in the right ballpark and at least you're treating the right thing, even if that relief is transient. That is someone who might do better with, say, surgery. Yeah. So these are like, the Tenels and Phalans are in there with Homins and Brudzinski's and Koenig's, the ones that everyone remembers them, but they don't work that well. Yeah, but Weber and Rene and all the epidems, on and on and on. Well, I did want to just mention that we talked a little bit about the misdiagnosis of this, that it should be the first two and a half fingers, so the thumb, the pointer finger, and the middle finger, the radial side. And if you see different distributions than that, you should think maybe this is coming from somewhere else. Maybe it's a different nerve impingement. Maybe it's coming from the cervical spine, especially if it's bilateral, Paul. But if someone does truly have bilateral carpal tunnel syndrome, Paul, I was reading about this and it came up in a morning report recently that actually bilateral carpal tunnel syndrome, Paul. I was reading about this and it came up in a morning report recently that actually bilateral carpal tunnel syndrome can be a herald for later development of cardiac amyloidosis. It often precedes it by several years, which I thought was super cool and terrifying. So I'm now praying I don't find anybody with bilateral carpal tunnel syndrome. There are some other systemic, like rheumatologic diseases, hypothyroidism, some other things that can cause carpal tunnel syndrome as well. But, you know, amyloidosis, Paul, you know I worry about stuff like that. Well, sure, and I would say that any listener who actually makes the diagnosis of cardiac amyloidosis by bilateral carpal tunnel, if you could just write into the show and let us know, that would be super-du. The other example actually that Ted gave is actually jackhammer used to, by the way, which I've actually seen in my own practice. So you can get bilateral carpal tunnel just from sort of the repeated trauma of handling a jackhammer. So that's something else to be mindful of. So it's not impossible. It's just uncommon. Well, let's move on to down the body, Paul, to the foot and ankle. And this was another fantastic episode. This was with Dr. Joan Ritter. And this was, of course, again, produced and with graphics by great Dr. Paul Nelson-Williams. Paul, let's start off with talking about ankle sprains. I think we are probably used to seeing these in primary care. Everyone remembers the rice therapy, throw some NSAIDs at a person for them. But what did you learn about bracing in this episode? It's like this has been a common theme for this episode that the listeners are listening to now, and that you want to be a little bit careful with bracing. It can be helpful in terms of protection, but it's probably best to be able to brace in the way that preserves at least dorsiflexion and plantar flexion. If you have someone completely immobile or you put someone, say, in a boot for an ankle sprain, for a long period of time, they might lose proprioception or you might impair their proprioception. And by doing so, that person might be set up for subsequent injury later on. So you want to be very careful in terms of the protection that you do. It's useful, but it should be done in a thoughtful and sort of conservative way and not sort of, again, bracing for someone in perpetuity, I think was the point that Dr. Ritter made. Yeah. And talking through the different types of braces a little bit, I think it's interesting to think about these. The sterip brace is the one that's, it's usually white plastic with some green cushion inside. And that allows the patient to continue their plantar flexion and dorsiflexion at the ankle, but it protects them from the eversion and inversion movements that often result in a lot of the sprains. So that's a nice brace, and it does allow some movement. If you put someone in one of those lace-up ankle braces, that's going to control movement in multiple planes. And if you really want to immobilize somebody, that would be like a walking boot. And as we said, you don't want to keep people in the immobilizers for too long because you want them to maintain that mobility, the muscle strength there, and their proprioception. Paul, any other things you want to talk about for ankle sprain before we move on to talking about the Achilles? No, along the lines of sort of maintaining and preserving proprioception, I guess the other sort of takeaway point is to not be shy with physical therapy, or at least even prescribing exercises to maintain those things. I think that's, oftentimes, it's so satisfying to get satisfying to get the diagnosis or like, okay, if this person doesn't need imaging that you, some of the auxiliary stuff that is actually probably the most important stuff might get glossed over. So, but it's important to either prescribe exercises for the patients that you think are able to do them, or even have a low threshold to send the physical therapy just to, to rehab in a way that prevents subsequent ankle injuries, because once you had your once you're gonna be prone to more injuries. So I thought that was also a helpful thing to emphasize. Yeah, and some of the stretches we mentioned in the show notes were like, they can pretend to be tracing the letters of the alphabet with their toes, that'll move the ankle, stretching their Achilles. And speaking of the Achilles, Paul, you know, the Achilles tendon, I heard that the Achilles tendon rupture, tell me if I'm wrong, Paul, I might be wrong. I heard that the Achilles tendon rupture is often very subtle and patients don't even notice it when it happens. It's, I love being set up like this, Matt. That is actually pretty incorrect is my understanding in that the Achilles, the complete Achilles tendon rupture is often very dramatic, at least the way patients describe it.
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Or I think even if you read the literature, someone says they felt like they got shot in the back of the leg. Like it's, it's, it is a discrete point in time that is dramatic and there's a pop felt is often how it is described. So if someone has a complete rupture, oftentimes they know it. I think that the partial tears may not happen as commonly, which is why you have to do the right testing to make sure that you're not missing it. Right. And you're alluding to this calf squeeze test, which the eponym is the Thompson test, but it's a calf squeeze test where you can have the patient laying down on the table or they can have their leg supported by a chair with their shin facing down and you squeeze the calf muscle and that should elicit a plantar flexion movement if the Achilles is intact. And you can compare both sides or you should compare both sides, Paul, right? Because I'm told that if you're good enough, you could even diagnose a partial tear by an asymmetry in how much each side moves when you do the squeeze test. And frankly, I think we're that good. I think we could do it. I have faith in us. I love it. Yeah, we are that good, Paul. Now, part of what I thought was the history of the tendinitis, Achilles tendinitis, that it's kind of like plantar fasciitis where those first steps of the day may be really painful. I somehow had missed this. And it's the same kind of pathophysiology, right? Like at nighttime, your plantar fascia is kind of tightening up because the way you're sleeping, the position your foot's in, that's why those night splints help. And the same thing happens to the Achilles. Like a lot of people, the Achilles is shortened when you're sleeping. So when you take your first steps of the day and stretch it out, it can be painful. That can be a sign of Achilles tendonitis. And for anyone who complains of like posterior heel pain, you got to think about the Achilles. And Paul, what kind of Achilles diagnoses should we be thinking about? Well, the tendonitis, I mean, is the Achilles tendonitis is the one that I think most commonly about. So, and that's the one where a classic history would be, say, a runner who increases their training or starts going up hills more often or that kind of thing. So anyone who increases, I hate to say wear and tear because that's not exactly accurate, but increases sort of the, their, their movement at the Achilles, that's the patient might have sort of this gradual onset of pain. And so unfortunately with runners specifically that the counseling around what to do next is actually to stop running, which I think is a hard thing to counsel a lot of runners for us. That's, that's the tendonitis. If you're not worried about the complete rupture is probably the next thing. And that one, most of the Achilles tendon injuries require a significant amount of rehab and rest. And unlike a lot of things in musculoskeletal stuff are not amenable to steroid injections. That's one area that you're not going to be putting steroids into because you actually can increase the risk of rupture if they haven't ruptured it already. So don't do that. Now, Paul, what if I presented with a burning pain on the medial side of my ankle? Maybe it goes up my leg a little bit. And, you know, let's say that I've gained some weight and I just have not been wearing well supportive, like shoes that have good support. And Paul, you notice that I have an acquired flat foot deformity. What might I be, what might be going on there? No, I love when you pitch underhand. So this is a diagnosis that I don't know about you, Matt. I had not thought much about or really heard much about prior to this episode, but apparently it's common. I probably have missed it, but this is what you're describing is posterior tibial tendon dysfunction, which is exactly as you say, it happens in an older, I think it's more common to women, if I'm not mistaken, and overweight can overweight can certainly be a risk factor for it and sort of this burning medial ankle pain. And then it's associated with flat foot because the posterior tibial tendon actually helps support the arch and kind of keeps things sort of pulled up. So if you have dysfunction of that, then you sort of lose that arch in the foot and end up with this acquired flat foot. And one of the manifestations of that is our new physical examination, our new favorite physical exam sign, which is what, Matt? This is the too many toes sign, Paul. And how about you tell people all about it, Paul? Well, thank you for the chance to. The too many toes sign. So like with all these things, you should have the patient take their shoes and socks off, which I think is probably the first step that many of us may potentially fail. I won't put that on you. But and then after you you do that, you actually look at the patient from behind and typically you should see maybe like two, two and a half toes kind of peeking out laterally there. And someone who does not have a flat foot or posterior tibial tendon dysfunction, if they do, you might see more toes than that. So more toes sort of peeking out laterally. And that is the so-called too many toes sign. And that, that points you along with these historical and key points that we gave you towards the diagnosis of the posterior tibial tendon dysfunction. So say we made the diagnosis, we compliment the patient on how many toes that we've seen, they're mystified by the exam. Then what do we do to actually manage this? Well, Paul, this one can, there's a lot of things. I mean, of course, NSAIDs may be part of it and some activity modification, you know, relative rest, but the orthotics to support the arch may be helpful. And again, low threshold to refer these patients to physical therapy. I was doing some more reading on this because it just, I wasn't that familiar with it. Apparently, if it's really bad, sometimes they'll immobilize people with either even plaster casts or a walking boot. And in really severe cases, patients may need surgery to move the tendon somehow, Paul. So definitely outside of our purview. But I think people should look out for this. And the reason we wanted to highlight on this episode is because I think maybe a lot of people hadn't heard of it if they're like us. So with the last section here, Paul, I wanted to move into myositis and myopathy. This was number 348 with Dr. Lisa Christopher Stein. This one was produced by me with graphics by Andrea Perdigau. And Paul, the thing I wanted to start off as saying is that myopathy, myositis, I mean, there's these inflammatory myopathies. We classically thought of these as dermatomyositis and polymyositis. That's what was always taught when I was coming up in school. But now the nomenclature and just the splitting these into these distinct phenotypes and subtypes has become much more sophisticated. So dermatomyositis, there's a couple of different flavors of that, but that's rash and muscle weakness, proximal muscle weakness. But polymyositis, there's a whole bunch of other ones. Some of them overlap with rheumatologic diseases. There's some autoimmune mediated necrotizing myopathy. There's a whole bunch of them, Paul, that it's really a spectrum of different diseases with different prognosis and treatments. But in general, these are rare disorders. You should think of them if someone has muscle weakness and then extra muscular manifestations, which may be the skin, arthritis, interstitial lung disease, to name a few. Paul, tell me, what are some clinical features that struck you about that she taught us about in this episode? Yeah, no, I think it's important to recognize that we're not going to, at least I'm not going to be making the specific niche diagnosis if there's a myositis there. I think the important part for the primary care doctor is to at least sort of recognize the broad features that that should prompt a referral to a specialist. I think that's things that we talked about. I didn't quite have the mental framework for this prior to this episode, but if you're thinking about something like myositis, it's predominantly weakness and fatigue. This is not typically a painful diagnosis, or I should say that you're not going to see pain in isolation. That's not going to be your presentation of myositis. You can have weakness without pain.
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Then you're probably outside the realm of myositis. And then the great example in terms of differentiating sort of weakness from fatigue, because I think we all see fatigue in our offices and it's a challenging diagnosis to work up at the best of times. But weakness and myositis is simply the proximal muscle weakness is you ask the patient, so say you were watching a movie or in the movie theater, you're one of those chairs were just kind of sunk deep down inside and there's a fire. Would you be able to kind of get out of the chair and rush to the exit? Or would you need someone to kind of physically pull you out of the chair? And if they, even with the place burning to the ground, they would still need help getting out of the chair, then you're probably more in weakness territory than you are necessarily in overall fatigue. So I thought that was a really helpful way to at least sort of get those basic features kind of defined before moving on to the more niche testing and that kind of stuff. Yeah, exactly, exactly. And some of the other features we might recognize, ask about rashes, dermatomyositis, the rash is often itchy, which I found helpful. I think looking for the heliotrope rash, Yeah. joints of the hands. And patients may have new onset Raynaud's phenomenon. That could be a clue. The scalp may be involved. And Paul, we learned, we know some stuff about scalp and hair loss now. And this one, if someone has itching of the scalp and a burning pain, you know, you could think about dermatomyositis. And she said that that's often one of the more prominent features that the symptoms that is bothering the people most, actually, more so than the weakness is the itching, which was complete news to me. So, Paul, let's talk, let's move on to the diagnostic workup a little bit here. How about the physical exam? I know you're a big physical exam geek, so let's geek out on the physical exam. I do love it. Increasingly, it seems less and less helpful, but we did get some pointers in terms of how to make sure that we're assessing for weakness appropriately and really kind of making sure that we're testing specific muscle groups. So we went over, at least in terms of talking about the neck flexors, which are important to assess with myositis, and then also the hip flexors and extensors. You can be fooled. I don't want to say patients are trying to trick us. They just want to do well for these examination maneuvers. And if you don't have them positioned correctly, they might recruit other muscle groups and you're not really evaluating the muscle groups that you're hoping to. So to mitigate that, especially with the neck flexors, it's helpful to actually assess the patient while supine. And that way they're not sort of using their shoulders and you actually sort of gently hold down the forehead and ask them to push up. You're not pushing down their neck. You're not choking out the patient, but you're applying sufficient pressure that they have to resist it. And then similarly for hip flexors, you want the patient supine and then actually have your foot, your foot, you have your hand relatively close to the patient's knee so that you're resisting specifically that muscle group. And then for hip extension, ideally the patient should be prone and sort of the same thing. You want to be a little bit away from the actual joint that you're evaluating to really give full resistance to that. So she gave some ways to sort of do targeted muscle strength testing. And then the grip strength mat I thought was super cool. I don't know why that one resonated so much, but to remind me what her, like, because the way I've been doing it, where I think, all right, just grab my fingers as hard as you can is probably not the best way to do it. So how did she start doing it? Right. So you, yeah, so she actually said just you flex your fingers, but you flex to the first palmar crease, which is right here. So you're just really flexing your PIP and your DIP joints. And then you're trying to pry up the fingers there. And patients can't really cheat. It just really isolates those groups that you're looking for. Inclusion body myositis is one of the ones where she said that they can get distal muscle weakness. And so that's what you'd be looking for there. So totally different than the way I normally test. On the labs, the lab workup is fairly standard CBC, CMP, ANA, thyroid, and inflammatory markers. The thing that is not standard is, so the ANA is often positive in the myositis, but anemia is uncommon, and the inflammatory markers are often normal, which is, you know, Paul, I had no idea. That would not be what I expected. Right, yeah, I think we talked before with these autoimmune diseases, I feel like you almost always see anemia. And I think that would be my expectation, and also the inflammatory markers, especially with the symptoms that these patients are having. For some reason, mentally, I would expect those things to be wildly elevated. And it turns out that's not the case. So you're not ruling out the diagnosis of those things come back normal. If anything, that might actually be supportive evidence. So other things you might think about, MRI of the thigh muscles is sometimes used to look for potential sites for biopsy and also just to identify muscle inflammation. Patients could have interstitial lung disease, so getting a CAT scan of the lungs is something that can be done. And she said she actually, for the initial imaging, often does a CAT scan of the abdomen, chest, abdomen, and pelvis as part of just a cancer screening workup, especially if they have dermatomyositis and age-appropriate cancer screening. If they're men, she'll even do PSA testing and testing of a prostate exam. And there are a lot of specific antibodies and muscle biopsy and things that they can use to really drill down what the actual diagnosis is. But Paul, with the end of our time here, I wanted to talk a little bit about what we in primary care, like what is our role here? Because the case we gave her was a patient who was on a statin. And do you remember what she said about statins or why we should at least think about the statins? Yeah, a couple of things. And I think she blamed a torvastatin, not blamed, that's the wrong way to say it, but said a torvastatin is often implicated is probably the best way to say it in part because we also tend to go high dose with that too. So you just go guns a blazing with a torvastatin. I think she did make the point that for most patients, a statin rechallenge is appropriate and probably okay, but she would start low and go slow. So rather than sort of, okay, let's just go back to 80 milligrams every single day, maybe do 20 milligrams a couple times a week, see how the patients tolerate it and not just kind of come in guns a-blazing and sort of restart at a lower level and then kind of up titrate to tolerability as opposed to just restarting at the prior dose that you had discontinued because these patients can be sensitive to the statin side effects. Yeah, and yes. And her group did discover the autoimmune, this autoimmune statin myopathy that is something that exists. It's a necrotizing myositis or myopathy. So her group did discover that, but she said that once that's been ruled out, you can put people on statins as you're saying, Paul, but the start low, go slow approach, which is kind of counterintuitive, but she said, you know, you still want to protect patients from cardiac disease. Patients actually can exercise, Paul. You know, they don't necessarily need to do heavy resistance training, but they can do some exercise. That's actually been shown to be beneficial. And then in primary care, Paul, because these patients are going to be exposed to things like steroids and because they're going to be on immunosuppressive medications, you should think about getting vaccinations before those meds are started, assessing their bone health, and then sun protection, Paul, especially if they have some of the conditions that have photosensitive rashes they need to wear really heavy, she said like SPF 70 or above. And you told your hat story, Paul, where her dermatologist told you to wear a hat because your coverage up top was not what she would want it to be for you, Paul. She was very, very nice and said I should consider incorporating a hat into my wardrobe, which I thought was Yeah, not complaining.
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The links will be in the show description here. We had fantastic discussions with all these guests. But, Paul, all good things must come to an end. In this episode, I think it's time for an outro. So, Paul, if you will. our Curbsiders Digest, recapping the latest practice-changing articles, guidelines, and news in internal medicine. And we're committed to high-value practice-changing knowledge. And to do that, we need your feedback, so please subscribe, rate, and review the show on Apple Podcasts or on Spotify. You can also email us at askcurbsiders at gmail.com. This episode is not available for CME, but the three episodes we talked about are available for CME through vcuhealth at curbsiders.vcuhealth.org. I wanted to give a special thanks to our production team. The show is produced and edited by the team at Podpaste. Elizabeth Proto runs our social media and Stuart Brigham composed our theme music. And with all that, Paul, until next time, I've been Dr. Matthew Frank Watto. And I remain Dr. Paul Nelson-Williams. Thank you and goodbye.
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From the JAMA Network, this is the JAMA Medical News Podcast, discussing timely topics in clinical medicine, biomedical sciences, public health, and health policy, featured in the Medical News section of JAMA. This is Jennifer Abasi for JAMA Medical News. Between 2012 and 2015, years before the Time's Up and Me Too movements galvanized countless women to come forward with accounts of sexual harassment and assault, researchers at the University of Pittsburgh asked a group of midlife female study participants if they had ever experienced these traumas. The questions might have seemed out of place to some. The researchers, led by Rebecca Thurston, were investigating the association between menopausal symptoms, specifically hot flashes, and early signs of atherosclerosis or hardening of the arteries, a risk factor for cardiovascular disease. Why ask about harassment and assault in a study about heart health? Thurston is a professor of psychiatry, psychology, and epidemiology, and to her, including the questions made sense. She's long been interested in how gender-based power inequities influence women's health. Sexual harassment in the workplace and sexual assault, she says, are an expression of this power dynamic. Thank you. events such as sexual harassment and assault are potent stressors, and she suspected that they could have some bearing on women's cardiac health. A post hoc analysis of the study of midlife women was recently published in JAMA Internal Medicine, and it suggests that she was right. Women who reported a history of sexual assault or workplace sexual harassment had poorer physical and mental health outcomes than those who didn't. Unlike previous studies that have looked at similar associations, this one considered both sexual harassment and sexual assault. It also included objective measures of physical health rather than relying exclusively on self-reported outcomes. Thurston recently spoke with me about her study. equipped them with various ambulatory equipment to measure some of their menopausal experiences. That was actually not part of this particular analysis. But we did a pretty good workup of their blood pressure, their height, their weight, their medical history. We had them go about their daily activities for a few days, come back, and they filled out a battery of questionnaires, which included the trauma questionnaire that inquired about sexual harassment and sexual assault, as well as mood, anxiety, and sleep. And we looked at, really, how do self-reported sexual assault, self-reported sexual harassment, particularly workplace sexual harassment, how these related to both the physical aspects of health that we are measuring as well as psychological factors and sleep. And how did you assess sexual harassment and assault? Two questions, actually. So it was pretty brief. We asked women whether they had experienced a workplace sexual harassment, and that's pretty much it, ever, and they self-defined what that constituted. And we also asked women whether they had experienced unwanted sexual contact. And then we went a little bit further to explain what we meant by unwanted sexual contact. So we said by sexual contact, we mean any contact between someone else and your private parts or between you and someone else's private parts. When I was reading your study, I was just wondering if that would include non-physical contacts. So being shown private parts, for example, which is something that we know has come up in the news. Right. And you're raising a really good point. We did not assess non-contact sexual violence. So this is really getting at contact sexual assault, which is a subset of sexual assault. There are other kinds of sexual assault, like flashing, as you mentioned, that were not assessed here and probably relate to some of the prevalence estimates that we got. Let's talk about the findings. So what did you learn? We found that 19% of the women reported a history of workplace sexual harassment and 22% reported a history of sexual assault with relatively minimal overlap between those two groups. So they were not the same women. We found that women with a history of sexual harassment had approximately two-fold odds of hypertension relative to women who did not have a history of sexual harassment, as well as a two-fold odds of poor sleep, approximately two-fold odds of poor sleep that fell within the clinically significant ranges for sleep problems such as insomnia. When it came to sexual assault, we found that women with a history of sexual assault had an almost three-fold odds of depressive symptoms in the range of major depressive disorder and a two-fold elevated odds of anxiety and poor sleep in clinically significant ranges. Okay, so overall, what does this suggest? It suggests that sexual harassment and sexual assault have implications for women's physical health and mental health. And what factors did you adjust for? We considered a range of covariates, so things like age, race, ethnicity, socioeconomic status, medication use. We also considered things like physical activity and health behaviors, alcohol use. But those did not play really any role in these associations, so they actually didn't make it into the final models. Were you surprised at all by your findings, or was this what you expected to find? I was surprised by the range of outcomes that we found related to sexual harassment and sexual assault. And I'll say there was one other finding that we reported when we reported on these findings for the North American Menopause Society. We also found that women with a history of sexual harassment had a three-fold odds of triglycerides in the clinically significant ranges. So I was surprised just by the range and pervasiveness of the outcomes across bodily systems that we saw related to harassment and assault. I also was somewhat surprised that we saw somewhat of a divergence with sexual harassment related somewhat more to the physical health indices and sexual assault more related to mental health and sleep. So I think those were some of the things I was surprised about, but what I was not surprised about is that we did see relationships writ broadly because we know that stress and stressful experiences are important to health, mental health and physical health. I think we're taking it a step further here and looking at somewhat more gendered or gender-predominant, female-predominant stressors. What are the potential mechanisms here? So how does being sexually harassed or sexually assaulted potentially affect a woman's long-term health? This is a great question, and there's a really deep literature linking stress and health. So what are those physiologic mechanisms that can relate stressful experiences to physical health outcomes? Number one, we tend to think about our behavioral mechanisms, health behaviors, smoking, physical activity, substance abuse, dietary factors. And we looked at those very carefully. So first, we didn't have any smokers in the study. And we looked at all the other health behaviors pretty carefully. And that did not explain these associations, particularly between sexual harassment and hypertension, as well as the triglycerides binding. Now, we also think about more direct physiologic mechanisms, whether it's autonomic nervous system dysregulation. So, for example, the balance between the sympathetic and parasympathetic branches of the autonomic nervous system are important for blood pressure and hypertension and can really be disrupted in terms of sympathetic predominance when it comes to situations of chronic stress. The HPA axis dysregulation is also important. We know that stressful experiences and traumatic experiences, we have some data linking these experiences to endothelial dysfunction, vascular endothelial dysfunction. So these are just a few of the many potential mechanisms that can link stress to physical health outcomes, particularly hypertension. Now when it comes to mental health outcomes, I think we can all pretty much agree that these experiences are stressful and they likely have implications for mental health and psychological functioning. Most of the women in your study were white and well-educated. Do you think these associations that you found are true for other groups of women? Well, we had a pretty decent representation of minority women in terms of that we had about a third of women were minority. So they were certainly not the majority in the sample, but they were a substantial minority. Most of the non-white women in this study were African American. So where I really think the caveats are here is that we can't really generalize beyond those two groups. So how Latinas are experiencing sexual harassment, sexual assault in terms of prevalence and impact on health, Asian women, et cetera, we can't necessarily generalize to those groups here. What do you suspect? I would suspect it's the same. These are oftentimes universal experiences for women, sadly, and it would make sense to me that the psychological impacts and physical impacts are probably, or at least correlates, are probably similar. I wanted to ask about men as well. We know men can be sexually harassed and sexually assaulted. Do you think there could be effects on health, both mental and physical, for men as well of these experiences? Absolutely. So sexual harassment and sexual assault do occur in men. They, best we know, they are not as prevalent, and they also tend to, in the case of sexual assault at least, not be quite as severe or impairing for men. But it does happen.
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Now, one thing that is important to keep in mind in the case of sexual harassment, sexual assault, these are oftentimes in part an assertion of hierarchical power relations. So you tend to see more of a power imbalance in male and female situations, particularly in the workplace, but it does happen in men and it's likely important for men's health as well. I just think that men are relatively understudied. What do you want women who have experienced sexual harassment or sexual assault to know about how it could potentially affect their health? Well, there's a lot to know here. So first is to know how to recognize when you're being harassed. Unfortunately, we've oftentimes normalized many of these experiences and tried to tell women that you're not being harassed or these are not toxic exposures or this is okay and this is normative and you're the problem for thinking that there's a problem here. So supporting women's definition and what their experiences are is really quite important and important for women to listen to in themselves. So that's number one. So first is recognition about what's happening. Number two is that these are pretty toxic experiences. So if you're in a relationship or you're in a workplace that has a lot of harassment and assault or any harassment and assault happening, the best thing to do if you can is to either report the situation or get out of the situation. Now, all of that is easier said than done. Oftentimes, women who are in harassing workplaces, for example, it's not so easy to get out in that money is really quite important. So the financial component, the dependence on work and oftentimes workplaces that are not great for people's health is there and I don't want to ignore that. We saw in our own sample that the women who were more financially strained were more likely to report a history of sexual harassment. So getting help as best you can is important, not simply putting up with it and tolerating it. If you can, try to get out, try to address the situation. And also, at least we have the recognition that these are challenging situations to address. What can physicians do to support the health of women who may have experienced these things in their past? So number one is educating health care providers about the prevalence of these problems and just how common they are. Number two is about their implications for health, that these are important when you're thinking about health to have a sense of a woman's sexual assault history. It's also the recognition that the woman or man may not report these experiences to the provider even when asked. It really takes a lot of trust for people to come forward with these experiences. So it may be developing a relationship over time and not assuming that if you get a no that that's necessarily meaning that that's not happening. So to address that, there's universal education for patients, having educational materials available as well, and providing patients with materials to know where to go if it's happening to them, regardless of disclosure. Partnering with local agencies and support services to be able to refer people to appropriate care once they report a history of sexual assault or even current sexual assault. And ideally having behavioral health care providers or victim services advocates on site. That really reduces that tendency to lose people between referral to them actually getting care and treatment. And then finally, ongoing follow-up. So it's not a one-and-done scenario, following up with people and maintaining that ongoing relationship with patients. Now, women and men are increasingly coming forward to talk about workplace sexual harassment and sexual assault. What do you want us to remember when we hear these accounts? Remember that over-reporting is rare. Under-reporting is typically the rule. So when people are reporting, to take it really seriously, that most likely you can trust their word for it. And understanding also that these experiences people are having are important for their mental and physical health, not only at the time, but may have implications for years down the road. So really the imperative is to try to help people to get out of these situations and then also to receive appropriate care, mental health care, ongoing physical health care as they need it. In the United States, an estimated 40 to 75 percent of women have experienced workplace sexual harassment, and over one in three women have experienced sexual assault. Thurston told me that for most women who are sexually assaulted, the first incident occurs in late adolescence or early adulthood. Younger women are also more likely to be sexually harassed than older women. Thurston emphasized that the study can't prove causality, but the data do suggest that there could be long-lasting health effects of these experiences. As we were putting the finishing touches on this episode, JAMA Internal Medicine published another related study that caught my attention. This paper comes out of Harvard Medical School and the University of California, San Diego. Researchers there found that Google searches around sexual harassment or sexual assault were 86% higher than expected in the months after the MeToo movement began. In fact, the post-MeToo period corresponded with the greatest number of searches for sexual harassment and or assault terms ever recorded in the United States, with 40 to 54 million searches from October 15, 2017 to June 15, 2018. Searches related to reporting and preventive training for sexual harassment and assault also shot up during that time. The researchers concluded that the Me Too movement may have reduced the stigma of sexual harassment and assault and that more people are seeking help. That's it for this episode of JAMA Medical News. To listen to more podcasts and subscribe, Thanks for listening.
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Hello and welcome to a very special episode of the Lancet podcast coming to you on Monday the 20th January 2014. My name is Nikolai Humphries. Today we publish a series of papers on health in the Arab world or to give the series its full title health in the Arab world a view from within. The series focuses on what are essentially the priority health issues in the Arab world. These were based on evidence interpreted mainly by scholars from the region and the series adopts a multidisciplinary approach that includes medical, public health, social and political perspectives. To frame this series and really give perspective, I'm joined on the line from the occupied Palestinian territories by one of those scholars, Dr. Rita Jackerman, from the Institute of Community and Public Health, Beresite University. Rita, it's my pleasure to welcome you to the podcast. Thank you very much. Leafing through the papers that make up the series, of which there is one article, five series papers, a collection of comments and essays, it becomes clear that this was an audacious and ambitious undertaking. I'm hoping you could expand on this by sharing the journey, how this series came to being with our listeners. Well, it was quite a journey because of a variety of reasons. The first was here was a chance for people from the region, Arabs, as well as international scholars who have been working in the Arab world, to be able to say something about the Arab world, the way the Arab world sees themselves. And so that was a wonderful opportunity, but it was a daunting one as well. It was daunting because what we needed to do is play the balance between providing firm evidence, but at the same time infusing this evidence with analyses through our own eyes. And that was quite a challenge, and I think we did well with it. The other challenge was that we were working in teams all over, all over the world, all Thank you. And when you're in different parts of the world, it's even more difficult. But we managed to pass by this thanks to the Faculty of Health Sciences at the American University of Beirut, who organized meetings periodically for the team to work together and discuss over two or three days, and also for the group that was responsible for overseeing what's happening, which is composed of eight people from all over the world. And it was quite a rich experience, actually. It ended up being something equally important as the production of the papers themselves. Yeah, and an interesting point was that from the outset, there was a strong consensus to steer from the sort of traditional conventional approach of a health systems analysis. And instead, the goal was to describe the region by emphasizing in particular the major political determinants of health. Could you explain the rationale behind that? Of course, but I think it has recently become quite obvious why ultimately the political is determinant. Take a look at what's happening in the Arab region. All these uprisings and counter-revolts and so on and so forth. And historically, just like the present, we have had one wave after the other of political violence. So therefore, exposure to political violence in its various forms has been a crucial element in determining what happens to health, whether it is in communicable diseases or non-communicable diseases or mental health or what have you. For example, very recently, look at what's happening in Syria. And recently, although we did not have some communicable diseases prevalent in some areas, now they are rising again because of the millions of refugees from Syria, not only Syrian ones. There are Iraqi refugees leaving Iraq, and there are even Palestinian refugees who used to live in Syria who are now refugees in Lebanon. It's a remarkable situation, which brings in all sorts of health problems, communicable, non-communicable, but also mental health problems, including human insecurity, distress, ill-being, etc., etc. There was also a decision not to focus on the theme of health and the Arab Spring as a whole. My question, Rita, is what were some of the reasons for not pursuing that angle, captivating as a title as that may be? It might be captivating, but it would have been untruthful. To be able to discuss health in the context of something so rapid and transitional is incorrect. I mean, there are changes taking place every day, and we do not know what will happen tomorrow. It's extremely difficult to be able to assess what's happening to health under conditions of such a ferocious transition, which includes not only revolutions, but terrible counter-revolutions and meddling from outsiders, what have you. I mean, take a look at Syria. There are so many countries other than Syria who are involved in that conflict. There is no way you could do service to the situation when you don't know what would be happening tomorrow. I think we would be able to analyze the consequences once uprisings and political turmoil subside, but not before. Could I ask you to share some of the key messages from the series that resonate most with you? With me, but not necessarily with everybody, because I have my own way of understanding what we've done. Maybe somebody else would have other messages. There are messages that will be put forth by each of the paper authors. But in my view, there are several messages that underlie these messages, which I hope readers will pick up on. One, we are here, we are active, we are alive, we do research, we even love our children, and we go on with life despite all the political conflict and wars and exposure to political violence around us. It's a testimony to what I think you would call in the West resilience, which I would call something else here, capacity to endure and resist. It's a statement about doing work, trying to improve public health, bringing the evidence related to public health so that we can inform policy. All of those things are the underlying and, I think, beautiful messages. That's what we're doing. And I want to tell you something. Doing this work and doing research and trying to influence policy helps all of us in our region to survive very trying times. It gives meaning to life. Thank you. That was a very poignant response. And I'm wondering if you would consider any of those messages to be overlooked by the rest of the world in terms of what we define as global health? Yes, of course. I mean, the Lancet editorials mentioned how the Arab world is invisible in the eyes of global health makers, global health researchers, etc. But there's more to it than just invisibility. I think it's worse than just invisibility. In general terms, Arabs are understood first and foremost as terrorists, Muslims, the other, even though the Arab world has not only Muslims but has Christians and others living in it. But that whole impression, when you say Arab, there's fear, there's a lack of understanding, to say the least. There's a cultural discord, which I think the world has opted to avoid instead of facing. Instead of facing, take a look at what happens with the global health agenda, for example. It almost never fits the Arab world. The focus of the global health agenda usually is Africa, Latin America, and Asia. We're not here. We're just not here. And that series helps cement the idea or raise the idea that, well, there's a whole region in this world which is here and which needs attention and at least needs some sort of understanding and better efforts at developing global agendas which are compatible with our needs and better effort at incorporating our views from within into discussions of global health. Thank you. That leads me nicely into my final question, which is what should an observer reading this series looking from outside take away? And what about observers looking from within? Would they even be different? That's an interesting question. I think we would see things slightly differently. There are similarities and differences probably because of the different views are part and parcel of the position of the person in the context. So the view from within would be, aha, we do have research. Aha, it is being published. And aha, we're being heard. And aha, this will encourage us to do more. And we've got to get together. The collective is of the essence. And this is what we need to do, more collective work so we can continue to be heard, so that we can influence not only policies at the level of the Arab world, but global health agendas as well. At the outsider level, I'm just hoping, it depends, because some people don't want to deal with the Arab world, but those who have an open mind might be saying, aha, these people are producing interesting evidence. And it's not just solid scientific evidence. It's evidence with a different flair. For example, we develop our own metrics sometimes. Quite often we use international metrics, but when those are not relevant to context and culture, once we pilot them, we develop our own.
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So maybe the reader who has an open mind would say, aha, these people are innovative, they have something to say, and quite clearly, despite the turbulence around them, they are capable of producing quality research with a heart, because the aim of our research is to improve the lot of health among Arab people. Dr. Rita Jackerman, on that note, thank you for joining the Lancet podcast. Thank you very much.
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Hello out there. This is Dr. Kathy DeAngelis, the Editor-in-Chief of JAMA, the Journal of the American Medical Association. And this week I'm going to tell you about the February 18, 2009 issue of JAMA. As usual, we will start with the cover. I've had a few people tell me, why do you bother with the art? This is a medical scientific journal. Well, guess what? I hope you're all professionals out there, or even the patients who might be listening, I think, would enjoy art. And if you're a professional, for heaven's sake, you have to be more than just a scientist. Art is good. The cover this week is a painting by Robert Scott Duncanson, who lived from 1821 to 1872. It's a painting of the Mayan runes in the Yucatan, painted in 1848. It's American, of course. Those of you who haven't seen the Mayan runes should take a trip. That's good for you too if you're a professional. The first article deals with herpes zoster treatment with tumor necrosis factor or TNF-alpha inhibitors. The tumor necrosis factor, that's alpha TNF-alpha inhibitors, are associated with an increased risk of bacterial infections. But whether they are also associated with reactivation of latent viral infections is not known. In an analysis of data from a prospective cohort of patients initiating treatment with biological agents for rheumatoid arthritis, Dr. Andrzej Strongfeld from the German Rheumatism Research Center in Berlin and colleagues assessed whether treatment with TNF-alpha inhibitors is associated with higher risks of herpes zoster as compared with treatment with conventional disease-modifying anti-rheumatic drugs. The authors report that treatment with monoclonal anti-TNF alpha antibodies, that is, and the limibab and infliximab, appears to be associated with an increased risk of herpes zoster. In an editorial, Dr. Richard Whitley and John Guanan from the University of Alabama School of Medicine discussed the evidence linking TNF-alpha inhibitor therapy with reactivation of latent varicella zoster virus and the implications for patient care. The second article deals with the incidence of methicillin-resistant Staphylococcus aureus central line-associated bloodstream infections. To assess the trends in the incidence of MRSA central line-associated bloodstream infections in adult and pediatric intensive care units, that's the ICUs, Dr. Duran Burton from the CDC and colleagues analyzed 1997 to 2007 data reported to a voluntary Centers for Disease Control and Prevention National Infection Surveillance Network. The authors found that during the decade of study, the incidence of MRSA central line-associated bloodstream infections declined in adult ICUs and remained stable in pediatric ICUs. In an editorial, Dr. Michael Klimo from the VA Medical Center in Richmond, Virginia, discusses the importance of identifying the infection control practices that may be associated with these reductions in MRSA infections. The third article deals with GUCY2C expression and colorectal cancer survival. Dysregulation of guanylyl cyclase C, that's GUCY2C, that's a paracrine hormone receptor and intestinal tumor suppressor, is associated with neoplastic transformation, and GUCY2C is a marker expressed by colorectal tumors. In a prospective study of patients with colorectal cancer, Dr. Scott Waldman from Thomas Jefferson School of Medicine and colleagues tested the utility of assessing GUCY2C expression quantified by reverse transcriptase polymerase chain reaction in histologically negative lymph nodes to identify occult metastasis and examine the association of GUCY2C expression with time to recurrence. The authors report that expression of GUCY2C in lymph nodes free of tumor cells by histopathology was independently associated with time to recurrence and disease-free survival in patients with lymph node negative colorectal cancer. GUCY2C. That sounds like something straight out of Star Wars, doesn't it? The fourth article is the clinician's corner and deals with cancer survivors and unemployment. Many cancer survivors have the desire and ability to return to work after cancer diagnosis and treatment. However, the association of cancer survivorship with unemployment is not clear. In a meta-analysis of data from 26 studies that included adult cancer survivors, healthy controls, and employment as an outcome, Professor Angela de Beur, Control Intestinal Occupational Health in the Netherlands, and her colleagues found that cancer survivors were more likely to be unemployed than healthy individuals. The authors report that survivors of breast and GI cancers and cancers of the female reproductive organs and patients living in countries or times with atopic eczema and intention deficit hyperactivity disorder in a population-based sample of children and adolescents. And this study was done by Dr. Joachim Schmidt from Technica University from Dresden, Germany. We also have three commentaries in this issue. The first, Transformation of Healthcare at the Front Line. This one was written by Dr. Patrick Conway from DHHS and Dr. Carolyn Clancy from AHRQ. The second, Clinicians in Quality Improvement, a New Career Pathway in Academic Medicine. This one's by Dr. Kavish Sojana and Dr. Wendy Levenson, both from the University of Toronto School of Medicine. And the third commentary is a JAMA classic celebrating 125 years of JAMA, and this one deals with penicillin treatment of syphilis. And this one was written by Dr. John Douglas from the CDC. The JAMA patient page has information for your patients about syphilis. And if you think syphilis is a thing of the past, you better read that JAMA classic and the patient page. The medical news and perspectives. The United States Food and Drug Administration is doing too little to police conflicts of interest administration. There's also an article about long-term risks of bisphosphonates probed, the world in medicine, heart risk in South Asians, targeting ticks, Ebola restaurants, Thank you. age 13 to 17 years in the United States in 2007, and recommended immunization schedules for person age 0 through 18 years in the United States in 2009. I suggest you take a look at that. A piece of my mind, this one written by Dr. Paul Rousseau from the Medical University of South Carolina. The title is Southern Comfort. And no, this is not an alcoholic beverage. It's a beautiful piece of my mind. And I quote from it, this was a family that had known suffering as a way of life. Nothing was easy. And the readers respond, how would you manage a 76-year-old patient with multiple medical problems and recurrent clostridium difficile colitis? Go to www.jama.com, read the case, and submit your response, which may be selected for online publication. The submission deadline is February 25th. And author in the room teleconference, we invite you to join Dr. Stephen Schroeder March 18th from 2 to 3 p.m. Eastern Time when he will discuss smoking cessation in patients with psychiatric illness. That's it for this week. Thanks very much for listening. Please let me know if you have suggestions to make this podcast more educational or interesting to you. This is Dr. Kathy DeAngelis, Editor-in-Chief of JAMA, speaking to you from beautiful and frigid downtown Chicago, where the wind is blowing mightily, but our patients are always our top priority.
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Okay, welcome. My name is Divine. This is going to be episode 283 of the Divine Intervention podcast. And again, this is a combo podcast as I've been doing in recent times. That's what I did in episode 282. I'm going to be talking about a lot of risk factors and prognostic factors. But this is also going to be a rapid review series. So this is going to be series 47 for Step 2CK. And again, I also want to send a reminder. Again, if you're studying for the USMLE Step 1 exam, I have a super comprehensive course. It's 30 hours long. It's taking place between the 27th to the 30th of this month. Still have some spots available. So if you want to sign up, just shoot me an email through the website and I will give you some more information. And then if you're studying for Step 2CK, the previous 10-hour course, I've expanded it. It's now a 16 and a half hour course because I want to, my goal is to include some expanded internal medicine content and cover many of the new changes that are currently tested on the exam. Like those things with professionalism, ethics, communications, there's gonna be a lot of bio stats. And again, I'm gonna expand the medicine content, the PITS content, the OB-GYN content. So again, if that's something you're interested in, I have the course from the 4th to the 6th of February, and then I have the MBME test against strategies course on the 3rd. So again, if you're interested, again, just shoot me an email. I've gotten quite a pretty decent number of signups. So there's still some spots available. So if you're interested again just shoot me an email i've gotten quite a pretty decent number of signups so there's still some spots available so if you're interested just shoot me an email and i'll be happy to point you in the right direction okay so let's let's go right into it right so what if they give you a question um about a patient and they tell you that this patient you know has been a long-term smoker and then this person has a this person has been a long-term smoker and then this person over the last three weeks you know they've lost like 10 pounds they notice like some blood in their urine right and the creatinine has been going up if you see that and let's say maybe it's like a guy that also has like this new varicose but i hope in that circumstance you think about renal cell carcinoma right so renal cell carcinoma remember it's kind of a high yield cancer to know for exams obviously the biggest risk factor for that talked about that adenosine before is smoking right but remember that it can cause a varicose cell right especially like Especially like when you have like a left sided varicose cell. Because if you remember, the renal cell carcinoma can involve the renal vein. Right. And once it involves the renal vein, that will obstruct flow from the testicle on the left. Remember the gonadal veins on the gonadal, the adrenal vein on the left. They have like weird drainage, right? So the stuff on the right, remember like the gonadal vein on the right drains straight up into the IVC. But the gonadal veins on the left, the adrenal veins on the left, they drain into the renal vein, the left renal vein, which then crosses and then goes and drains into the IVC, right? So if you see a left-sided varicose cell,term smoker you know think about renal cell carcinoma and then please don't forget that renal cell carcinoma um that's really kind of high you to know um the perineal plastics right you know so as we do with erythropoietin right so it produces zippo so that can cause a polycythemia in the patient and then another thing you want to keep at the back of your mind with renal cell carcinoma is the fact that um classically right if you were to many many people think that once you get on once you take step 2ck they don't bother about histologic descriptions anymore and we show the best right people that have renal cell carcinoma you you'll typically find um clear cells on uh on histology right when you're looking at the malignancy, right? So what are some prognosis things your friends at the NBME love to test with this stuff? Well, the big thing you want to know is that these things, they love to, like they can say, oh, they'll give you a question about a person that has renal cell carcinoma. And then they ask, oh, what's the most likely location of metastasis, right? If you see a question like that, you want to think about mets to the lungs. Renal cell carcinoma loves to metastasize to the lungs, right? And you can even extend that knowledge to like Wilm's tumor, right? Wilm's tumor also, if it metastasizes, is going to be to the lungs. Remember, hopefully you can differentiate between Wilm's tumor from a neuroblastoma. Remember, Wilm's tumor is going to be a flank mass. It's going to be non-calcified, right? And it does not cross the midline. It's very high yield to know, right? In comparison with neuroblastomas, right, that are going to cross the midline, right? And then they will, so they love to cross the midline. That's one important thing. And then I think another important thing I should mention is that they are also calcified as well, right? And, you know, neuroblastomas love to metastasize to bone, right? So that's a higher thing to know. And one other thing I would say that's also important is that they can ask you like, oh, which of the following is the most important predictor of prognosis for renal cell carcinoma? That's actually going to be extension into the renal vein. Once it goes into the renal vein, right, it's basically taking a route towards the systemic circulation, right? So obviously that's like metastasis central at that point. But in general, for malignancies, what is the most important predictor of prognosis in a person that has a malignancy? So it's going to be one of two answers on an exam. So it will either be that the malignancy has metastasized obviously if something has met already it's bad right but then and the key predictor of prognosis is also like lymph node involvement right so if it involves lymph nodes so the thing i will encourage you is because sometimes your friends at the mv are really smart and they'll put two of these things right so like they'll put like presence of metastasis lymph node involvement if they put both pick the presence of metastasis because the fact that something has got into a lymph node yes it's metastasized but that does not necessarily mean that it is already systemic right so i think that's a very high yield thing to keep in mind for exams and then next one other one we're just going to talk about straight up is they love to ask about obstructive sleep apnea on mbm exams and ask for the risk factors right so the thing is it's actually high yield to know the risk factors by age right so if you're dealing with obstructive sleep apnea on NBM exams and ask for the risk factors, right? So the thing is, it's actually high yield to know the risk factors by age, right? So if you're dealing with obstructive sleep apnea in a kid and they ask you for the biggest risk factor, I really hope that you're picking the answer that talks about the person having adenotonsillar hypertrophy, right? So they have like just big tonsils, big adenoids, right? So that obstructs airflow, right? And then another thing that can cause obstructive sleep apnea, the biggest risk factor in adults is going to be obesity, right? So obesity is the most important risk factor for obstructive sleep apnea in an adult, right? But again, as you know, they love to put all these questions where they talk about patient-specific risk factors, right? So if, for example, they give you a question about a person that, you know, has a BMI of like 26, and then they tell you that the person has a history of like asthma-based symptoms that are worsened by the administration of an NSAID, you know, like aspirin-exacerbated respiratory disease, then in those circumstances, you want to pick nasal polyposis as the biggest risk factor, as the most important risk factor for obstructive sleep apnea in that patient, right? Because remember, people that have aspirin-exacerbated respiratory disease, right, they love to form nasal polyps, and those nasal polyps can obstruct the airway, right, especially the nostrils, and that can increase the person's risk of having obstructive sleep apnea, okay?
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I think it's kind of like the big kind of like the big thing I want to I want to mention here. Right. And then some of you may wonder, oh, divine, what's the pathophysiology behind aspirin exacerbated respiratory disease? Well, it's pretty straightforward. Right. So we know the pharmacology behind our acedonic acid. Right. So we know that our acedonic acid loves to do the same thing where it can either go down the cyclooxygenase pathway where you make prostaglandins, right? Or the lipoxygenase pathway where you make leukotrienes, right? So the thing is, if you give aspirin, aspirin is an irreversible inhibitor of COX-1 and COX-2, right? So if you inhibit COX-1, inhibit COX-2, you're going to have more flux through the lipoxygenase pathway pathway, right? And the lipoxygenase pathway leads to the formation of leukotrienes. And leukotrienes, they can cause bronchoconstriction. They can cause many of those asthma-based symptoms, right? So that's why it's very important. As a person that's trying to treat aspirin exacerbated respiratory disease, they can ask you for the drug of choice in treatment. The answer that you actually want to go after on exams is going to be like a leukotriene inhibitor, right? Remember, you can inhibit leukotrienes in one of two ways. You can give a leukotriene receptor antagonist something like Montelukast or Zafrelukast, right? Remember, those are the leukotriene receptors. Sometimes the NBMA may get cute. Instead of calling it the leukotriene receptor, then we call it the CYSLT1 receptor, right? But alternatively, you can also give something that inhibits lipoxygenase right so um it's almost like the aspirin of the lipoxygenase pathway in this case that's going to be xyluton z-i-l-e-u-t-o-n right although you kind of want to be careful there because that drug can cause a you know liver toxicity right and then what if they give you a question about a patient and they tell you that, oh, this patient has a newborn. Newborn has like a white reflexes of a red reflex. And then you ask him for the most likely malignancy this person may develop in the future. Well, I would hope with that you're thinking about that kid as a newborn having a retinoblastoma. Having a retinoblastoma. Now, the thing with a retinoblastoma, it can uh you know it's like arabic mutation those people tend to have osteosarcomas in the future right they tend to have osteosarcomas in the future and sometimes they may even ask you what is the most likely location of an osteosarcoma on an mbm exam right it's going to be the knee most times almost like 90 percent of mbme questions that involve osteosarcomas it's going to be a knee problem. And then one thing I kind of want to speak to right now is something that the MBME has been doing in recent times that I don't know, I've just seen too many people get questions wrong as a result of some of these things, right? I call these things alternate MBME vocabulary, right? So what do I mean by that? Basically, what the MBME does is they will take something that you know and just give it a different name. I mean, that's like a classic, classic, classic thing, right, that they love to do with the more recent, the newer NBME exams. Right. So let me just go through some classic things where it has one name that most of us know. But sadly, your friends at the NBME have elected to give it another name that many people may not be very familiar with. Right. example what are some key ones right like so like osteosarcoma instead of calling osteosarcoma on an exam they may call it osteogenic sarcoma right so that's something you want to be aware of another classic one they love to do is a neural tube defects right you want to know that another name for neural tube defects on mbm exams is spinal dysrathism right they may call it a spinal dysrathism on a test uh This other one, you've heard me say it's, you know, ad nauseum, so you want to keep it in mind, right? Like salmonella bodies and laminated calcifications. That's a classic one. Another classic thing they love to do, nephrotic syndrome, right? So remember, nephrotic syndrome, whenever a person has nephrotic syndrome, you're going to find fatty casts in your urine, right? You're going to find lipid casts. So essentially on NBM exams, they may call nephrotic syndrome lipoid nephrosis, okay? Lipoid nephrosis, L-I-P-O-I-D. That's something you want to be aware of. Another classic thing they love to do is they can give you a question about a person with IgA nephropathy. Remember IgA nephropathy, typically people have their symptoms like two to six days after the onset of an upper respiratory infection, right? So sometimes on MBM exams, instead of calling it IgA nephropathy, they may call it a synpharyngitic nephropathy, okay? They may call it a synpharyngitic nephropathy. And then another classic one they love to do is Kawasaki's disease, right? So remember Kawasaki's disease, high fevers for a couple of days in a lateral anterior cervical lymphadenopathy right strawberry tongue they may have a rash on the palms and soles and again remember the mbm is smart they will very likely not put a rash on the palms and soles they can see that the person has edema of the palms and soles or they can tell you that the person has disquamation of the skin over the palms and soles right if you see that you want to think want to think about Kawasaki's, right? Another name for Kawasaki's disease on an NBM exam is something called mucocutaneous lymph node syndrome, okay? And you may be like, come on, Devon, you've got to be kidding me. Trust me, I'm not kidding, right? Mucocutaneous lymph node syndrome, right? Mucocutaneous lymph node syndrome. Okay, so let's continue. Now, what is is the biggest what if they give you a question about a patient and they tell you that this patient was started on um on uh you know like trimethoprim sulfamethoxazole right for for pcp prophylaxis you know in hiv and then they notice that the person a few days later person develops like perioral cyanosis, right? And when they show you that, you know, this person's O2 sat is completely fine, and this person's PAO2 is completely fine. If you see that, I'd really hope that in those circumstances, you're thinking about methemoglobinemia, right? So remember, whenever you take like a drug that's a very powerful oxidizing agent, that can cause methemoglobinemia, right? So for example, what are those drugs, right? It can be a drug like TMP-SNX, right? It can be a drug like a nitrate, right? It can be a drug like Dapsone. Remember, we use Dapsone as PCP prophylaxis in people that, you know, for some reason, they cannot take TMP-SNX. And we also use Dapsone to treat leprosy, right? Remember, we can use a combination of Dapsone, rifampin, and clofazine. That's another use for dapsone. Another one that just came to mind is dapsone can also be used to treat dermatitis herpetiformis. That's associated with celiac disease. I had to think about that for a second, right? So those are all uses for napsone, right? So those are all questions they can frame in the context of a person getting methemoglobinemia, right? So what's the pathophys behind methemoglobinemia? It's actually pretty easy, right? So all the iron that you have in your hemoglobin is in the ferrous form. It's in the Fe2 plus form, right? But if you take a powerful oxidizing agent, right? If you remember from college, oxidation is an increase. Basically, when your oxidation number, when your charge becomes more positive, it means you're becoming oxidized. So if you take a powerful oxidizing agent, essentially the person can go from Fe2 plus to Fe3 plus. Fe3 plus is ferric. Ferric iron cannot carry oxygen.
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And obviously in those circumstances, how do we treat the person? Well, actually, some things we can do, we can give the person, come on, Devine, what are you thinking about? You can give the person methylene blue, right? You can give methylene blue, that's the drug of choice. You can give vitamin C. And then another thing that you may see on exams that you may probably never have heard of in any resources is cimeridine. Cimeridine is, you know, it's an acid-reducing medication. It's a H2 blocker that we use to, you know, bring down people's acid production. Essentially, right, you're blocking the action of histamine from those enterochromaffin-like cells that we find in the stomach, right? So cimeridine is actually pretty good at slowly lowering a person's methemoglobin levels, right? So it's just one of those weird things you may see on a test they may be like what you ever heard of this before right well now you've heard of it right and the thing is if the mbme is really smart if they wrote this question about a person like with tmp smx and they put like oh the person started for pcb prophylaxis uh because obviously i remember you know you do that if the person cd4 is less than 200 and you know they put methembinemia as an answer. You can almost bet that your friends at the NBME, one of the answers they will throw down for you is G6PD deficiency. G6PD deficiency. So you may say, oh, Devine, wow, that's true. How would I have differentiated between G6PD deficiency and methemoglobinemia? Well, let me give you a few tips here. My tips here, first things first, if the question is about a girl, it cannot be G6PD deficiency and methemoglobinemia. Well, let me give you a few tips here, right? My tips here, first things first, if the question is about a girl, it cannot be G6PD deficiency, right? Because I would hope that at this point, you know that G6PD deficiency is X-linked recessive inheritance, right? X-linked recessive inheritance is going to be in a boy on your test. That's one good thing that will help. And usually, people that have G6PD deficiency on MIM exams, they're not going to have like physical signs of cyanosis. Their hemoglobin will be low, but they won't have like perioral cyanosis or any of those weird things, right? And then G6PD deficiency, right, usually there will be some kind of trigger, right? And the trigger can be drugs, but the thing is other things that can trigger G6PD deficiency can be an infection, right? It can be like a really bad infection because when you have bad infections, right, you're going to really need your oxidative burst pathway, right? But to almost like recycle the oxidative burst pathway, you kind of need or, you know, to deal with all those free radicals and stuff and reactive oxygen species, that glutathione pathway needs to work well, right? And you need NADPH from the pentose phosphate pathway, right? Remember G6PD, glucose 6-phosphate dehydrogenase is the reclimitin enzyme of the oxidative phase of the pentose phosphate pathway, right? So they will give you that, right? And they may even give you a blood smear. You may find like those Heinz bodies or those bite cells, right? Or they give you like a geographical association, like the person is from like Southeast Asia or like some African country, probably likely going to be G6PD deficiency as against methemoglobinemia, right? So just things you want to keep at the back of your mind. So I think since we're right at minute 17, I'm just going to go ahead and pause here. But maybe let me say one thing, right? So what is the biggest risk factor for methemoglobinemia? It's actually the use of a nitrate, right? So they can give you a methemoglobinemia question easily. And a person that has a history of angina that is being treated with nitrates, right? Or they can give you like methemoglobinemia question in a person that's having chest pain in the setting of an MI, right? Remember, we give nitrates to people that have MIs to help their chest pain. Although obviously, right, you don't want to give it to a person with an RCA in fact, right? Because those people are preload dependent, right? So you don't want to tank their preload and then cause problems. And then again, as I said at the beginning, if you're interested in signing up for the Step 1, Step 2 CK courses, feel free to shoot me an email and I'll be happy to point you in the right direction. And again, I also offer one-on-one tutoring for many exams. Step 1, Step 2 CK, Step 3, preclinical med school exams, 30-year shelf exams. If you're a medicine resident, I actually tutor for the medicine boards and the medicine in training exam. And then, you know, please subscribe to the channel, Thank you. subscribe to that. And then I also have this podcast on Apple Podcasts, on Google Podcasts, and on Spotify. So please, you know, any subscription, any bit of encouragement definitely helps. And then my life lesson today is about insecurity. So I think one thing that's important amongst people is, or is like actually a fairly prevalent problem amongst many people especially amongst the many um med students is insecurity right they always feel that they are they are lower than what they are the thing is it's actually very important in life to have some sense of self-esteem right and maybe this may be a series that i may talk about like along with my life lessons but i I think maybe one thing I want to say about feeling insecure is stop comparing yourself with other people, right? When you compare yourself with other people, you're always going to, your mind is naturally going to focus on all the inadequacies you have and on all the amazing things about other people, right? So just think about yourself better, right? I think really this insecurity of a thing is something that you need to be very intentional about. It requires a very fair amount, like a wee bit of emotional intelligence. And I think another thing too that also maybe is like a related concept. I don't even know if it's maybe even related to what I'm talking about. But it's just the importance of not trying to please everybody, right? That's one thing I used to do a lot in the past where I used to try to just help people out as much as I can. I'm not saying I don't like helping people. Don't get me wrong. I mean, to this day, it's one of my primary models in life is to help people, right? Because again, what's the point of you being on this earth if you're not doing any good in people's lives, right? But the thing is, you don't always have to say yes to everything, right? You know, sometimes in life, you should say no, right? The asserting is not everything you're supposed to agree to because when you're like a yes man or a yes woman, and people know that, oh, they can toy with your emotions, they will just pretty much just walk all over you, right? Like there are some people where they're in a relationship with someone and let's say, oh, they're like, oh, you know what? I'm a Christian. But then someone that they've met, that they've fallen for that, oh, they're like, man, this person is great. I love this person so much. The person kind of pressures, pressures, pressures them, right? And they then don't set boundaries. And then they do things that they don't want to do just because they feel insecure, just because they feel that, oh, they could never get someone better than the spouse that they currently have, right? I mean, like, I've heard this story many times for many people doing things that are unseemly, doing things that they just really did not want to do in the first place, right? So I think just don't, you don't always have to say yes to people, right? It's hard, but the thing is, and people may think you're mean initially, but over time, they'll begin to respect you because you have boundaries, right? So the thing is, you have to first respect yourself so that other people can respect you, right? So don't always be a yes man, right?
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Right. Because, again, if you if your life revolves around wanting to please people, you're going to get in trouble. Right. In fact, like I mean, as for me as a Christian, like if if I said, oh, I'm always going to please people, then there will be things that I will do that are not consistent with the Bible. Right. So, again, people are not always going to be happy with you. There's always going to be someone that hates you or hates something about you, right? So you're not always going to be able to please everybody, right? So just do what is comfortable for you. Do what agrees with your values. Do what agrees with your principles and then deal with the consequences, right? And usually you'll be blessed for it in the end, right? You usually come out on top in the end when you do that. So thank you for listening to this podcast. I'll see you in the next episode. Thank you and God bless you. See you next time.
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Hello and welcome to the latest podcast from the Lancet Neurology. I'm Neil Bennett and today I'm joined on the line by Dr. Nicholas Abend, who is Assistant Professor of Neurology and Paediatrics at the Children's Hospital of Philadelphia. Dr. Abend is one of the authors of a review article in this month's issue about electrographic seizures and electrographic status epilepticus in critically ill children and neonates with encephalopathy. Dr. Abend, many thanks for speaking to us today. Can you start by explaining what are electrographic seizures and electrographic status epilepticus? Electrographic seizures are defined as abnormal, paroxysmal, electrographic events that have to stand out from the EEG background and evolve in frequency, morphology, and spatial distribution. So the definition of electrographic seizures that we see on EEG is really the same as what we define seizures for many other EEG settings, such as the epilepsy monitoring units. Within electrographic seizures, I think they can be classified as two big types, and these are electroclinical seizures, which are sometimes also called convulsive seizures or clinically evident seizures, in which there's some sort of clinical manifestation to the seizure. Or a second type would be EEG-only seizures, which are sometimes called non-convulsive or subclinical seizures, in which we see the electrographic seizure on EEG, but we don't see any associated clinical change, either at bedside watching the patient or with time-locked video. Another difference between electroclinical and EEG seizures is that traditionally, electroclinical seizures can be of any duration. So a very brief seizure, even a split second with a clinical change, would be a seizure, such as myoclonic seizures. In contrast, for the EEG-only seizures, people have traditionally defined these as lasting 10 seconds or more, and this is used as a way of trying to differentiate seizures from various periodic or rhythmic patterns, although it's really based on nomenclature, and there isn't great data that this 10-second distinction has implications for management or outcome. And then the final definition to think about is electrographic status epilepticus. And this has been variably defined. Sort of most broadly, people have defined it as an enduring epileptic disorder with altered consciousness throughout. And this provides a pretty good sense for the disorder, but it's hard to really use enduring as a quantitative measure of seizure burden in clinical practice or research. A more recent guideline by the Neurocritical Care Society in 2002 defined status epilepticus as five minutes or more of continuous clinical or electrographic seizures or recurrent seizures without a return to baseline. So throughout this recent guideline, they've sort of considered electroclinical seizures and electrographic-only seizures as equivalent in terms of definitions and management implications. And the idea here was to define status epilepticus as occurring after only a brief period, five minutes, since it would help prompt rapid management by clinicians. The last definition that people have tried to use in some studies where they wanted to distinguish between patients with a low seizure burden and a high seizure burden has been to define electrographic status epilepticus as 30 minutes or more of seizure within a one-hour period. So this could be a single 30-minute seizure, or it could be multiple brief seizures that total 30 minutes in an hour. And this is the definition that was proposed in the recent American Clinical Neurophysiology Society EEG terminology guidelines, and it's been used in some of the studies trying to address the impact of seizures on outcome. Now your review article is about electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy. Can you tell us a little bit about the epidemiology and risk factors in these populations? Epidemiology advancement has been one of the exciting areas in the last several years. So I'll start with neonates, where we know that seizures are very common. Probably about 2 per 1,000 term births will experience neonatal seizures, and they're due to a large array of heterogeneous etiologies, such as hypoxic ischemic encephalopathy, infection, cerebral dysgenesis, strokes, metabolic disorders, and very rarely epilepsy syndromes. And in neonates, a couple of trends have emerged from the literature that really suggest the importance of EEG monitoring in neonatal seizure diagnosis and management. So the first is that unfortunately we can't predict which babies are going to experience seizures very well. For example, studies that have used clinical criteria such as Sarnod encephalopathy scores and APGAR scores and pHs weren't very predictive. Even EEG background hasn't been highly predictive. Seizures occur in only half of babies with abnormal EEG backgrounds, although a normal EEG background does suggest seizures are unlikely. The second issue that's led to the sense that EEG monitoring is required for neonatal seizure diagnosis and management has been that clinical seizure diagnosis is difficult. And studies have looked at expert neonatologists and clinicians reviewing videos of events in neonates. And some of these studies have suggested that these expert reviewers only have correct identification of seizures as of events as seizures or not seizures in about 50% of babies with poor inter-rater agreement. Other studies have shown that we both under-diagnose and over-diagnose seizures based on clinical observation alone. In one study, staff identified only 9% of 526 seizures as being seizures, so a substantial under-diagnosis. And in the same study, 78% of 177 paroxysmal events were considered seizures but didn't have any EEG correlate, suggesting the potential that without EEG monitoring, we also have overdiagnosis, leading the babies to get exposed to anticonvulsants that they may not need. And the final trend suggesting the importance of EEG monitoring has been the realization that even if we were good at identifying seizures clinically, unfortunately most seizures in babies have no clinical correlate. A number of studies have shown that only the minority of neonatal seizures seen on EEG have a clinical correlate that can be appreciated, and this is particularly common after these babies receive anticonvulsants, where we see an electroclinical uncoupling or dissociation after administration of phenobarbital or phenytoin, in which electrographic seizures may persist while the clinical manifestations cease. There are a couple of conditions that have been studied in a lot of detail in neonates. One of these is hypoxic ischemic encephalopathy, including babies receiving therapeutic hypothermia. And several studies from different centers have shown that about 30% to 50% of babies with HIE, undergoing therapeutic hypothermia, experience electrographic seizures. About 10% to 20% of those babies are experiencing status epilepticus, and about half of those babies have exclusively subclinical or EEG-only seizures, which we wouldn't identify by clinical observation alone. A second group that's undergone a lot of study has been babies undergoing cardiac surgery for congenital heart disease, where a number of studies have shown perioperative EEG-only seizures in 6 to 20 percent of patients. And the third group is babies undergoing ECMO, where several studies have reported electrographic seizures in 10 to 30% of babies. There have been more recent studies looking at the pediatric population. For example, one of our studies looked at 100 critically ill children who were enrolled consecutively and underwent EEG monitoring if they were in the PICU with an acute neurologic disorder and altered mental status. We identified electrographic seizures in 46 of 100 consecutive children. Nineteen of these patients with seizures were experiencing status epilepticus. And for both the patients with seizures and status epilepticus, the majority experienced non-convulsive or EEG-only seizures. It was the minority of patients who had any clinical correlate to their seizures. And this type of data has really been replicated across a large number of studies in critically ill non-neonatal children now, with a number of studies showing anywhere from about 10 to 40 percent of patients who undergo EEG monitoring with a variety of etiologies, for example, hypoxic ischemic brain injury, traumatic brain injury, or stroke, or CNS infections, will experience electrographic seizures. Across many of these studies, about 25 to 75 percent of children experience only EEG seizures, which would be missed without EEG monitoring, despite the best clinical observation. Several studies have explored whether these critically ill children have an electromechanical uncoupling, like described in neonates, or whether they're just receiving paralytics that cover up any clinical manifestation. And several studies have found that it's actually the minority of patients experiencing EEG-only seizures who are also receiving paralytics. In one study, 50% of patients with EEG-only seizures hadn't received any paralytics. So we think that in critically ill children, there's evidence for this electromechanical uncoupling like we see in neonates, and that we aren't simply blocking the manifestations of seizures with paralytics. In an effort to get more information about epidemiology in critically ill children, the review paper describes a recently published data set from the Critical Care EEG Monitoring Research Consortium.
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This study was much bigger than many of the single center studies. Electrographic seizures occurred in 30% of the 550 subjects, and these were sufficiently high seizure burden to be classified as status epilepticus in 38% of those patients. 36% of the patients had no clinical correlate associated with any of the EEG seizures. And in multivariable analysis, risk factors for seizures included younger age, particularly less than two years, clinical seizures prior to EEG monitoring onset, an abnormally EEG background, interictal epileptiform discharges, or a diagnosis of epilepsy. These risk factors have been replicated in many of the single center studies as well. Consistent clinical risk factors across studies have included younger age, convulsive status epilepticus or acute seizures, and acute structural brain injury, including traumatic brain injury. Electrographic risk factors have been the lack of EEG reactivity, epileptiform discharges, or background discontinuity. And can you explain what effect do these seizures have on outcome? Yeah, I think that is really a key question underlying all of this work. Clearly, we know that brain injury can cause acute symptomatic seizures, and the question is whether the occurrence of these seizures can worsen the underlying brain injury. If it does, then potentially identifying and managing these seizures could be a neuroprotective strategy that could improve neurodevelopmental outcomes in our patients. I'll just summarize a little bit of the data related to the impact of seizures on outcome. One study by Gluckman and Lancet, 2005, was an analysis of the CoolCap study. 218 neonates were randomizedOLCAP versus normothermia. And as part of this general study, they also had amplitude-integrated EEG monitoring. Seizures identified with amplitude-integrated EEG monitoring were associated with a more unfavorable outcome. A second study by Van Rouge in Pediatrics 2007 looked at high-risk term infants undergoing amplitude-integrated EEG. They found among the overall group, there was no difference in seizure burden among those with poor or good outcomes. However, in the subset of patients with hypoxic ischemic encephalopathy, patients with poor outcome had a significantly higher seizure burden than patients with good outcome. A third study in neonates by Glass in Journal of Pediatrics 2011 found that among 61 neonates undergoing hypothermia for HIE, the presence of seizures were associated with more moderate to severe injury on MRI scans. And in terms of neurologic outcomes, a study by McBride in Neurology 2000, with asphyxia, the presence of electrographic seizures was associated with increased risks for severe cerebral palsy, death or cerebral palsy, or microcephaly. The issue with many of these studies, though, is that they don't adjust for the underlying brain injury severity, and it may be that patients with worse brain injury have worse outcomes and experience acute symptomatic seizures. Some recent studies have tried to do more adjustment. For example, a study by Glass in Journal of Pediatrics 2009 looked at 77 term babies with HIE. They had a complex seizure scoring system and severity of injury on MRI scoring system that really got at the overall seizure burden and timing and the amount of brain that looked injured on MRI scans. And they found that even after adjusting for the amount of injury present on MRI, patients with severe seizures had lower IQ scores at four years than patients with mild or moderate seizures or no seizures. And this was a substantial reduction in IQ. For example, babies with no seizures had an IQ of 97, whereas those with severe seizures had an IQ of 67. Babies with congenital heart disease have been studied extensively regarding outcome. And one of the most recent useful studies was by Bellinger in Circulation 2011. They looked at 159 adolescents who had been followed ever since they were newborns with detransposition of the great arteries, and they did detailed neuropsych testing as adolescents. They found that the occurrence of seizures in the postoperative period was the medical variable most consistently associated with worst neuropsych outcomes. And these were scores greater than one standard deviation below the expected mean on some of these tests, suggesting they are clinically significant. There have been some recent studies looking at the impact of seizures and outcome in critically ill children. In a study by Kirkham in intensive care medicine in 2012, 204 critically ill children in neonates were studied, and they found that even in multivariable analysis, which included age, gender, etiology, and various coma and index of mortality scores, the presence of electrographic seizures was associated with an increased risk for seizures for unfavorable outcome with an odds ratio of 15.4. In a study by our group published by Topgen in Critical Care Medicine in 2013, 200 children were prospectively enrolled if they were in the PICU and underwent EEG monitoring for an acute neurologic disorder and altered mental status. The EEGs were scored as no seizures, seizures, or status epilepticus. We looked at outcome, including mortality, and whether they had a worsening in their pediatric cerebral performance category scores. Overall, 21% of our patients had seizures and 22% had status epilepticus. In multivariate analysis, even after adjusting for age, their neurologic disorder category, their PRISM scores, and their EEG background, the presence of electrographic status epilepticus was associated with increased mortality with an odds ratio of 5.1 and an increased risk of worsened pediatric cerebral performance category from admission to discharge with an odds ratio of 17.3. In contrast, just having electrographic seizures but not electrographic status epilepticus was not associated with an increased risk for unfavorable outcome. In the multicenter study I described earlier, we looked at 550 patients with an outcome of mortality. 18% had electrographic seizures, and 11% had status epilepticus. And in multivariate analysis that included age, sex, prior neurodevelopmental and neurologic disorders, EEG background categories, and neurologic diagnosis categories, the presence of electrographic status epilepticus was associated with an increased risk for mortality. However, the presence of just electrographic seizures was not associated with an increased risk for mortality. So overall, I think what we're seeing in both neonates and children is that there's a dose-dependent or threshold effect in which seizures, especially if they're a high seizure burden, do have a clinically relevant impact on outcome, and that this outcome persists even in studies that adjust for the severity of the injury and the type of injury. Clearly, we still need data, though, addressing whether EEG-guided management to identify these seizures and then treat them actually improves outcome. Finding that these seizures are associated with worse outcome does not necessarily mean yet that we have appropriate management strategies to intervene to improve outcome. An important focus of your review is the use of different EEG strategies for monitoring and identifying seizures in clinical practice. What does the evidence suggest is the best approach? I think that is a really clinically relevant question that many people are trying to think about and develop institutional pathways to help guide management. We've already talked about some of the risk factors for seizures, which might help identify patients who need management. Another important aspect is considering how long to monitor these patients. There's data that most seizures are identified with one or two days of EEG monitoring. For example, in neonates, a study by Lynch in Epilepsia 2012 found that with babies with HIE, the maximum seizure burden occurred at 22 hours, although there was substantial variability between about 6 hours and 90 hours. A study by Wusthof in Journal of Child Neurology 2011 in babies with hypoxic ischemic encephalopathy undergoing hypothermia found that seizure onset was highly variable and occurred during hypothermia, rewarming, and rarely in babies upon return to normothermia. And at least in our practice, this has led us to monitor most neonates where we're worried about seizures for about one to two days, but to monitor babies with HIE undergoing hypothermia for longer. We generally monitor them while they're hypothermic, rewarming, and for about 12 to 24 hours after returning to normothermia. Additional data is available in critically ill children. A number of studies have found that about 80 to 95 percent of seizures are identified within 24 hours of monitoring. There's never been a study that's monitored everyone for a long period of time, say a week. So there's probably a slight tail here that the studies haven't picked up. And if we monitored everyone for longer, we would find slightly more seizures occurring later. But I think the data now suggests that monitoring for one or two days will identify the majority of patients. In a survey that we did, published in Neurocritical Care 2010, we asked 330 physicians how long they monitor if seizures are not identified. And the majority of respondents said that they monitored for 24 hours and then discontinued if seizures were not identified. People tended to monitor slightly longer, 48 hours, if periodic epileptiform discharges were present or if patients were comatose.
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A number of studies have looked at this in neonates, for example, by Glass and Pediatric Neurology 2012. They surveyed an international group of neonatologists and neonatal neurologists and found that 24% monitor at-risk newborns with EEG, 24% monitor with amplitude-integrated EEG, 19% monitor with both, and 34% don't do any EEG monitoring. The majority of patients are monitored for more than 60 minutes. A survey addressing similar issues in the pediatric population, published by our group in Journal of Clinical Neurophysiology 2013, surveyed 61 institutions in North America, the United States and Canada, and identified that over one year there was a 30% increase in the patients who underwent EEG monitoring. In the United States, the year the survey was conducted, a median of 10 patients per month were undergoing EEG monitoring in the pediatric intensive care units. There's some data that all of this monitoring does impact seizure burden. Probably the best study looking at this was by Van Rouge, published in Pediatrics 2010. They studied 33 neonates with hypoxic ischemic encephalopathy. All of the babies underwent amplitude integrated EEG monitoring, so they knew whether seizures were occurring and the overall seizure burden for all babies. However, the babies were randomized so that the doctors taking care of them either managed them exclusively with clinical information or with clinical and amplitude integrated EEG information. And they found that when the doctors had access to the amplitude integrated EEG data, the babies were exposed to a lower seizure burden. And this makes sense. If the majority of seizures in neonates are EEG only, then if we don't have some EEG data in order to help guide our management, we won't target all of the seizures for treatment. But it's the best data to date that this approach of EEG monitoring does lead to a lower seizure burden exposure in our patients. In the pediatric population, our group published a study in Neurocritical Care 2011 where we looked at 100 consecutive patients who underwent EEG monitoring, and we found that this monitoring led to management changes in 60% of critically ill children. The most common changes related to anticonvulsant adjustments, either initiating or escalating medications for seizures, or rarely discontinuing medications because events were found to be non-ictal. Overall, the data out there has led to several guidelines. The first was published by the American Clinical Neurophysiology Society related to EEG monitoring in neonates in the Journal of Clinical Neurophysiology 2011. EEG monitoring was suggested for a variety of uses, but most often to detect electrographic seizures in high-risk neonates. The guideline included a list of many neonates considered to be high-risk, and these included babies with acute neonatal encephalopathy, cardiac or pulmonary risks for brain injury, CNS infections, CNS trauma, inborn errors of metabolism, stroke, or genetic or syndromic diseases involving the central nervous system. The guideline recommended monitoring neonates at high risk for seizures with conventional EEG for 24 hours. If seizures were identified, the guideline suggested that monitoring should continue until the patient was seizure-free for 24 hours. And the guideline indicated that the first hour of EEG should be interpreted as soon as possible, with review of the EEG tracing at least twice per every 24-hour epoch. And the idea here is that initial rapid review and frequent reviews of the EEG are needed if we're going to use this data to truly impact clinical management. The second related guideline was from the Neurocritical Care Society, published in Neurocritical Care in 2012, addressing the evaluation and management of status epilepticus. The guideline addressed children and adults, and while most related to the management of convulsive status epilepticus, there were some parts that were related to EEG monitoring. For example, status epilepticus was defined as five minutes or more of continuous clinical or electrographic seizure activity or recurrent seizures without recovery to baseline. So in this guideline, all of the recommendations are made similarly for clinically evident convulsive status and electrographic status epilepticus. The guideline continues to suggest that the treatment of status should occur rapidly and sequentially until all electrographic seizures are halted. So we shouldn't just stop the convulsive seizures. We need to just as aggressively identify and try to stop the electrographic-only seizures. They suggest that we should try to initiate EEG monitoring as rapidly as possible if we suspect ongoing seizures, and that most patients who are comatose should undergo monitoring for 48 hours if we're trying to identify nonconvulsive seizures. They list some of the patients who may be at risk for nonconvulsive seizures as patients who have had recent seizures or status without a return to baseline, patients who are comatose, including after cardiac arrest, patients with intracranial hemorrhages, including traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage, and other patients with suggested non-convulsive seizures due to altered mental status of unknown or other etiologies. I think the final issue related to clinical implementation relates to quantitative EEG. If we're going to try to identify and manage seizures in these patients, we have a lot of EEG to read. 24 hours displayed at 15 seconds per page yields 5,700 pages of EEG to review. And one approach to this has been to try to use quantitative EEG trends, such as amplitude-integrated EEG or density spectral array EEG, in order to better and more efficiently identify seizures. A number of studies have looked at the efficacy of amplitude-integrated EEG for identifying seizures in neonates. For example, a study by Shellhaus in Pediatrics 2007 looked at full-array EEG, which was converted to amplitude-integrated EEG tracings and reviewed by six neonatologists. They found that using amplitude-integrated EEG, the reviewers identified only 40% of the records with seizures and only 26% of the actual seizures. So while amplitude-integrated EEG does seem to work for many seizures, it is certainly not perfect or nearly as good as conventional EEG for seizure identification. A number of studies have looked at factors related to seizure identification by amplitude-integrated EEG. Some factors are modifiable. For example, the neonatologist's level of amplitude-integrated EEG experience matters. However, unfortunately, some are also not modifiable. Some seizures are simply not visible in the amplitude-integrated EEG channels and would require more extensive EEG channels in order to identify. Additionally, seizures that are short in duration, have a low amplitude, or evolve slowly are often not identified with amplitude-integrated EEG. Several studies have looked at issues that might improve seizure identification. Wusthof in Journal of Perinatology 2009 found that placing electrodes centrally rather than on the forehead improved yield. Fan Rouge in Archives of Disease of Childhood in 2010 found that adding a second amplitude integrated EEG channel was helpful. And Shaw in Pediatrics 2008 found that use of simultaneous amplitude and regular EEG improved sensitivity for seizure identification. There's been less study looking at the use of quantitative EEG trends in non-neonatal critically ill children. Our group in the Journal of Clinical Neurophysiology looked at 21 consecutive PICU patients. We converted their full-array EEG into eight channels of density spectral array EEG. We then had eight neurophysiologists review these transyncs in order to determine whether seizures were present or not. The idea of density spectral array EEG is that if a seizure increases the amplitude of the tracing, this is shown in warmer colors, and if seizures increase the amplitude of the tracing, this is shown as higher values on the vertical axis. We found that overall, CDSA could miss some seizures. The overall sensitivity was about 70%. We also found that CDSA could identify some artifacts as seizures. The overall specificity was about 85%. So like amplitude-integrated EEG, DSA seems to have some role, but it's certainly not perfect, and it can both over-diagnose and under-diagnose seizures. A second study by Stewart, published in Neurology 2010, looked at 27 PIC-UEG tracings that were converted to density spectral array and amplitude integrated EEG and reviewed by three neurophysiologists. They found that the overall median sensitivity for seizure identification with density spectral array was 83% and with amplitude integrated EEG was 82%. However, for individual patients' tracings, the sensitivity varied from 0 all the way up to 100%, suggesting for some patients this works very well, and for other patients it does not work well for seizure identification. A study by Ackman in Epilepsy Research 2011 found that some factors impacting seizure identification included some modifiable factors, such as interpreter experience and the display size. Two hours was better than four hours. But there were also some inherent characteristics to the seizures that we couldn't modify, such as spike amplitude, seizure duration, and seizure frequency. So overall, I think there's data that electrographic seizures and status epilepticus are common in critically ill children and neonates with acute encephalopathy. Most of these seizures are EEG-only seizures, which we couldn't identify without continuous EEG monitoring.
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We don't have ideal data yet, and there's certainly work to be done, but our belief is that there's enough data from animal models, supportive physiologic evidence in humans, and epidemiological evidence linking a high seizure burden to worsened outcome, that we should pursue identification of seizures and treatment of electrographic seizures and status epilepticus in critically ill neonates and children. However, we all clearly recognize that the treatment for seizures can have adverse effects, and future study is needed to better define how aggressive we should treat these seizures when we find them. Although we certainly don't advocate the urgent or aggressive treatment of every brief self-limited seizure, since treatment might lead to side effects that are worse than the seizures. Our general aim is to avoid a high seizure burden through the use of anticonvulsants with tolerable side effects. Clearly, decisions about how to best treat these seizures in an individual patient need to be tailored to that patient's unique clinical circumstances and medical comorbidities and might reasonably vary across patients. Finally, can you tell us what are some of the most important topics of future research in this area? Yeah, I think this is one of the exciting fields because there's a lot of work to be done. First, I think we need better basic science research identifying the molecular mechanisms whereby electrographic seizures or status epilepticus could lead to neurocognitive deficits in epilepsy. And as we improve our understanding of these molecular mechanisms, we'll have a better understanding of the impact of these seizures and potential ways to intervene. So all of the lab research that's going on now and that we describe in this review paper I think is very exciting in addressing this issue. The second is that clinical research is needed to elucidate the effect of varying seizure burdens on neurodevelopmental outcomes. And in these studies, we need to control for the brain injury type and severity, and also the coexisting medical illnesses. This type of work needs to establish whether some seizure types or durations are more injurious than others, and whether the effect of these seizures is modulated by age, the etiology of the brain injury, or other clinical variables. Third, we need to figure out what is the optimal approach for managing these seizures in status epilepticus. This approach might be different in patients of varying ages, etiologies, and comorbidities, but we need to better understand which drugs work and how we should use these medications in this setting. Finally, putting those things together, we need to determine whether identification and management of these seizures using the optimal approaches actually improves neurodevelopmental outcomes. Clearly, work is still needed, but if we can identify and manage electrographic seizures without causing potentially harmful adverse effects, then this might serve as a neuroprotective approach, which could lead to improvement in our patients' neurodevelopmental outcomes. Dr. Abend, many thanks indeed for taking the time to speak to us today. For more details or to download the review, visit thelancet.com. Many thanks for listening. See you next time.
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This audio summary is sponsored by MerckMedicus.com, your source for unbiased medical information. Now accessible by PDA, smartphone, and BlackBerry. Welcome to the New England Journal of Medicine audio summary for the week of July 12, 2007. I'm Dr. Lisa Johnson. This week's issue features articles on clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations, PEG interferon and ribavirin for 16 or 24 weeks in chronic hepatitis C, neural tube defects and folic acid fortification in Canada, Medicare services and costs for previously uninsured adults, and primary care and pay for performance in England, a review article on management of an inherited predisposition to breast cancer, a case report of a woman with headaches, weakness, and stroke-like episodes, and a perspective article on Virginia Tech and the restructuring of college mental health services. And another that asks, is zero the ideal death rate? Clinical Outcomes of Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations by Gad Renert from the Carmel Medical Center in Haifa, Israel. Breast cancer is the leading cause of all deaths from cancer among Israeli women. To some extent, the high proportion of cases in young women reflects the high prevalence of hereditary breast cancers in Jewish women. In this national population-based study, 10-year survival rates were estimated for women with a BRCA1 or BRCA2 mutation as compared with women without a detected mutation. A BRCA1 or BRCA2 mutation was identified in 10% of the women who were of Ashkenazi Jewish ancestry. The adjusted hazard ratios for death from breast cancer were not significantly different among mutation carriers and non-carriers. Among women who were treated with chemotherapy, the hazard ratio for death among BRCA1 carriers was 0.48. Breast cancer-specific rates of death among Israeli women are similar for carriers of a BRCA founder mutation and non-carriers. Patricia Harchie from the National Cancer Institute writes in an editorial that learning whether a patient who has just been given a diagnosis of breast cancer also bears one of the cancer-causing mutations in the BRCA1 or BRCA2 genes may add little to the clinician's ability to select a therapy or predict the course of disease once the grade and receptor status of the tumor and the age of the patient are taken into account. The study by Rennert and colleagues supports that line of reasoning. Reliable data on clinical outcomes in carriers are essential in helping patients and clinicians decide whether to test for mutations and how to use the results. Genotype 2 or 3, by Mitchell Schiffman from the Virginia Commonwealth University Medical Center in Richmond. The currently recommended treatment for patients infected with hepatitis C virus, HCV, Genotype 2 or 3, is PEG interferon plus 800 milligrams of ribavirin daily for 24 weeks. Approximately 80% have a sustained virologic response with this regimen. This trial determined whether similar efficacy could be achieved with only 16 weeks of treatment with PEG interferon-alpha-2a and ribavirin. More than 1,400 patients with HCV genotype 2 or 3 were randomly assigned to receive 180 micrograms of PEG interferon alpha-2a weekly plus 800 milligrams of ribavirin daily for either 16 or 24 weeks. This study failed to demonstrate that the 16-week regimen was non-inferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks, 62% versus 70%. In addition, the rate of relapse was significantly greater in the 16-week group, 31% versus 18 from the National Institutes of Health, writes that gene expression profiling and large-scale genomic marker analysis have already delivered tantalizing insights into the variable nature of disease progression and treatment response in people with HCV infection. In addition, they provide important tools to guide therapeutic options. How can we harness these advances for the clinical management of infection with HCV? A customized management and therapeutic regimen would be designed for each patient. In the context of the study by Schiffman and colleagues, patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity, who are black, older, and male, should be treated for 24 weeks. And whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration. Reduction in neural tube defects after folic acid fortificationification in Canada by Philippe de Walls from Laval University in Quebec, Canada. In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural tube defects was historically higher in the eastern provinces than in the western provinces. These investigators assessed changes in the prevalence of neural tube defects in Canada before and after food fortification with folic acid was implemented. More than 2,400 subjects with neural tube defects were recorded among 1.9 million births. The prevalence of neural tube defects decreased from 1.58 per 1,000 births before fortification to 0.86 per 1,000 births during the full fortification period, a 46% reduction. Furthermore, the risk reduction appeared greatest in regions in which the rates were highest before the fortification program was implemented. The observed reduction in rate was greater for spina bifida, a decrease of 53%, than for anencephaly and encephalocele, decreases of 38% and 31%, respectively. Use of health services by previously uninsured Medicare beneficiaries by J. Michael McWilliams from Brigham and Women's Hospital in Boston, Massachusetts. Uninsured near-elderly adults, those older than 50 years of age but younger than 65, receive fewer basic clinical services, are more likely to experience health declines, and die at younger ages than insured adults in the same age group. These adults may enter the Medicare program with greater morbidity and may require costlier care than they would have had they been insured before age 65. In this study, longitudinal data were used to assess self-reported health care use and expenditures among adults who were privately insured or uninsured before Medicare coverage began at the age of 65 years. Among almost 3,000 adults with hypertension, diabetes, heart disease, or stroke diagnosed before 65 years of age, previously uninsured adults who acquired Medicare coverage at the age of 65 reported significantly greater increases in the numbers of doctor visits and hospitalizations and in total medical expenditures than did previously insured adults. In analyses adjusted for supplemental and prescription drug coverage, previously uninsured adults with these conditions reported more doctor visits, more hospitalizations, and higher total medical expenditures from ages 65, These findings suggest that the additional cost of providing Medicare coverage before age 65 may be offset by reductions in Medicare costs after age 65. Management of an Inherited Predisposition to Breast Cancer, a clinical practice article by Mark Robson and Kenneth Offit from the Memorial Sloan Kettering Cancer Center in New York. A family history of breast cancer, especially of early onset, is a clearly established risk factor. Although up to 15% of healthy women will have at least one first-degree relative with breast cancer, this article addresses the treatment of women from families with multiple generations with breast cancer, often early in onset. Risk can be transmitted by either men or women, and the probability that a child will inherit a parent's susceptibility is 50%. A germline mutation in the BRCA1 or BRCA2 gene is the most commonly detectable cause of a heritable risk of breast cancer. However, only about 40 to 50 percent of families with multiple cases of female breast cancer but no cases of ovarian or male breast cancer are linked to these genes. Mutations in other genes may also increase breast cancer risk, but extensive investigation fails to detect a cause in many families. Although imperfect, annual mammography is recommended for women with BRCA mutations beginning between the ages of 25 and 30 years, when breast cancer risk begins to increase. For women without documented BRCA mutations who have a substantial familial risk of breast cancer, screening is suggested to begin at an age that is 5 to 10 years earlier than the youngest age at diagnosis in the family. This article reviews the empirical models that estimate a woman's risk of having breast cancer, specialized breast cancer surveillance, screening for other cancers, and strategies for reducing risks. Thank you. a case record of the Massachusetts General Hospital by David Greer and colleagues. A 58-year-old woman with type 1 diabetes was admitted to the hospital because of a two-week history of increasing fatigue and word-finding difficulties and a two-day history of right arm weakness. Three years before admission, an episode of word-finding difficulty had occurred, associated with headache and mild right-sided facial weakness. MRI had revealed a punctate subcortical lesion in the left parietal white matter. The symptoms resolved spontaneously within a few hours.
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She had a 30-year history of type 1 diabetes, complicated by retinopathy, neuropathy with gastroparesis, nephropathy, and cardiovascular disease. Neurologic examination upon the current admission showed mild disorientation, inattention, progressive cognitive difficulties, a right ptosis, diffuse motor weakness that was worse on the right side than on the left, neuropathy with a small fiber-stocking distribution, and right-sided dysmetria. A brain biopsy was performed on the 14th hospital day. Quality of primary care in England with the introduction of pay-for-performance by Stephen Campbell from the University of Manchester in the United Kingdom. In 2004, the United Kingdom committed $3.2 billion to a new pay-for-performance contract for family practitioners. During the first year, the levels of achievement exceeded those anticipated by the government, with an average of 83.4% of the available incentive payments claimed. However, the quality of care in English family practices had already begun to improve in response to a wide range of initiatives, including national standards for the treatment of major chronic diseases and a national system of inspection. This report presents data from a longitudinal study that measured the quality of care before the Pay for Performance program was introduced and after its introduction. The quality of care in the categories of coronary heart disease, asthma, and type 2 diabetes improved between 2003 and 2005, continuing the earlier trend. However, the increase in the rate of improvement between 2003 and 2005 was significant for asthma, P less than .001, and diabetes, P equal to .002. Scores for coronary heart disease also increased, but the change in the rate of improvement was not significant, P equal to .07. These results suggest that the introduction of pay for performance was associated with a modest acceleration in improvement for two of these three conditions. Falling Through the Cracks Virginia Tech and the Restructuring of College Mental Health Services A perspective article by Miriam Shookman, a national correspondent for the Journal. life, some disturbing facts about his mental health history have emerged. At various points during Cho's college career, Virginia Tech police officers, professors, and students recognized that he was mentally troubled. But although state psychiatric evaluators once briefly committed him to a psychiatric hospital, it is unclear whether anyone from the school monitored him after his release. These discoveries have left investigators wondering whether the killings could have been prevented, and college mental health specialists debating the best way to keep other disturbed students from falling through the cracks. Colleges and universities are regulated under the Higher Education Act, which has absolutely no standards whatsoever for mental health, notes Joanna Locke, a program director at the Jed Foundation, a New York-based organization aimed at preventing campus suicides. And yet, U.S. colleges are full of stories of troubled students who become suicidal. It is impossible to know what difference outpatient mental health care might have made for Cho. The counseling piece is a critical part in the college environment, and there truly was no counseling, said emergency physician Marcus Martin at the Governor's Investigatory Panel meeting in Fairfax on June 11. And it is not clear whether tech's leaders were aware of the crisis. Is Zero the Ideal Death Rate? A perspective article by Thomas Lee from Partners Healthcare System in Boston. Massachusetts recently joined New York, New Jersey, and Pennsylvania in reporting death rates associated with cardiac surgery for individual surgeons, another wave in the tide of public reporting that is sweeping the country. Such reporting raises questions about distinguishing the goals that define one's work from the targets used to measure success. For hospitals and physicians, minimizing death and complications is an undisputed goal. But is zero the ideal target for measures of performance with respect to death and complications? As strategies for improving health care by measuring quality are implemented through pay-for-performance contracts and public report cards, subtle but important differences among performance measures are emerging. The simplest performance measures describe compliance with a standard of care, such as administration of aspirin after acute myocardial infarction in the absence of contraindications. But for a second type of measure, no ideal standard of care exists, so perfect performance cannot be defined. Instead of measuring defects, data are used to describe variation. The question is, do rates of death and complications fall into the first category or the second? At first glance, these measures have a clear goal, zero. However, public performance measures that push providers toward apparent perfection in these areas can have unintended, perverse consequences. This week's images in Clinical Medicine features a 57-year-old man who had end-stage renal disease and was admitted to the hospital because of infection of a left upper extremity fistula. Blood cultures grew methicillin-resistant staphylococcus aureus. Visual inspection revealed marked subconjunctival hemorrhage. Ophthalmologic examination showed vitreous debris and retinal traction, which were consistent with endogenous endophthalmitis. The images in clinical medicine also feature a 70-year-old man who was admitted to the hospital for evaluation of thickening of the skin. Four years earlier, he had undergone kidney transplantation for end-stage renal disease. Two months before this admission, hemodialysis was reinitiated because of allograft failure. At that time, magnetic resonance angiography of the transplanted kidney with gadolinium enhancement showed no evidence of renal artery stenosis. Nephrogenic fibrosing dermopathy is an uncommon sclerosing skin condition that has been associated with the use of gadolinium in patients with renal failure. A letter to the editor in this week's issue reports on a 37-year-old man who had been jogging in a thunderstorm, listening to his iPod, when an adjacent tree was struck by lightning. Witnesses reported that he was thrown approximately 8 feet from the tree. He suffered second-degree burns, including in the external auditory meatus bilaterally. Both tympanic membranes were ruptured, and he had a severe conductive hearing deficit as well as a mandibular fracture. Although people may be struck directly by lightning, it is more common for the lightning to jump to a person from a nearby object, a phenomenon known as a side flash. Although the use of a device, such as an iPod, may not increase the chances of being struck by lightning, in this case the combination of sweat and metal earphones directed the current to and through the patient's head. And finally, the polling results are in from our new interactive feature, Clinical Decisions. The case presented three treatment options for a 30-year-old woman with mild persistent asthma who desired to cut back her treatment. More than 6,000 votes were cast. The detailed polling results are published at NEJM.org. This concludes the summary of the July 12th issue of the New England Journal of Medicine. We're interested in your feedback about ourbiased medical information. Now accessible by PDA, smartphone, and BlackBerry.
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Welcome to the Radiology Review Podcast, your on-the-go source for radiology education with your host, Dr. Matt Covington, a board-certified radiologist. Please follow the podcast on Twitter at RadRevPodcast. Send emails to theradiologyreview at gmail.com or visit the website theradiologyreview.com. Welcome back to the Radiology Review Podcast. On this episode, I will be talking about iodinated contrast media from the non-interpretive skills document that the ABR has made available. If you haven't seen that yet, I have a link in my show notes where you can check that out. This is not a comprehensive review of iodinated contrast media, but does cover some highlights on pages 23 through 26 of the ABR Non-Interpretive Skills Study Guide. On later podcast episodes, I will cover additional information on contrast media that you need to know for the ABR core exam and ABR certifying exam. I will present this in a question-answer format, and I have selected this topic based on listener feedback that I have received from more than one follower on Twitter, and the invitation is open to any of you to follow me on Twitter and send me a message on topics that you think would be helpful if I cover, and I will do my best to cover as many of those topics as I can. Without further ado, let's get into the topic of this podcast, Iodinated Contrast Media from the ABR Non-Interpretive Skills Study Guide. First question, what do we use most commonly, ionic or non-ionic iodinated contrast media? And when I say what do we use most commonly, I mean what is used most commonly in a radiology imaging center, ionic or non-ionic iodinated contrast media. The answer to this question is that non-ionic contrast media is most commonly used, and that is due to a superior safety profile. In comparison to non-ionic contrast, ionic contrast is less commonly used because it has safety issues due to the much higher osmolality of ionic contrast compared to human plasma, and that higher osmolality of ionic contrast media increases rates of adverse reactions in comparison to non-ionic agents, so these are not commonly used in the United States. Ionic contrast media also can disassociate in solution, whereas non-ionic agents are more stable and do not dissociate. I would remember for board examinations that non-ionic contrast media tends to have a lower rate of reactions and is therefore more commonly used. Next question. Do we most commonly use low osmolality or isoosmolality non-ionic iodinated contrast agents? What is more commonly used, low osmolality or isoosmolality non-ionic iodinated contrast agents? Low osmolality agents are most commonly used, so if you got that right, give yourself a pat on the back. Some examples of low osmolality agents are ihohexol, iopramide, ioversol, and so forth. There is only a single isoosmolar agent that is approved for use in the U.S., and that is iodixanol. The study guide does state that a single isoosmolar agent is approved. And according to the ABR-NAS study guide, what is a proposed use of that isoosmolar contrast? So I previously said we more commonly use low osmolality agents, but what is a proposed use for an isoosmolar contrast agent? The answer to this is that isoosmolar contrasts may be used for intra-arterial injection because they are reported to cause less discomfort than other contrast agents. So tuck that away in your brain. Isoosmolar contrast can be used for intra-arterial injection due to improved patient comfort with an intra-arterial injection compared to low osmolality agents, but for intravenous injection, low osmolality, non-ionic iodinated contrast agents are preferred. What is an estimate of the percentage of patients injected with iodinated contrast media that will have a reaction of any type? And this is according to the ABR study guide. I've looked into the literature on this, and there is certainly a range in terms of the percentage of patients that will have a reaction of any type after receiving iodinated contrast. But what is an estimate that is reasonable according to the ABR study guide? And the number I'm looking for is up to 3%. And the study guide says some reports suggest that the rate is lower than this, so they are giving you the upper bounds of this percentage. So tuck away in your brain, up to 3% of patients may have a reaction when they receive ioninated contrast. Next question. Acute adverse ioninated contrast reactions may be considered physiologic or allergic-like. What is the difference between these types of reactions? So again, what is the difference between a physiologic or an allergic-like reaction? A physiologic reaction is dose-dependent. These reactions are less common than allergic-type reactions, and these reactions more often are mild compared to allergic-type reactions. The cause of physiologic reactions are direct toxic effects of the contrast agents. An allergic-like reaction has a poorly understood mechanism, but it is not thought that these are an antigen-IgE antibody response that is typical of other allergic reactions. That is why the ABR terms these allergic-like and not simply allergic reactions, because you do not get that antigen IgE antibody response. However, symptoms are similar to those of a true allergic reaction, and allergic-like reactions are not dose-dependent. They can happen with any dose. So physiologic reactions are dose-dependent and are a direct response to the material you injected. Allergic-like reactions are not dose-dependent, and the mechanism of these is unknown, but it is not antigen, IgEE antibody driven. Next question. Do you need to be exposed to iodinated contrast before you can develop an allergic type contrast reaction? Is prior exposure necessary to develop an allergic type contrast reaction to iodinated contrast? Unlike a bee sting, you do not need to be sensitized to iodinated contrast in order to react. Next question. Iodinated contrast reactions may be mild, moderate, or severe. What are some examples of mild, physiologic, and allergic type reactions? So it's interesting here that the study guide does split up reactions based on whether they may be physiologic or allergic-like, and they expect you to know what symptoms may be associated with a physiologic reaction versus an allergic-like reaction. Let's start with physiologic. What are some examples of mild physiologic reactions? Examples for physiologic mild reactions include transient nausea, vomiting, flushing, warmth, chills, headache, anxiety, taste alterations, mild hypertension, and transient vasovagal reaction. These are all mild because they are transient, and in general these do not require medical therapy for management. What are some examples of mild allergic-like reactions? And according to the study guide, mild allergic-like reactions include a small number of hives, pruritus, mild cutaneous edema, an itchy or scratchy throat, nasal congestion, and sneezing. And notice these are all reactions that are very similar to a true allergic reaction with hives, itching, edema, congestion, sneezing, so that part is easy. And these are mild symptoms that are self-limited and these do not progress in severity. And the definition of mild symptoms is that they are self-limited and do not progress in severity. What are some examples of moderate physiologic and moderate allergic type reactions? Moderate physiologic reactions include extended nausea, vomiting, chest pain, vasovagal reactions that are responsive to treatment but may not resolve on its own initially. And I will review that one more time. Moderate physiologic reactions, extended nausea, vomiting, chest pain, vasovagal reactions that are responsive to treatment. According to the study guide, what are moderate allergic-like reactions? And you can take much of what was mild and just make it a little more severe. Instead of a small number of hives, we now have diffuse hives for moderate, diffuse erythema, facial edema without dyspnea, wheezing with no or mild hypoxia, and all of these with stable vital signs. So a key for moderate is that you do not have dyspnea and your vital signs are stable, but findings are more diffuse and more severe than mild. And according to this study guide, moderate symptoms are more pronounced symptoms that require medical management. And I would really drive that home. If they give you anything on a test question where the patient has stable vital signs, but it requires medical management, then that is a moderate reaction. What are some examples of severe physiologic and severe allergic type reactions? Severe physiologic reactions include vasovagal reactions that are not responsive to treatment, arrhythmias, seizures, hypertensive crisis, pulmonary edema, and cardiopulmonary arrest. So all of these are scary. What are severe allergic-like reactions?
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So a few points that deserve mentioning. Cardiopulmonary arrest can result from severe physiologic or severe allergic-like reactions. Severe reactions are potentially life-threatening, whether physiologic or allergic-like, and these reactions require prompt management to avoid morbidity or death. What about pulmonary edema? Is that related to a physiologic or an allergic-like reaction? And if you rewind, you would hear that pulmonary edema was listed as both a severe physiologic and a severe allergic-like reaction, as well as cardiopulmonary arrest. Next question. And when I say type, I mean physiologic or allergic-like. So what is the most commonly encountered contrast reaction in terms of severity and type? And the answer is that contrast reactions are most commonly mild. I don't think that will be surprising to any of you. So mild severity is most common, and it is also most common to be of the physiologic type. So mild physiologic reactions are most common. And the most common symptoms, according to the study guide, are warmth, metallic taste, and nausea. Next question. What is the frequency of allergic-like reactions, according to the ABR non-interpretative skills study guide? So frequency of allergic type reactions, or I should say allergic-like reactions because that's the term that ABR uses. I told you before that up to 3% of patients will have a reaction of any type, but when we're speaking purely of allergic-like reactions, according to the ABR study guide, less than 1% of patients will have an allergic-like reaction, and most of those will be mild. So the answer here, less than 1%, is the frequency of an allergic-like reaction. Next question, what is the frequency of severe life-threatening allergic-like reactions according to the study guide? So one more time, frequency of severe life-threatening allergic-like reactions. We know this will be less than 1% because that was the frequency of any allergic-like reaction. And the frequency they give you for severe allergic-like reactions is a range of 0.01 to 0.04 percent. If I were you, I would remember 0.01. That seems to be easier. Put in your mind that less than 1 percent of patients will have an allergic-like reaction, and less than 0.01 percent of patients will have a severe allergic-like reaction. What are risk factors for adverse reactions? Think about that for a moment. Risk factors for adverse reactions are prior allergic-type reaction to the same class of contrast media. The study guide says that has a five times increased risk if you have had a prior allergic type reaction, and the other risk factor they provide are other allergies and asthma, and that has a three times increased risk. Next question, does a known shellfish allergy are allergic to other iodine-containing products such as betadine, are they at increased risk of an allergic-type reaction? And the answer is no. Such allergies are not thought to increase risk for an iodinated contrast reaction. I found that surprising when I first learned that, but it is true that being allergic to other types of iodine-containing products does not seem to increase an individual's risk for an iodinated contrast reaction. Does a prior allergic-like reaction to gadolinium contrast increase the risk of an iodinated contrast reaction? Well, this is something that's mentioned in the study guide, and the answer is no. If you have reacted to gadolinium, it is not thought that you will have an increased risk of reacting to iodinated contrast. What underlying diseases may be exacerbated by iodinated contrast administration? Can you think of any? Think about what we screen for before we give contrast, and that may help you come up with the answers of chronic kidney disease or acute kidney injury, because we do screen patients with known renal issues to make sure their renal function is adequate for contrast. There are also other non-renal conditions that iodinated contrast administration can exacerbate, and those include cardiac arrhythmias, congestive heart failure, myasthenia gravis, and severe hyperthyroidism, which gets into the Jod-Basedow phenomenon, if I said that right, J-O-D-B-A-S-E-D-O-W. And we're going to take a quick aside and talk about the Jode-Basedow phenomenon because board exams do like to potentially test on this topic. This is not in the ABR non-interpretative skills syllabus, but I feel it's so important that we're going to talk about it now anyway. So what is the Jode-Basidal phenomenon? What this phenomenon is, is hyperthyroidism that happens when a patient has thyroid disease, such as goiter, Graves' disease, toxic multinodular goiter, or autonomous hyperfunctioning nodule in the thyroid. But this person with underlying thyroid disease lives in an area where iodine is deficient from the diet. So if you give this person iodine, such as with iodinated contrast or with medications like amiodarone, the thyroid finally has the iodine it has been craving and is able to pump out thyroid hormone, and the patient suddenly develops clinical hyperthyroidism, which often develops within days of administration. Next question, and this is now back to the non-interpretative skills study guide. What about using iodinated contrast in a patient with thyroid cancer or hyperthyroidism who are planning iodine-131 therapy. So you have a patient who is planning iodine-131 therapy. How does that impact your ability to give them iodinated contrast? The answer, I hope you already know, is that you should not give iodinated contrast to these patients within four to six weeks before planned I-131 treatment. The iodine from the contrast can saturate the thyroid, which will then prevent the thyroid from taking up the I-131 and therefore interfere with effective I-131 therapy, which we do not want to do. You should always screen patients for any recent iodinated contrast administration prior to giving them iodine-131 therapy. The range I do think you should know for radiology board exams is not to give iodinated contrast within four to six weeks of I-131 treatment. Next question, who should be premedicated prior to receiving iodinated contrast? To phrase that in another way, are there patients for whom you should premedicate before you give them iodinated contrast? According to the ABR syllabus, policies vary by site, but it is generally agreed that patients should be premedicated if they have had a prior moderate or severe allergic-like reaction to the same class of contrast agent. Mild allergic-like reactions do not require premedication, but if a patient has had a moderate or severe allergic-like reaction and you are planning to give these same class of contrast agent, you should premedicate them. Does premedication eliminate the risk of iodinated contrast? And the answer is no. It only reduces the risk of a contrast reaction, but there is nothing we currently have available that eliminates the risk of iodinated contrast reactions, even if a patient has undergone a complete premedication regimen. What is the definition of a breakthrough reaction? Think about that for a moment. What is a breakthrough reaction according to the ABR non-interpretative skills syllabus? A breakthrough reaction is a contrast reaction that occurs despite premedication. What are some commonly accepted premedication regimens? I do think it's worth your time to remember these and even potentially to memorize some specific medication dosages and the times at which medications may be administered. According to this syllabus, some commonly accepted premedication regimens include giving patients oral corticosteroids 12 to 13 hours before contrast media injection. And an example from the ABR syllabus is 50 milligrams prenazone by mouth, 13, 7, and 1 hour before injection. And an example from the ABR syllabus is 50 milligrams prenazone by mouth, 13, 7, and 1 hour before injection, and 50 milligrams diphenhydramine, also known as Benadryl, by mouth 1 hour before injection. So one more time, for this option, you can give 50 milligrams prenazone by mouth, 13, 7, and 1 hour before injection, and 50 milligrams of Benadryl 1 hour before injection. Another example from the syllabus is 32 milligrams methylprednisolone by mouth 12 and 2 hours prior to contrast injection. Next question, what about premedication for kids getting iodinated contrast? So you do still need to premedicate kids who have had a prior allergic type reaction if it's moderate or severe. And one example regimen from the syllabus is 0.5 to 0.7 mg per kg prednisone PO at 13, 7, and 1 hour prior to contrast with up to 50 mg Benadryl PO 1 hour before injection.
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I think they are much less likely to ask you about the pediatric one because, first of all, they've given you a range, and it requires calculation based on a patient's weight, and it would be so much easier just to ask you about the adult regimens. But similarities here for kids are the prednisone by mouth, 13, 7, and 1 hour before injection. That is the same drug, route, and interval as for an adult, as well as the up to 50 milligrams Benadryl by mouth one hour prior to injection. For an adult, you typically would just give the full 50 milligrams of Benadryl. So there are similarities there. Next question. What do you do if the need for CT imaging is urgent and it is unsafe to wait 12 or more hours to scan the patient? So you're in an urgent situation, what are you going to do? According to these syllabus, if a patient may be seriously jeopardized by waiting to complete a standard premedication regimen, you can consider a rapid regimen despite limited evidence of efficacy. One example of a rapid regimen that they provide is IV hydrocortisone, 200 mg every 4 hours until the study is performed, and during imaging and after imaging until, quote, at least 2 doses, unquote, have been administered. You can also give 50 milligrams of Benadryl by mouth one hour prior to contrast injection. If you can't even wait that long and it is really critical to get a contrast enhanced scan, the syllabus says that you should scan without premedication based on a risk versus benefit determination. For this, I would try to remember the rapid option provided for contrast premedication therapy, which is 200 mg IV hydrocortisone every 4 hours until the study is performed, along with 50 mg of Benadryl 1 hour prior to contrast injection. Next question, what is the only proven benefit of corticosteroid premedication regimens? Think about that for a minute. I already told you it doesn't eliminate the risk, but what is the only proven benefit of premedicating a patient? The only proven benefit, according to this syllabus, is a reduction in the number of mild reactions in average risk patients. It is unknown whether premedication protects against moderate or severe contrast reactions. That is interesting because we only typically premedicate patients who have had a moderate or severe reaction. The ABR still advocates to premedicate patients who have had a prior moderate or severe contrast reaction, but we need to be aware that premedication is only proven to reduce the number of mild reactions in average risk patients. Next question. If a breakthrough reaction does occur, is it more likely to be of the same severity, lesser severity, or worse severity than the initial contrast reaction? So you've premedicated a patient, you inject the contrast, they have a breakthrough reaction. Is that breakthrough likely to be of the same, lesser, or worse severity than what they had previously experienced? The answer, according to this syllabus, is that breakthrough reactions are 80% of the same severity, 10% of less severity, and 10% of more severity than the initial contrast reaction. So most will be the same as what they had before, 10% will be better, and 10% will be worse in terms of severity of the reaction. Next question. If a patient has a breakthrough reaction, can you pre-treat and re-inject with contrast again in the future? So let's frame that in a slightly different way. You pre-medicate a patient. They have a breakthrough reaction despite the pre-medication. What do you do in the future? And the answer is that you should still pre-treat and re-inject with contrast if the scan is clinically necessary in the future. If the breakthrough reaction happened again, you would expect it to be still of the same severity as the prior reaction. Remember, 80% are of the same severity, and this again needs to be a risk-benefit determination whenever you give a patient iodinated contrast and they have had a prior moderate or severe reaction. Final question for this episode, what is the greatest risk associated with premedication for iodinated contrast? What are some of the cons in terms of risks that are associated with premedication for iodinated contrast? And according to the syllabus, the greatest risk is the delay of imaging. That is interesting. It is not risk from corticosteroids, but the greatest risk is the delay of imaging, especially in inpatients due to delayed diagnosis and subsequent delay in treatment. Also, the longer patients are in the hospital, that increases the time they have to acquire a hospital-acquired infection, and it also increases hospital length of stay, which has associated costs to the patient, etc. So to avoid this risk of the delayed imaging, you can consider performing a rapid contrast premedication regimen if you think that delayed imaging may cause these problems. Other more rare risks of premedication include hyperglycemia from corticosteroid administration, worsening infection, peptic ulcer disease, steroid psychosis, and tumor lysis syndromes, all from steroid administration. I hope this is helpful to you, and I imagine I've covered many topics that aren't necessarily in a lot of other board preparation resources, so I do hope that that is something that is of benefit. I congratulate all of you that wrote to the ABR, and I also congratulate the radiology field as a whole, including the American College of Radiology, for advocating for you residents and petitioning the American Board of Radiology to consider a virtual option for the ABR core exam in 2021. And it is now my understanding that the ABR has agreed to provide a virtual option, which is great news because you now have a date you can plan on that should not be delayed, so you can aim your study accordingly. And my understanding is that the fourth-year residents will take the virtual ABR core exam around February, and the third-year residents will take the exam around June. However, the ABR has yet to update their website as of June 23, 2020, so stay tuned. According to the ABR website, as of June 23, 2020, the only exam dates listed for the core exam are June 3-4 and June 7-8, 2021, so check back for updates. Again, a reminder to follow me on Twitter. I have been posting nearly daily tips for the ABR core examination. Otherwise, feel free to email me at theradiologyreview at gmail.com and check out my website where you can find many free resources for radiology board preparation. Thank you for listening to this podcast. Remember to work hard, imaging interpretation, or course of treatment. ¡Gracias!
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Hey folks, just a quick reminder that this podcast is not meant to be used for medical advice, just good old-fashioned education and all patient information has been modified to protect their identity. Welcome back clinical problem solvers! My name is Arsalan Durakshan, I'm a third year internal medicine resident at Johns Hopkins Hospital and I'm very excited to introduce tonight's show, which will be a clinical unknown with none other than Robby, who's in the hot seat. So as a quick reminder to the audience, Robby is completely blinded to this case, and he'll provide his thought process as the information is presented to him. The goal of these cases is for you to pause and think about the case in parallel and see your similarities and differences in your thought process to Robbie's discussion. So tonight's case presenter will be Dr. Fatima Al-Khanezi. Dr. Al-Khanezi graduated from Columbia School of Medicine, and she's currently an internal medicine intern at Johns Hopkins Hospital. She did a fantastic job taking care of this patient and organizing this case to be presented. So without further ado... A 76-year-old man presented in December with two weeks of intermittent fevers and chills. He developed fevers and chills a few days after receiving a corticosteroid injection to his back. He presented to a hospital where vitals revealed tachycardia and a temperature of 103 Fahrenheit. His blood pressure was normal. He had no headaches, cough, sore throat, abdominal pain, diarrhea, rashes, myalgias, back pain, or joint pain. He had no sick contacts. His exam, except for tachycardia and fever, was without any focal findings. Blood cultures times two, urinalysis, urine culture, and chest x-ray were normal. His lactate was 1.2. His fever and tachycardia resolved after Tylenol and IV fluids, and he was discharged from the ED. His fever returned that night to 102.5 Fahrenheit, but he managed it at home conservatively with Tylenol and a cold washcloth. His fever resolved by the morning, but again that evening, fever recurred to 103. He ultimately improved over the next few days, was afebrile, and was able to return to his job as a college professor. He remained well for the next week, but then on the day of presentation, 12 days after the initial onset of his symptoms, had re-experienced fevers and severe chills at work. He returned to the ED. Of note, his wife had noticed that he had been intermittently, quote-unquote, less sharp over the past two weeks. So the fevers and chills here just established that the patient has inflammation, And the question they're often grappling with is what is the nature of this inflammation and where is it? And in terms of answering the first question, by far and away, the most common cause of acute inflammation is infectious in origin. And so our bias will be focusing on establishing what infection is at play here. And over time, if the fever persists without a clear infectious cause, expanding our bucket to include other causes of fever, such as rheumatoid diseases, malignancies, drugs, etc. I said from the get-go to you all that there's no way I'm going to be able to solve this case by myself, so I'm going to use Charmaine's help here real quick. So, Charmaine, help me out. When we're thinking about infections, what's your quick checklist for initial focus of infection that we often check in our hospitalized patients? So in terms of the infection, I always like to think about the buckets like bacterial, viral, and then the fungal. And like the things that we want to like make sure to rule out that are common are like pulmonary sources of infections, and then intra-abdominal, and also like thinking about urinary sources as well are like the quick buckets that I usually go through. Yeah, that's absolutely terrific. I think if you think of all comers who come to the hospital with an infection, it's either in the lungs, the urine, in the skin in the form of cellulitis, or rarely intra-abdominal, usually hepatobiliary, and sometimes just bacteremia of unclear radiology. And here we have the benefit of a lot of data that essentially makes all those diagnoses, the common causes of a fever, much less likely. So the chest x-ray being normal, the urine culture being normal, the blood cultures being normal, make all those diagnoses less likely. We don't have a set of liver panels, a set of LFTs here to give us a sense of the possibility of a pedobiliary infection, so that's something to keep in the back of our minds. And I'll go back to one dominant feature here, which is that there's a relative paucity of localizing this inflammation. So as we start to say fever plus cough goes to the lung, fever plus dysuria goes to the urine. Here, there's really a lack of localizing symptoms to tell us where the inflammation is coming from, except one feature at the bottom, which is that his wife noted that he was less sharp. I'm tempted to map that on to some sort of cognitive dysfunction. And the challenge is, as we talked about in altered mental status, the presence of encephalopathy in a febrile patient doesn't really necessarily localize to the brain. This could still be an extracranial infection manifesting as encephalopathy. So we still have to step back and not completely jump to the brain, even though that's our only localizing symptom. The one other thing I'll add is it's always tempting to jump to what has happened in the recent past, and it's hard to ignore the fact that a corticosteroid injection had just occurred in the back. It'll be really helpful to know exactly where in the back that occurred, whether or not that was proximal to the spinal cord, because that would open up a whole variety of infections involving the vertebral column, including vertebral osteomyelitis and epidural abscess. So to summarize, Charmaine's approach is terrific. When someone's acutely inflamed, think pneumonia, think cellulitis, think urinary tract infection, think hepatobiliary infection and bacteremia of unclear source. Here, none of those things are really panning out. So we're going to have to broaden our differential diagnosis. Unfortunately, the localizing symptoms that we have with the altered mental status isn't specific enough to zero in on the central nervous system. And we'll have to figure out how the tantalizing history of the corticosteroid injection in the back. His past medical history includes hypertension, hyperlipidemia, hypothyroidism, obstructive sleep apnea, benign prostatic hyperplasia, herniated lumbar discs, and chronic back pain. And his injection was in the epidural space and also anxiety and depression. In terms of social history, he was a professor at a local college in the East Coast. He lives with his wife and they have a house in a wooded area where he visits frequently. He does not recall a tick bite. He has had no recent international or domestic travel. He's a never smoker, no drugs, rare alcohol use. His medications included levothyroxine, lisinopril, simvastatin, tamxelosin, and as needed, zolpidem and clonazepam. On the day of admission, his exam showed a temperature of 102, heart rate of 116, his blood pressure was 176 over 86, and his oxygen saturation was 97% on room air. He had no sinus tenderness. His cardiopulmonary exam was normal except for tachycardia. His abdominal lymph node and skin exam were normal. He was alert and oriented times three, his cranial nerves were intact. His strength was five out of five in the bilateral upper and lower extremities, and he had no spinal tenderness. Terrific. So part of what we do when we are trying to understand pneumonia specifically is we label the infection as community-acquired or healthcare-associated. I think it's important to extend that exercise to really any infection. And part of what we're doing when we're saying what is the infection at play is understanding truly what is in the patient's community. And here we have a couple of pieces of data to help us figure that, help us understand this person's community a little bit better. So he's a professor at college, and I think it wouldn't be unreasonable to extrapolate potential exposure to college-age students. Specifically, Epstein-Barr virus and cytomegalovirus may be at play owing to that exposure. Sometimes you hear about the transmission of Neisseria meningitidis at colleges specifically, but it's nothing unique about colleges. That infection tends to aggregate in places where a lot of people are in smaller spaces.
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And that raises a whole variety of potential exposures, not limited to something in the soil, like nocardia infection, for example, or actinomycosis, or actually arthropod-borne infections like mosquitoes and ticks. This is where the time of the year is actually really, really helpful. And I recently learned from an amazing New England Journal case that I won't spoil for you, that mosquito-borne infections are incredibly unlikely in the wintertime, but actually tick-borne infections are still fair game all the way out through the late autumn and maybe even early winter. That's really something that I didn't know before. And so because I'm going to entertain that possibility, it's probably a good idea to pause and reflect and ask, well, what infections can be transmitted by ticks? Charmaine, you want to tag this together? I'm not going to be able to recall all of them. So let's work through it together. So tick plus infection, what comes to mind? So Lyme disease is one that comes to mind. And other like rickettsial diseases are the two big ones that I think of. Awesome. Yeah, I think, you know, when you said Lyme, it reminded me to actually sort of start bigger at the Borrelia species. So there's Borrelia causing Lyme disease, but there's also Borrelia in the form of recurrent fever. So there's a couple of spirochetes under the Borrelia species that can cause recurrent fever syndromes that are transmitted by ticks. Rickettsia is a very, very important consideration transmitted by ticks, primarily because of the morbidity associated with Rocky Mountain spotted fever. There are a couple of other Rickettsial organisms that are variably present across the world. In the U.S., there's rickettsia acarii, which is important to think about. It causes a vesicular rash and a fever, as well as murine typhus, which is endemic in Texas and California. In terms of thinking about other tick-borne infections, so there's a whole class of ehrlichiosis, which is human granulocytic ehrlichiosis and human monocytic anaplasmosis. There's a whole variety of other tick-borne infections that merit consideration as well, including babesia and tularemia, and a list of viral infections that can be transmitted by ticks, not the least Powassan virus, which we're learning more and more about. So the only reason I'm running that possibility is because I think still in December, tick-borne infections are fair game. And as you just heard me go through, there's a whole long, long list of infections that we'll have to think about. So the question will be which of those map onto the clinical syndrome that he has. I zeroed in on that because there's not much in the past medical history to help me work with in terms of either a vulnerability to infection via immunosuppression or an autoimmune diathesis to help me start thinking about autoimmune diseases early in the game. Looking at the medication list real quick, I don't see any big hits between medications and fever with what he's on right now, nor do I see any immunosuppressive medications like prednisone. So moving on to his exam, I was really hoping as soon as I saw that temperature of 102 that I would see a heart rate of 68, and I would go back to Reza's amazing pearl from episode number three, I believe, with relative bradycardia, which would be another tip off to what organisms are at play. And I think what the exam does for us here, looking at it again real quick, is it essentially tells us that the patient is sick, but we have no idea where they're sick from. So they're febrile, the tachycardic, and the cardiopulmonary exam is normal, the abdominal exam is normal, the lymph node exam is normal, and so is the neurologic exam. And so again, this is a question of where is this inflammation coming from? And we might have to rely on a unique signature of laboratory parameters or other advanced diagnostic testing to help us understand where exactly this inflammation is coming from. So for initial labs on presentation, his white count was 7.6, 85% PMMs. His hemoglobin was 14.2, his platelets were 367. His BMP was normal with a baseline creatinine of 1.1. His liver functions were normal except for an ALT of 55, with the upper limit of normal being 40. His COAG's were within normal. His ESR was normal, but his CRP was elevated at 7.2. His lactate was normal. His TSH was 0.98. His UTox was negative. His UA was without pyuria or hematuria, just trace ketones. Respiratory viral panel was negative. For initial imaging, his chest x-ray showed no consolidations, just a trace left pleural effusion. He had a CT chest abdomen pelvis width contrast, which showed simple cysts in the liver, cholelithiasis without evidence of cholecystitis, an enlarged spleen at 15 cm, mild bilateral perinephric and perivasicular stranding, and he had a CT head which showed mild paranasal sinus disease that could be reflective of acute on chronic left maxillary sinusitis. Ampicillin sulbactam was administered for sinusitis while blood cultures were pending. I will not ever get those tests again. I don't get it. So, you know, again, we're just looking at the labs. We'll talk about the imaging in a second. And I think just as a general tip to clue you into when you're entertaining tick-borne diseases for whatever reason, and maybe I'm a little bit biased towards that because we haven't really found a localizing source of infection. And by virtue of their vascular nature, tick-borne diseases tend to behave that way. So I might be over-representing them this early on. But a clue to their presence is almost always the presence of thrombocytopenia and hepatocellular dysfunction. Now, Lyme disease is a notorious exception to that. Patients with Lyme disease aren't usually febrile. They usually have normal platelets, and they usually have normal LFTs. But in general, when you're thinking about tick-borne infections and you exclude Lyme for a second, that's the pattern that you typically see, either leukopenia, thrombocytopenia, and transaminitis. So here, I'm struck by the absence of those things, and that helps me dial down my enthusiasm about a tick-borne infection. And really, the value of the labs is to say, hey, you know what? You have time. The Y count isn't markedly elevated. The kidneys are doing okay. The liver's doing okay. Take your time and think about what's going on. But really offer more information than that to me right now. The imaging findings are actually pretty helpful. And the chest x-ray with the left pleural effusion, when considering an effusion, it's almost always important to think about what's going on next to that effusion. And on the left side, next to a left side of pleural effusion would be the pulmonary parenchyma and the subdiaphragmatic structures. So I'm tempted now, with nothing going on in the pulmonary parenchyma, to map on that left pleurofusion to whatever is going on in the spleen. The caveat there is that the splenic disorder may be independent to the pleural disorder, or that that might just represent an autoimmune diathesis with splenic involvement and pleural involvement. But you can easily see how a tiny little effusion with a markedly enlarged spleen may be simply explained by a big spleen. So focusing on that, tune into, we're just referring back to all our episodes. Is that what we're doing here? Is this like a setup? I can't tell. So, is it episode four? I think it's episode four. Shame on me for forgetting. So, in episode four, we had a patient with spondylomegaly who turned out to have a diagnosis. I won't tell you because you listened to episode four. But the first step is, is the problem in the spleen because of the problem in the liver? Meaning that because of portal hypertension, there's water buildup in the spleen, and that's causing the spleen to be big. Here, that's not the case. So the question is, what is making the spleen big if it's not water? And you're down to three things. Too many red blood cells, too many white blood cells, or too many random molecules.
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The red blood cells category, I'll let you watch the video, but we're not going to talk about that because the hemolym is normal. So here we're now down to why is the spleen presumably filled with white blood cells? And the answer to that comes by analyzing what causes an increase in white blood cells in any location, including the spleen. Infection, autoimmune disease, certain drugs, certain cancers, and within the spleen, you always have to keep in mind the possibility of a myeloproliferative neoplasm. Here, I won't expand on the other buckets except infection because of what we talked about in the first aliquot. Acute fever is infectious until proven otherwise, and we really haven't done anything to prove otherwise yet. So, there are three kinds of infections to keep in your mind when you're entertaining infectious spunomegaly. Mononucleosis-type infections like EBV and CMV, tick-borne infections like human monocytic ehrlichiosis and human granulocytic anablasmosis as an example, and then finally granulomatous infections like tuberculosis and histoplasmosis. I'm kind of cheating there because you all know that there are some infections that live in red blood cells that cause big spleens that includes malaria and babesia. We won't talk about those now again because the hemoglobin is normal. So here, we have something to help us focus in on the source of inflammation, and that is the spleen. And the question is, why are those white cells infiltrating the spleen? I'm tempted to think infection acutely, and those are the three classes of infections I'm thinking about. Mononucleosis, tick-borne, and granulomatous. The question is then, how do we use the other data that we have to filter between those two things? Bilateral perinephric and perivasicular stranding is incredibly nonspecific. I've seen that occur in raging pyelonephritis, and I've also seen that occur in absolutely nothing. And I don't know much beyond my clinical experience that's telling me all this. There may be some data that actually tells you this is a value, but from my clinical experience alone, I'm not tempted to use that. And another reason I'm not tempted to use that is because it's bilateral. The vast majority of pyelonephritis is unilateral, and I'm tempted to put that to the side right now. But it does remind me that there are infections that hematologically seed the genitourinary system. So the stranding may be on account of that, but I actually don't know how to use that information right now. And finally, the sinus disease, way too nonspecific. I've already talked too much about the spina medulla here. And the reason I talked about that so much is because my mind is discarding the paranasal sinus disease. I guarantee you if I took a CT of Reza's sinuses, they would be mildly positive right now. Robby, I haven't said a single word on the podcast yet. I know, that was a cue to say something. Hey guys, Reza's under the weather. Wish him well. He's going to be great. He's going to be great. Love you, Robbie. The syndrome and then the spleen being big helps me zero in most on that possibility. But keep in mind granulomatous infections and the possibility of a mononucleosis syndrome given the college exposure. very inappropriate responses. For example, do you know where you are? He'd say, in the bed. He was laughing inappropriately. He had significant apraxia, where he really struggled to perform routine tasks for him, such as putting on his CPAP machine, which is something that he did every day at home. He was also having some trouble walking. His having more urinary incontinence had no nuchal rigidity, though, and no photophobia. A bedside LP was unfortunately unsuccessful and out of concern for meningoencephalitis. He was brought into vancomycin, ceftriaxone, ampicillin, and acyclovir. In terms of his labs, his CMP showed a mild hyponatremia to 132 from 135 on admission. His creatinine is now 2.2 from 1.1 on admission and actually peaked at 3 later that evening. His BUN is 33 from 15 on admission and his bicarb is as low as 16 with an anion gap of 20. His ALT normalized to 38, but now his AST was elevated to 45 with the upper limit of normal being 37. His bili and ALK-FOS were normal. In terms of his CBC, he now had a leukopenia to 3.6, and his white count was 7.6 on admission, the lower limit of normal being 4.5. And on DIF, he had only 9% lymphocytes, with the lower limit of normal being 24%. He also had 16% bands, and his bandemia peaked at 29% that evening. His hemoglobin was 13. His platelets more than halved at 136 from 367 on admission. His fibrinogen was 364. His D-dimer was 10.6. His LDH was 280. his lactate was 2.8, his ferritin was 2200, and a PF4 was sent for his thrombocytopenia, which was negative. His blood smear showed a decreased number of platelets, but no schistocytes. In terms of other labs that had come back, his HIV was negative, his serum PCR for CMV, HSV1 and 2, EBV were negative. His hep B and C antibody screens were negative. His RPR was negative. His T-spot was negative. His blood cultures were no growth to date, and his urine culture showed mixed flora. His ANA and RF, a rheumatoid factor, were negative. He had an LP under fluoro, which showed one white blood cell, one red blood cell, normal glucose at 55, mildly elevated protein at 59, with the upper limit of normal being 45. On CSF studies, his EBV, CMV, HSV, VZB PCRs were negative. His enterovirus was negative. His Lyme antibody was negative. His RPR was negative. His West Nile was negative. His cryptoantigen was negative. His AFB showed no growth, and his CSF cultures were no growth. He had an MRI brain, which revealed chronic microvascular ischemic disease and nonspecific microhemorrhages in the right parietal and temporal lobes. His MRI spine showed his known degenerative disc disease, but no evidence of infection, this is just how well you could synthesize every lab or imaging that we could possibly do in a hospital. Oh, my God. Wow. By the way, this is an incredibly astute workup. Seriously, I think every time my mind starts to collect some thoughts, you're like, tell me it's negative. So I'm going to try to summarize. So our initial dilemma was trying to localize this inflammation. And now we then get the clue that the spleen is involved and maybe the kidneys are involved. And the case then evolves to involve the central nervous system with some fairly specific findings, including apraxia and abnormal behaviors. In the context of those specific disorders of cognitive function, it's very reasonable to assume that the focus of inflammation lies within the CNS. And here, I'll jump quickly to the LP. And before that, I'll say that the vast majority of subacute meningoencephalitis, which this would be since the inflammation is two weeks old, is either viral, autoimmune, or completely undiscovered. So the pretest probability of a pyogenic bacterial infection in somebody with having these symptoms for two weeks is fairly low. And the CSF results are essentially compatible with that. The challenge is knowing how long after the antibiotic exposure did this data arrive, because you always have to be open to the fact that the CSF was made less inflamed and sterile because of the antibiotic therapy. But I'll know that in general, 24 hours is a relatively safe time period between antibiotic administration and utility of the cell count as diagnostic information, though the yield of culture results drops rapidly. Here, I think that discussion is less relevant because there's only one white blood cell. And so the inflammation, if present, certainly isn't very, very prominent. The elevated protein is a clue that there's something truly going on within the CNS itself, but it's certainly not something dramatic like a pyogenic bacterial infection. So we're left with considering the whole slew of viral causes of meningoencephalitis, which you have largely tested for.
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After considering viral infections, it's really important to consider the possibility of atypical bacterial infections. And again, this is the same atypical bacteria that will run for infections anywhere outside the body. They essentially are either granulomatous in nature, like salmonella, brucella, or tuberculosis. They're either spirochetes, like leptospirosis or Lyme disease, rickettsial organisms, and essentially all the other tick-borne infections can cause a prolonged meningoencephalitis, so can fungal disease. And here, I think that the presence of localization within the CSF and the elevated protein, along with the viral studies, localizes to the possibility of an atypical bacterial infection, such as the ones that I mentioned, and or the possibility of a fungal infection, which is made a little bit less likely by the fact that there's only really one white blood cell and we haven't empirically treated for fungal infections. With that dramatic change in mind, we'll move on to analyze the rest of the data here, which essentially evolves to include the dropping of the white count, the dropping of the platelet count, and the beginning of the involvement of the kidney. Let's tackle the easiest one first. Usually, kidney dysfunction in the face of systemic illness represents acute tubular necrosis in 75% of cases. And so, that result, while clinically meaningful, is rarely diagnostically informative. And so oftentimes the kidney dysfunction doesn't actually occur because of a signature of a systemic disease. A notable exception to that is the most recent Core IM hoofbeats segment where localizing the kidney involvement was key to getting the diagnostic test as Dr. Stephanie Sherman walked us through. So there are caveats to that, but here, without the urinalysis pointing us in a specific direction, I'm tempted just to say that the kidney dysfunction for now is just a reflection of this person being very sick. The leukopenia and the thrombocytopenia, again, map on to what we talked about earlier with tick-borne infections. And both leukopenia and thrombocytopenia are inherently nonspecific in the face of systemic illness. But when the hypothesis for a tick-borne infection is building more and more and more, I think that they offer more signal than they do noise here, especially when coupled with the presence of marked bandemia. That is nearly a pathognomonic of a bacterial infection here. So the exposure history with the woods, the presence of leukopenia, thrombocytopenia, and an atypical meningoencephalitis help us zero in on the possibility of that set of atypical bacterial organisms, which are either spirochetes, rickettsial organisms, and other tick-borne diseases, the list we went through a little bit earlier, and a whole variety of granulomatous infections. I'm tempted to go be most suspicious of tick-borne illnesses primarily because of the epidemiology we have here. Acyclothyr was discontinued and doxycycline was added empirically to his regimen. A Foley was placed, which drained almost one liter of urine instantly. The following day, his fever and tachycardia had resolved. He was much less confused and was alert and oriented times three. His labs demonstrated an improvement with sodium to 135, a creatinine now down to 1.4, but a mild transaminitis with an ASD and an ALT both rising to 55. In terms of his CBC, his white count had recovered to six and his platelets were 60. It's a great reminder that you have to think about urinary retention, especially in someone who's altered. And I'm grateful for that reminder in this case. It does tell us that the creatinine here was likely, again, much more noise than it was signal. So there's a great case in the Journal of General and Internal Medicine, and if we can find it, we'll put it in the show notes, that essentially makes the argument to have a schema for doxy deficient states. And his improvement with doxycycline strongly supports that notion. Again, we'll never know if his improvement was because of doxy, was because of time, was because the fact that he's no longer at home and in the hospital and doesn't have exposure at home. We'll never know. But it's hard to ignore the timing of the rapid improvement with doxy. This, coupled with all that we've talked about with the evidence building for tick-borne diseases, I think lands us on the schema for tick-borne infections. And I'd say that with a moderate degree of confidence. Again, it's hard to know that for sure, but I think we built a fair amount of evidence to say, what is the tick-borne infection that's going on here? Off the get-go, for the reasons I mentioned, we should exclude Lyme, not just because the data came back negative for it, but also because a febrile syndrome with hematologic parameters is incompatible with Lyme disease alone. The possibility of another Borrelia species like Borrelia miyamotoi is certainly plausible, but the epi for that is it's not widespread enough to be at the top of my list. Moving on to the Rickettsial diseases, Rocky Mounted Spotted Fever is an important diagnosis to make, and unfortunately we can use its relative lethality to guide us here. It's hard to believe that somebody would survive two weeks without untreated Rocky mounted spotted fever. And when you layer in the fact that over 90% of patients have two things, a centripetal rash and a headache, I think that diagnosis is not at play. The epidemiology for other rickettsial organisms is also out the window here. They do exist, but they don't quite occur as much on the East Coast, and the syndrome is not perfect for them. The other tick-borne infections that we talked about, the remainder of them, tularemia does not respond to doxy, neither does babesia. Viral tick-borne infections may have improved spontaneously here, and we'll always entertain that possibility, but they also don't respond to doxycycline. So we're honestly down to the two infections that are in the ehrlichiosis category, human granulocytic anaplasmosis and human monocytic ehrlichiosis. The principle of parsimony would tell us to always seek a single diagnosis, but in reality, that principle fails in a variety of situations, including immunosuppression, such as HIV, when somebody is advanced, CD4 count less than 50, you probably should be hunting for multiple infections. And I encourage you to apply that same philosophy to tick-borne infections. It's not unheard of that patients actually have multiple tick-borne infections by virtue of either having the same tick or just being exposed to ticks all the time. So with that caveat, it's hard to commit to a single diagnosis when entertaining the possibility of the Ehrlichia organisms. But I will say that human granulocytic anablasmosis is much more common on the East Coast and is much more likely to cause leucopenia. So for that reason, I'm leaning towards that primarily, again, because it's more common on the East Coast and it's a more leucopenic organism. But again, it's very, very hard to tell and always be open to the possibility that your patient has multiple tick-borne infections. His Lyme and Babesia antibodies were negative, but his Ehrlichia PCR was positive for anaplasma phagocytophilum. On his final day, he continued to be afebrile, was well-appearing, and his mental status had returned back to normal. His creatinine returned back to baseline at 1.1. His AST and ALT peaked at 76 and 82 respectively, but by the time of discharge were downtrending. On CBC, he actually developed a leukocytosis to 15, which downtrended to 12 by the time of discharge, and his platelets were recovering at 130. His constellation of fevers, chills, confusion, leukopenia, bandemia, thrombocytopenia, and transaminitis are consistent with human granulocytic anaplasmosis. Although human granulocytic anaplasmosis is much less common in the winter months, a small number of cases have been reported in December, and in fact, there is a small annual spike in cases in October slash November, which is when the patient's symptoms started. Optimal duration of therapy is unclear, but should generally be a minimum of five to seven days, depending on the fever curve and clinical response, and based on the severity of his symptoms, he was treated with a 10-day course. From an ID standpoint, he's now back to baseline with no recurrence of his fevers, but unfortunately did continue to have urologic issues with his BPH and recently presented to the like resting diaphoresis.
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I've never sat here and gotten sweaty. It's happening.
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This is Dr. Marty Freed, Dr. Shreya Trivedi, and Dr. Kari Blum. This is the Core IM Five Pearls podcast brought to you by Clinical Correlations, bringing you high yield evidence-based pearls. Today we are talking about iron deficiency anemia. Special thank you to Dr. Polz, an associate professor and program director of NYU's GI, as well as David Green, a hematologist at NYU. Both have peer-reviewed this podcast. Also, shout out to Dr. Shapiro, editor-in-chief of Clinical Correlations. All right, let's get started with five questions on the pearls we'll be covering. Test yourself by pausing after each of the five questions. Remember, the more you test yourself, the deeper your learning gains. Question one, screening for iron deficiency anemia. Should patients be screened for iron deficiency? If so, who and how often? Question two, referral for a diagnostic endoscopy. What are the indications for referral for a diagnostic endoscopy? Question 3. Dosing for oral iron. How should you advise patients to take oral iron? What is optimal dosing? Question 4. Indications for IV iron. What patients would you consider IV iron in? What are the risks? And question five, a throwback question. What is a medication overuse headache? So screening patients for iron deficiency is not something I usually think of proactively doing because so many patients get CBCs. It's something more that I reactively do as I find I'm chasing down these hemoglobins less than 11 in my females or 13 in my males. Yeah, so pretty much anyone who walks into the ER will most likely get a CBC if labs are drawn. And there are tons of PCPs out there who are still sending CBCs with yearly annual exams. So is there consensus among experts at who should get a screening CBC? So the USPSTF actually has never commented on screening in the general adult population for this before. They do comment on screening in pregnant women and children, but there's insufficient evidence to make a recommendation. All right. I don't know much about pregos or children. I'm an internist. But the CDC says yes, screen non-pregnant premenopausal women every 5 to 10 years using a hemoglobin or hematocrit. And say a woman has risk factors for iron deficiency such as a personal history of it or heavy menstrual periods, maybe think about screening more often, i.e. yearly. However, it's important to keep in mind that these recommendations don't appear to be based on a rigorous trial, but rather on the high prevalence of the disease in this population, somewhere around 10%, and also the low cost of the test, the relative ease and effectiveness of treatment. This recommendation is quite old and hasn't been updated since 1998. All right, so the bottom line here is asymptomatic patients at high risk for iron deficiency of anemia should probably be screened. But recognize this recommendation is based on outdated professional society guidelines. The interval of repeat screening is also not clear. Anywhere from 5 to 10 years, or if higher risk, screen yearly. Okay, so you have a patient who you find is anemic with additional labs revealing that they are, in fact, iron deficient. Low ferritin, low transferrin saturation. Does this patient require diagnostic endoscopy? Luckily, the British Society of Gastroenterology has formal recommendations that can guide us. Both upper and lower endoscopy should generally be performed in all postmenopausal females and men of any age with iron deficiency anemia. Hmm. So sounds like the decision to screen depends more on the demographic these patients fall into. Right. One way to think of this is in terms of positive likelihood ratio. There's data from NHANES that estimates the positive likelihood ratios for GI malignancy in various demographics with iron deficiency anemia. So if you look at premenopausal women with iron deficiency anemia, there were no cases of malignancy. Among postmenopausal women with iron deficiency anemia, 0.2% had GI malignancies discovered. And men with iron deficiency anemia were at an even higher risk. 2% had GI malignancies. So from these data, we can gather that finding iron deficiency anemia in premenopausal women doesn't really increase the risk of a GI malignancy. But for men and postmenopausal women, the presence of iron deficiency anemia increases the likelihood that the patient has a GI malignancy by 10 times. Hmm. That being said, every patient's different. So don't ignore concerning family history or other risk factors for malignancy in your premenopausal women, especially as we're finding more and more young patients are being diagnosed with colon cancer. So true. Prior data can guide us, but it's important to look at each case individually. But the key teaching point for me from the British guidelines that Carrie just went over is to do scoping from both ends. I'm not sure I would have referred for both upper and lower endoscopy. Honestly, my knee-jerk reaction would have been, crap, I need to rule out colon cancer as a cause of blood loss. But I really might have forgotten about the upper GI causes of blood loss too. And studies show that you're probably not the only one, Shreya. A cohort of men and postmenopausal women from primary care clinics provides more evidence for performing both upper and lower endoscopy. They found that less than half of patients with iron deficiency anemia were referred for endoscopy within three months, and even fewer were scoped from both ends. More notably, the authors did find several cases of missed malignancy in the population that was not scoped. Eesh, no bueno. Back to our case. So say this patient of ours who is anemic and iron deficient on labs is in fact premenopausal with menorrhagia. In the past, I might have given ferrous sulfate TID and call it a day, but I feel like there's more to the story than that. There are some things that are widely agreed upon and things you should tell your patients when prescribing oral iron. Number one, tell them iron should not be taken with foods that interfere with its absorption. This is true because foods that are high in calcium reduce iron absorption. So not just milk and cheese, but other calcium-rich foods, such as greens, like kale and broccoli, or salmon, or even almonds. Ah, that sounds like my very basic breakfast, lunch, and dinner, probably in that exact order. Oh man, that does not sound like mine, and I wish my patients ate like that. But either way, just make it simple for your patients and recommend not to have their iron with food. The second thing you should likely say to your patients is have it with citrus or vitamin C. Remember, most dietary iron is in ferric 3-plus form, and in the acidic environment of the stomach becomes ferrous 2-plus form, which is much more easily absorbed. So, ascorbic acid or vitamin C has been theorized to help improve absorption. And increasing doses of vitamin C have actually shown a dose-dependent response to iron absorption when taken together in healthy volunteers. It ranges from no change in ferrous sulfate absorption with vitamin C with lower doses to a 48% increase in elemental iron with higher doses of vitamin C. Oh man, you guys are bringing me back to the biochem days with the ferric and ferrous iron forms. In that regard, it's not a good idea to mix taking iron with antacids or PPIs. This would make it a less acidic environment and keep the iron in a ferric or 3 plus form, which is less readily absorbed. Lastly, it is agreed upon to avoid the enteric-coated formulations, which are released too distally in the GI tract. Pop quiz, where is iron absorbed? Hmm, proximal duodenum. Right, and because it's released distal to the proximal duodenum, the estimated bioavailability of the enteric-coated preparation was only 30% of the regular oral preparation. These enteric-coated formulations are marketed to decrease prevalence of GI upset and reduce dosing schedule, but comes at a cost of its absorption. I had this patient who had been taking over-the-counter iron, and despite her taking for months and being compliant with it daily, her iron studies did not budge. And there I was about to order Celiac and all these other tests, and thankfully she pulled out her pill bottle from her purse and saw that it was the enteric-coated kind. We got her on the regular iron preparation and saw a much better improvement in her symptoms and her labs. Nice save, Shreya. You know, one thing that is not widely agreed upon is the best dose.
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This regimen contains approximately 200 milligrams of elemental iron a day, of which only approximately 25 milligrams of this is actually absorbed. Wow, I didn't realize only 10% of iron is actually absorbed. Yeah, and that's the reason behind the less-than-ideal dosing of three pills a day. But now there's debate about the optimal way to reverse iron deficiency. A randomized control trial in the American Journal of Medicine in 2005 showed that incrementally higher doses of 15, 50, or 150 milligrams of elemental iron in patients older than 80 all produced the same increase in hemoglobin and ferritin by 60 days. And the only significant difference was... Drumroll. Increased side effects of abdominal discomfort, nausea, and constipation in the high-dose group. So that study suggests that the elderly may benefit equally from fewer pills of iron without sacrificing effectiveness and reducing the GI side effects. So this makes me feel a lot more comfortable starting at a low dose and if tolerated, going up. And here's even more evidence that may change the current paradigm of iron dosing. A study in Blood in 2015 looked at iron absorption in 54 non-anemic iron deficient women. The study authors gave radio labeled oral iron at various doses and various intervals. Blood was then drawn and tracer was measured to determine how much iron was absorbed and whether this correlated with hepcidin levels. You guys remember hepcidin back from step one? Oh yeah. It's a protein that increases with serum iron levels and blocks iron absorption from the gut. So the study found that hepcidin levels strongly negatively correlated with the percent of iron absorbed and that any dose with greater than 60 milligrams of elemental iron, the equivalent of one pill of 325 milligrams of ferrous sulfate, produces a hepcidin increase that lasts between one and two days. So what are the implications of that study? Since hepcidin effects fades by about 48 hours, perhaps iron should actually be given every other day. But we do still need more data on the efficacy and adherence to these schedules. Great point, Marty. This is really an intriguing basic science study that may have more important clinical implications. The jury is still out, though, and this will definitely make me more forgiving if my patient can't tolerate two times or three times a day dosing. Perhaps we should even be starting patients on every other day dosing, especially if they can't tolerate the GI side effects. And I guess the last thing we should cover is how long to replete for. For short, there are many different organizational guidelines that address iron deficiency in general and repletion duration specifically. But generally, I'd say it's a good idea to replete three to six months to target ferritin of 100 or transferrin saturation of 20%. We'll link a systematic review of guidelines in the show notes. Guys, great discussion on oral iron. but to switch gears, who are good candidates for IV iron? So most people who get IV iron fall into one of three categories. First, you have your patients who have poor tolerance of oral iron due to side effects, primarily constipation that's not relieved with a stool softener. Then your second group are your malabsorbers, such as your celiac disease patients or IBD patients or even post-bariatric surgery patients. And lastly, your third group are those whose rate of iron loss is difficult to keep up with using oral iron. Yeah, I had this young female with a hemoglobin A8 from heavy menstruation, really symptomatic with fatigue, despite trying many different OCPs to control her bleeding. So while OB-GYN was trying to figure out the best OCP for her, we decided to get her on IV iron infusion and she felt much better after. That's a great example of ongoing blood loss. The other patients in whom you'd want to think of IV iron for is your dialysis patients or CKD patients on erythropoietin. They have a loss of iron due to lots of phlebotomy and blood left in the HD circuit, which deplete iron stores. Studies estimate that end-stage renal disease patients have an average loss of 2 grams per deciliter of hemoglobin annually. In addition to those reasons, you have to remember that these end-stage renal patients are often on calcium-containing phosphate binders, which interfere with iron absorption. And for that reason, CKD patients are at very high risk for iron deficiency anemia. But the good thing is that your dialysis patients interface with the medical system at least three times a week, which makes it very convenient to give IV iron. Okay, now I know IV iron is an option for my patients who can't tolerate oral iron GI side effects, have malabsorptive disorders, end-stage renal disease, or have ongoing iron loss. Over 103 trials found that no increased risk of severe adverse effects with IV iron. In fact, the incidence of severe adverse reactions such as anaphylaxis is less than 1 in 200,000 for IV iron that did not include that high molecular weight iron dextran. Now let's compare that to giving PAC-RED blood cells, which we'll eventually have to do if our hemoglobin drops below 7. The severe adverse events rate for infusion with packed red blood cells is 1 in 21,000, according to 2012 data. That's really interesting food for thought when you put the incidence of serious reactions from IV iron and IV packed red blood cells next to each other. I think the takeaway here is that the risk of reactions with IV iron is quite low. So for our throwback question from our five pearls on headaches, let's review medication overuse headache. Yeah, let's go over that one. That was the one you guys said you knew the least. And now as Marty knows very intimately, super high yields for the boards. Yep. So medication overuse headache is going to happen when a patient already has a pre-existing headache disorder, and they're using these abortive medications in very high frequencies. And you're going to notice their episodic headache changes to chronic or almost daily in nature, like 15 or more days a month. So the key feature is increased frequency of headaches in the context of using lots of abortive medications. Be alert to medication overuse headache if your patient is using abortive medications more than 10 times a month. That means basically two to three times a week. So we just defined medication overuse headache. This is not to be confused with medication-induced headache. Common drugs that induce headaches include nitrites, phosphodiesterase inhibitors, or hormones. Alright, let's get to the takeaway points. Pearl 1. Asymptomatic patients at high risk of iron deficiency anemia should probably be screened, but this recommendation is not evidence-based and is based on outdated professional society guidelines. The interval of repeat screening is also not clear. Pearl 2. Men and postmenopausal women without a history of overt bleeding should be referred for both upper and lower endoscopy. There is a decent chance of malignancy and even greater chance of other GI pathology that can be intervened upon. Pearl 3. The exact optimal dose of oral iron is not known and likely depends on the individual patient, but when choosing a dose, one should consider the pharmacology of hepcidin-induced malabsorption and balance this with the patient's side effect burden. Pearl 4. IV iron is safe without increased risk for significant adverse reaction or infection. It is quicker and more effective than oral iron in repleting stores and should be routinely used in the appropriate populations, for example, those poorly tolerating oral iron, side effects, malabsorptive diseases, and stage renal disease, or ongoing blood loss that oral iron cannot keep up with. Pearl 5. If you notice your patient's headache changes from intermittent to a chronic daily headache while using lots of abortive medications, consider medication overuse headache. All right, thanks for listening. If you have any questions, please email us at coreimpodcast at gmail.com or tweet us at at coreimpodcast. We're also on Facebook and Instagram at coreimpodcast. Opinions expressed in this podcast are our own and do not represent the opinions of NYU or other affiliated institutions. Do not use this podcast for medical advice. Instead, see your own healthcare provider for medical care. All right. Thanks for joining us. See you guys next Wednesday. Take care.
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Welcome to Psyched, the psychiatry podcast for medical learners by medical learners. In this episode, we'll explore a topic that we're sure many listeners are eager to learn about. And this is our first Psyched episode on a topic of geriatric psychiatry. This episode, we'll be learning about Thank you. at the University of Toronto in my third year. And I'm joined by my two co-hosts, Sena Gok, who's an international medical graduate who is passionate about psychiatry. And we're also joined by Mark Fraccaro, who's a psychiatry resident physician in his fourth year at the University of Calgary. Hi, everyone. Hey there. Hi, thanks for having me. All right. And of course, we are also really grateful to have our special guest expert, Dr. Leslie Weisenfeld, to share her expertise. Dr. Leslie Weisenfeld is a geriatric psychiatrist and psychiatrist-in-chief at Mount Sinai Hospital in Toronto, where she leads the Geriatric Consult Liaison Psychiatry Service. Dr. Weisenfeld is also an associate professor in the Department of Psychiatry in the Faculty of Medicine at the University of Toronto. Dr. Weisenfeld received her medical degree from the University of Toronto and completed her geriatric psychiatry subspecialty at Mount Sinai School of Medicine in New York. She holds a master's degree in healthcare management from Harvard School of Public Health. Dr. Weisenfeld's research has focused on hospitalized older patients, in particular patients with behavioral disturbances due to delirium, dementia, and mental illness. And Dr. Weisenfeld has earned a number of teaching awards and has been recognized for her teaching by the American Psychiatric Association. Dr. Weisenfeld, it's a pleasure to have you joining us today. Thank you for having me. It's wonderful to be with you and always good to talk about older adults. Thank you. All right. So I think we'll get things started by going through the learning objectives for today's episode. So by the end of the episode, listeners should be able to define major neurocognitive disorder as per DSM-5 diagnostic criteria, identify differential diagnoses for cognitive decline, and list differentiating clinical features. Outline an approach to the assessment of a patient presenting with cognitive decline, including the role of a comprehensive history, psychometric tools, and other investigations. And finally, to classify the major subtypes of neurocognitive disorders, their epidemiology, and clinical presentations. I'll hand things over off to Senna to get us started. Yeah, so I'd like to list the diagnostic criteria of major neurocognitive disorder to set the stage. Formerly known as dementia, major neurocognitive disorder is characterized by evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains. Learning and memory, language, executive function, complex attention, perceptual motor, and social cognition. This cognitive decline must be severe enough to impair one's function at a minimum requiring assistance for complex instrumental activities of daily living. Before diagnosing dementia, one first has to rule out delirium. Lastly, the constellation of symptoms cannot be better explained by another psychiatric condition such as major depressive disorder or primary psychotic disorder. Please note that for ease of use, we will be using the term dementia. Dr. Weisenfeld, do you have any comments regarding the diagnostic criteria for dementia? Well, I mean, I think a few comments I'd make where you already made one of them. I think that it's worth keeping in mind that although the DSM made a big shift in terms of some of the language to starting to use that term neurocognitive disorder, many other disciplines, especially neurology and internal medicine will be more familiar with using the term dementia. So we need to keep that in mind, especially when we're psychiatrists making diagnoses. And I think the other thing I would mention, and I'll talk about it a little bit more when we talk about our case is, although you listed an absolutely accurate the DSM around some of the key domains of cognition. Another way to kind of keep that list kind of clear in your mind is what we used to talk about in terms of the seven A's, things like anus agnosia, amnesia, aphasia, agnosia, apraxia, altered perception, and apathy. And that's just another way to try to remember. And I'll talk about that a little bit more when we talk about the assessment of people when we're wondering about if they have dementia or neurocognitive disorder. Wonderful. Thank you so much. So could you teach upon the difference between a major neurocognitive disorder and a mild neurocognitive disorder? Absolutely. So one thing to keep in mind, and I think it's true as we go through almost all of the many pages of the DSM, that we're always trying to keep in mind, you know, what would be kind of useful in terms of diagnosis and also what helps patients and practitioners. So mild neurocognitive disorder, and bear with me because you can have a mild version of a major neurocognitive disorder, but mild neurocognitive disorder refers to a degree of cognitive implying that's not quite as substantial as the so-called major, and that isn't interfering with activities of daily living in the same way. So you can think of it either as a condition that might precede major neurocognitive disorder, but for many people, they might have this mild neurocognitive disorder and not proceed on to dementia or the major neurocognitive disorder. So the key thing is it's less severe in terms of the actual symptoms themselves, in terms of their interference with daily living. And often because of that, family or the person themselves may have a sense that there may be something wrong, but not as strong a sense that there might be something wrong in terms of the functioning and the impact. Okay. We will definitely go over the clinical vignette for the major neurocognitive disorder further in the episode. So, when I was reading the SM5 criteria, I see that flags are warning signs of declines in these six domains we just talked about. Could we maybe give some examples to understand them a bit better? Sure. You mean in terms of what it might look like if you're interviewing a patient, you're thinking about that? Yeah. So maybe talking about executive function first, and maybe also worth making the point that back in the day, I think often when we were making diagnoses, people, especially practitioners or psychiatrists or family doctors might sometimes refer to dementia as a memory disorder. But I think it's been clear for years, for decades, that dementia is much more than a memory disorder. So if we think about what you've mentioned, so executive functioning, for example, is about almost how we kind of organize ourselves, how we think about being, I'll use executive on purpose, but how we were kind of almost like the executive assistant for our own activities. So what does that mean? It means how we plan, how we think about what we would do. I knew that I had to get to this podcast opportunity at a certain time, so I had to figure out when did I have to get home, when did I have to start, what button did I have to press? So executive functioning is really how we organize ourselves, how we plan, how we abstract, how we think about connections between things. So it's much more than memory. It's much more than language. It's a real kind of higher level coordinating function of our brain. Cognition is how we pick up the cues for things, how we think about, you know, if I'm watching your face and you're paying attention to me in a certain way and you look like you understand how I can make use of that, right? How we pay attention to things is much more than memory as well. And perceptual motor is probably just as it sounds. We need to coordinate ourselves in space. What does that mean? If I have to parallel park, I have to do a lot of looking. I have to coordinate. I have to figure out what to do with my hands. I have to look in my mirror. I might have to look on a screen that's now on the fancy cars that have those opportunities to figure out how to parallel park. So figuring out how to make use of information in front of you, and figuring out what to do with your body, what to do with your movements, is part of one of the many things that our brains do that is much more than memory. Of course, memory is a big part of making a diagnosis of dementia or major neurocognitive disorder as well. But in many ways, it's often the easiest one to take stock of. And it's very easy to ask a family member or a person how they're doing in terms of forgetting to pay their bills or remembering people's faces.
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Just the going back to like the differences between like the mild neurocognitive and major neurocognitive, something that like, I sometimes wonder, or like our patients wonder, or their families is like, what's normal aging? Is there a like an expectation that you may have some mild decline in some of these cognitive domains and like quote unquote normal aging versus a mild narrow cognitive disorder? That's a great question, Luke. Of course, what I sometimes say, and I don't want to make light of the person's experience or the experience any of us are going to have when we get to be 70 and 80 or 90. But I often say to my patients that in the same way as we get wrinkles and gray hair, as we get older, there are also changes in brain function. And, you know, that doesn't mean that they're welcome necessarily. And that doesn't mean that they are kind of good, bad or indifferent. It means they're just part of normal aging. So part of normal aging is losing some ability to remember things as quickly and some ability to learn new things. You know, many of us will have older adults in our lives who are very wise and have a really good memory for the past, but maybe not quite as good a memory for some of the things that have happened in the last day or the last week. it's podcast already, we're thinking about that sort of normative distribution. We're thinking about whether or not how you do compared to the other 80-year-olds with a similar level of education, a similar level of experiences. And that's why it's actually kind of tricky to make a diagnosis sometimes because we're asking a person to think about how they do in comparison to themselves. We'll talk about the baseline when we talk about the patient that's coming up. And we're also taking stock of what is normal for an 80-year-old or a 70-year-old or a 90-year-old for each kind of education or social experience. And we have actually more older adults in the world than we've ever had in the history of older adults. So we're learning about what is typical for a 95-year-old when 30 or 40 or 40 years ago, there weren't as many 95 year olds as there were. And we have a patient named Julia, who's a 78-year-old female who's presenting to our clinic with her son, Chris, for an assessment on referral from her family physician. And the referral letter notes that Julia and her son, Chris, have had concerns about Julia's memory decline over the past one and a half years or so. So when interviewing this patient and their son, what sort of questions are you asking in order to begin to narrow this broad differential for a memory decline or cognitive impairment? So I'd probably start by maybe stating the obvious, but I think it's still worth stating that the first thing I'd be thinking of when Julia comes in with her son is that she's actually probably pretty scared. One of the things people are pretty worried about as they age is dementia. And going back to your great question, Luke, I think people are often wanting to feel reassured that maybe it's just normal. And in the same way, they've had to accept some frailty and some slowing of other things that they'll have to accept this. But the first thing that I always try to keep in mind before I ask any questions is, you know, what is Julia and herself, what are they most worried about? Because I think that helps to set the stage for how we ask the questions and, and just making sure that even though, of course, and I'm going to answer your question, we're going to go through all of the things that people need to ask about. But I'm sure you can appreciate that, you know, someone coming when they're wondering about dementia or wondering about Alzheimer's, which is one of the commoner kinds of dementia that people at least are familiar with. They're really scared. They're hoping to be reassured, but they're often pretty scared. So in terms of some of the history approaches then that I would take, I think there's a couple of ways you could start. I'll just give some examples. You could either start by the usual history taking of psychiatry, which is asking a little bit about the temporal course. What are the things that have most worried Julia and her son? And just open up with kind of open-ended questions about what are the kinds of things that have brought them, you know, to this level of concern. That usually leads to the usual kind of, you know, medium to long description of some of the things that they've noticed, some of the things that have changed. The key things to kind of think about as you're taking that history just in general, and please feel free to interrupt me and tell me more about what you'd like to hear about first, you know, is what is the time course, right? So when did those worries start? What was the context in which they started to notice things? And who's observed them? Because one of the things that's true for almost all of us is some people who are seniors or older adults have a lot of people in their lives who can notice things pretty quickly and pretty sort of seamlessly over time. And other people might say, look, I don't usually see my mom except for once a year at Christmas time. And at Christmas time, I saw that she wasn't able to, you know, make the same dinner that she normally makes. And forgive that gendered example, but that's a pretty common thing that people will say if they don't see their parents very frequently. So it's good to think about what is the time course and how did one discover it in terms of some of the things that were discovered. And with that, it gives you a chance to also ask about someone's kind of usual level of functioning. So asking about both what are called ADLs, activities of daily living, I'll talk about those in a sec, and instrumental activities of daily living are usually the functional kinds of things that you want to start with. So activities of daily living are kind of like just what they sound like. They're about getting dressed, being able to like brush your own teeth, feed yourself, you know, pretty, they're called basic for a reason. The kinds of things you have to do really just to kind of manage even the most general kind of independence. Those are not usually the activities that people notice first because they come a little bit later. The instrumental activities of daily living are more the kinds of things you need to maintain full independence, managing your finances. If you're still working, being able to work successfully in your job. Many people are working into their 60s and 70s and even 80s. So it's always worth making sure that we don't make assumptions that people are retired. Cooking, making grocery lists, driving, looking after other people in your family, those are more, you know, those are more of the kind of higher level functions. And so it's in some ways a very humbling reminder when we take those histories that there are lots of ways to live a life and lots of divisions of labor. So the other thing I try to keep in mind, even in the more modern ways of asking questions, is there often are cultural and gender divisions of labor that we have to be particularly attuned to as we think about what someone is still doing and what they've stopped doing. Some people have never managed the family finances. So the fact that they're not managing them is actually almost immaterial. Some people have never driven. And so we don't have a lot of information if they've never driven before. So starting with the kind of functional kinds of concerns is usually where I would start. And then as I move through the functioning kinds of concerns is when I start to go through, and I was mentioning them earlier to Senna, some of the kind of domains of cognition, or basically what I think of as all the things our brains do that, you know, that make us, you know, humans and functioning, they start to go through those one by one. Do you want me to go through those or do you want to ask me another question? Yeah, maybe we could briefly go through those before we move on to the next question. Sure, sure. So again, I usually go kind of one by one through language and executive functioning and the things I mentioned before. So, you know, well, maybe I'll start first. I first start with memory because memory is probably the thing that people are most kind of ready to talk about. So good to explore short term memory. So how easily is it for someone to remember, you know, things that they just were asked to do before? Common kinds of things to ask about are to ask if people ever have experiences where, you know, they wander into a room and they meant to get something and then they forget.
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Very common for people to have loss of short-term memory before they lose their long-term memory. So one thing I'll often ask family members who are often giving some history, you know, is, you know, do you notice a difference between the things that your mom can remember from 30 or 40 years ago on a really beloved trip versus how well she can remember that you visited her last week or that you called her last week? And often that's when family will say, oh, yes, there is a big difference. She's really good at one of those, but not so good at the other. In terms of memory, there's also memory for names, for faces, recognizing people. And almost every kind of domain has an overlap with another kind of domain. So as you can probably imagine, you can ask questions about language and often I'll ask, does your mom forget the words for things? Is she sometimes saying things like, you know, that thing, that thing that does the thing that does the thing. That's often a thing you will see people do when they are struggling with the word for something. And so giving people examples of what language loss might look like often helps to take a better history than just saying things like, have you noticed any changes in your mom's language? And thinking about executive function, I was mentioning that to Sena earlier, is usually about asking about planning and coordinating and problem solving and decision making. And so sometimes it feels a little bit more literally abstract as a question than some of the other ones. But usually asking people to really just kind of consider whether or not the person they're bringing, usually it's a parent or a loved one, whether or not they've noticed just changes in someone's judgment, changes in the way that they might have approached a difficult decision or a planning decision. And that's where, you know, again, if you'll forgive the slight sort of gendered comment, if someone is bringing in someone who normally cooks a family meal or coordinates things for a holiday, asking about whether or not they're still as able to do that as they used to, or whether or not they've given that over to a younger family member and sort of asked if they can maybe stop doing that. I should say that people have every right to stop doing all the big family dinners they used to. And sadly, in the pandemic, this is actually why it's been harder to tell how people are doing because a lot of the coordinating has been kind of out of sight and out of mind and much less. But the key thing with executive functioning is to really ask about problem solving and judgment issues. And sadly, it's often in that domain that we find out that people might have been taken advantage of. So it can be an important question to ask, you know, have there been any kind of decisions that your loved one has made, or situations where they've been in some sort of jeopardy, maybe someone has offered them some quick, you know, kind of get rich scheme, or someone tried to sell them something, some financial product that they otherwise would have been a little bit more savvy about. You know, one of my very dear mentors and colleagues says that, you know, people who might be trying to scam someone are better able to tell who might have cognitive impairment even faster than physicians and family, because they can pick up on someone who might be a bit vulnerable and a bit sort of lost in terms of being able to make decisions. So going through, and I haven't gone through all of them, but going through language, memory, executive functioning, concentration, in addition to all of the kind of functional issues is important. And then taking oneself through all of the, what I would describe as kind of more specific kind of medical psychiatric sort of screening type symptoms that will help you to distinguish between whether this might be a dementia or major neurocognitive disorder, or whether this might be a different psychiatric or neurologic or medical problem that's making someone look like they have a cognitive disorder. Yeah, actually, that was going to be my next question because, yeah, like a decline in functioning affecting cognition, concentration. These are features of many different medical conditions or, of course, psychiatric conditions that people can present with. So I'm wondering, Dr. Weissenfeld, if you could take us through the differential for this type of presentation and maybe what are some of the things you're looking out for in past medical history and past psychiatric history that would be important in this assessment? Absolutely. So maybe I'll start with depression, which might be obvious. So I'll mention depression for a couple reasons. One of the commonest diagnoses that families have in their own mind in situations where psychiatrists or neurologists end up diagnosing dementia is this question of depression. And that's because the other, one of the other common features of someone who has dementia, in addition to having some functional decline, is often apathy. So in other words, not really being kind of initiating things, not being as active, not engaging in their usual activities. So of course, that often mimics depression, right, in terms of amotivation, indifference, things like that. So really, really important to try to distinguish between whether or not the functional decline and the sort of flatness and maybe even some of the mistakes that somebody might be making in whether it's driving or bill paying or whatnot is related to a depressive illness, either a new depressive illness or a chronic depressive illness or a dementia. The reality is that if somebody hasn't had a history of depression in their whole life and hasn't had any major stress or like grief or bereavement or major, major medical illness, it's pretty unlikely for someone to have a first onset of depression in later life compared to the epidemiologic likelihood of it being the beginning of a dementia, but it's really important to screen for depression. I have the impression often in practice that understandably we all kind of are hoping to have a more treatable disorder. So there tends to be almost a kind of therapeutic tug towards wanting to really, really make sure to rule out a depression. And it's an important part of the differential. But when we see people who've been diagnosed with what looks like a first episode depression for the first time in their older life, many of those folks turn out to be diagnosed with a dementia within a few years of that. And so it really speaks to how that sort of apathetic and kind of slowed and less functioning presentation, although it might look like a depression, and depression should be in the differential, often doesn't turn out to be the main diagnosis. So it's just good to keep that in mind, as well, that sort of therapeutic wish to have something a bit more treatable as opposed to something that's more progressive. Other common things to think about are people who have a primary psychotic illness. So the folks who are in their 70s or 80s who've had schizophrenia in particular since their 20s or 30s will often have executive dysfunction. They'll have cognitive changes with that disorder. And so it is often actually pretty hard to distinguish between a new onset of a dementing or cognitive disorder. On top of that, it becomes a bit clearer over time, like almost everything else that gets worse, unfortunately. But the differential certainly if somebody has a known psychotic illness would be whether or not the actual symptoms or the cognitive changes are more related to the index psychotic illness as opposed to a new dementing illness. Many, many, many medical conditions, of course, can also cause changes in functioning. So I won't list them all, but I will say that probably the big differential to keep in mind when there's been a cognitive decline is to think about delirium. So, of course, delirium is usually thought of, and rightly so, according to the DSM and all of us, as a more acute change in cognition, fluctuating levels of attention related to a medical problem. But in order to make that diagnosis and really know that it's acute, you have to have kind of visibility into the person. So if people live alone, if people don't have a lot of collateral kind of people in their life who could tell you the difference between whether it was chronic or not, making that sort of distinction between whether someone has an underdiagnosed dementia or had a cause for delirium that has just not been seen in its acute phase, because, you know, especially during the pandemic, but not exclusively, if an older adult lives alone and doesn't have a lot of people who know them, it'll be hard to see the beginning of a delirium for that person compared to if this is someone who has a spouse or family living in the same home or a job or things like that. So it's always worth keeping in mind that there may be a delirium. And then probably more broadly, any number of medical conditions can cause slowing of cognition, functional problems, executive dysfunction.
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So almost anything that is sort of bad enough medically to slow you down and to make it hard to focus and hard to remember things, which are many things, is probably bad enough to be considered in the differential, which is why when we're doing a workout for dementia, although we're not looking to test for everything, the key thing in history is to take a pretty good medical history. And I would say a medical history, both of kind of known conditions and also kind of under-treated ones. And I would probably say the last thing, although there's probably more things I could say, are to take a history around medication changes. So people who are being prescribed new medications that may cause changes in cognition. So anticholinergic medications, most kind of, I would say commonly in the sense to think of, it's not as if people are on tons of anticholinergic medications these days, but, you know, keeping in mind anything that's sedating, all the things people use for allergies, people use for nausea. What I sometimes say to my patients is to say, are you taking anything that made you feel kind of dry and sleepy? Anything that made your mouth dry is probably anything that can make your brain dry, which might seem like a very unsophisticated way to say it, but patients often relate to like, oh, yeah, you know, that's a new allergy medicine I was taking, especially because people take a lot of over-the-counter medicines that they think are safe that could be making them more confused over time. Wow, yeah, certainly like a lot of things to keep in mind to ask about in past psychiatric and past medical history, but then also screening for, like you said, anything that might have been missed or might be overlooked or can mimic these changes in cognition and functioning. And then kind of going, oh, so yeah. I was going to say, and substances. So I think one of the ways that are often kind of somewhat, you know, ageism brains do as practitioners is, you know, we forget that, you know, older adults, like younger adults, you know, maybe both using or trying substances for the first time, especially things like cannabis, alcohol, and other opioids. So I think the thing to keep in mind is to really take the same thoughtful, comprehensive history for an older adult as you would for a younger person, because I think we don't want to have conscious or unconscious biases around who might be trying substances or turning to them for the first time, or who might have chronic disorders related to substance use that haven't been treated or diagnosed just yet. Sorry to interrupt you, Luke. No, no. And I mean that right there, we're going to go past without mentioning that. And I think that shows that it's something to be mindful of and to make sure that you screen around. So then continuing with like our assessment, working through the HPI, the past medical and psych history, medication, substances, moving on to like family history. Are there important factors that you're looking for on family history? I guess like, of course, family history of dementia, but sometimes people don't know like exactly if they, if there have been formal diagnoses of dementia in the past. So what what sort of things are you looking for asking around in family history? So you hit it right there. I think we do. I think if we do ask about family history of cognitive decline, but what is particularly important to ask about is the age of onset of that diagnosis or decline. Because, you know, Alzheimer's or other dementias, including some of the commoner ones like vascular dementia, these are diseases at aging. You're more vulnerable to these disorders by getting older. You know, 65 years and older, you might have a 5% chance of dementia. 85 and older, maybe a 25% chance. So the reason I'm mentioning that is that a family history of dementia is like having a family history of really long lived people. So what I always ask about is, is there a history of anyone who was diagnosed with a memory problem, or a serious dementia, or who had to go into a nursing home or long term care facility because of their dementia? And then the next question I always ask is, how old were they? And if someone says, oh, it was, you know, age 85 or 90, more likely there's not any particular extra genetic burden for the person that you're assessing. If someone says, actually, you know, my father had dementia diagnosed in his 50s or his early 60s, then it's more likely that there's a genetic vulnerability risk. There isn't necessarily anything sadly to do about that other than to potentially think about whether testing would give more information. But the key thing is the age of onset when you're thinking about family history. And then thinking about a family history also of some of the neurologic disorders that also have a genetic vulnerability, things like Huntington's, which is maybe more obvious, Parkinson's disease. So, you know, any of the kind of neuropsychiatric or neurologic disorders that can have associated with them, cognitive impairment as well, as opposed to some of the other disorders that we might screen for in psychiatric illness, which have a much more kind of genetic connection. You know, when we think about dementia, it's most commonly a disease of aging for most people. Okay. And then finally, like going to the last part of our history, usually ask questions around like social history, screening for psychosocial factors. And I think we already touched upon a few of those that you would ask about, especially when assessing functioning or change in functioning. I'm wondering if you have any more comments on things you'd want to ask about in social history. And actually, I have a particular question about like education level. Is that something that's important? And yeah. Yeah. first language. I think one of the bigger mistakes that we make sometimes in assessment as we go on to some of the actual assessment tools is if someone is speaking the same language as me, so I speak English as my first language, if someone is relatively fluent, I might make an assumption that that's the language in which they learn, that's the language in which they're most comfortable. And I might then make some mistakes in terms of how I do the assessment in terms of formal cognitive testing. So I want to ask about access to education. When I say access to education, I say that because sometimes some people in many countries have less access to education, but might describe a kind of occupational history and a responsibility for things in terms of their family business that clearly suggests that they have a higher level of functioning than maybe the grade level of education. So we're often trying to fill in the gaps sometimes if people haven't had as much access to education. But the key thing is, you know, highest level of educational attainment, what kind of occupational history people have had, and what their role has been perhaps in their family or their, you know, their spouse or relationship or their household gives you a bit of a sense of their functional status, recognizing some people might be managing the money in the family, even though they have a relatively lower level of education, because in fact, they have a kind of higher IQ or intellectual functioning that maybe doesn't seem to fit as much with how far they were allowed to go in school. So I think that's probably the most critical. And then thinking a little bit about culture, recognizing with our usual striving for some cultural humility, we can't know all of the differences of how someone might have done functionally in their family based on their culture, but exploring a little bit about what kind of options that might have been available to them in their own culture and in their own family, I think gives us a sense of baseline for someone. But I think those are probably the most important things that will affect our assessment. I would say there's a corollary there, which is to get a bit of a sense of how dementia and cognition and cognitive impairment fits into how that particular cultural group or family culture is about dementia diagnoses themselves. So over time, I've learned that many families, you know, out of respect for their older adults, will really struggle to tell a really detailed history about how someone is functioning, because part of their respect and deference may lead them to have a lot of difficulty answering my questions. They'll tend to really describe their family member in much more positive and high functioning terms than is actually true. And so I will increasingly, as I've learned this, try to ask, is there anything that gets in the way of you, you know, telling me a little bit about like how well or badly the person you care about is doing, because you want to make sure that you're, you know, supporting their dignity. And I think there's different ways to ask that question. But I've just learned through experience that sometimes it's really, really, really hard for people to speak really honestly about how a grandmother is doing in terms of their cognition.
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Great. Yeah. Thank you so much. Dr. Weisenfeld, you mentioned that there are some overlaps between dementia and depression that can be confused. Before developing these, could we say there are some psychiatric disorders that makes an individual more prone to developing dementia at any age? That's a great question. The science is still evolving on that. I think that, you know, there's some data that, you know, would suggest that kind of chronic depression might put you at higher risk for developing dementia. I was mentioning before that some of the executive dysfunction that's associated with schizophrenia, you know, I think some people might say that puts you at risk for dementia. Others would say that it puts you at risk for being diagnosed with dementia, as opposed to necessarily having dementia per se. You know, certainly vascular, I'm not sure this is what you meant, but certainly having, you know, vascular risk factors, which is not quite the same as having a psychiatric condition, certainly puts you at risk for having dementia as well. Are there other conditions that you were wondering about in particular? You mentioned also language barrier and maybe having possible trauma or immigration history could be also say that these could be contributing factors or maybe not necessarily? So PTSD. Yeah, I'm not sure that they would be so much risk factors in terms of the biology of dementia per se, but certainly if people have other disorders which impact their ability to do well on testing. So I'll give you an example. Sometimes people who are very anxious will become then very anxious if you put testing in front of them when you're doing cognitive testing. So it's, I would say, more the risk that some of the symptoms of the disease may kind of cloud the picture of making a formal or a more kind of secure sort of diagnosis of dementia per se. But from the sort of biology of dementia, because dementia, you know, dementia, you know, is almost by definition, degeneration and changes in terms of the consent. And, and, and although as we, as we learn about psychiatric disorders, almost all of them have, have those kinds of impacts. I don't think that we know that things like PTSD or other kinds of conditions put you at risk for dementia as much as the symptoms may cloud those, those kinds of presentations. All right. I'm just going to move us along and give us more of that information from the vignette to help answer some of the questions for our patient Julia here. So from the assessment with Julia and her son present to provide some helpful collateral information, we learned that she began having difficulties with her memory that have progressed over the last one and a half to two years. She has trouble remembering appointments and recent interactions with family members. She has difficulty following instructions and even forgot to turn off the stove on several occasions. She used to be fairly independent financially, but has now resorted to having her son help. In conversations, she is often repeating herself and has difficulty remembering the names of some objects or even people, though not close family. She would often say things such as, you know what I mean, or that thing. She has seemed down and sad more often than in the past, but screening around depression reveals that she doesn't quite meet criteria for major depressive disorder, major depressive episode at this time. She has no significant past psychiatric history and she's fairly healthy for her age. She has osteoarthritis and occasionally takes Tylenol to manage the pain. She's had frequent UTIs in the past, but is denying any urinary symptoms right now. She doesn't use any substances. She has a history of hypothyroidism, but takes Synthroid. She's relatively sedentary at this time due to her arthritic knees and hips. There are no concerns regarding nutrition. On family history, you learn that her older sister had memory problems in her 80s, and her son thinks that she may have had Alzheimer's and recalls that she had to be moved to a supportive living home before she passed. So I'm going to move on to the next question. It's getting into the DSM criteria, but according to the DSM-5, we require evidence of impaired performance on standardized neuropsychological testing or with another form of quantified clinical assessment. You know, I often thought to myself reading the DSM, like, what does this even mean? What sort of quantified assessments can we do with our patients to aid in our diagnostic process? And when do we have to, or when is it useful to ask for like a separate neuropsychological evaluation, for example. Sure. So I'm assuming, Mark, that in terms of neuropsychological evaluation, I'm assuming you mean beyond the mini mental, the mocha, the things that you would already do. Yeah, exactly. Yeah. So for most people, when the history, you know, as Julia's does, you know, really kind of lays itself out with that sort of impairment, you have reliable collateral or somebody in the family or a loved one who can describe the level of functioning that's declined. It's unlikely that additional neuropsychological testing, which is often quite a long battery test that kind of goes, as you can imagine, kind of in much more depth through each particular domain, it's unlikely that those kinds of additional tests actually change your diagnosis or change your management. So the kinds of situations where it may be more helpful to think about more extensive neuropsychological testing would be these kinds of things. Situations where you have somebody who had really, really high educational or functional attainment and who maybe is scoring perfectly on their, you know, the MOCA or the mini mental state exam, but feels themselves or their loved ones feel like there's something that seems to be off, something seems to be getting in the way. You know, the mini mental and the MOCA and the RUDAS, which is more for people who have cultural or language differences, you know, are pretty good for people who've had kind of high school or early university education. They're pretty good at kind of matching up with how the kind of history that we would take. But distinguishing between either mild cognitive impairment or mild neurocognitive disorder and major neurocognitive disorder is trickier. And, you know, often as clinicians, we will kind of try to make a bit of a judgment call with our patients about, you know, whether we will have kind of a watchful waiting approach and just kind of, you know, kind of keep an eye on someone with kind of serial testing using the other tests, or whether or not there's a particular drive from the person themselves to, you know, kind of really get more information that might distinguish. In many situations, the neuropsychological testing just tells you more of what you already know. It tells you that we're at the border zone between a major neurocognitive disorder and something more mild as opposed to telling you something quite a lot different. The other kinds of situations where it can be useful, which I was alluding to before, is when you're really not sure whether or not this is someone with depression or the beginning of dementia when, you know, the degree of apathy or the degree of mood disturbance compared to what compared to the degree of cognitive impairment, it's just really hard to tell in terms of the symptoms that you've been able to elicit the functioning. And that can be especially true in somebody who has a known mood disorder where you're wondering, you know, if someone has, let's say, lifelong bipolar illness or, you know, polar depressive disorder, whether you're really wondering whether or not they've got an extra disorder, unfortunately, that's evolving. I also find it helpful sometimes in people who are really anxious, even though having a psychological testing does not make people less anxious, but sometimes being able to have more in-depth assessment of each of the cognitive domains is helpful. And I would say lastly, sometimes when someone has maybe a kind of less typical amnestic or less typical memory focused or memory predominant dementing illness, having a bit more emphasis on some of the other domains of cognition can be helpful. You know, the mini mantle doesn't really include executive functioning as its, you know, focus or even any kind of aspect of it. The MOCA has at least more executive functioning assessment. But almost any more detailed, any test that's more detailed will just, you know, give you that much more data for the patient or for their family. And it becomes, I think, especially important if people have, are still working in a later life, right? If someone is still working in a fairly capable or high impact job, often they're a little bit more interested or motivated to have some clarity about whether or not they can still work in such a job or not. Whereas if someone is retired and, you know, they're more comfortable with kind of watchful waiting, you know, they may not be quite as interested in getting a detailed assessment. Awesome. Yeah.
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I was wondering about the role of the physical exam in the assessment of a patient presenting with cognitive impairment and what sort of things do we include in it? What sort of features are we on the lookout for? So I think about the physical and neurologic exam as being both a way in which you can start to distinguish between what kind of what types of dementia. So looking for some of the features that might lead you to think about vascular Lewy body, we'll talk about those, I think a little bit later. And then just like generally looking for, you know, anything else that speaks to kind of frailty and vulnerability. So typically, and it's especially important to keep in mind as we do more virtual assessments, since we can't see everybody's quite so well, we would look at gait, we would be looking for signs of Parkinsonism. So looking for mass bases, tremor, slowing, rigidity, looking at posturing, and then looking for involuntary movements, which might just be kind of twigs to think about other neurologic conditions that one hadn't normally thought of. So the usual kind of physical inspection and then, you know, doing some motor exam, particularly because some of the features of some of the specific kinds of dementia will be important in terms of deciding between Alzheimer's vascular lewy body and some of the other types of dementia themselves. Great. And moving on then from the physical exam to our laboratory investigations, and maybe just specifically thinking about like blood work, what sort of things are we including in there? What are we screening for? Sure. So this will be true also probably around thinking about imaging. So I think one of the other things that's really important when we do this so-called dementia workup, which, you know, I think that term gets used a lot, is to recognize that really what we're looking to do, you know, is to see if there are any other medical conditions that are making cognition worse. It's some other thing. But we know we are looking for any conditions that might be worsening cognition. So the reason why I say that is I think it's really important that patients and families know that we're not going to make the diagnosis of dementia with a blood test, because I think often we forget to explain to our patients and families why we're doing these tests in the first place. So I'll often say, look, we're going to try to do some medical workup so that we can see if there's anything that's making it worse. And I'll often say, just as I said to you, that it's a chance. There's a chance that we might find something that explains all of this, all of the cognitive changes, more likely, we'll either find nothing, which will at least reassure us that there's nothing worse, that's worse or contributory that's going on, or we might find something that, you know, is, you know, is, you know, somewhat modifiable. When I was training, we used to talk about reversible causes of dementia. And I think that term has really kind of gone out of favor, because we don't often find so called reversible causes of dementia, we find, you know, some medical conditions that might be optimizable, so that we can at least, you know, reduce the cognitive burden that's contributing to somebody's impairment. So we would typically do because of that, we would do CBC, we might do extended electrolytes, you know, liver function, kidney function, we would do TSH, for sure, B12 and folate have kind of coming at it, falling out of favor in terms of the likelihood of benefit for any person, you know, including a dementia workup. But I think most people would probably include that still as part of their workup. And then anything and everything else would really be related to what the medical history that we've gathered so far. If someone has diabetes, we might do a hemoglobin A1C to see the status of their blood sugar control. But anything and everything else would really be because we've taken either a medical history that suggests that there's something else we want to kind of clarify, whether it's in kind of an optimized state. Or if we've taken a history that suggests there's an underdiagnosed medical treatment, you know, part of the workup for that as well. So it's not really that large a workup when you think about it. Many people who will come to me, at least for assessment, have actually had all of this done at least in the last six or 12 months by their family doctor. And that's why I think it's really important that families understand that we're not making the diagnosis with blood work. We're looking to see that we can at least exclude anything that might be making things worse in terms of cognition. And then moving on to that idea of neuroimaging, then what are the indications for it? And who receives it most of the time? Oh, so those are, those are two different questions. They should be, they should know it's a good question. No, no, they should be the same. The reason why I'm smiling a little bit, you know, is many, many people will receive, you know, a CT scan or brain imaging as part of their dementia assessment. And I think that many of us would say that would be a standard of care to have at least one set of imaging. And yet, you know, most of the consensus guidelines really highlight that the people in whom brain imaging really either changes the diagnosis or affects their management is a relatively small group of people. So most recommendations suggest that, you know, that we should for sure make sure to do brain imaging in anyone who's under 60, so a younger age onset of cognitive impairment. Anyone who's had a really rapid decline, so someone who's got kind of a multi-week or multi-month history as opposed to the sort of gradual decline that we typically hear, you know, when we take a history. Anyone who's had a decline in the last couple of years. So I think most of us would say that if there hasn't been any imaging and we've got like a two-year history, that at least we would want to do one set of imaging to be reassured that there isn't an unexpected but unusual finding on brain imaging. Again, going back to my other point that I was saying about blood work, I think it's really important to tell patients and families unless there's something atypical that we're doing brain imaging to make sure there isn't something unexpected, as opposed to making the diagnosis of dementia through brain imaging. Anybody who's got unexplained, you know, neurological findings, you know, we talked about the physical exam, but anybody who's got, you know, unusual findings like seizures, really bad headaches, any kind of motor findings that are unusual. And then anyone who has a history of a serious medical illness. So if someone has a history of cancer, especially cancer that might be stasticized to the brain, you know, we want to do brain imaging. There's a triad condition called normal pressure hydrocephalus, which involves gait changes, urinary changes, and cognitive changes. We talk about it a lot on exams. It doesn't show up a lot in life. But the key thing is to be alert to that as well. And anybody who's got a major kind of unusual gait. So I think your question was great earlier about the physical exam. Even if we're doing virtual assessments, we want to see if we can get people walking and make sure we get a good view of them. And so the people who should have a CT scan at least are anybody who might fall into any of those categories, including having a decline that's over the last couple of years. So usually what that means is, you know, if you're getting ready to make a diagnosis of dementia or you think someone has a dementia, if they have not had at least one set of brain imaging to go ahead and do so. But as surprising as it may be, even that last piece has been not so much controversial, but I think for a long time, it was more about the list of like young age of onset and focal signs and serious kind of unexplained symptoms. And some people would say you probably didn't even need brain imaging to really make the diagnosis. But I think a certain amount of kind of caution has led us to say, look, at least do one set of brain imaging in order to be certain that there's not something unexpected that you've missed. Excellent. And I'm wondering if you could speak to the role of some of that more advanced imaging, like the functional imaging or the ligand-based imaging? When is that indicated? How useful is it? Yeah. So it's not part of this sort of the usual standard, you know, unless, you know, there's something particularly unusual about someone's presentation.
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So, you know, we learn more when we look at the brain. We can see it more clearly. The way I think of it is it's almost like digital cameras have gotten better and better and better. That doesn't necessarily mean that we know what to do with that information in terms of what's different to do with it. So I think those kinds of functional and more advanced neuroanatomical studies, they're often done if someone's in a research trial or if someone's in a particularly young age group when we're trying to figure out if there's something more unusual that's happened in terms of the diagnosis of dementia. But if somebody has, as I think Julia did, a relatively later age of onset with gradual decline, those kinds of extra imaging are not really required. Kind of in line with the same theme of more investigations. I'm wondering about the role of genetic testing for individuals with dementia or in their family members. Can you speak to us a bit about that? Sure. Quite similar to what I was saying earlier about young age. So if someone has a younger age of onset of cognitive decline, then probably any number of the more additional kinds of tests of wider breadth of testing, and including genetic testing may be helpful to define that. Arguably, it allows for at least more information for that person to have in terms of their own kind of prognosis and possibly the prognosis for other people in their family, which is why it's sort of like all other kind of genetic testing, a bit tricky, right? If I decide to get, if I have, you know, a 50-something-year-old age of onset in my own cognitive decline, and I decide to get genetic testing, then that has implications potentially for my kids, potentially for my siblings. And so I think that the key thing, you know, and genetic counselors will do this much better than me, is to make sure that people can distinguish between information that will be actionable for them, and information that may, you know, be actionable for their family members, as opposed to just getting more information that you can't really do anything with. And I think that's not unique to dementia. But a good genetic counselor will help someone to decide whether or not they're the kind of person where the more information is helpful or whether or not they feel like, you know, if it's not going to really change their own experience, their own access to treatment, you know, their own prognosis that, you know, really the information is of less utility. And I think everybody's different, right? You know, this from cancer screening and cancer genetic testing as well, that we are not always so good at predicting how people will use that information. So they really need a chance to think about how impactful it is in terms of their own thinking about their own lives and that of the other families with whom they share genetic material. But in general, it is not part of the standard workup to have genetic testing. And it's definitely not part of any kind of standard pre-symptomatic or asymptomatic screening. So we don't, you know, put people through screening in order to think about whether or not they should have other kinds of assessments if they have no cognitive changes whatsoever. Yeah. Thank you for going through that, Dr. Weissenfeld, because like, even in my limited experience right now, like we have encountered patients and their families who like wonder about imaging and genetic testing, because as you said, like there are advances in these tests. And I'm sure like if people read up or Google like dementia and like advances in research, they learn about these things and they have questions about what these tests are, should we use them? Are they indicated? Can they help us? And so having some of that knowledge to be able to guide a discussion around what these tests are, that they might be helpful for learning a bit more about what's going on, but may not lead to like management changes, I think is really important to know how to have those discussions with patients and their families. Yeah, and I should say, I mean, I hope for all of us, if we're in the practitioner role that, you know, we also need to probably keep our own, as you alluded to, kind of like values in check. So even in my describing that, you know, I might have, you know, a value around kind of whether it changes management and that, you know, someone else might say, well, I really want to kind of know my status, even if it doesn't change that. So I think to your point, you know, I would usually want to open that up for discussion around, you know, what will be the yield and what are people hoping for? And I think one of the things we've learned about screening for lots of disorders is there's often an assumption that earlier is better, more knowledge of your condition, you know, in terms of the, you know, kind of measured self. We have watches that tell us all sorts of things. We measure all sorts of things and we have our steps. So I think one of the things that I've been, you know that I reflect on is there's an assumption that more knowledge, more imaging, more everything will be somehow better. And I do think we need to caution patients and families around what the limits are in terms of what we can do with that information. Wonderful. Thank you, Dr. Reisenfeld. Now I will continue with our clinical case. So Julia completes a mental status exam in your office and scores 21 out of 30. She does not have previous MMSE scores to compare this to. She loses points on registration, delayed recall, day of the week, end date, and serial 7s. Her physical exam was fairly unremarkable aside from a slightly slow dentalgic gait that she explained was due to her sore hips and knees. Similarly, a review of the blood work completed by her GP prior to the referral did not reveal significant red flags. Her T-shape is within normal limits and has been for the last several years. An MRI is eventually completed and shows evidence of enlarged ventricles as well as generalized corticolatrophy with more pronounced focal atrophy of the hippocampus. Based on your clinical assessment of Julia, including the subsequent investigations, what is your preferred diagnosis for the cause of Julia's cognitive decline? So most likely, and this is one of the commoner dementias, most likely she has dementia slash major neurocognitive disorder of an Alzheimer's type, because that's the kind that is most likely associated with the kind of gradual decline. And although imaging doesn't always distinguish between types of dementia, that kind of what you just described, Senna, that kind of general atrophy, particularly around the hippocampus and the ventricles looking a bit bigger. Basically, if we were to picture it, although I know this is not a visual conversation, we would imagine, you know, more space, more space around all the ventricles so that the brain looks a little bit too shrunken compared to the way it would look if there wasn't any atrophy is very common in people who have an Alzheimer's type dementia. So I guess on that topic of different types of major neurocognitive disorders, you mentioned Alzheimer's dementia being one of the or being the most common type. What are some of the other common types of major neurocognitive disorder? I think the DSM lists a few different etiology specifiers that can be added to the diagnosis. Sure. So you're right. So Alzheimer's is the commonest. And second to that is vascular dementia, what used to be called stroke-related dementia, but it's now been called vascular dementia for a while. A mixture of the two is also pretty common. In fact, some people debate as to whether that might turn out to be actually the commonest, even though most references still list Alzheimer's as the most common. Then after that probably is Lewy body dementia and frontal temporal dementia, which is much less common. And there's a whole number of other kinds of conditions that can cause dementia, alcohol-related dementia, HIV-related dementia. But the ones that I just listed are probably the commonest in terms of, you know, what you might see in visual practice. And, yeah, do you think, Dr. Roswell, do we have some time to maybe go through these different, yeah, etiologies in a bit more detail? Absolutely. Yeah, maybe Alzheimer's. Sure. So maybe just going back to even when we think about history. So, you know, what I was saying earlier before, the kinds of dementias and the course that might be a little bit different and some of the kind of related symptoms. I'll kind of talk it through a little bit that way. In terms of Alzheimer's dementia, you know, it is often described as kind of like the more typical kind of dementia that people imagine. It typically has a more gradual course.
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And I didn't think there was much wrong with mom. And then there was another one a few months later. And then, you know, a year after that, I realized, wait a minute, you know, this has been going on for a while and it's not just to isolate the episode. So the very common way in which you hear family members talk about a story that ends up being more consistent with the pathology of Alzheimer's dementia is that kind of, you know, there was a thing, there was another thing. And then I realized, you know, there was a collection of decline. And then I realized there was some functional changes associated with that. So very commonly, you know, associated with this kind of gradual pattern. This was a visual medium, you would see me kind of making a gradual slope with my hand. And, you know, very much one of a description of kind of changes in memory. So unlike some of the other dementias that I'll mention, people are often really clear in their own minds when they give the history, not the patient themselves, sadly, but their family members and saying that there was a change in memory, often short-term memory deficits, you know, ahead of long-term memory deficits. So forgetting people's faces, forgetting people's names, forgetting to show up at certain appointments, not paying bills. So often it's this kind of gradual decline, most commonly in people's 70s and 80s, although you can have early onset Alzheimer's dementia for sure. But most commonly sort of 70s and 80s are often described as either gradual or somewhat insidious in terms of its onset. And as Senna referenced with our case, Julia, the kind of common kinds of things you would see on imaging would be the sort of atrophy, particularly the hippocampus, and also in the temporal lobes and the parietal lobes. So it, you know, progressed to affect all of the lobes, but the sort of temporal parietal distribution in terms of brain imaging is usually what you'd see. And so that's probably the, you know, the commonest kind of dementia. You'll see memory changes for sure, but over time, you'll see all of the other domains affected as well. It's just more common that you would see memory first in an Alzheimer's type dementia. In terms of vascular dementia, which is maybe kind of obvious, it's one of the ones where the source of it is right in its title. It's, as I was mentioning, it's probably either the second most common or together with Alzheimer's, the combination, you know, may turn out to be over time as we look at these demographics and epidemiologic information, maybe even tied for first place. But with vascular dementia, the sort of profile is first you have somebody with, you know, vascular events or vascular risk factors. So it may seem obvious, but typically you would have someone who has a stroke. So you'll hear the history of someone says, oh, I heard that my mom might have had a change in her like language or her motor functioning right away. I think somebody called it a stroke or someone might have called it a TIA. That'll be kind of like the history that you'll hear from family. And then you'll hear this description of, you know, she had this stroke or this change in either her motor or sensory or cognitive functioning. It was more acute. It seemed to be kind of come on pretty quickly. And very commonly you'll hear that it came on quickly and then sort of plateaued. And then another event happened and the sort of notion of a stepwise deterioration. So basically with each event that happens, a change in cognition where someone doesn't kind of get restored back to their previous level of functioning is the common kind of sort of history of decline. So it can sound gradual if there isn't a lot of collateral information. So that is a bit tricky if you don't have a lot of kind of index kind of data points, but most common you'll hear the association between stroke or an event that's called a stroke and then some change in cognitive functioning. And the other piece of the history with vascular dementia, which is the same as the risk factors for stroke is you'd want to get a history of a history of high blood pressure, diabetes, somebody who might be overweight, you know, someone who might smoke, someone who's known to have high cholesterol. So the picture of a vascular dementia is very much, you know, the same pictures you would have for, you know, somebody who has, you know, a cardiovascular kind of pathology in general. You would hear this story of cognitive changes often associated with these kind of stroke like events that kind of collect over time. And the brain imaging would reflect that as well. And so over time, it might seem more gradual, but overall, it tends to be associated with events. And that's why if somebody, if you come across someone who thinks they had a stroke-related dementia, but doesn't really describe having a stroke, that's a history that you want to kind of poke at a little bit and see whether or not that diagnosis makes sense. I think sometimes when we know there are a lot of vascular risk factors, if we don't have a clear history of a stroke, we might still sometimes invoke that diagnosis. And that's when we might say that there might be a mixed Alzheimer's and vascular picture, because there just seems to be like an abundance of vascular risk factors that would have put someone at risk for these kind of small strokes or small declines over time. But the key thing is, is to listen really carefully for, for cognitive changes related to events that seem like they were more acute and acute on onset that are more consistent with some sort of vascular event. In terms of Lewy body dementia, that dementia is really kind of a constellation of cognitive changes together with more kind of specific, what we sometimes call pathodermic features. In fact, another set of criteria which you can look up are the McKee criteria, which are often invoked related to Lewy body dementia. But the key thing with Lewy body dementia is the cognition often has a kind of fluctuating course, which can feel really tricky because we use that word to describe delirium as well. But the pattern of cognitive decline in lewy body dementia is to sometimes have, you know, days, you know, where someone's cognition might be a little bit better, but other days where it's a little bit worse and that kind of fluctuation together with, you know, signs and symptoms of Parkinson's or Parkinsonism. So tremor, bradykinesia, you know, falls, rigidity, and also visual hallucinations. There are other criteria that are not, you know, in our kind of list of things as required, but the key thing to begin to make a diagnosis of Lewy body dementia is to have this, you know, kind of combination of Parkinsonism, fluctuating cognition and visual hallucinations. Keep in mind that you can get visual hallucinations in Alzheimer's as well. So I think because those criteria are set up so precisely, there can be kind of a leap to making the assumption that all people with cognitive impairment and visual hallucinations must have Lewy body. But in fact, these are very common features to have psychotic symptoms in almost every kind of dementia, including vascular and Alzheimer's. And most typically in Lewy body dementia, you'd be looking for those features to come on together. So Parkinsonism, cognitive impairment, and visual hallucinations. And in particular, the visual hallucinations that you want to be kind of particularly kind of alert to are ones that are very well sort of delineated and detailed. So for example, someone who sees a little animal that is, you know, beside their bed, someone who sees really bright flowers, someone who sees really detailed scenes is more likely to have lewy body dementia pathology than someone who just, you know, kind of sees something in the shadows or sees something kind of more like an illusion or, you know, very subtle hallucination. You know, people sometimes talk about the Lilliputian hallucinations. People know the story of Gulliver's Travels. So also the idea of these little kind of animals, kind of things looking very robust and bright and detailed is kind of the classic Lewy body dementia hallucination. So that's an important thing to pay attention to as well. Other things that can be present in Lewy body dementia that would be what we would call supportive of that diagnosis would be people who have REM sleep disorders or people who've had a severe sensitivity to neuroleptics. So it's maybe obvious if you have Parkinson's and you're probably going to have this neuroleptic sensitivity, more likelihood of having EPS or stiffness in response to a neuroleptic or into psychotic medication. And so that's another thing to pay attention to if you've got all of those kind of features all at once.
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Sure. I guess this just shows the importance of getting the timeline down in that assessment and the HPI. And then like when assessing the cognitive domains, really like figuring out the order in which some of these deficits started to present themselves. And, and then of course, if, if it's in the context of, of strokes or, or mini strokes. Yeah. And I guess the, the final one and one that I, I think many people like find interesting is that frontotemporal dementia and the, how that can present. And from, from my reading and experience, it could present very different compared to the other types of dementia. I'm wondering if, yeah, we could touch upon that before we finish things off. Sure, absolutely. So frontal temporal dementia, you're right, is, you know, it's almost like a whole other category of sorts. And for a few reasons, one, it's most commonly a younger person's dementia. So it tends to be a bit over-called in an older person when there's some executive dysfunction and tends to be underappreciated because when, you know, a 55-year-old person, I'll talk about the criteria in a moment, you know, presents with cognitive changes as well as some unusual changes in their behavior, there are other disorders that often come to mind, including things like mania or psychosis. So, you know, there are a few different variants of frontal temporal dementia. And, you know, generally, you know, there's a behavioral variant where people can have either behavioral disinhibition, you know, changes in their personality, being disinhibited sexually, you know, kind of acting in very different ways, you know, hence the tendency sometimes to wonder about mania within that differential diagnosis. Sometimes people are even diagnosed with bipolar illness, late onset bipolar disorder, and then that diagnosis then changes to include frontal temporal dementia. So there's a behavioral variant, which often includes either disinhibition or the opposite of disinhibition, so apathy, and profound apathy, so being like inert, like almost like a real, like slow down, not doing anything. Again, you can imagine that, you know, that condition can sometimes be diagnosed with depression, if diagnosed as depression in the early days before it becomes clear that it's a frontal temporal dementia. And often like changes in personality that will feel like really cold. So sometimes people talk about loss of sort of social connectedness or even kind of what people sometimes will describe as loss of empathy. And so real personality changes that can be part of this behavioral variant together with cognitive changes. And another example of something that will seem kind of unusual, so you want to kind of keep it in your memory bank to look for it, you know, is what is sometimes called hyper-orality. So like, you know, eating things and like mouthing things that you wouldn't normally be mouthing. So it's quite unusual. And again, as I'm sure you and your listeners can imagine, we'll be easily mistaken for other things. It'll be mistaken for mania is probably the commonest kind of condition that is in the differential, but even sort of substance use. So if you can imagine if someone develops frontal temporal dementia, they might be turning to substances and then people might be wondering if that's a substance induced change. So I think the key thing to think about is if you are seeing someone with a really kind of altered mental status and an altered personality and altered behavior to try to kind of have some way to remind yourself that frontal temporal dementia should be somewhere in the differential, the behavioral variant in particular. There's also a language variant. So people with frontal temporal dementia sometimes kind of present or kind of their dementia shows itself as really being almost exclusively a language dementia. And so really struggling with, you know, using the right words for things or being able to produce language. And that can be especially hard to diagnose because, you know, language is how we do all the other assessments in dementia, right? If we think about the mini mental, so much of what people have to do is to be able to understand language and produce language in response to almost all of our questions. And so again, kind of thinking, reminding ourselves that there can be this very language specific dementia that can, you know, make people really struggle. And the way that I often think of it is if someone's functioning is a whole lot better than how they do in the usual interview or how they do on their testing is I try to remind myself to think about the language variant of frontal temporal dementia. So if someone is managing to take a bus, you know, three buses to get to work, but somehow can't produce speech, then, you know, thinking about them having a language, kind of almost like a majority language variant of a dementia, sometimes called primary progressive aphasia is one of the kinds of language variants is important. And that's kind of true for almost all dimensions. Whenever there's this kind of incongruence between functioning and how someone performs on a test, you know, it's important to think about some of these more unusual, more focal dementias as well. And so thinking about frontal temporal dementia, which is a mouthful, means really thinking about behavior and thinking about language much more than we might be thinking about it in other kinds of dementias and really being attuned to these, to the likelihood these are younger onset dementias. It doesn't mean you can't be 85 and have a frontal temporal dementia. But as you heard from the earlier discussion, executive dysfunction is actually part of many dementias. So it's not really unique in that sense. The key thing is if you have younger age of onset, really kind of altered sort of social functioning and personality and behavioral functioning with relative sparing of memory per se in ways that we can evaluate it, it's more likely that you have a frontal temporal dementia picture to diagnose, especially if there's a rapid progression. So it's a little bit faster, sadly, than other dementias. It's really quite a storm, if you will, especially when you think about the age range is sort of 40 to 60. Many people are still like, you know, at work, they're actively, you know, parenting, if they're parents, they have, you know, often quite a lot of functional demands on their plate. So it's, it usually comes to attention a little bit more quickly, because people aren't expecting it, they're not expecting all of those kinds of symptoms that somebody who's between sort of 40 and sort of 60 years old. Wow, yeah. And thank you so much for going through each of those different specifiers. I feel like each one of them we could do like a whole podcast episode on. It's really, really fascinating. Can I say one more thing? I think you're right. And of course, I'm biased because I'm fascinated by it. That's why I've chosen geriatric psychiatry. But I think the other thing to keep in mind is that, you know, there's a framework, which is also in the DSM around sort of behavioral and psychological symptoms of dementia and basically the behavioral consequences of any number of these dementias. So I think I would just add that the other part of this sort of inventory, both in terms of taking stock of the functional changes of any dementia is also sort of taking stock of what are some of the kind of changes in terms of someone's, you know, behavior towards their family members, towards, you know, care providers, because, you know, I think there's a whole other, there is also a whole other talk around the fact that although people are often being brought to attention, you know, because of the memory piece and the kind of changing changes in kind of their independence for many people and their families over time, it's often things like, you know, getting lost, you know, not being able to manage stove safety, you know, potential risks of both mood disturbance or agitation or aggression that are really kind of the things that are the heavy burden in dementia and the kinds of things that lead to institutionalization needs for extra care and things like that. So also taking an inventory with any of our assessments around, you know, those kinds of more kind of externalizing behaviors and risk issues in terms of safety is important with any of these dementias because it can happen in all of them. Yeah, it is certainly very important to think about all these components that you walked us through and see the changes in functioning of the individual. Are there any final thoughts or things that we haven't covered in the assessment of dementia and would you like to add anything?
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And so the early phase often requires all of our usual empathy and psychological and kind of counseling skills as we help people kind of adapt to a diagnosis that although there is treatment, it doesn't have, you know, as good a prognosis as we'd like it to have compared to, you know, kind of all of the disorders where we have a little bit more therapeutic optimism. And I would say, you know, the sequential review of, as I was alluding to before, not only the progression of the dementia, but the behavioral impacts on the person and their family, you know, the caregiver impacts for people who are really devoting quite a lot of their life to supporting their loved one with dementia, you know, is a big piece of the sort of serial assessment. I think too much in psychiatry, we probably talk a lot about like that index assessment and how we make that diagnosis. And of course, most of our care people with psychiatric and neurocognitive disorders included is about how do we support people over time with their illness experience, right? What is it like to have dementia? If you're the person who has it, and what is it like to have dementia of a person in your family is often the, you know, the work and the care that's needed over time. Yeah. Thank you so, so much again, Dr. Weissenfeld for, for chatting with us today. And I think now like looking back on everything that we've covered, you know, before doing this episode, I felt like the assessment for dementia or major neurocognitive disorder seemed like it's so daunting. There's so much that that you can need to go through almost feeling like a checklist of things you need to ask and and assessments to do. And I think you really highlighted, I think it's like the most important part is learning about the patient as a person, learning about their life before them coming to see you for the assessment, learning about their values, learning about what, yeah, they're just who they are, what their goals are for the future too. And, and also like learning about their, their family or like the supports that they have. Cause that's I think what's just so important in how you then communicate this diagnosis, which of course comes with it. It's, it's it's a heavy diagnosis and comes with a lot of burden and um yeah so that's like a takeaway that that i got from from our talk today and i think that was really helpful for me as a learner and i'm sure that our listeners will also come away from this really appreciating that discussion yeah like you uh took exactly what I was going to say before I could say it. Yeah, and I think we're just scratching the surface in terms of topics that can be covered, you know, with dementia and geriatric older adult psychiatry in general. So I think there's there's a lot more to come in this topic in the future for the podcast and the listeners. So I think that's great. Yeah, thank you again so much, Dr. Weisenfeld. My pleasure. Thankiatry at the University of Toronto, as well as the Canadian Psychiatry Association. The views expressed in this episode are not intended to represent the views of either organization. This episode was produced and hosted by Luke Fraccaro, Senna Gok, and Mark Fraccaro. Our theme song is Working Solutions by Olive Musique. Special thanks to our special guest expert, Dr. Leslie Weisenfeld. You can provide feedback by email at psychedpodcast at gmail.com. And for more information, visit our website at psychedpodcast.org. Thank you so much for listening.
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I'm Rachel Gottbaum and I'm talking to Alta Scharro. She's a professor of law and bioethics at the University of Wisconsin Law and Medical Schools in Madison. She's written a prospective article called The Celestial Fire of Conscience, Refusing to Deliver Medical Care in this week's issue of the New England Journal of Medicine. So Professor Scharro, you say some doctors, nurses, pharmacists are refusing to deliver health care for reasons of conscience. Can you give us some examples of what you're talking about? Let me start with an example involving a pharmacist here in Wisconsin. This pharmacist refused to fill a birth control prescription that was brought to him on a weekend by a woman who was already on the last day of her existing pill pack. The pharmacist not only refused to fill the prescription, but he refused to give the prescription back to this woman so that she could find another pharmacy to fill it for her. His statement to the pharmacy board here in Wisconsin was that he felt that in any way facilitating her ability to obtain birth control pills represented facilitating abortion. This is only the beginning, however. We also have examples in Wisconsin of refusals to fill prescriptions for emergency contraception. In that case, the woman was unable to obtain that in time, and she did in fact become pregnant and subsequently had to have a first trimester abortion. Is this behavior among these health care professionals legal? It depends upon the state that you're in. What we are seeing is a pattern of bill introductions across the United States that would statutorily protect professionals who refuse to provide these services. Let me give you as an example the initiative in Wisconsin, but it's actually not singular. There are very similar bills in at least three other states. It says a physician, a pharmacist, a nurse, or any other health care provider can refuse not only to perform a service, but can refuse to refer a patient for the service to another health care provider, and can refuse to even inform people that such a service is available. And the services that are listed include not only abortion, but emergency contraception, sterilization, in vitro fertilization, any therapy that involves embryonic stem cell or fetal tissue research, or any service that involves withholding or withdrawing futile medical care from the terminally ill. This is a recent trend. Why is this coming up now? I think it's coming up now because of two things very closely intersecting. One is, as patients demand more autonomy, so do their physicians. And the physicians now feel more and more often entitled to say, I don't like this, I won't do this, as opposed to feeling like they have a special obligation to put the patient's requests and the patient's interests first. And second, we are at a moment of profound debate about the role of religion in our individual, professional, and public lives, and a moment at which the political forces organized around religions have become particularly powerful, so that religion becomes the way in which some professionals now express this greater entitlement to autonomy. They say, as a professional, if I'm obligated to either provide a service or refer for the service or even tell you about the service, it forces me to violate my own religious beliefs and therefore it should be unconstitutional for the government to force me to provide these services. In your view, is it ever justifiable for health care professionals to refuse to deliver medical care on the basis of personal beliefs? Well, I do think that as a profession, there is absolutely a collective obligation to provide all medical services that are legally available and to provide them on a non-discriminatory basis. That said, if collectively a group of professionals, whether it's the group of pharmacists at a particular drugstore or it's the group of physicians in an OBGYN practice at a local hospital, are capable of ensuring that collectively they can give every patient every service to which he or she is entitled. If within that little group they are willing to agree that one doctor doesn't have to do certain things that another doctor does, that is unobjectionable. What is not acceptable is the idea that as a profession, the profession can act as super legislators and essentially decide which services will be, in fact, available to patients and which will not. What is happening is that they are saying my role as an individual, as a Catholic or a Methodist or a Lutheran is more fundamental than my role as a physician or a pharmacist or an ambulance driver. And that's what's changed is this question of which is the most important hat you're wearing at that moment when you're dealing with the patient. So what's going to be the outcome of this? Well, one interesting outcome that's already emerging is a set of bills that attempt to counter the trend. In Illinois, we had a governor's order that pharmacies, not pharmacists, but pharmacies must provide all legally written prescriptions to their patients. And if the pharmacy can figure out a way to let some pharmacists recuse themselves, that's fine. But the pharmacy has the obligation. California has introduced similar kinds of legislation. And in the United States Senate, Senator Santorum and Senator Kerry have joined to introduce legislation concerning religious freedom that would essentially allow acts of religious conscience only to the extent that they do not prevent patients from obtaining legally prescribed medicines or services. So we're now beginning to see the battle lines drawn with different kinds of legislation at the federal and state level both being debated at the same time. Alta Sharrow is a professor of law and bioethics at the University of Wisconsin Law and Medical Schools in Madison. She's written a prospective article called The Celestial Fire of Conscience, Refusing to Deliver Medical Care in this week's issue of the New England Journal of Medicine.
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