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disease. Fever is found in 30% of patients, and it described as Pel – ebsteins fever 
characterized by weeks of febrile period, interspersed by several weeks of afebrile 
period. 
• Pruritis is seen in 25%of patients  
• Alcohol induced pain in the affected area


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Internal Medicine 
 
 421• Others symptoms include Weight loss, profuse sweating, weakness, fatigue, anorexia, 
cachexia  
Hematological findings  
• Normocytic normochromic  anemia 
• 1/3rd of patients may have leukocytosis 
• Eosinophila 
• Lymphopenia may be found in advanced disease 
• Platelets count is variable (normal or increased in the early stage and decreased in the 
late stage) 
• ESR is elevated 
• Bone marrow involvement – late in the course  
Immunologic findings  
• Progressive loss of immunologicaly compet ent T-lymphocytes leads to impaired cell 
mediated immunity which increases susceptibility to viral infections ( herpes zoster, 
CMV) and   fungal infections (e.g. Crypto coccus and Candida) infections . Moreover 
patients will have increased risk of reactivation of latent Tuberculosis infection. 
 Biochemical findings  
• 
↑Ca2+ , ↓ Po 4-3, ↑Alkaline Phosphatase, ↑LDH indicates poor prognosis  
• Hyperuricemia, ↑ Transaminases and ↑ bilirubin.  
Diagnosis  
• Lymph node biopsy:  histological ex amination of an excised lymph node. 
• Feature: the distinctive multinucleated, polyploidy cell with a characteristic Owel- eye  
appearing Reed-Stern berg  (RS)  cells on an appropriate inflammatory background. 
Classification  Histologically Hodgkin’s disease is classified in to four groups.  
These are listed depending on worsening order of prognosis as follows:  
1. Lymphocytic predominant 
2. Nodular sclerosis 3. Mixed cellularity 4. Lymphocytic depleted


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These are listed depending on worsening order of prognosis as follows:  
1. Lymphocytic predominant 
2. Nodular sclerosis 3. Mixed cellularity 4. Lymphocytic depleted  
Clinical staging  
Stage 1:   Only affecting one lymph node area


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Internal Medicine 
 
 422Stage 2 :  2 or more lymph node areas on the same side of the diaphragm involved  
Stage 3:   Disease involving lymph nodes above and below diaphragm; splenic 
involvement is included here. 
Stage 4:   Extra-nodal site involvement (Liver, bone marrow and other extra nodal sites) 
Depending on the presence or absence of constitutional symptoms the stages are further 
classified as A (no constitutional symptoms) and B (presence of constitutional symptoms.) 
 
Treatment  
1. Radiotherapy  – mainstay for stage I and II diseases; used for stage III and IV with 
chemotherapy . 
2. Chemotherapy  
• Cyclical chemotherapy for stage III and IV diseases  
• In stage I and II patient with bulky disease  
E.g.  - Mediastinal widening by 1/3rd  
Lymph node > 10 cm in diameter 
The commnly used combinations of chemotherapy include  
o MOPP: mustine, vincristine (oncovine), procarbatine, predinisolone  
o ABVD : adramycin, bleomycine, vinblastin, decarbazine  
o This combination therapy is either used alone or MOPP – ABVD hybrid given for 
6 cycles (or 4 cycles after full remission). 
3.  Relapse cases are  better treated with autologous Bone marrow transplantation with 
total body irradiation and high dose chemotherapy.   
Prognosis – depends on stage  
Five-year survival being  Stages I and II:  85%   Stage   III A:  70%  Stages III B & IV: 50%


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Internal Medicine 
 
 423B. Non Hodgkin’s Lymphoma (NHL) 
 
Predisposing diseases/ factors to NHL  
• In HIV infected patients there is an increased incidence of lymphoma often at 
unusual sites like CNS; usually B-cell origin with high or intermediate grading. 
• Immunosuppression  increases the risk of developing  NHL  
• Others : Celiac disease, dermatitis herpetiformis and angioimmunoblastic LAP 
predispose to T-cell lymphomas 
• Infections: e.g. Helicobacter infection  is associated with ↑ frequency of MALTOMAS 
• Autoimmune diseases may cause NHL 
Clinical features  
• Superficial lymphadenopathy with a classic tr iangular  distribution (the three vertexes 
ling over the cervical and the two epitroch lear lymph nodes, while the base lies over 
abdominal organs and lymph nodes.)  
• Constitutional symptoms are encountered less commonly when compared with HD 
and if present indicates dissemination. 
• Oro-pharyngeal involvement is seen in 5-10% cases: have involvement of 
Waldeyer’s ring including the tonsils adenoids and paratonsilar areas  
• Anemia, neutropenia (infection) and thrombocytopenia may follow - bone marrow  
involvement or may be autoimmune in origin 
• Abdominal organs and lymphnode involvement is more common in NHL than HD  
• Other organs: skin, brain, testis, GIT, or thyroid involvement is frequent.  
Laboratory findings:   
1) Hematological findings  
• Normocytic normochromic anemia due to autoimmune hemolytic anemia


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• Other organs: skin, brain, testis, GIT, or thyroid involvement is frequent.  
Laboratory findings:   
1) Hematological findings  
• Normocytic normochromic anemia due to autoimmune hemolytic anemia 
• Cytopenias or leukoerythroblastic features  
• Lymphoma cells in may be seen in the peripheral blood sometimes 
• Bone marrow biopsy may show focal or diffuse  involvement  
2) Immunologic markers  are used for classification 
3) Chromosomal findings: various forms of translocations identified 
Blood chemistry  
• Uric acid level is elevated 
• Liver enzymes are abnormally elevated


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Internal Medicine 
 
 424• LDH ↑ (in rapidly proliferating and extensive disease hence has prognostic 
implication.) 
Prognostic features: 
• Histology  
• Staging 
• Age > 60 years – unfavorable  
• Poor performance status 
• Multiple sites of extra nodal involvement  
• ↑ LDH 
• Bulky disease (mass > 5 cm in diameter) 
• Prior history of low grade disease  
• AIDS or other causes of imunosupression related 
Treatment  
Low – grade  malignancy : 
No need of treatment if the patient is asymptomatic  
1) Local radiotherapy  is indicated for stage I, Iε or stage  II 
2) Combination chemotherapy  for advanced cases 
Chlorambucil or cyclophosphamide  or repeated courses of fludarabine  
3) BMT (bone marrow transplantation) 
4) INF - α 
Intermediate – grade  malignancy  
 Localized disease  
Initial combination  therapy with CHOP  (cyclophosphamide, Hydroxodunorubicin 
(Adriamycin), Vincristine (oncovin) and prednisolone) followed by irradiation .  
Disseminated diseases : Combined Chemotherapy is the treatment of choice. 
     
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, 
Malignacies of Lymphoid cells, pages 641-655.


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Internal Medicine 
 
 4254.  Disorders of Hemostasis  
 
Bleeding Disorders 
Learning objectives: at the end of this topic students are expected to:-  
1. Know common causes of hemiostatic disorders 
2. Differentiate clinically between primary and secondary hemiostatic disorders 3. Know possible causes of thrombocytopenia  4. Know clinical approach to a patient with thrombocytopenia  
5. Understand how to approach a patient with drug induced thrombocytopenia 
6. Be able to recognize cases of ITP and refer to an appropriate set up 7. To be introduced with some of vascular causes of bleeding 8. Know commoner causes of coagulation abnormalities with their peculiarity and similarity   
 
Abnormal bleeding may be due to:- 
1. Primary haemostatic disorders  : bleeding disorders resulting form either platlet or 
vascular abnormalities  
• Vascular disorders 
• Thrombocytopenia 
• Functional platelet defect 
2. Secondary haemostatic disorder : resulting from problem in the coagulation pathway 
• Defective coagulation  
 
1)  Disorders of the plat elet and vessel wall ( primar y haemostatic disorders) 
• Patients with platelet or vessel wall disorders usually bleed in to superficial sites such as 
the skin, mucous membranes, or genitourinary or GI tract.  
• Bleeding begins immediately after trauma, and either responds to simple measures such 
as pressure and packing or requires syst emic therapy with glucocorticoids, 
desmopressin, plasma fractions and platelet concentrate.


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• Bleeding begins immediately after trauma, and either responds to simple measures such 
as pressure and packing or requires syst emic therapy with glucocorticoids, 
desmopressin, plasma fractions and platelet concentrate.  
Common platelet vessel wall disorders are: 
• Thrombocytopenia 
• Von willebrand’s disease (VWD)


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Internal Medicine 
 
 426• Drug induced platelet dysfunction  
 
Platelet Disorders  
• Platelets are produced from fragmentation of megakaryocytes in the bone marrow 
results in platelets of which 1/3 sequesters in the spleen, 2/3 circulates for 7-10 days.  
• Platelet count in a normal adult ranges from 150,000 – 450,000/ml. 
• When platelet count is reduced there will be reactive marrow megakaryocytosis  
• Platelet count varies during menstruation i.e. rises during ovulation and failing during the 
onset of menses.  
• It is also Influenced by nutritional state: decreased in sever fe2+, folic acid, or vitamin B 12 
deficiency.  
• Platelets are acute phase reactants hence may be increased in patients with systemic 
inflammation, tumors, bleeding and mild iron deficiency hence the term secondary or 
reactive thrombocytosis is used. It is mediated by cytokines IL-3, 6, and 11. 
 
Thrombocytopenia:  May follow any of the following three mechanisms  
• Decreased bone marrow production  
• Increased splenic sequestration or  
• Accelerated destruction of platelets  
To determine the etiology one should do  
• Careful examination of peripheral morphology 
• Assessment of marrow morphology by ex amination of an aspirate or biopsy 
• An estimate of splenic size by bed side palpation supplemented by ultrasonography. 
Impaired production of platelets:  
• Is commonly associated with stem cell injury


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• Assessment of marrow morphology by ex amination of an aspirate or biopsy 
• An estimate of splenic size by bed side palpation supplemented by ultrasonography. 
Impaired production of platelets:  
• Is commonly associated with stem cell injury  
• Affect multiple hematopoietic cell lines, hence there is varying degree of accompanying 
anemia and leucopoenia  
• Bone marrow aspirate or biopsy show reduced number of megakaryocytes  
Common causes are:- 
• Marrow aplasia  
• Fibrosis or  
• Infiltration of the marrow with malignant cells


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Internal Medicine 
 
 427Less commonly : 
• Cytotoxic drug use 
• Rarely congenital megakaryocytic hypoplasia and thrombocytopenia  
Splenic sequestration:  usually follows conditions causing spleenomegaly such as  
• Portal hypertension 
• Spleenic infiltration with tumor cells as in myeloproliferative disorders or lympho 
proliferative once) 
Accelerated destruction:  
• Non immunologic :- associated with abnormal vessels, fibrin thrombi and heart 
valve prosthesis 
o Vasculitis, hemolytic uremic syndrome, TTP,  
o DIC 
• Immunologic:  platelets coated with antibody, immune complexes, or compliments are 
rapidly cleared by mononuclear phagocytes in the spleen or other tissues; may follow 
viral or bacterial infections, drugs, etc  
• Drug – induced thrombocytopenia  
       Drugs that may cause thrombocytopenia  
o Chemotherapeutic agents – especially carboplatin, alkylating agents, anthracyclines, 
antimetabolites 
o Antibiotics – sulfonamides, penicillines, cephalosporines 
o Heparins – Highest incidence is with unfractionated products  
o Cardiovascular agents – Thiazide diureti cs, rarely angiotensine converting enzyme 
inhibitors  
• Most drugs induce thrombocytopenia by eliciting an immune response in which platelets are 
innocent bystanders. The best proof of drug induced thrombocytopenia is prompt rise in the platelet count when the suspected drug is discontinued 
• Most recover within 7-10 days of discontinuation, some with platelet count of 10,000 to


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innocent bystanders. The best proof of drug induced thrombocytopenia is prompt rise in the platelet count when the suspected drug is discontinued 
• Most recover within 7-10 days of discontinuation, some with platelet count of 10,000 to 
20,000/ml may have sever hemorrhage and hence need temporary support with glucocorticoid, plasmapheresis, or platelet transfusion; and patents should be instructed to avoid the offending drug in the future. 
• Heparin induces a paradoxical white th rombus formation leading to consumptive 
thrombocytopenia.


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Internal Medicine 
 
 428Idiopathic /Immunologic Thrombocytopenic Purpura  
Immunologic thrombocytopenias are divided on the basis of the pathologic mechanism, the 
inciting agent, and the duration of the illness. Accordingly they are classified as acute and 
chronic.  
Acute ITP :  
• Usually follows viral upper respiratory infection common in children aged 2-6 yrs  
(accounts for 90% of pediatric cases) 
• 60% recovers in 4 to 6 wks and > 90% recover within 3 to 6 months. 
 
Chronic ITP:  
• It is common in adults and run a more indolent course.  
• Women age 20 – 40 are afflicted most commonly and outnumber men by a ratio of 3:1.  
• It presents acutely or more often with prior history of easy bruising and 
mennometrorhagia. 
• There is immune mediated platelet destruction as  well as functional platelet dysfunction.  
 
Investigation 
• Platelet count, complete blood count, serology for HIV, screening for SLE  
• Bone marrow aspirate to look for reactive thrombocytosis ( increased megakaryocytes)  
• Ultrasonography of the abdomen to look for spleenomegaly  
 
NB- HIV infection is common cause of imm unologic thrombocytopenias in young adults. 
 
Treatment :  
It depends on age, severity, and anticipated natural history.  Specific treatment may not be necessary unless platelet count is < 20.000/ml  
1) Steroids :  
• Symptomatic patients with chronic ITP are placed on prednisone 60 mg/day for 4 to 6 
wks; then tapered slowly over another few weeks.


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1) Steroids :  
• Symptomatic patients with chronic ITP are placed on prednisone 60 mg/day for 4 to 6 
wks; then tapered slowly over another few weeks.  
• Those patient who fail to maintain a normal platelet count after a course of steroid are 
eligible to splenectomy (steroid responsive but dependent patients are most likely to 
respond to splenectomy)


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Internal Medicine 
 
 4292) Intravenous immunoglobulines (IVIG)  or anti-Rho (win Rho) (reserved for those with 
sever thrombocytopenia and clinical bleeding who are refractory to other measures) 
3) Platelet transfusion  is considered only in those with eminent CNS bleeding as a temporary 
measure. 
4) Emergency splenectomy  (for those who are desperately ill and refractory to medical 
measures) 
5) Antiretroviral treatment  for those dually infected with HIV increases platelet count. 
 
NB: Failure to respond to splenectomy may signi fy presence of accessory spleen which may be 
evidenced by peripheral blood smear examination for Howell jelly body  which appears in the 
circulation of asplenic patients. Such patients may need Immunosuppressive therapy or 
Plasmapheresis. 
 
Vascular bleeding disorders  
1) Hereditary hemorrhagic telangiectasia  : is an autosomal dominant disorder  
2) Acquired vascular defects: 
• Simple easy bruising : benign disorder seen in women of child bearing age. 
• Senile purpura : due to atrophy of connective tissues of cutanous vessels  
• Purpura associated with infection : follow vascular damage by infecting organs or 
immune complex deposit e.g. meningococcemia, dengue fever. 
• Henoch – Schonlein’s syndrome : is immune complex (type III) hypersensitivity. Is 
characterized by purpuric rash on the buttock and extensor surfaces; abdominal pain; painful joint swellings; hematuria. It is usua lly self limiting; however, some times may


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characterized by purpuric rash on the buttock and extensor surfaces; abdominal pain; painful joint swellings; hematuria. It is usua lly self limiting; however, some times may 
cause renal failure.  
 
2) Coagulation Disorders ( Secondary Hemostatic Disordrs ) 
• Hemophiliac A  
• Hemophiliac B 
• Von will brand’s disease  
Hemophilia A (hemophilia) 
• Commonest hereditary disorder  
• Sex linked but 33% may not have family history and results from spontaneous 
mutations.


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Internal Medicine 
 
 430Defect : Absence or low level of plasma factor VIII 
Clinical feature  
• Profuse post circumcision hemorrhage in infants; 
• Recurrent painful hemarthroses and muscle hematomas  
• Spontaneous intracerebral hemorrhage is important cause of death  
• Transfusion related disorders: Hepatitis (HBV, HCV) and HIV infection are frequent 
complications of repeated Coagulation factor transfusions.  
 
Table VI-4-1:  Correlation of coagulation factor activity and severity in hemophiliac and 
factor IX deficiency  
Coagulation factor 
activity(% of normal)  Clinical manifestation   
< 1 Sever disease  
Frequent spontaneous bleeding 
Episode from early life                     
Joint deformity and crippling 
1-5  Moderate disease  
Post traumatic bleeding  Occasional spontaneous episodes of bleeding 
5-20  Mild disease  
Post-traumatic bleeding  
 
Diagnosis 
1) Typical clinical presentation  
2) Activated partial thromboplastin time(APTT) 3) Factor VIII clotting assay  
Treatment :  
Factor VIII replacement or treatment with Desmopressin. 
Spontaneous bleeding is usually controlled if patient’s factor VIII activity is > 20%.  
For major surgery or serious post traumatic bleeding or hemorrhage occurring in dangerous sites Factor VIII level should be raised to 100% and maintained above 60% until healing occurs. Unit of Factor VIII needed can be calculated by the following formula:


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Internal Medicine 
 
 431X = % rise in factor VIII x weight (kg) 
 K Where K = 1.5 for Factor VIII,  
                  = 1 for Factor IX and 2 for Factor XI; 1 unit of Factor  VIII = 1% VIII activity  
 
Table VI-4-2. Comparison between di fferent coagulation disorders  
 
 
Features  Hemophiliac  Factor IX 
deficiency  Von willi brand’s disease 
 
Inheritance  Sex linked recessive Sex linked recessive
 Autosomal dominant
 
Site of bleeding  Body cavities, joint & intramuscular spaces
 Body cavities, joint & intramuscular spaces
 Both mucocutaneous  & other mentioned sites 
 
Platelet count  N N N 
Bleeding time  N N Prolonged  
Prothrombin time (Pt)  N N N 
partial thromboplastine time (PTT)
 Prolonged  Prolonged  Prolonged or normal 
VIII Low Normal  Low  
VWF Normal  Normal  Low 
Factor IX  N Low Normal  
 
Von will brand’s disease  
• Has both functional platelet abnormality (abnormal platelet adhesion) and low factor VIII 
activity 
• Inheritance is autosomal dominant with variable degree of penetrance.  
• Defect is reduced synthesis of VWF which facilitates platelet aggregation and carrier of 
Factor VIII (protecting it from premature destruction ).  
Treatment:  
• Intermediate – purity F VIII concentrates (containing both F VIII and VWF)


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Internal Medicine 
 
 432• Desmopressin  
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Disorders of Hemostasis, pages 673-694. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition 
Medicine, Disorders of hemostasis and coagulation, pages 127-136.


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Internal Medicine 
 
 433CHAPTER SEVEN 
DISEASE OF METABOLISM AND ENDOCRINE SYSTEM 
 
1. Introduction to Diseases of the Endocrine System 
 
• Like the nervous and the immune systems the endocrine system main function is being 
a media of intercellular communication for a proper function of the body.  
• This is achieved by organic compounds called hormones. Hormones are directly 
released into the blood therefore are said to be produced by “ductless glands”. Some 
hormones are bound to carrier proteins for transport but it is the free form that is 
physiologically active. These hormones first bind to plasma membrane of the target cells’ 
receptors .Then a series of cascade reactions (biochemical reactions that initiate and accelerate themselves which are mediated by cyclic AMP) or by direct enzyme induction 
on the nucleus should occur before the nucleus of the cells is influenced to send a 
command for an action. 
• The release of hormones is controlled by feedback of serum level but also the 
physiologic, morphologic and biochemical effects of hormones could play a role.  
• These hormones are finally inactivated in target tissues with the exception of thyroid and 
insulin which are degraded in the liver and kidneys as well. 
• The state of endocrine function is evaluated by level of hormone or the metabolic effects 
of the hormone. With few rare exceptions both high and low levels of hormone result in 
disease.


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• The state of endocrine function is evaluated by level of hormone or the metabolic effects 
of the hormone. With few rare exceptions both high and low levels of hormone result in 
disease.  
E.g. High level of thyroid hormone results in hyperthyroidism while a low level of 
hormone results in hypothyroidism. 
• Endocrine functional assessment is very import ant in clinical practice but with serious 
challenge for resource limited nations like ours. Hormone levels are too low making routine laboratory determination difficult and as a result very sensitive assay are needed 
which are not routinely available due to expense and special expertise needed. 
• The other challenge result from the very nature of pattern of hormone secretion during 
the day making it necessary to take samples at specific times of the day  or doing interventions to suppress or stimulate hormone production whenever the levels are border line for decision making.


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Internal Medicine 
 
 434Homeostasis 
Feed back control, both negative and positive, is a fundamental features of endocrine system. 
Each of the major hypothalamic –pituitary hormone axes is governed by a negative feedback, a process that maintains hormonal levels within a relatively normal range.  
The Hypothalamus 
The hypothalamus produces different releasing hormones that stimulate the pituitary gland.  
• TRH stimulate the production of TSH 
• CRH stimulate the production ACTH 
• GnTH stimulate the production LH/FSH 
• GHRH stimulate the production GH 
The hypothalamus is affected by negative (inhibitory) feedback from the pituitary gland as well 
as from serum level of different hormones or their metabolic effect.  
The hypothalamus produces antidiuretic hormone (ADH) which participates in control of fluid and electrolyte and Oxytocin which participate in uterine contraction after delivery. These two hormones are released in the posterior part of the pituitary gland. 
 
The pituitary gland  produces trophic hormones that st imulate the peripheral endocrine glands. 
• Thyroid stimulating hormone(TSH) stimulates the thyroid gland to produce T
3 and T 4 
• Adrenocorticotrophic hormone (ACTH) stimulat es the adrenal cortex to produce cortisol. 
• Luteinizing hormone (LH)/Follicular stimul ating hormone stimulate the ovaries or the 
testis.  
• Growth hormone is also produced by the anterior pituitary and influence body growth


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• Luteinizing hormone (LH)/Follicular stimul ating hormone stimulate the ovaries or the 
testis.  
• Growth hormone is also produced by the anterior pituitary and influence body growth  
• Prolactin is also produced by the anterior pituitary and influence lactation in females. 
The peripheral glands produce specific hormones:  
• The  thyroid glands produce Thyroid hormone (T 3 and T 4 ) 
• The adrenal glands produce Cortical 
• Ovary and testes produce hormones that control sexual activity and reproduction. 
Other endocrine organs   
• Pancreas: produces insulin  and glucagon 
• Liver: produces  somatostatin  
• Kidneys: produce : renin, angiotensin, erythropoietin, Vit-D 
• Stomach: produce gastrin  
The target cells  execute the command delivered by hormones.


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Internal Medicine 
 
 4352. Diabetes Mellitus 
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define Diabetes Mellitus . 
2. Describe the pathophysiology of  Diabetes  Mellitus. 
3. Understand   the epidemiologic significance of Diabetes Mellitus. 
4. Understand the different types of Diabetes Mellitus. 
5. Identify the clinical manifestation of Diabetes Mellitus. 6. Understand the diagnostic approach of Diabetes Mellitus. 7.  Identify acute and chronic complications of Diabetes Mellitus. 
8. Manage patients with acute complications Diabetes Mellitus . 
9. Understand the prevention  of chronic complications of  Diabetes Mellitus 10. Understand the course and prognosis of Diabetes Mellitus . 
 
Diabetes Mellitus:  is a common endocrine disorder characterized by: 
• Hyperglycemia 
• Manifesting often with symptoms and signs of osmotic diuresis such as polyuria and 
polydypsia 
• Calorie loss, generalized weakness, polyphagia and weight loss.  
Resulting from either an absolute deficiency (Type 1) or a relative deficiency (Type 2) of the 
hormone, Insulin.   
• These disorders are associated with reversible and acute complications such as 
ketoacidosis, which becomes fatal if treatment is delayed. 
• Disabling chronic complications affecting vision, kidneys, the nerves the vessels and the 
heart are common in those who are diagnosed very late, or in those who are not on 
proper medical follow up and care. 
 
Etiology and Classification:


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• Disabling chronic complications affecting vision, kidneys, the nerves the vessels and the 
heart are common in those who are diagnosed very late, or in those who are not on 
proper medical follow up and care. 
 
Etiology and Classification:  
Type 1 DM  (formerly known as insulin-dependent DM)  
• Usually occurs in childhood or early adulthood (age less than 30) 
• Patients are usually thin.


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Internal Medicine 
 
 436• They require insulin for survival and develop ketoacidosis when patients are not on 
adequate insulin therapy.  
• This accounts for 10% of cases of DM.  
• Oral hypoglycemic agents will not be effective to lower the blood glucose level. 
• Type 1 DM is due to β-cell destruction, with absolute deficiency of insulin, which is of 
multifactorial causes such as genetic predisposition, viral and autoimmune attacks on 
the beta islet cells.  It may be immune mediated or idiopathic . 
 
Type 2 DM  (formerly non insulin-dependent DM)  
• Usually occurs in people >40 years of age 
• Most (about 60%) of the patients are obese.  
• Type 2 DM occurs with intact beta islet cell function but there is peripheral tissue 
resistance to insulin.  
• There may be some decrease in insulin production or a hyperinsulin state.  
• These patients are not prone to develop ketoacidosis but may develop it under 
conditions of stress.   
• Patients do not require insulin for survival at least in the earlier phase of diagnosis.  
• The blood sugar level can be corrected by oral hypoglycemic agents. 
Other specific types   
A. Genetic defects  of β-cell function:  MODY 1 , MODY 2 , MODY 3 etc 
B. Genetic defects in insulin action  : Type A insulin resistance  , Lipodsytrophy syndromes 
C. Diseases of the exocrine pancreas: Chromic pancreatitis , Pnactreatectomy , 
hemochromatosis 
D. Endocrinopathies : Cushing’s syndrome, pheochromocytoma , acromegaly


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C. Diseases of the exocrine pancreas: Chromic pancreatitis , Pnactreatectomy , 
hemochromatosis 
D. Endocrinopathies : Cushing’s syndrome, pheochromocytoma , acromegaly  
E. Drug- or chemical-induced DM (beta-blockers, oral contraceptives , glucocorticosteriods  
 Gestational onset DM  (GDM): is when diabetes onsets during pregnancy and resolves with 
delivery. These patients are at a higher risk for developing DM at a later date. 
 
Epidemiology 
 
• Globally 124 million people are said to be affected by DM, of which 97% are type 2 
cases.


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Internal Medicine 
 
 437• In USA 1 to 2% of the general population has abnormal fasting blood sugar level, and 
20% of above 60 years have diabetes.  
• In Asia, particularly urban India, prevalence DM has climbed to 11%, while in South 
African urban Indians it is as high as 18%.  
• Amongst Pima Indians in America the prevalence of DM is very high (up to 50%) making 
genetics predisposition an important factor. 
• Africa is not free from this disease which traditionally is considered the disease of the 
affluent societies of the first world. In Tunisia the prevalence of DM is 4%, in South Africa 
5%, in Tanzania 0.9%.  
• In Ethiopia one community based study showed that the prevalence of DM in Gondar 
area of northern Ethiopia was found to be about 0.5%, and about 4.7% among older than 40 years.  
• Emigrants from Ethiopia to Israel hav e shown a higher prevalence of 8.9%.These 
findings imply that the incidence of disease increases with increasing age, as well as either the dietary habit or sedentary and stressful life style of the developed countries. 
 
Mechanism of Disease in Diabetes Mellitus  
Insulin is produced by the β-cells in the islets of Langerhans in the pancreas. Insulin secretion is 
stimulated by amino acids and parasympathetic nerves. It is inhibited by glucagon.  
The Biochemical actions of Insulin include: 
• Switches off hepatic glucose production (inhibits Gluconeogenesis) 
• Increase uptake and utilization of glucose by muscle


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The Biochemical actions of Insulin include: 
• Switches off hepatic glucose production (inhibits Gluconeogenesis) 
• Increase uptake and utilization of glucose by muscle  
• Inhibits lipolysis and by doing so prevents ketogenesis. 
• Enhances uptake of amino acids into muscle for protein synthesis and inhibition of 
breakdown of proteins 
Mechanism of disease in Type 1 Diabetes 
Type 1 diabetes mellitus is believed to be due to autoimmune destruction of beta cells.  
• The triggering agent (i.e. - a viral infection) will expose these cryptic (hidden) self 
antigens to which the immune system has not developed tolerance. Therefore an 
autoimmune process is set-up destroying self tissue, in this case the beta cells of the islets of Langerhans. 
• The other mechanism of injury is molecula r mimicry between trigger antigen (virus) and 
β-cell antigen. or instance Coxsackie virus antigen and that of glutamic acid


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Internal Medicine 
 
 438decarboxylase (GAD) found within the β-cells  has similar chemical structure, so that the 
antibodies produced to fight the foreign antigen of the virus also cross react with 
antigens of self tissue bearing GAD hence destroying it . 
 
Natural history of type 1 diabetes 
• The disease is progressive going through phases of antibody production, then phase of 
impaired GTT followed by an abnormal FBS, and finally culminating in an abnormal FBS 
with Ketonemia.  
 Honeymoon period:  
• In young people who are diagnosed for the first time to have overt DM, the DM may 
have been precipitated by acute metabolic stressful conditions (such as infection or pregnancy).  In such circumstances, the increased metabolic demand for insulin, may 
lead to a relative insulin deficiency, and patients become symptomatic, and may need 
exogenous insulin to control their symptoms. 
• With the return to baseline metabolic demands, when the stressful event abates, the 
pancreatic reserve may be adequate to maintain normal or near-normal blood glucose. Such patients may undergo a period of transient “cure” during which time they may not require exogenous Insulin to control their blood glucose level. Because of this, such patients are said to be in a “ HONEYMOON ” period.  
• This is unfortunately is transient and the patients will be needing insulin again when the 
progressive destruction of β-cells leads to absolute insulin deficiency.  
Mechanism of   Type 2 disease:


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• This is unfortunately is transient and the patients will be needing insulin again when the 
progressive destruction of β-cells leads to absolute insulin deficiency.  
Mechanism of   Type 2 disease:   
• In Type 2 DM insulin resistance plays a central role in the pathogenesis.  
• In obesity, increased production of non-esterified fatty acids, leads to resistant of 
peripheral organs to insulin which leads to increased gluconeogenesis in the liver, and decreased peripheral uptake and utilization of glucose by muscles . 
• Initially there is hypersecrtion of insulin by β-cells, to overcome the insulin resistance. 
But later on β-cells fail to respond to the level resistance. Then β-cell number is 
decreased and amyloid is deposited in islets.


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Internal Medicine 
 
 439 Predisposing factors for Type 2 DM 
1) Genetic Predisposition  plays an important role. The evidences are :- 
• Concordance among identical twins is upto100% 
• Concordance among fraternal twins is  20% 
• Familial aggregation history is common and up to 50% of siblings and 33% of 
children of diabetics develop diabetes. 
2) Environmental factors :  
• Obesity  
• Physical inactivity  
• Diet  
 
Natural history of type 2 diabetes  
Stage 1 : Insulin resistance:  increased glucose and Non Esterified Fatty Acids (NEFA ) 
Stage 2 : Increased insulin secretion : compensatory hyperinsulinemia         
Stage 3: Impaired glucose tolerance                   
Stage 4 : Overt type 2 diabetes                         
 
Clinical features: 
Features of increased osmolality 
• Polyuria: increased volume and frequency of urination due to osmotic diuresis induced 
by hyperglycemia. 
• Polydepsia- increased feeling of thirst and drinking excess water/fluid due increased 
blood osmolality  
• Blurring of vision: swelling of the lens due to increased osmolality. 
Features of calorie loss 
• Polyphagia:  feeling of hunger , a need to eat several times a day 
• Generalized weakness-  
• Weight loss 
Some patients may be Asymptomatic mainly Type 2 patients and GDM  
Diagnosis is made incidentally during routine medical checkup, ANC follow up etc.  
Therefore it is advisable to screen patient for DM, if following risk factors are present:  
• Obesity (BMI >25 kg/m2),


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Diagnosis is made incidentally during routine medical checkup, ANC follow up etc.  
Therefore it is advisable to screen patient for DM, if following risk factors are present:  
• Obesity (BMI >25 kg/m2),  
• First-degree relative with DM


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Internal Medicine 
 
 440• History of gestational DM or delivered a baby weighing more than >4kg ( 9 lb ) 
• Hypertensive,  
• Hyperlipidemia HDL <35 mg/dl or triglyceride level >250 mg/dl,  
• History of impaired fasting glucose or impaired glucose tolerance glucose on prior 
testing. 
 Table VII-2-1 Criteria for the Diagnosis of Diabetes Mellitus:   
 
 
 
 
   
 
 
• Random  is defined as without regard to time since the last meal 
• Fasting is defined as no caloric intake for the last 8 hrs. 
• Oral glucose tolerance test : blood glucose is measured after ingestion of 75g 
anhydrous of glucose dissolved in water. 
• The patient is said to have impaired glucose tolerance (IGT) if the fasting plasma 
glucose is >110 mg/dl and <126 mg/dl. 
Source:  Modified from American Diabetes Association, 2004. 
 
 
  
 
          
 
 
 • Symptoms of diabetes plus random blood glucose concentration 
≥11.1 mmol/L ( 200 mg/dL )   OR 
• Fasting plasma glucose of  >126 mg/dl (7 mmol/L)  OR 
• 2-hour postprandial plasma glucose >2 00 mg/dl after a glucose load 
of 75 g ( during oral glucose tolerance test) 
 
N.B. These criteria should be confirmed by repeat tests on a different day.


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Internal Medicine 
 
 441Somogyi phenomenon :  refers to hyperglycemia secondary to a period of drug-induced 
hypoglycaemia with metabolic compensation (increased gluconeogenesis and sympathetic 
outflow). If controlling high glucose becomes a pr oblem (especially a.m. glucose), consider 
checking for hypoglycemia in the time leading up to high readings. 
 
Treatment: 
Goal of therapy . Eliminate symptoms and prevent the complications of diabetes.  
• In resource limited setup preventing acute complications that result acute 
dehydration, coma and premature death.  
• Prevention or delaying the occurrence of chronic complications: with tight blood 
glucose control to  to achieve a near normal  blood sugar level significantly 
diminishes risk of developing chronic complications 
• In children one should also aspire to achieve normal growth and development. 
Biochemical Goals 
• FBS <130 or RBS<200 (Acceptable blood glucose control.) 
• FBS<100 or  RBS<160 ( ideal but usually di fficult to achieve by current technology) 
A. Non pharmacologic Therapy 
1) Diet therapy . Patients should be given proper advice about their diet.  
• Maintenance of a normal Body Mass Index should be the prime target through 
recommending calories intake according to age, sex and physical activity. 
• Alcohol ingestion should be limited  
• Diet should include 60% to 65% carbohydrates, 25% to 35% fat, and 10% to 20% 
protein.  
• Patients are advised to significantly decrease cholesterol intake.


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• Alcohol ingestion should be limited  
• Diet should include 60% to 65% carbohydrates, 25% to 35% fat, and 10% to 20% 
protein.  
• Patients are advised to significantly decrease cholesterol intake. 
• Avoid simple sugars (e.g. sugar, soft drinks, honey, and other sweets)  
• High fiber diet such as vegetables slow the absorption of digested food in the form of 
simple sugars 
• Fresh fruit such as water melon and lemon can be freely taken as opposed to 
oranges bananas that must be taken with caution. 
• Dividing meal into four to six equal parts may helps in achieving stability in   some 
cases  
2) Exercise : has multiple positive benefits to diabetic patients including : 
o Cardiovascular risk reduction


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Internal Medicine 
 
 442o Reduce blood pressure  
o Maintain muscle mass  
o Reduction in body fat and helps in losing weight. 
o It is beneficial to both Type 1 and Type 2 patients  
• Therefore regular exercise 20-30 minutes, aerobic exercise such as jogging, walking, 
swimming etc 3 – 4 days is recommended. 
• N.B Patients on Insulin treatment should be cautious to avoid hypoglycemia 
3)  Weight reduction  
• Maintain normal BMI of 20 and 25, Weight loss increase sensitivity to insulin and 
may lead to decrease in the demand of exogenous insulin or the dose of Oral 
hypoglycemic agents. 
 
4)  Patient education . Involving patients in the their own treatment plan essential.The  
patient  can be involved in his care through regular health education to achieve the ideal 
knowledge, attitude which is ccrucial to proper management of DM.  
Areas of Patient Education  
o Patients should be made to understand DM is needs lifelong treatment and follow 
up  
o Goal of treatment should be set together with the patient 
o To avoid excess alcohol intake and, smoking 
o Benefit of weight reduction, diet and regular exercise 
o Proper foot care 
o Hypoglycemia causes , symptoms and simple first aid management 
o Complications of diabetes 
o Insulin injection technique  
o Self glucose monitoring 
 
B. Pharmacologic therapy . 
1. Insulin   
• Beef, pork, and recombinant human insulin (Humulin) are available. Humulin is generally


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o Complications of diabetes 
o Insulin injection technique  
o Self glucose monitoring 
 
B. Pharmacologic therapy . 
1. Insulin   
• Beef, pork, and recombinant human insulin (Humulin) are available. Humulin is generally 
preferable and tends to be less immunogenic than beef or pork insulin and therefore there is less insulin resistance secondary to anti-insulin antibodies.  
• Type 1 DM patients must be started on insulin at the time of diagnosis.


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Internal Medicine 
 
 443• The average daily insulin requirement is appr oximately 0.3U/Kg/day (25 units /day) in a 
person with type 1 diabetes in whom the production of endogenous insulin is assumed to 
be nil. 
 Table V-2-2 Different preparations of insulin based on their duration of action:  
Preparation  Onset of 
action  Peak action and Duration of action  Clinical sue and rout of administration  
Short acting (crystalline /regular)  30-60 min  P : 1-4 hrs D: 4-6 hrs  Used in ketoacidosis for rapid control of high sugar and acidosis.  It can be administered IV , IM or SC  
Intermediate-acting insulin (NPH or 
Lente)  1 to 3 
hours  P: 6- 12 hrs  D:18-26 hrs  Used for ambulatory long term control of sugar level 
Given not more than twice a day  
Rout of administration is limited to SC  
Long-acting insulin (Ultralente PZI): 
Long acting (NPH, 
isophane)  Onset 4 to 8 P:14-  24 hrs D: 28- 36 hrs  Not available for use in our  country 
 
 
Side effects:  
• The most serious complication of insulin is hypoglycemia. 
•  Hypersensitivity, atrophy or hypertrophy of injection sites may also occur, sometimes. 
 In type 1 DM  For patients diagnosed with DM presenting with Ketoacidosis  
• Glucose control is initially obtained with a sliding scale using regular insulin. Measure 
serum glucose every 6 hours and give sub cutanous regular insulin depending on RBS measurement.


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Internal Medicine 
 
 444• Once the glucose is stabilized with regular insulin 6 hourly injections, 2/3 of the last 24 
hrs insulin requirement is given, in the form of intermediate acting insulin, as S.C 
injection per day.  
• If the total daily requirement of insulin is greater than 40 units , 2/3 of the total insulin 
requirement given as an AM dose ( in the mo rning ) and 1/3 third is  given as a PM 
dose( evening ).  
• If the intermediate-acting agent does not give adequate control of daytime blood 
glucose, a short-acting agent may be added.  
The other option for patient diagnosed before developing acute complications 
• Start with 20- 25 units of Humulin  insulin (equivalent to daily insulin production by islets) 
S.C, daily 
• Gradually increase the dose by 3- 5 units very 4- 5 days till acceptable level of blood 
glucose is achieved 
Intensive insulin therapy : to achieve near normal blood glucose level  
• An insulin pump , which administers continuous SQ insulin infusion with mealtime 
boluses, or  
• Multiple daily insulin injections  with frequent blood glucose determinations. 
• Another option is the use of a long-acting insulin (such as Ultralente) to provide a base 
of insulin delivery augmented by regular insulin at mealtimes.  
• This type of treatment approach needs a lot of commitment from the patient and the


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• Another option is the use of a long-acting insulin (such as Ultralente) to provide a base 
of insulin delivery augmented by regular insulin at mealtimes.  
• This type of treatment approach needs a lot of commitment from the patient and the 
physician. It helps to achieve near normal blood glucose level and thus delays the development of chronic complications. It may be complicated by frequent bouts of hypoglycaemia. 
  
2. Oral hypoglycemic agents   
These groups of drugs are widely used in type 2 patients whose hyperglycemia has failed to be controlled with conservative measures. a) Sulfonylureas: s timulate pancreatic beta cells to secrete insulin.  
Dose:  Glyburide  2.5 to 20 mg PO or   
Glipizide  5 to 20 mg PO  
• Glyburide is more likely to result in glycemic control when used once a day 
than is glipizide. Glyburide should be used in a twice-daily dosing if 20 
mg/day total is required.


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Internal Medicine 
 
 445• The effectiveness of sulfonylureas declines up to 10% annually as the failure 
of beta-cell function progresses.  
b) Metformin : reduces blood glucose levels by improving hepatic and peripheral tissue 
sensitivity to insulin without affecting the secretion of insulin.  
• Metformin is used as monotherapy or in combination with sulfonylureas or 
insulin for type 2 DM.  
• It is especially useful in overweight patients because it does not cause weight 
gain.  
• Hypoglycaemia is not a problem with metformin.  
• Metformin also appears to improve plasma lipid and fibrinolytic profiles 
associated with type 2 DM.  
o Dose : Initial dosage is 500 mg PO daily until initial nausea and 
anorexia are tolerated and then increased to 500 mg BID. 
o The dosage can be increased by 500 mg weekly to maximum dose of 
2500 mg if reasonable glycemic control couldn’t be achieved. 
o Use with or after food may lessen the GI side effects.  
• Side effects : Lactic acidosis (rare). Risk is mi nimized if metformin is avoided 
in patients with renal disease, CHF or pulmonary disease.  
c) Alpha-glycosidase inhibitors:   
• Acarbose and Miglitol :  are oral agents that reduce the absorption of 
carbohydrates, thus reduce postprandial hyperglycaemia. 
• Alpha-glycosidase inhibitors can be used as monotherapy or in combination 
with insulin or sulfonylureas.  
• Start with Acrarbose 25 mg with evening meal , may be increased to a 
maximum dose of 50-100 in weeks


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• Alpha-glycosidase inhibitors can be used as monotherapy or in combination 
with insulin or sulfonylureas.  
• Start with Acrarbose 25 mg with evening meal , may be increased to a 
maximum dose of 50-100 in weeks   
• In general, this group of drugs is less effective than other classes 
d) Thazolidinediones  : reduce insulin resistance and increase peripheral glucose 
utilization  
Pioglitazone :   15- 45mg /day in a single daily dose  
Rosiglitazone :  2- 8 mg total daily dose given once or in two divided doses   
These new group of drugs decrease insulin and sulfonylurea requirement  Side effects: idiosyncratic hepatocelluar injury


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Internal Medicine 
 
 446The use of Insulin in type 2 DM ,  
• Insulin is usually added to an oral agent when glycemic control is suboptimal at maximal 
doses of oral medications.  
• An intermediate-acting agent is used starting with a low dose and increasing as needed for 
glycemic control (such as 5 to 10 U of NPH increasing as needed).  
• Adding NPH at bedtime is generally more efficacious than using it during the day.  
• If using only insulin, start with an AM (morning) injection. The dose can be increased by 5 
U every 3 to 7 days until adequate control is achieved.  
• If early morning hyperglycemia is a problem, intermediate-acting insulin can be given twice 
daily as a split dose.  
 
Follow up of patients:- Since this is a lifelong disease regular follow up of patient is crucial.   
Points to give emphasis during follow up 
• Symptoms of hyper or hypoglycemia  
• Wight  
• Blood pressure 
• Visual acuity 
• Examine the oral cavity  
• Examination of the feet 
• Examine Injection site 
• Laboratory tests: blood or urine sugar and urine albumin or protein.  
 
Acute complications of  Diabetes Mellitus  
1. Hypoglycemia 
2. Diabetic Ketoacidosis 
3. Hyperosmolar Comma 
 
1) Hypoglycemia  in the diabetic patient is caused by  
• Overdose of insulin or hypoglycemic agents 
• Missing of meal  
• Strenuous exercise


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Internal Medicine 
 
 447Clinical manifestations 
Early : one may feel the effects of sympathetic stimulation such as cold sweat, tremor, hunger or 
palpitations.  
Late:  If early symptoms are neglected then symptoms of the effect of hypoglycemia on the brain 
(Neurogenic manifestations) such as dizziness, blurring, headache, nightmares, and coma may 
occur.  
Management  
• Any patient with diabetes losing consciousness should always be considered 
hypoglycemic until proven otherwise by blood sugar determination and should be 
managed by rapid IV  administration of gluc ose or PO/ NG tube administration of any 
concentrated sugar solution.  
• Prolonged unconsciousness requires continuous 10% IV glucose administration.  
 
2)  Diabetic Ketoacidosis 
Definition:  is an acute metabolic crisis in patients with diabetes mellitus characterized by: 
• Hyperglycemia (blood glucose level may range from 250-600 mg /dl )  
• Metabolic acidosis (ketosis)  
• Hypotension and features of dehydration  
 
DKA was formerly considered as a hall mark of ty pe 1 DM. However, currently it is known that 
some type 2 DM patients who are being treated by oral hypoglycemic agent may also develop 
DKA.  
 Precipitating factors:   
DKA may occur after sever days of worsening diabetic control, or may appear suddenly within 
few hours. Some of the precipitating factors are: 
• Intercurrent infection 
• Poor compliance with insulin or discontinuation of insulin 
• Dehydration


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DKA may occur after sever days of worsening diabetic control, or may appear suddenly within 
few hours. Some of the precipitating factors are: 
• Intercurrent infection 
• Poor compliance with insulin or discontinuation of insulin 
• Dehydration 
• Stressful conditions such as, trauma, surgery or of emotional crisis 
• Excessive alcohol ingestion


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Internal Medicine 
 
 448Pathogenesis:  
Any event that decrease insulin availability or   cause stress that increase the insulin demand, 
lead to sever insulin deficiency and the effect of counter regulatory hormones such as glucagon, 
cortisol, epinephrine and growth hormone becomes  overwhelming. This biochemical changes 
bring about:  
 Increased production of glucose by the liver and increased glycogen degradation to 
glucose 
 Decreased glucose uptake and utilization by muscles 
 Lipolysis: enhanced break down of free fatty acids and subsequent ketogenesis.  This 
increases blood levels of keton bodies such as acetoacetic acid, β-hydroxybutyric acid, 
and acetone, resulting in metabolic acidosis.  
 The above biochemical processes result si gnificant hyperglycaemia and Ketoacidosis, 
which are responsible for the clinical manifestations of DKA. 
 Signs and symptoms :  
 Volume depletion : dehydration- dry tongue and bucal mucosa , poor skin turgor  and 
hypotension  
 Kussmaul respiration : deep and fast breathing resulting from metabolic acidosis   
 Acetone ("fruity") odour of breath: due too acetone  
 Nausea and vomiting and frequent complaint of abdominal pain.  
 Mental status changes : lethargy and confusion which may evolve into coma with sever 
DKA 
 Cerebral edema: an extremely serious complication of DKA is seen most frequently in 
children. 
 Signs of infection , which may be precipitating DKA , should be looked for


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DKA 
 Cerebral edema: an extremely serious complication of DKA is seen most frequently in 
children. 
 Signs of infection , which may be precipitating DKA , should be looked for 
 A history of diabetes (unless first presentation).  
 
Laboratory Diagnosis: 
1. RBS: hyperglycaemia  can be diagnosed with RBS determination. Blood glucose  level is 
usually high ( averaging 500 mg /dl )  
2. Urine dipstick for ketones :  ketosis  can be determined with bedside reagents. This test is 
97% sensitive. Serum keton level can also be measured to confirm hypereketonemia.  
3. Arterial blood gas analysis  : can diagnose metabolic acidosis which is indicated by low 
serum bicarbonate level ( usually below 10 mEq / L )  and low blood PH ( < 7.35 )  
4. Additional laboratory evaluation


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Internal Medicine 
 
 449a) Electrolytes:  
• Serum K+ level: look for hyperkalemia or hypokalemia 
• Serum Na+: tends to be low because of dilution as the osmotic effect of hypergycemia 
increases ECF volume. 
• Serum osmolality is high  
b) BUN, creatinine, 
c) CXR, urine culture and sensitivity, blood cultures should also be done to identify an 
infectious process. 
 
Treatment of DKA: Acute management  
1. Supportive therapy :  
• Airway maintenance, supplemental oxygen as needed, and treatment of shock.  
2. Fluid replacement :  
Fluid replacement corrects dehydration caused by glucose induced osmotic diuresis. The 
fluid deficit in patients with DKA averages 3-5 L, which should be promptly replaced. Hence give 5- 6 L of fluid in the 1
st 24 hours. 
o Initially 1 L of normal saline (0.9 % NaCl) is given over ½ an hour. 
o Continue with 1 L of normal saline/hr for the first 2-3 hours 
o Then ½ normal saline (0.45 % NaCl) at slower rate till the patient is well 
hydrated. 
o This will rehydrate the patient and ensure adequate renal perfusion.  
o When the serum glucose level falls to 200-300 mg/dl, change the IV fluid to 5 % - 
10 % DW to prevent hypoglycaemia. 
o Carefully monitor the urine out put  
3. Insulin:  
Insulin is administered to increase glucose use in the tissues, to inhibit ketogenesis, and to counter balance the effect of counter regulatory hormones. 
Dosage and administration:


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o Carefully monitor the urine out put  
3. Insulin:  
Insulin is administered to increase glucose use in the tissues, to inhibit ketogenesis, and to counter balance the effect of counter regulatory hormones. 
Dosage and administration:   
• 20 Units of regular insulin, 10 U IV and 10 U IM is given with the initial fluid resuscitation. 
Then 5-10 /hr units or regular insulin is given per hour till the blood glucose level drops 
to 250-300mg/dl


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Internal Medicine 
 
 450• Blood glucose determination is done every hour. The expected rate of fall in serum 
glucose is 75-100 mg/dl/hr.  
• When blood glucose reaches a range of 250 to 300 mg/dl, 5 -10 % glucose solution 
should be infused to prevent hypoglycaemia. 
• Insulin infusion should not be stopped until the Ketonemia clears. It is preferable to give 
5% or 10% DW with insulin injection, rather than stop the insulin, because insulin is 
still required to clear the acidosis and ketotic state.  
• Shift to sliding scale when keton clears, until precipitating cause is well controlled.  
• Shift to intermediate insulin when patient’s blood sugar and precipitating factor is under 
complete control. 
4. Potassium replacement :  
• Serum K+ level may be increased initially because of K+ ion movement from ICF to 
ECF in metabolic acidosis.  Later, the serum K+ becomes low because of both renal 
loss of K+ and the movement of K+ ions back to ICF as the acidosis is corrected.  
• Patients with DKA are expected to have a potassium deficit of 300-400 mEq, which 
should promptly be replaced. 
• Start replacing potassium as soon as the patient has adequate urine output.  
• Potassium chloride (KCl) is infused at a rate of 20 -40 mEq/hr. 
• Monitor serum K+ level closely.  
• Oral potassium can be given if IV potassi um is not available. Encourage patients to 
eat potassium rich fruits such us banana. 
5. Close follow-up of patients


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• Monitor serum K+ level closely.  
• Oral potassium can be given if IV potassi um is not available. Encourage patients to 
eat potassium rich fruits such us banana. 
5. Close follow-up of patients  
• Monitor serum glucose and potassium  as well as urine output hourly.   
• Maintenance fluids  should consist of 0.45% (½ strength) saline with additives as 
indicated; 150 to 200 ml/hr adjusted according to urine output.  
• Evaluate for potential precipitating factors,  including infection, pregnancy, Myocardial 
infarction, inappropriate use of insulin.  
• Diet.  Oral intake may resume when mental status of the patient improves and nausea 
and vomiting are controlled. Initial diet should consist of fluids, and solid diet is may not 
be resumed until ketoacidosis is corrected.   
3) Hyperglycemic Hyperosmolar State ( Non-Ketotic Hyperosmolar Coma  ) 
• Usually occurs in elderly type 2 DM patients that do not develop ketosis.


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Internal Medicine 
 
 451• It is often precipitated by serious intercurrent illnesses such as myocardial infarction, 
stroke, pneumonia, sepsis etc.  
Symptoms : 
• Such patients present with several weeks history of polyuria, weight loss, and 
diminished oral fluid intake that is followed by mental confusion, lethargy or 
comma.  
Physical examination :  
• Patients have extreme dehydration, hypot ension, tachycardia and altered state of 
consciousness or comma. The dehydration is caused by a hyperglycemia induced osmotic diuresis, when it is not matched by adequate fluid intake. 
Laboratory : Very high serum blood glucose level (may range from 600- 1200mg/dl)  
Treatment involves  
• Fluid replacement : administration of IV fluids and  
• Bringing down the blood sugar rapidly by using rapidly acting insulin preparations  
• Identifying and treating the precipitating factor  
 
Chronic Complications of Diabetes Mellitus  
• The chronic complications of DM affect many organ systems and are responsible for 
majority of morbidity and mortality associated with the diseases. 
• Prevention of chronic complication is one of the major goals of care of the diabetic 
patients. This is attempted by achieving as near normal blood glucose level as possible.  
• Several studies have shown that with tight blood glucose control, the occurrence of 
chronic complications can be delayed by several years. 
1. Retinopathy :


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• Several studies have shown that with tight blood glucose control, the occurrence of 
chronic complications can be delayed by several years. 
1. Retinopathy :   
• Is one of the commonest chronic complications and one of the leading causes of 
blindness in developed countries. 
• Symptoms may include difficulty of reading , blurring of vision,  shadowing which 
may later on progress to total blindness,  
Classification of Diabetic retinopathy 
a) Background retinopathy : early changes which is often asymptomatic 
• Microaneurysm: occlusion of capillaries gives rise to distention and eventual 
rupture of vessels


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Internal Medicine 
 
 452• Dot hemorrhages: -increased permeability of capillaries and from ruptured 
aneurysms  
• Hard exudates: proteins and lipids leak due to increased permeability of 
capillaries 
b) Maculopathy : which manifests with impairment of central vision loss 
c) Proliferative retinopathy: asymptomatic unless complicated by hemorrhage 
• Characterized by new vessels formati on which is stimulated by ischemia  
d) Advanced diabetic disease :  may cause  severe vision loss  to the extent of 
complete blindness 
• Extensive fibrovascular proliferation  develops following ischemia and 
necrosis. 
• Retinal detachment  results from the deformity created by extensive fibrosis 
• Vitreous hemorrhage  refers to blood in the vitreous hemorrhage. 
Management              
• Laser therapy 
• ASA 100 mg /day may prevents further  occlusion of small capillaries 
• Surgery : Viterotomy removes blood clots and fibrosis that obstruct vision 
 
2. Neuropathy 
Symptoms: include 
• Burning sensation, numbness 
• Constipation or nocturnal diarrhea 
• Impotence 
• Foot ulcer 
Classification of Diabetic Neuropathy 
a) Polyneuropathy: 
• Is the commonest neuropathy, characterized by distal symmetrical, 
predominantly sensory impairment which manifests with tingling 
sensation, numbness, burning sensation etc.  
• It is often progressive and may lead to total loss of sensation and 
absence of deep tendon reflexes.


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predominantly sensory impairment which manifests with tingling 
sensation, numbness, burning sensation etc.  
• It is often progressive and may lead to total loss of sensation and 
absence of deep tendon reflexes. 
b) Radiculopathy : characterized by neurogenic pain. It is often self limiting 
c) Amyotropy : atrophy of proximal muscles mainly around the hip girdle


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Internal Medicine 
 
 453d) Autonomic Neuropathy: may manifest with :- 
• Postural hypotension 
• GI manifestations: gustatory sweating, gastroparesis, nocturnal diarrhea 
• Genitourinary manifestations: neuropathic bladder, erectile dysfunction 
(impotence) 
e) Mononeuropathy: paralysis of a specific nerve or nerves  
E.g. diplopia due to of third and sixth nerves palsies  
 
Neuropathy management 
• Symptomatic treatment : pain control 
• Diarrhea control 
• Treatment of impotence  
 
3. Nephropathy : is a common complication in DM.  
  Clincal fetures 
• Periorbital edema (eye or facial puffiness),pedal edema , anasarca 
• Anemia, Uremia and osteodystrophy in patients with end stage renal diseases 
Laboratory:  Progression from micro albuminuria Æ Macroalbuminuria 
Management 
• Tight blood pressure control 
• ACE- inhibitors:  decreases progression of renal diseases 
• Renal transplantation or Dialysis in End stage renal diseases 
4. Diabetic Foot Ulcer 
The following are underlying mechanism for diabetic foot ulcers 
• Neuropathy   
o Loss of pain sensation exposes to injury 
o Loss of sweating results dry skin that is susceptible to injury 
• Vascular:  poor blood supply to the foot causes decreased healing of wound poor 
recovery from secondary infections. 
• Abnormal Pressure loading : due to neuropathy (Charcot’s joints) or anatomical 
deformity of the feet. Since the foot is not in a normal anatomic position it is exposed to


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recovery from secondary infections. 
• Abnormal Pressure loading : due to neuropathy (Charcot’s joints) or anatomical 
deformity of the feet. Since the foot is not in a normal anatomic position it is exposed to 
abnormal load and pressure sores develop.


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Internal Medicine 
 
 454Symptoms and signs of foot ulcer : numbness and burning, aching pain, swelling, darkening, 
abscess and cold extremity 
Foot care: should be essential part of diabetes care  
 Put on comfortable shoe 
 Check for pebbles in shoe 
 Examine the foot daily to detect problems earlier 
 Wash dry and oil the feet 
 Take caution during nail cutting 
 Treat athletes’ foot or any other foot infection as early as possible 
 Remove corn  
 Do not use hot water to wash the feet 
 Stop smoking  
 
References:   
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Asthma,     pages 2152-2180. 
2) Diabetes in Africa, Geoff Gill et al pp123-131 
3) Management of Diabetes Mellitus, A Manual for Use in Ethiopia , Second edition, 
F.T. Lester 
4) Management of Diabetes Mellitus: coping with limited facilities, J. Abdulkadir, A. 
Reja. , EMJ V39,N4 ,2001,pp 349-365 
5) Clinical features, complications, and mortality in type 2 patients in Addis, Abeba, 
Ethiopia 1976-1990. F.T.  Lester, EMJ 1993:31:109-125


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Internal Medicine 
 
 4553. Thyroid disorder  
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define different forms of thyroid disorders. 2. Describe the pathophysiology of diseases of the thyroid. 3. Understand   the epidemiologic significance of diseases of the thyroid. 
4. Identify the clinical manifestation of diseases of the thyroid, with special emphasis on 
hyperthyroidism and hypothyroidism. 
5. Understand the diagnostic approach of diseases of the thyroid.  
6. Manage patients with common thyroid diseases. 7. Understand the prevention of some preventable thyroid diseases. 
 
Introduction:  
• The thyroid gland normally weighs 20gm and is visible in thin women. The basic unit of 
thyroid structure is a follicle which is spherical in shape, filled with colloid, and 
encompassed by single epithelial cell layer. The colloid consists of thyroglobulins in 
which thyroid hormones are stored. About 40 follicles form a lobule, a group of lobules form a gland.  The hormones produced by t he thyroid gland are referred to as tri-
iodothyronine (T
3) and thyroxin (T 4).  
 Thyroid disorders: 
• Manifest with qualitative or quantitative alteration of thyroid hormone secretion, 
enlargement of thyroid, or both.  
• Decreased production of these hormones leads to what is referred to as hypothyroidism, 
which results in a state of declined metabolic activity.


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enlargement of thyroid, or both.  
• Decreased production of these hormones leads to what is referred to as hypothyroidism, 
which results in a state of declined metabolic activity.  
• Increased production on the other hand leads to hyperthyroidism, which in turn results in 
a state of increased metabolic activity.  
• Goiter is a diffuse or focal enlargement of the thyroid gland that may be metabolically 
hyperactive, hypoactive, or normoactive  (Euthyroid) 
 Transport and Metabolism of hormones    
• Of the total hormone in the blood, 80% is found in the form of T4 and 20% in the form of 
T3
.


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Internal Medicine 
 
 456• Ninety nine percent of hormones is bound to carrier proteins (thyroglobulin) and is not 
physiologically active, and it is only the remaining 1%, which is found free in the serum, 
which is physiologically active.          
The advantages of carrier proteins are: 
• They are reservoirs to replenish free hormone level 
• They buffer any fluctuation in gland secretion 
• They protect against hepatic degradation and renal excretion of the hormone  
 Standard lab tests measure protein bound hormone level so that results depend on the concentration of these proteins. Therefore the hormone level alterations could be apparent like 
when the thyroglobulin (TGB) level shifts or real when the TBG remains constant but hormone 
level varies.  
• Conditions in which TBG is increased are  : pregnancy, contraceptive (estrogen ) , 
androgen , infectious hepatitis         
• Conditions in which TBG is decreased  are :  steroid, chronic liver diseases                                
 
                  Metabolic actions of thyroid hormones:   
Acting through nuclear receptors, these hormones play a critical role in are to regulate        
• Cellular  differentiation during development  
• Maintain thermogenic and metabolic homeostasis in adults  
  Regulation of hormone production: 
• Hypothalamic TRH stimulates pituitary production of TSH, which in turn stimulates 
thyroid hormone synthesis and secretion.


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• Maintain thermogenic and metabolic homeostasis in adults  
  Regulation of hormone production: 
• Hypothalamic TRH stimulates pituitary production of TSH, which in turn stimulates 
thyroid hormone synthesis and secretion.  
• The presence of adequate thyroid hormone sends a negative feedback signal that 
inhibits TRH and TSH production.  
• When the level of thyroid hormone in the serum decreases the production and release of 
TRH and TSH is enhanced. 
TSH,  secreted by thyrotrope cells of the anterior pituitary, plays a pivotal role in control of 
pituitary - thyroid axis and serves as the most useful physiologic marker of thyroid hormone function.


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Internal Medicine 
 
 457 
Thyroid function tests:        
1. Serum T 3 and T 4 level : measures the total bound (99 %) and free (1 %) hormone level in the 
circulation. This gives some clue about serum level of thyroid hormone, but has limitation 
since serum level of the hormone is influenced by conditions affecting the level of carrier 
proteins.  
T3 and T4 levels are elevated in hyperthyr oidism and decreased in hypothyroidism. 
 
2. Serum TSH level:  is the most important test to asses thyroid hormone function. 
• In hypothyroidism , TSH level is elevated, as a result of feedback effects of low thyroid 
hormone level. It is a very sensitive test and, because it usually becomes elevated even 
before thyroid hormone (T3 and T 4) level decline below normal. 
• In hyperthyroidism , TSH level is decreased, because the elevated thyroid hormone 
concentration, leads to suppression of TSH release, through a negative feedback mechanism. It is a very sensitive tes t, because TSH may be suppressed even when 
thyroid hormone level are not elevated above normal range. 
3. Radioactive iodine uptake (RAIU):   by the thyroid gland 24 hrs after administration of the 
Iodine ( I
131) isotope, assesses the rate of iodine uptake by the thyroid gland which 
demonstrates the degree of glandular activity.  
• Increased uptake in hyperthyroidism, and decreased uptake in hypothyroidism. 
• This test is especially useful in diagnosing ectopic hormone production


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demonstrates the degree of glandular activity.  
• Increased uptake in hyperthyroidism, and decreased uptake in hypothyroidism. 
• This test is especially useful in diagnosing ectopic hormone production  
4.  Thyroid stimulating antibodies , circulating antibody against T 3 and T 4 is an evidence for 
autoimmune disease of thyroid glands.  
 
Common disorders of Thyroid gland                   
A. Sick euthyroid syndrome (SES) 
B. Simple nontoxic goitre (SNG) 
C. Hypothyroidism D. Hyperthyroidism                                                  
i. Graves    
ii. Toxic multinodular goiter(TMNG) 
iii. Toxic solitary nodular (TSN) iv. Jodbasdow phenomena


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Internal Medicine 
 
 458E. Thyroiditis 
F. Thyroid carcinoma             
 
Epidemiology of Thyroid Diseases is Ethiopia 
• Simple nodular goiter is very common in areas where there is serious iodine deficiency. 
• Among 373 patients seen at the Endocrinology unit of Tikur Anbessa teaching hospital, 
between 1986 to 1991, 68% of all cases came for a thyroid disorder. Of these 44% were 
thyrotoxic, 24% has solitary nodules, 29% simple toxic goiter, while thyroiditis and hypothyroidism were rare.  
• Among the thyrotoxics 42% were due to Graves’ diseases, 32% due to Toxic 
multinodular goiter, and 22% due to toxic nodule.   
 
A. Sick Euthyriod Syndrome (SES)                                
• This is a state in which serum level of thyroid hormones is abnormally low or high but 
patients are not symptomatic.  
• Such clinical condition often results from severe illness, physical trauma, stress during 
which the thyroid hormone level may be low.  
• In elderly patients taking drugs containing Iodine, serum level of thyroid hormones may 
be abnormally high. Patients however remain asymptomatic probably due to decreased 
impact on peripheral tissue.  
 
B.  Hyperthyroidism 
 
Definition:  Hyperthyroidism is a hypermetabloic state, resulting from excessive thyroid 
hormone function.   
Thyrotoxicosis  is defined as the sate of thyroid hormone excess. 
Etiology:   
Common causes of hyperthyroidism include: 
• Graves‘diseases 
• Toxic multinodular goiter 
• Toxic adenomas


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Internal Medicine 
 
 459Graves’ disease:   
• Is the most common cause of hyperthyroidism in the third and fourth decades. It is 
common in women.  
• This is an autoimmune diseases caused by abnormal thyroid stimulating immunoglobulin 
of IgG class which has long acting thyroid gland stimulating effect. 
• It causes a diffuse, symmetrically enlarged thyroid gland, with normal to slightly soft 
consistency.   
• It is associated with ophthalmopathy, dermatopathy and pretibial myxedema. 
• There is hyperthyroid state.  
 
Toxic multinodular goiter:   
• It usually develops insidiously in a patient who has had a nontoxic nodular goiter for 
years.  
• The thyroid gland is irregular, asymmetric and nodular in nature. 
• This clinical condition may occur when a nontoxic multinodular goiter has been exposed 
to excess iodine intake or when one of the nodules become autonomous (fails to fall 
under control of TSH-T 3 ,T4) feedback axis  
Solitary hyperfunctioning adenomas:   
• The thyroid gland contains a smooth, well-defined, soft to firm nodule that shows intense 
radioactive uptake on scan with absence of uptake in the rest of the gland.  
• Most patients with solitary adenomas do not become thyrotoxic. When they do, they are 
usually less toxic than those with Graves’ disease, and they do not develop 
ophthalmopathy or pretibial myxedema.  
Autoimmune thyroiditis/  Hashimoto’s thyroiditis :  
• Normal-sized or enlarged nontender thyroid gland.


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usually less toxic than those with Graves’ disease, and they do not develop 
ophthalmopathy or pretibial myxedema.  
Autoimmune thyroiditis/  Hashimoto’s thyroiditis :  
• Normal-sized or enlarged nontender thyroid gland.  
• Thyroid antibodies, when present, are high in titer.  
• This disorder improves spontaneously but frequently recurs.  
Excess exogenous thyroid hormone administration:   
• May occur because of dosage errors or occasionally in individuals taking large doses of 
thyroid hormones to lose weight or increase their energy.  
• The thyroid gland is normal or small in size.  
Subacute thyroidits and viral thyroiditis:


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Internal Medicine 
 
 460• Tender, diffusely enlarged thyroid gland with a normal or elevated T4 and an elevated 
ESR.  
• Probably of viral origin and may manifest as a sore throat.  
Rare causes:  Radiation thyroiditis, thyroid carcinoma, excessive TSH stimulation, excessive 
iodine intake, struma ovarii, and trophoblastic disease.  
 
Clinical features: 
• Metabolic changes:  elevated basal metabolic rate, weight loss with increased appetite 
heat intolerance and sweating  
• Cardiovascular effects:    
o Weakness, dyspnea on exertion 
o Palpitation ,  sinus tachycardia  , atrial fibrillation in the elderly 
o Systolic hypertension , high output failure  with wide pulse pressure  
• Gastro Intestinal symptoms: loss stool or  diarrhea ( may be the first sign of thyroid 
storm) 
• Skin and hair changes:  the skin  is warm and moist because of peripheral vasodilation 
, fine silky hair is characteristic finding  
• CNS and neuromuscular effects  
o Nervousness, hyperactivity, irritabilit y, dysphoria, emotional lability, poor 
concentration  
o Fine Tremor  
o Muscle weakness and fatigue proximal myopathy 
• Genitourinary manifestations  :Polyuria, dysmenorrhea, oligomenorrhea or 
amenorrhea 
• Ophthalmopathy 
o Wide stare and lid lag   ( i.e. slow closing of the upper  lid when the eye moves 
down ward , revealing sclera between  the lid and cornea ) may occur in any form 
of hyperthyroidism  
o Exophthalmus: true thyroid exophthalmus is seen only in Graves’ diseases,


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down ward , revealing sclera between  the lid and cornea ) may occur in any form 
of hyperthyroidism  
o Exophthalmus: true thyroid exophthalmus is seen only in Graves’ diseases, 
occurring in approximately 50 % of cases.  
¾ The eyes are pushed forward because of mucinous and cellular infiltration 
of extraocular muscles 
¾ There is inflammation of the conjunctiva and surrounding tissue


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Internal Medicine 
 
 461¾ The patient may complain tearing, eye irritation, pain and double vision. In 
sever case vision may be threatened. 
• Other findings 
o Gioter 
o Gynecomastia  
 
Features specific to Graves’ disease 
• Thyroid gland is diffusely enlarged  and smooth in consistency , bruit/thrill  may be 
heard over it 
• Ophthalmopathy :  exophthalmus  
• Thyroid dermopathy : pretibial myxedema which is non inflamed indurataed plaque 
• Thyroid acropathy : clubbing 
Diagnosis: 
• TSH is elevated in 98 % of patients. It is the best screening test.  
• Serum T3 and T4 level ( free or total ) may be raised  
• Antithyroid antibodies: antimicrosomal antibody and antifollicular cell antibody, 
antithyroglobulin antibody, thyroid-stimulating antibody; elevated especially in autoimmune thyroiditis. 
 
Treatment : 
Graves’ disease:  
1. Antithyriod drugs: 
• Inhibit the oxidation of iodine and coupling of iodotyrosines, thus decrease the synthesis 
of thyroid hormone. PTU in addition decreases the conversion of T4 to T3 in peripheral 
tissues  Dose:   Propylthiouracil:  100 to 150 mg every 8 hours, or  
Methimazole :  15 to 60 mg divided every 12 hours depending on severity of 
illness.  
• Although blockade of hormones synthesis is rapid, clinical improvement occurs after few 
weeks or months, because a large pool of stored hormone continues to be released from thyroid.  
• The patient becomes euthyroid 2 to 3 months after beginning therapy.


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Internal Medicine 
 
 462• Propylthiouracil may achieve results faster because it prevents the peripheral conversion 
of T 4 to active T 3.  
• After clinical improvement, the dose of the medication is tapered to the lowest dose to 
maintain euthyroid state and the drug is continued for 1 - 1 ½ yrs. 
• A free T 4 level should be checked after 1 month of therapy and then every 2 to 3 months.  
Side effects /drug toxicity  
• Skin rash or joint pain 
• Agranulocytosis 
Advantages of Atithyroid drugs: 
• Hospitalization , surgery and anesthesia are avoided 
• The occurrence of post treatment hypothyroidism is less likely   
Disadvantages:  
• Permanent remission occurs in fewer than 50 % of patients  
• Treatment success depends on patient compliance to treatment  
2. Radioactive iodine  
• Iodine 131, 5 to 15 mCi, a single dose of 131 I, causes a decrease in function and size of 
the thyroid gland in 6- 12 weeks.  
• Approximately 75 % of patients with Grav es’ disease are made euthyriod by a single 
dose. 
• Those who are still thyrotoxic after 12 weeks are given a second dose. Additional dose 
can be given if needed.  
• Eventually, almost all patients are cured in this way.  
• 131 I treatment may be   preceded and followed by antithyroid drugs.  
Advantages: 
• Hospitalization , surgery and anesthesia are avoided 
• The rate of cure is almost 100% 
• Little patient compliance is required  
Disadvantages: 
• There is a risk of treatment induced hypothyroidism


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Advantages: 
• Hospitalization , surgery and anesthesia are avoided 
• The rate of cure is almost 100% 
• Little patient compliance is required  
Disadvantages: 
• There is a risk of treatment induced hypothyroidism  
Pregnancy is an absolute contraindication to 131I therapy. 
 
3. Inorganic iodine  rapidly controls hyperthyroidism by inhibiting hormone synthesis and 
release from the gland.


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Internal Medicine 
 
 463• One drop of saturated potassium iodide solution in juice is taken daily.  
• This should not be used as the sole form of therapy.  
• It may be used alone for 7 to 10 days before surgery to decrease the vascularity of the 
thyroid gland. 
Surgery: Subtotal thyriodectomy  - usually reserved for those who are unable to take 
antithyroid drugs  
Preparation for surgery: 
• Operation on thyrotoxic patient produces the risk of thyroid storm; therefore, treatment 
should be initiated with atntithyriod drugs, long enough in advance for patients to return 
to a euthyriod state before surgery. Inorganic iodine may be given to decrease 
vascularisation before surgery. 
Advantages of surgery 
• Cure of hypothyroidism is rapid 
• The success rate is high , most patient are cured  
• Patient compliance is required for shorter period 
Disadvantages 
• The patient must be hospitalized , and surgical and anesthetic risks are incurred 
• Surgical complications include : hypothyroidism and recurrent laryngeal nerve paralysis 
 
Other symptomatic treatments:  
• Propranolol:  80 to 200 mg/day in divided doses every 6 hourly, will reduce symptoms 
of tachycardia, palpitations, heat intolerance, and nervousness but will not normalize the metabolic rate. It should not be used alone except in the case of transient 
hyperthyroidism secondary to autoimmune (viral) thyroiditis. 
 Ophthalmopathy:   
o Smoking can worsen ophthalmopathy. Ophthalmopathy may also worsen


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hyperthyroidism secondary to autoimmune (viral) thyroiditis. 
 Ophthalmopathy:   
o Smoking can worsen ophthalmopathy. Ophthalmopathy may also worsen 
(usually transiently) with radioactive iodine.  
o This can be prevented by treatment with prednisone (0.5 mg/kg PO for 3 months 
starting 2 to 3 days after radioactive iodine). However, this carries the risk of 
prednisone exposure.


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Internal Medicine 
 
 464o Symptomatic treatment for ophthalmopathy includes artificial tears or 
methylcellulose drops for the discomfort, patching or prisms for diplopia, diuretics 
and raising the head of the bed for circumorbital edema. 
 Treatment of other causes of hyperthyroidism  
• Toxic multinodular goiter  is treated with surgery or I-
131. 
• Solitary hyperfunctioning adenomas are treated with I-131 or surgery.  
• Autoimmune thyroiditis  is transient and does not require definitive treatment except in 
those patients with recurrent hyperthyroidism. Propranolol may be used alone if symptoms are mild. Antithyroid drugs may be needed for a short time in some patients. 
• Subacute thyroiditis  and viral thyroiditis generally self-limited but should be treated 
with aspirin 650 mg QID. In more severe cases, prednisone may be used at 40 mg PO QD, tapering to 10 mg each day over 2 weeks, and then continued for 1 month after patient becomes asymptomatic. Resolution of symptoms usually occurs in 1 to 6 
months, and relapse is common. Hypothyroidism may occur but is rare. 
 
Thyroid storm 
Definition:  A severe life-threatening form of hyperthyroidism. 
Etiology:  Increasing stress such as trauma or illness may cause this in a previously mildly 
hyperthyroid patient. 
Signs and symptoms:  Have signs and symptoms consistent with thyrotoxicosis (tachycardia, 
heat intolerance, weight loss), as well as fever, confusion, agitation, weakness, dyspnea, 
diarrhea, and shock.


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hyperthyroid patient. 
Signs and symptoms:  Have signs and symptoms consistent with thyrotoxicosis (tachycardia, 
heat intolerance, weight loss), as well as fever, confusion, agitation, weakness, dyspnea, 
diarrhea, and shock. 
Treatment : 
When suspected, treatment should be instituted immediately.   
Supportive therapy: 
• Control fever:  Fever is controlled with acetaminophen and a cooling blanket. If fever is 
not controlled within several hours, concurrent infection should be suspected. Other 
signs of hyperthyroidism may require seve ral days of therapy before improvement is 
seen. 
• Propranolol 20 to 40 mg QID to control tachycardia, tremor, 
• Fluid and electrolytes  : should be replaced


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Internal Medicine 
 
 465Antithyriod treatment  
• Propylthiouracil:  250 mg PO QID (Or methimazole  20 to 40 mg PO or per NG Q6-8h).  
• Alternative is 0.5 g of sodium iodide in 1 L of NS over 12 hours.  
• Give steroids  equivalent to about 300 mg of hydrocortisone per day (100 mg IV TID 
Q8h). Dexamethasone has some theoretical advantage because it prevents conversion 
of T 4 to T 3 peripherally.  
• Avoid aspirin  because it may increase circulating active T 3 and T 4 by reducing protein 
binding. 
       
C.  Hypothyroidism 
 
Definition:   
Primary hypothyroidism:  refers to a thyroid hormone deficiency as a result of thyroid gland 
disease. Secondary hypothyroidism : results from TSH deficiency.  
Tertiary hypothyroidism:  results from thyrotropin-releasing hormone (TRH) deficiency. 
Etiology: 
Without thyroid enlargement 
• Hypothyroidism frequently develops following treatment of Graves’ disease with 131I 
therapy or thyriodectomy.  
• Idiopathic hypothyroidism: is idiopathic atrophy of the thyroid gland. It is one of the 
commonest causes of hypothyroidism. 
• Developmental defects and TSH or TRH deficiency are less common causes. 
With thyroid enlargement 
• Chronic thyroiditis /Hashimoto’s thyroiditis  is one of the most common causes of 
spontaneous hypothyroidism.  
• Drugs, iodine deficiency, and inherited defects in thyroid hormone synthesis are rare 
causes. 
Signs and symptoms: 
• Fatigue, weakness, lethargy, slow movement, cold intolerance


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spontaneous hypothyroidism.  
• Drugs, iodine deficiency, and inherited defects in thyroid hormone synthesis are rare 
causes. 
Signs and symptoms: 
• Fatigue, weakness, lethargy, slow movement, cold intolerance 
• Slight to moderate weight gain , but appetite tends to be diminished  
• Carpal tunnel syndrome, edema of the face and extremities, 
• Hearing loss, hoarseness of the voice  
• Dry skin  , hair loss , sparse eyebrows with loss of the lateral half


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Internal Medicine 
 
 466• Pericardial effusion and ascites occasionally occur  
• Constipation 
• Menorrhagia, 
• Memory impairment 
• Psychosis may develop with long-standing hypothyroidism and may be precipitated by 
thyroid hormone replacement 
Physical examination  
• Thickened, puffy features is due to accumulation of mucinous mucoplysaccharide-rich 
material in tissues .This is known and myxedema 
• Yellowish dry skin  
• Nonpitting edema 
• Hypothermia  
• Bradycardia    
• A delay in return phase of Achilles and other deep tendon reflexes is a specific finding. 
• Loss of the lateral portion of the eyebrows ( madarosis ) 
Effect of hypothyroidism on organ systems  
• Cardiovascular system : Decrease in cardiac output ,Pericardial effusion  
• Respiratory system : Hypoventilation  ,Plural effusion 
• Gastrointestinal tract : Constipation 
• Nervous system: Decreased mental function , Psychi atric changes ( e.g. psychosis , 
depression )  
• Blood: Normocytic normochromic anemia.  
Cretinism : is sever hypothyroidism beginning in infancy infants may have  
• Hypotonia, umbilical hernia,  
• Delayed mental and physical development, and mental retardation may result if 
hypothyroidism goes untreated in the first few years of life. 
• Shot limbs and a large head , with a bread flat nose , widely set eyes , and a large 
tongue characterize this form of dwarfism 
• Other signs and symptoms typical of adult patients may also be seen   
 
Diagnostic workup:


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• Shot limbs and a large head , with a bread flat nose , widely set eyes , and a large 
tongue characterize this form of dwarfism 
• Other signs and symptoms typical of adult patients may also be seen   
 
Diagnostic workup:  
Thyroid function tests: 
1. Serum TSH level:


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Internal Medicine 
 
 467• Increased serum concentration of TSH is the earliest and the most sensitive indicator 
of primary hypothyroidism.   
• Low TSH value indicates a secondary (pituitary) or tertiary (hypothalamic) 
hypothyroidism.  Both are rare causes of hypothyroidism. 
• Serum T 3 and T 4 level are decreased   
2. Other laboratory abnormalities may include  : 
• High AST, low sodium, low blood glucose, elevated CPK,  
• Elevated cholesterol and triglycerides, 
• Mild normocytic normochromic  anemia,  
• Elevated prolactin levels secondary to high TRH levels, and 
• ECG:  flat or inverted T waves with minor ST-segment depression and low amplitude  
 
Treatment :  
Thyroid hormone replacement: L-thyroxin, a synthetic agent is the treatment of choice. 
The goal of therapy is to normalize the TSH. 
Initiation of treatment:  
Slow initiation:  
• Patients with severe hypothyroidism, older patients and patients with cardiovascular 
disease, may have an increased sensitivity to thyroid hormone, and are at risk of acute cardiovascular and other complications, if hypothyroidism is corrected too quickly.  
• Therefore, these patients should be given a very small dose of thyroid hormone initially 
(25 μg of L-thyroxin) which is gradually increased (every 2 to 4 weeks) to a full 
maintenance dose during 6-12 weeks period. 
Rapid initiation  
• Younger patients and patients with less sever hypothyroidism, may be started on slightly


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(25 μg of L-thyroxin) which is gradually increased (every 2 to 4 weeks) to a full 
maintenance dose during 6-12 weeks period. 
Rapid initiation  
• Younger patients and patients with less sever hypothyroidism, may be started on slightly 
higher dose ( 50 μg of L-thyroxin ) and advanced to a full replacement dose more quickly 
(e.g. , the dose may be raised to 100 μg two weeks and 125 -150 μg in another 2 weeks)  
• Check the TSH 2 to 3 months after changing the L-thyroxin dose.  
Maintenance therapy  
• Most patients require 75 -100 μg of L-thyroxin daily 
• When symptoms of hypothyroidism hav e resolved, the dosage should be further 
adjusted  so that serum TSH and thyroid hormone level  are maintained in the normal range


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Internal Medicine 
 
 468Cautions  
• Elective surgery should be avoided in hypothyroid patients because respiratory 
depression commonly occurs.  
• Increased sensitivity to narcotics and hypnot ics is also common in the hypothyroid 
patient.  
 
Myxedema Coma 
Definition:  Myxedema coma results from severe chronic hypothyroidism, which is left 
untreated, and is life threatening clinical condition. 
 
This serious condition may occur gradually ( over years)  or more acutely in response to  a 
precipitating factor such as  exposure to cold, infection, hypoglycemia, respiratory depressants, allergic reactions, or other metabolic stress. 
Clinical features:  
• Hypothermia, hypoglycemia, shock, hypoventilation, and paralytic ileus 
• Severely impaired level of consciousness 
• The mortality rate is 50 % -75% 
Treatment:  must be started rapidly, despite the risk associated with sudden hormone 
replacement  
L-thyroxin (T
4) 500 µg is given as IV bolus injection, followed by oral L- thyroxin 100  µg QID.  
Ancillary treatment:  
• Temporary use of glucocorticosteriods  
• Respiratory support  
• Hypothermia and heat loss should be avoided 
 
D.  Thyroid enlargement 
 
 Goiter 
• A goiter is a simple enlargement of the thyroid gland. 
• It is more common in females with the highest incidence in the second through sixth 
decades of life.


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Internal Medicine 
 
 469• Diffusely enlarged goiters are caused by i odine deficiency or excess, congenital defects 
in thyroid hormone synthesis and drugs (e.g., lithium carbonate) dietary causes such as 
cabbage, soybean, cassava etc. 
• Most are asymptomatic. It is unusual to have pain and rare to have hoarseness and 
tracheal obstruction.  
• Thyroid function tests should be performed on all patients with goiter because it can be 
associated with hypothyroidism, euthyroidism, or hyperthyroidism. 
 
Multinodular Goiter 
Etiology:  most often caused by iodine deficiency. 
Signs and symptoms: Symptoms: 
• Thyromegaly, occasionally with rapid enlargement and tenderness secondary to 
haemorrhage into a cyst.  
• Rarely, tracheal compression may occur, causing coughing or choking.  
• Some patients may complain of a feeling of lump in the throat. 
Physical exam 
• Many nodules of varying sizes are usually pal pable. Occasionally it may be difficult to 
distinguish from the typically lobulated, irregular Hashimoto’s gland. 
Diagnosis:   
• Thyroid function tests: Performed to rule out hypo or hyperthyroidism  
• Malignant transformation is rare, but should be considered if the gland is enlarging 
rapidly or hoarseness develops. 
Treatment:   
The main indications for treatment are compression of the trachea or esophagus and venous-outflow obstruction.  For nontoxic multinodular goiter , the treatments include: 
• Surgery 
• Raradioiodine therapy ,


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Treatment:   
The main indications for treatment are compression of the trachea or esophagus and venous-outflow obstruction.  For nontoxic multinodular goiter , the treatments include: 
• Surgery 
• Raradioiodine therapy ,  
• L-thyroxin suppression therapy:  decreases TSH level and help to decrease the size of 
the goiter.  
o Such therapy should not be given to patients with angina or other known heart 
disease unless the patient is hypothyroid.


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Internal Medicine 
 
 470o If thyroid enlargement persists despite adequate TSH suppression, a needle 
biopsy or subtotal thyriodectomy should be considered. 
For toxic multinodular goiter , options are 
• Antithyroid agent 
• Surgery 
• Radioiodine, and more recently  
• Percutaneous injection of ethanol in to the toxic nodule  
 
 Solitary Nodules 
• They are usually benign. 
• One should, suspect malignancy in a patient with a history of radiation exposure, rapid 
enlargement, hoarseness or obstruction, and a solid nodule that is cold on scan. 
Diagnosis:   
• History and  
• Radio iodine thyroid scan should be done on every patient with a solitary nodule. Hot 
nodules that take up the radioisotope are generally benign but fine-needle aspiration of a 
solitary nodule is prudent. 
Treatment:  
• Is indicated if signs of compression of trachea, esophagus, significant growth, and 
recurrence of a cystic nodule after aspiration.  
• Similar to multinodular goiter: surgery, thyroxin, or radioiodine for nontoxic nodule; 
Antithyriod agent, Surgery, radioiodine for toxic nodule. 
 
Subacute Thyroiditis/granulomatous thyroiditis 
Etiology: the cause is generally considered as viral. Mumps and Coxackievarus have been suspected as causes.  Clinical features: 
• Early symptoms : prodromal phase of malaise, upper respiratory symptoms, and fever 
that lasts 1-2 weeks. Then the Thyroid gland becomes enlarged, firm and tender, with 
pain radiating to the ears, neck, or arms.


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• Early symptoms : prodromal phase of malaise, upper respiratory symptoms, and fever 
that lasts 1-2 weeks. Then the Thyroid gland becomes enlarged, firm and tender, with 
pain radiating to the ears, neck, or arms. 
• Hyperthyroidism  may occur, due to thyroid hormone leaking from damaged follicles in 
to the circulation.


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Internal Medicine 
 
 471Disease course:  the thyroid pain and the hyperthyroidism subside in few weeks to months. The 
gland usually return to normal size, if enlarge ment persists, chronic thyroiditis should be 
suspected. 
Diagnosis ; 
• Acutely swollen, tender an painful thyroid gland associated with symptoms of 
hyperthyroidism  
• Radioactive uptake : low radioactive iodine uptake in the face of high serum T 3 and T 4 
level. This is because the follicles are damaged are unable to trap iodine. 
Therapy is symptomatic : because the diseases are self limited 
• Aspirin , NSAID and Corticosteroids ( in severe cases ) to relive the pain and tenderness 
• β-blockers can be used to relive symptoms of hyperthyroidism .  
 
Chronic Thyroiditis (Hashimoto thyroiditis)  
 
Etiology:  it is an autoimmune disorder that mainly affects women. Antithyriod antibodies are 
present in most patients. 
Clinical features  
• Thyroid gland enlargement : is the main clinical manifestation, is the result of 
autoimmune damage that leads to lymphocytic in filtration, fibrosis and weakens ability of 
the thyroid to produce hormone.  
• Pain and tenderness  of the gland in subacute thyroiditis  
• Hypothyroidism  is present in approximately 20 % of patients  
Diagnosis:  is suspected in any patient with firm, nontoxic goitre 
• Serology : high titer of antithyroglobulin antibodies, antimicrosomal antibodies 
• Thyroid function tests  are often normal unless the patient has hypothyroidism


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Diagnosis:  is suspected in any patient with firm, nontoxic goitre 
• Serology : high titer of antithyroglobulin antibodies, antimicrosomal antibodies 
• Thyroid function tests  are often normal unless the patient has hypothyroidism  
Therapy:  
• L-thyroxin often decreases the size of the gioter and it is useful even in patients with 
normal thyroid function 
 
Malignancies of the thyroid  
Epidemiology:  
• Thyroid cancer is common; it is found at autopsy in approximately 5 % of patients with 
no known thyroid diseases


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Internal Medicine 
 
 472• It is usually an indolent cancer and tends to  remain localized to the thyroid for many 
years , which is the reason for the low morality rate   
Etiology:   
• Genetic factors  : one form of thyroid cancer , medullary c.a. has familial tendency  
• Radiation exposure : the incidence of thyroid cancer is increased among atomic bomb 
survivors.  
Types/ Classification: 
• Papillary  carcinoma  : which accounts for 60 % of all thyroid cancer 
o Affects younger age group – 50 % of patients are younger than 40 years  
o Papillary Ca metastasize through the lymphatic system 
• Follicular carcinoma;  comprises 25 % of all thyroid cancer  
o Histologicaly resembles normal thyroid tissue ,  
o Follicular Ca metastasizes hematogenously 
• Medullary carcinoma : which accounts for 5 % of all thyroid cancers. Arises from 
parafollicular cells.  
o Produce calcitonin, patients may have diarrhea. 
o  May be associated with multiple endocrine neoplasia syndromes, MEN type  II  
o Approximately 20 % of these carcinomas are familial. 
• Anaplastic carcinoma:  account for 10 % of thyroid cancer, usually affects patients 
older than 50 years of age and is highly malignant.  
• Other rare malignancies  (lymphoma, sarcoma etc.); secondaries of other tumours 
Signs and symptoms:   
• A hard nodule in the thyroid is usually the first sign. 
• Late signs: hard, immobile thyroid, attached with skin, cervical or supraclavicular lymph


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Signs and symptoms:   
• A hard nodule in the thyroid is usually the first sign. 
• Late signs: hard, immobile thyroid, attached with skin, cervical or supraclavicular lymph 
nodes enlarged, hoarseness, Horner syndrome, throat/ear/head pain, stridor, dysphagia, 
venous congestion. 
Diagnosis: 
• Ultrasound: nodules 
• Scintigraphy/radioiodine uptake: cold nodules without or little uptake 
• CT/MRI of neck  
• FNA with cytology or biopsy  
• Serum Calcitonin level ,  
• Staging is based on : CXR, CT, bone scintigraphy


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Internal Medicine 
 
 473 
Treatment:  Always combine  
• Surgery:  total thyroidectomy and neck dissection 
• Radiotherapy: external radiation in Anaplastic carcinoma 
• Nuclear medicine: 131I ablative radiotherapy.  
• Give T4, as high a dose as possible, to suppress TSH-effect on remaining metastases.  
 Reference  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Diseases of the thyroid gland, pages 2104-2126. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3
rd edition 
Diseases of the thyroid gland, pages 457-467.  
3) The pattern of adult diseases in Adult Ethiopians and experience in their management. M. Mulugeta, EMJ , 1993:31:25-35 
4) Surgical goitre in Ethiopians Taye Mekuria ,Eth med jour 1977:15;169-172 
5) Experience with thyroid scintigraphy in Ethiopian patients Solomon Demena,EMJ 1993,31:1-7


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Internal Medicine 
 
 4744. Diseases of the adrenal gland  
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define different types of diseases of the adrenal gland. 2. Describe the pathophysiology of diseases of the adrenal gland. 3. Identify the clinical manifestation of diseases of the adrenal gland, with special emphasis 
on Cushing’s syndrome and Addison’s diseases. 
4. Understand the diagnostic approach of diseases of the adrenal gland.  5. Manage patients with common diseases of the adrenal gland. 
 
Common  Adrenal gland diseases  
1. Disease of the adrenal cortex  a) Resulting from excess production of hormones  
• Cushing’s syndrome : excess cortisol production 
• Primary hyperaldosteronism : excess production of aldosteron 
b) Inadequate production ; 
• Addison’s diseases : inadequate production of cortisol and aldosteron  
2. Disease of the adrenal medulla 
• Pheochromocytoma : excess production of catecholamine  
 
Cushing’s Syndrome ( Hypercortisolism) 
 
Cushing’s syndrome : is caused by excessive concentration of cortisol or other glucocorticoid 
hormones in the circulation 
Etiology:   
a) Bilateral adrenal hyperplasia (Cushing’s diseases)  is the commonest cause of 
Cushing’s syndrome. It is caused by increas ed pituitary secretion of ACTH. Pituitary 
tumors large enough to be seen by skull x-ray, are present in more than 10 % of these 
patients, and smaller basophilic adenomas are found in more than 50 % of patients.


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tumors large enough to be seen by skull x-ray, are present in more than 10 % of these 
patients, and smaller basophilic adenomas are found in more than 50 % of patients. 
b) Adrenal adenomas and adrenal carcinoma  may produce excess cortisol


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Internal Medicine 
 
 475c) Ectopic ACTH production by tumors  , such as oat cell carcinoma of the lung, 
carcinoma of the pancreas , bronchial carcinod tumors , and other, cause adrenal 
hyperplesia and Cushing’s syndrome 
d) Iatrogenic Cushing’s syndrome : is seen more often than spontaneous occurring 
syndrome. It is an expected complication in patients receiving long term glucocorticiod 
treatment for asthma, arthritis, and other conditions. 
Clinical features  
• Central obesity  is caused by the effect of excess cortisol on fat distribution. Fat 
accumulation in the face, neck and trunk, while thelimns remain thin. The “moon face ” , 
“buffalo hump”  ( cervical fat pad ) and supraclavicular fat pads  contribute to the 
Cushingiod appearance  
• Hypertension : result from the vascular effects of cortisol and sodium retention 
• Decreased glucose tolerance : is common, 20 % of patients have overt diabetes. This 
is a result of hepatic gluconeogenesis, and decreased peripheral glucose utilization. 
• Symptoms of androgen excess  (e.g. oligomenorrhea, hirsutism, and acne) may occur 
in women with Cushing’s diseases, because  of stimulation by ACTH of adrenal 
androgen production. 
• Purple striae : are linear marks on the abdomen, where the thin, wasted skin is 
stretched by underlying fat. Atrophic skin with senile purpura may also be seen. 
• Muscle wasting and weakness:  reflects the catabolic effect of cortisol on muscle 
protein.


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stretched by underlying fat. Atrophic skin with senile purpura may also be seen. 
• Muscle wasting and weakness:  reflects the catabolic effect of cortisol on muscle 
protein. 
• Osteoporosis:  is caused by increased bone catabolism. 
• Susceptibility to bruising:  is probably caused by enhanced capillary fragility. 
• Psychiatric disturbance , especially depression, are frequently seen. 
• Poor wound healing: due to impaired immune function.   
• Growth retardation  in children may be severe.  
       Diagnosis:  
1.  Overnight Dexamethasone suppression test :  is recommended as an initial screening test  
Administer dexamethasone 1 mg PO at 11 PM at midnight and measure serum cortisol at 8:00 AM the following day  The serum cortisol level should be <5 µg/dl in most individuals, indicating normal 
suppression of ACTH and cortisol by dexamethasone. Because this test is sensitive, the 
diagnosis of Cushing’s syndrome need not be considered further in these cases.


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Internal Medicine 
 
 476Patients with Cushing’s syndrome will have cortisol level > 5 µg/dl usually greater than 10 
µg/dl .This result indicates further study is needed.  
2.     The standard dexamethasone suppression test:  is the most relied up on test for Cushing’s 
syndrome  
 
Table VII-3-1 Standard Dexamethasone Suppression Test in the diagnosis of Cushing’s 
syndrome 
 
 Method 
Day Dosage of Dexamethasone Measurement 
1 
  2,3  
 
4,5 None ( baseline )    Low dose ( O.5 mg dexamethasone 
PO QID ) 
 High dose dexamethasone 2 mg every  QID 24 hrs urinary 17-hydroxycorticosteriod and 4 PM serum cortisol level  Repeat measurement on day 3  
 
Repeat measurement on day 5
  
 
Response 
Diagnosis  Suppression with low 
dose Suppression with 
high dose  
Normal  Yes  Yes  
Cushing’s diseases  No Yes 
Adrenal tumor  or ectopic ACTH 
production  No No 
 
3. ACTH measurement : may help to differentiate the cause of Cushing’s syndrome  
a. High normal or slightly elevated A CTHÆCushing’s diseases 
b. Markedly elevated ACTH  Æ Ectopic ACTH production 
c. Extremely low ACTH level Æ automatically functioning adrenal tumor is the 
source of excess cortisol. Pituitary secretion of ACTH is suppressed due to the excess cortisol


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Internal Medicine 
 
 4774. Serum cortisol level: in normal in individuals is highest in early morning and decreases 
throughout the day, reaching a low point at about midnight. Although the morning level may 
be increased in patients with Cushing’s syndrome, a loss of the normal diurnal variation and 
an increase in the evening level are more consistent findings.  
5. The 24 hrs urinary free cortisol excretion rate : is increased in most patients with 
Cushing’s syndrome  
6. Other tests: lukocytosis , with relatively low percentage of lymphocytes and eosinophils  
7. Radiologic findings  
a. Skull x-ray: enlargement of sella turcica in 10 % of patients with Cushing’s 
syndrome who have macroadenoma.  
b. CT scan with injection of contrast medium : detect approximately 50 % of 
pituitary adenomas 
c.  CT scan of the adrenal gland:  reveal most adrenal tumors. Uniform 
enlargement of both adrenal glands suggests an ACTH dependent Cushing’s 
syndrome ( ether Cushing’s diseas e o r the ectopic ACTH syndrome  ) 
Therapy  
1. Adrenal adenoma : complete surgical resection of the adenoma cures the disease , but 
patients may need cortisol replacement post operatively for several month s 
2. Ectopic ACTH syndrome: can be cured by treating or removal of the tumor that is 
producing the ectopic ACTH. 
3. Cushing’s Disease 
a. Pituitary radiation : is effective in children but it cures fewer than 1/3 of adult 
patients 
b. Bilateral adrenalectomy cures Cushing’s diseases .


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producing the ectopic ACTH. 
3. Cushing’s Disease 
a. Pituitary radiation : is effective in children but it cures fewer than 1/3 of adult 
patients 
b. Bilateral adrenalectomy cures Cushing’s diseases . 
Disadvantages  
• Patients will develop Addison’s disease  and need lifelong Cortisol 
replacement 
• Nelson’s syndrome : in which pituitary adenomas undergo rapid growth, 
perhaps because it is no longer inhibited by above normal level of cortisol . 
c. Transphenoidal pituitary surgery: 
• Is the treatment of choice, even when tumor cannot be seen on CT scan 
or MRI , transspheniodal exploration may disclose a microadenoma.


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Internal Medicine 
 
 478• Surgery is successful in 50%-95% of cases and is followed by normal 
pituitary and adrenal function as well as cure of Cushing’s diseases.  
 
A. Hyperaldosteronism  
Aldosteronism : is a syndrome associated with hypersecretion of the mineralocorticoid, 
aldosterone. 
Etiology:   
1. Primary aldosteronism:  the cause of excess aldosterone production resides with in the 
adrenal gland 
• Aldosterone producing adrenal adenoma (Conn’s  syndrome) : in most cases , 
unilateral small adenoma which can occur on either side  
• Adrenal carcinoma:  rare cause of aldosteronism  
• Bilateral cortical nodular hyperplasia /idiopathic hyperaldosteronism 
 
2. Secondary aldosteronism : the stimulus for excess aldosterone production is outside the 
adrenal gland. It refers to a appropriately increased production of aldosterone in response to 
activation of the renin-angiotensin system 
• Accelerated phase of hypertension 
• Pregnancy 
• Congestive heart failure 
• Other edema states : nephritic syndrome , CLD etc 
Pathophysiology:  The excess  aldosterone increase the reabsorption of sodium and excretion 
of potassium and hydrogen ions, in the distal renal tubules, which results progressive depletion of potassium and leads to hypokalemia. 
Signs and symptoms: 
• Moat patients have diastolic hypertension  resulting from sodium retention.  Patients 
may complain headache and symptoms of other organ damage


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Signs and symptoms: 
• Moat patients have diastolic hypertension  resulting from sodium retention.  Patients 
may complain headache and symptoms of other organ damage 
• Hypokalemia and associated symptoms : muscle weakness and fatigue.   
• Impairment of urinary concentrating ability
Æpolyuria and polydipsia. 
• Metabolic alkalosis  with paresthesia, possibly tetany 
ECG: 
• Evidences of left ventricular enlargement  
• ECG signs of hypokalemia : prominent U waves and cardiac arrhythmias


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Internal Medicine 
 
 479Laboratory Diagnosis:  
• Hypokalemia in hypertensive patients  is often the clue that triggers the search for 
primary aldosteronism :  
• Metabolic alkalosis  
• Serum aldosteron level : elevated aldosteron and metabolites in 24-h urine 
• Plasma renin activity : is the most important useful indicator of whether elevated 
aldosterone is primary or secondary. Increased plasma renin activity favours the 
diagnosis of secondary aldosteronism. While raised aldosteron level with reduced plasma renin activity suggests primary aldosteronism. 
• CT scan and MRI : may detect aldosteron secreting adenomas. 
Treatment: 
1. Surgery:  removal of solitary adenoma results cure of hypertension in about 60 % of 
cases and improvement in another 25 %.  Adrenalectomy is done after 4 week treatment 
with spironolactone (in case of adenoma, hyperplasia)  
In contrast only 20%-50 % of patients with bilateral hyperplasia are improved with 
surgery, even if bilateral adrenalectomy is performed. 
2. Medical Therapy: Spironolactone  inhibits the effects of aldosteron on renal tubule.  
In idiopathic form: Spironolactone (50-100 mg/d), possibly combined with potassium-sparing diuretics correct the hypokalemia and with  anti-hypertensive medication , high blood pressure can be controlled. 
 
References:  
3) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Disorders of  the adrenal cortex , pages 2127-1508-1515


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References:  
3) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Disorders of  the adrenal cortex , pages 2127-1508-1515 
4) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Disorders of the adrenal gland, pages 492-501.


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Internal Medicine 
 
 4804. Diseases of the pituitary gland 
 
1. Anterior pituitary diseases may result from:- 
i) Insufficient production of pituitary hormones: hypopituitarism  
ii) Excess production of pituitary hormones:  
a. Acromegaly,  
b. Cushing’s diseases 
c. Hyperprolactinoma  
iii) Local effect of pituitary tumours  
 
2. Posterior Pituitary diseases  
 
I) Hypopituitarism ( Insufficient production of  anterior pituitary 
hormones) 
• Hyposecretion may be generalized (hypopituitarism) or caused by the selective loss 
of one or more pituitary hormones. 
Generalized hypopituitarism 
Definition:  Endocrine deficiency syndromes due to partial or complete loss of anterior lobe 
pituitary function.  
Etiology: 1. Pituitary tumours  
• Chromophbic adenomas 
• Craniopharyngioamas 
2. Infarction of ischemic necrosis of the pituitary 
• Shock , especially post partum ( Sheehan’s syndrome ) or in Debates mellitus or 
Sickle cell anemia  
• Vascular thrombosis or aneurysm of the anterior cerebral artery 
• Hemorrhagic infarction : pituitary apoplexy  
3. Inflammatory /infectious process : meningitis ( tuberculus )  , pituitary abscess  
4. Infiltrative diseases: Sarcoidosis , hemochromatois ,  
5.  Iatrogenic : irradiation or Surgical removal of pituitary tumours or during operation for other 
bran tumours


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Internal Medicine 
 
 481Clinical features: 
• The onset is usually insidious and may not be recognized as abnormal by the patient, 
but occasionally it may be sudden or dramatic. The function of all target glands will 
decrease when all hormones are deficient (panhypopituitarism). 
• With slow progressive destruction of pituitary tissue , 
o Failure of GH and gonadotrophin secretion occurs early 
o TSH failure comes next  
o ACTH level falls finally  
 
1) Growth hormone deficiency  
• In children growth failure 
• In adults: increases adipose tissue and decreases lean body mass , leading to 
reduced strength and exercise capacity 
2) Gonadotrphine ( LH and FSH ) deficiency : 
• In women : amenorrhea and genital atrophy and  infertility, if there is associated loss 
of adrenal androgens , because of concomitant ACTH, deficiency , pubic and axillary 
hair may be lost , in women 
• In men:  loss of potency and libido, testicular atrophy, regression of secondary sexual 
characteristics, and decreased spermatogenesis with consequent infertility 
3) TSH deficiency:  symptoms and signs of hypothyroidism 
4) ACTH deficiency : leads to secondary type of adrenal insufficiency. This type of adrenal 
insufficiency differs from primary adrenal insufficiency in that :  
• There is no hyperpigmentation of skin and mucous membrane  
• Hyponatremia and Hypokalemia are minimal, since aldosteron production, which


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insufficiency differs from primary adrenal insufficiency in that :  
• There is no hyperpigmentation of skin and mucous membrane  
• Hyponatremia and Hypokalemia are minimal, since aldosteron production, which 
controls the balance of these electrolytes, mainly depends on the renin-angiotensin system. 
5) Prolactine deficiency:  postpartum failure of lactation 
Pituitary apoplexy  is a symptom complex caused by hemorrhagic infarction of either a normal 
pituitary gland or, more commonly, a tumor.  
• Acute symptoms may include severe headache, stiff neck, fever, and visual 
disturbances.


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Internal Medicine 
 
 482• Varying degrees of hypopituitarism may develop suddenly, and the patient may present 
in vascular collapse because of deficient ACTH and cortisol secretion. Often the CSF is 
hemorrhagic. 
Diagnosis: 
1) Evaluation of target organ function:  is often the first step in the diagnosis of 
hypopituitarism; this condition is often suspected because of failure o more than one target organ  
• Evaluation of thyroid function: T4, T3, TSH 
• Evaluation of ACTH secretion  
• Evaluation of prolactin levels : prolactin not regularly depressed 
• Evaluation of serum LH and FSH levels : helpful in postmenopausal women, not so 
much in others. 
• Measurement of GH hormone level:  may be undetectable under baseline 
condition, provocative maneuvers are needed to prove inadequacy of hormone 
production 
o Insulin induced hypoglycemia/ Insulin tolerance :  test is the most 
consistent effective test : Regular insulin at a dosage of 0.1 U/kg body weight 
is given IV over 15 to 30 sec, and venous blood samples are obtained to 
determine GH, cortisol, and glucose levels at zero time (before insulin administration) and 30, 60 and 90 minutes  later. The fall in serum glucose level is maximal at 30 minutes, is followed by a rise in GH level to a level 
greater than 8-10ng/ml n normal individuals. Blood cortisol level is also 
expected to rise. Failure to rise in the level of both hormones may suggest hypopituitarism. 
2) Imaging studies


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greater than 8-10ng/ml n normal individuals. Blood cortisol level is also 
expected to rise. Failure to rise in the level of both hormones may suggest hypopituitarism. 
2) Imaging studies  
• Skull x-ray of sella turcica (detects macroadenomas > 10 mm) 
• High-resolution CT or MRI if available 
3) Formal visual field testing 
 
Differential diagnosis:   
• Anorexia nervosa,  
• Chronic liver disease (alcohol, hemochromatosis),  
• Polyglandular autoimmune disease


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Internal Medicine 
 
 483Therapy:  
1) Treatment of the underlying cause the patients pituitary insufficiency  
Surgery:  
• If hypopituitarism is due to tumor and tumor is small and is not secreting prolactin, 
most favour Transphenoidal removal of the neoplasm.  
• Most endocrinologists consider bromocripti ne the initial treatment of prolactinomas, 
regardless of size.  
• With larger tumours and suprasellar extension, resection of the entire neoplasm, 
either transsphenoidally or transfrontally, may not be possible, and adjunctive 
irradiation may be needed.  
• After surgical or radiation treatment, other hormones may be lost as well, and 
replacement may be needed accordingly. 
• In pituitary apoplexy, Transphenoidal decompression of the often hemorrhagic tumor 
should be undertaken promptly 
Medical:  Treatment of granulomatous diseases 
2) Hormone replacement therapy  : treatment is directed toward replacing the hormones 
of the hypofunctioning target glands. 
• GH replacement : given for children with growth failure  
• Thyroid hormone replacement : given in usual replacement dose 
• Cortisol is given in the usual replacement dose 
• Estrogens and progesterone combination : may be given to women to restore 
menstrual function and Testosterone may be given to men to restore libido and 
potency 
 
II)  Selective pituitary hormone deficiencies 
Definition:  A clinical condition in which one or more pituitary hormones are deficient; may


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menstrual function and Testosterone may be given to men to restore libido and 
potency 
 
II)  Selective pituitary hormone deficiencies 
Definition:  A clinical condition in which one or more pituitary hormones are deficient; may 
represent an early stage in the development of more generalized hypopituitarism so evaluate patient regularly.  
Forms: 
• Isolated GH deficiency  is responsible for many cases of pituitary dwarfism. 
• Isolated gonadotropin deficiency  occurs in both men and women and must be 
distinguished from primary hypogonadism.


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Internal Medicine 
 
 484• Isolated ACTH deficiency  is a rare clinical entity. Symptoms of weakness, 
hypoglycemia, weight loss, and decreased axillary and pubic hair suggest the diagnosis. 
Plasma and urinary steroid levels are low and rise to normal after ACTH treatment. Clinical and laboratory evidence of other hormonal deficiencies is absent. 
• Isolated TSH deficiency  is likely when clinical features of hypothyroidism exist, plasma 
TSH levels are not elevated, and no other pituitary hormone deficiencies exist. Plasma TSH levels are not always lower than normal, suggesting that the TSH secreted is biologically inactive. 
• Isolated prolactin deficiency  has been noted rarely in women who fail to lactate after 
delivery. 
 
III)  Hypersecretion of anterior pituitary hormones (hypopituitarism) 
The anterior pituitary hormones that are most commonly secreted in excess are 
• GH hypersectretion: which manifests as an Acromegaly or, gigantism 
• Hyperprolactinoma:  
• Excess secretion of ACTH : results as in the pituitary type of Cushing's syndrome 
 
Gigantism and Acromegaly 
Definition:  Syndromes of excessive secretion of GH (hypersomatotropism) nearly always due 
to a pituitary adenoma of the somatotrophs.  
Clinical features: excess GH secretion may cause changes in bone, soft tissue and metabolic 
process.   Bone and soft tissue changes: 
1. Gigantism:  GH hypersecretion beginning in childhood before closure of epiphyses may


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Clinical features: excess GH secretion may cause changes in bone, soft tissue and metabolic 
process.   Bone and soft tissue changes: 
1. Gigantism:  GH hypersecretion beginning in childhood before closure of epiphyses may 
cause increase linear growth of long bones resulting gigantism. There is little bony 
deformity, soft tissue swelling or enlargement of peripheral nerves.  
Delayed puberty or hypogonadotropic hypogonadism may be present.  
2. Acromegaly:  GH hypersecretion beginning after epiphyseal closure, in adults, result soft 
tissue growth and bony enlargement, especially in acral areas of the skeleton, which may 
affect the patient’s appearance.  
• Enlargement of hands  (especially fingertips) and feet: increased ring, gloves 
and shoe size. 
• Coarsening of facial features


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Internal Medicine 
 
 485o Thick skin folds : brows and nasolabialfolds 
o Enlargement of the nose 
o Enlargement of mandible:  Prognathism, spreading of teeth  
• Body hair increases and the skin thickens  and becomes darker. 
• Excessive perspiration , offensive body odour may be noted. 
• Voice becomes husky , tongue enlarged  and furrowed.  
• Barrel chest deformity  may be noted.  
• Joint symptoms are common , crippling degenerative osteoarthritis may occur.  
• Galactorrhea may occur in women and menstrual irregularities/amenorrhea may 
be noted. Impotence is common in men.  
• Peripheral neuropathies  due to entrapment of peripheral nerves are common, 
as are headaches (due to pituitary tumor).  
• Bitemporal hemianopsia  (visual field defect) may develop due to the pressure 
effect of pituitary adenoma.  
• Enlargement of internal organs:  The heart, liver, kidneys, spleen, thyroid, 
parathyroid glands, and pancreas are also larger than normal. Cardiac disease in 
1/3 of patients.  
3. Metabolic changes:  
Poor glucose tolerance, a result of the anti-insulin actions of GH, is common. Over diabetes occurs in only 10% of acromegalic patients. 
Diagnosis: Diagnosis of Acromegaly depends on the clinical manifestations. 
• GH level : should be measured in the morning under basal condition. 
• A level higher than 10ng/dl favors the diagnosis of Acromegaly. 
• Glucose tolerance test:  to diagnose for possible DM


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• GH level : should be measured in the morning under basal condition. 
• A level higher than 10ng/dl favors the diagnosis of Acromegaly. 
• Glucose tolerance test:  to diagnose for possible DM 
• Skull x-ray:  in most cases the pituitary adenoma is large enough to distort the sella 
turcica and can be seen on lateral skull x-ray 
• CT or MRI (if available):  will help to visualize the tumor. 
• Other X-ray changes : Enlargement of sinuses 
Tufting of distal phalanges, cortical thickening.


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Internal Medicine 
 
 486Treatment:   
1. Ablative therapy ; 
• Transpheniodal pituitary adenomectomey : results  prompt normalization of GH in the 
majority of patients  
• Irradiation therapy radiation  is generally indicated, but be aware of danger of 
hypopituitarism. 
2. Medical therapy  is indicated if surgery and radiotherapy are contraindicated or have failed.  
• Give bromocriptine up to 15 mg/d PO in divided doses. 
 
Hyperprolactinoma /Galactorrhea 
 
Definition:  Hyperprolactinoma is a clinical condition re sulting from excess secretion of prolactin  
in men, or in women who are not breastfeeding. 
Etiology:  
1. Prolactin secreting pituitary adenomas (Prolactinoma),  are more common in women 
than in men, usually appearing during repr oductive years. Majority are microadenomas 
(< 10 mm in size). Men tend to have larger tumors (macroadenomas), which usually are 
suspected because of neurologic impairment and hypogonadism.  
2. Damage to the hypothalamus or the pituitary stalk: by tumors , granulomas and 
other process may prevent the normal regulatory effect of hypothalamic  dopamine on lactotrope activity , resulting hypersecretion of prolactin.  
3. Drugs:  drugs that inhibit dopamine activity, and thus interfere with its regulatory activity 
on prolactin secretion. Some of the drugs are phenothiazines, antidepressants, antihypertensives (methyldopa, reserpine) , opioids, cimetidine, metoclopromide, 
contraceptives etc  
4. Other rare causes :


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on prolactin secretion. Some of the drugs are phenothiazines, antidepressants, antihypertensives (methyldopa, reserpine) , opioids, cimetidine, metoclopromide, 
contraceptives etc  
4. Other rare causes :   
• Primary hypothyroidism  
• Chronic liver disease  
• Renal failure  
• Ectopic prolactin production from  tumors (paraneoplastic syndromes)


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Internal Medicine 
 
 487Clinical features: 
In women:  
• Galactorrhea:  is the direct result of prolactin excess.  
• Amenorrhea or menstrual irregularity  is due to inhibition of hypothalamic GnRH 
production by prolactin as well as the direct effect of prolactin on the ovaries.  
• Signs of estrogens deficiency  may be seen such as hot flushes and dyspareunia. 
In men: 
• Loss of libido and potency , hypogonadism.  
• Headaches, visual difficulties  result from the compression effect of tumors, which are 
often larger in men.  
Diagnosis: 
• Prolactin levels : are elevated. A serum prolactin level greater than 300ng/ml strongly 
suggests the presence of prolactinoma. Func tional causes such as drugs seldom 
elevate the prolactin level above 100-200ng/ml  
• Skull x-ray (lateral):  CT/MRI: are used to visualize the adenoma.  
• Visual field examination 
 
Therapy: 
Depends on the size of the tumor, and its manifestation. 
1. Surgical therapy: transsphenoidal surgery : cures most patients with small adenomas. 
2. Medical: Bromocriptine is remarkably effective in decreasing prolactin level, usually, to 
normal. It also reduces tumor size. 
Dose:   initial dosage 1.25 mg once or twice daily may need to be increased to 10-20mg 
daily for full effect. Side effects : headache, dizziness, fatigue. 
 
Larger tumors with suprasellar extension are not cured by surgery. Such


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Dose:   initial dosage 1.25 mg once or twice daily may need to be increased to 10-20mg 
daily for full effect. Side effects : headache, dizziness, fatigue. 
 
Larger tumors with suprasellar extension are not cured by surgery. Such 
macroadenomas may be initially treated with bromocriptine. If the tumor shrinks, there is a greater chance for successful surgery. 
3. Radiotherapy  is reserved for therapy-resistant cases. It may be used in conjunction with 
surgery and bromocriptine to further reduce tumor size and function.


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Internal Medicine 
 
 488IV) Posterior Pituitary lobe Disorders 
 
Central Diabetes Insipidus  
Definition:  A temporary or chronic disorder of the neurohypophyseal system due to deficiency 
of vasopressin (ADH), and characterized by excretion of excessive quantities of very dilute (but 
otherwise normal) urine, and by excessive thirst. 
 ADH is produced by cells in the supraoptic a nd paraventricular nuclei of the hypothalamus, 
travels down through the pituitary stalk and stored in the posterior lobe of the pituitary gland 
(neurohypophysis)  
 
Etiology:   
1. Primary/Idiopathic : account for approximately 50 % of the cases of diabetes insipidus. 
2. Injury to the hypothalamus  –pituitary  area:  may result from head trauma, neurosurgical 
procedures such as hypophysectomy.  
3. Less common causes : neoplasms, histiocytosis, granulomas, vascular lesions, infections 
(encephalitis.) 
Clinical features:  Onset insidious or abrupt; may occur at any age.  
 
• Polyuria: with urine volume f 3-15 L daily, result from the inability to reabsorb free water 
and to concentrate urine. Nocturia is almost always present, which may disturb sleep and cause mild day time fatigue or somnolence.  
• Thirst (polydipsia) : leads to increased fluid intake. A conscious patient with normal 
thirst mechanism and free access to water will maintain hydration.  However rapid and life threatening dehydration and hypovolemia ma y develop rapidly, if urinary losses are


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thirst mechanism and free access to water will maintain hydration.  However rapid and life threatening dehydration and hypovolemia ma y develop rapidly, if urinary losses are 
not continuously replaced, which may occur in unconscious patients or infants. 
In primary DI, only polydipsia and polyuria are present.  In acquired DI, signs and symptoms of associated lesions are also found.  
 
Diagnosis: 
1. Measurement of plasma osmolality:  in untreated patients helps to distinguish the cause 
of polyuria. In DI, the loss of free water leads to high osmolality (280-310 mOsm/kg). In psychogenic polydipsia excess fluid intake is primary and serum osmolality is low (255 -280 mOsm/kg )


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Internal Medicine 
 
 4892. Water deprivation test:  started in the morning by weighing the patient, obtaining venous 
blood to determine electrolyte concentrations and osmolality, and measuring urinary 
osmolality.  
Fluid intake is withheld, and voided urine is collected hourly and its osmolality is 
measured. Dehydration is continued until 
• Orthostatic hypotension and postural tachycardia appear,  
• 5% or more of the initial body weight has been lost, or  
• The urinary concentration does not increase by more than 30 mOsm/L in 
sequentially voided specimens for 3 hrs.  
At this point, serum electrolytes and osmolality are again determined, and  Five (5 U) of aqueous  vasopressin or 2 µg of desmopression is then injected SC.  
Urine osmolality is measured 1 hr later. 
 Table VII-4- 2 Interpretations of Water deprivation test 
 
Disorder Urinary osmolality in 
response to water 
deprivation Response to Vasopressin 
injection 
Normal response  Urinary osmolality increases  > 280 mOsm/kg No further increment in urine osmolality 
Central DI The urinary osmolality does not increase Urinary osmolality increases 
Nephrogenic DI The urinary osmolality does not increase The urinary osmolality does not increase 
 
3. Measurement of circulating ADH concentrations by radioimmunoassay  
 
Differential diagnosis:  
• Compulsive (psychogenic) water drinking 
• Nephrogenic diabetes insipidus. 
Treatment: 
1. Hormonal therapy:


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 490• Aqueous vasopressin SC or IM in doses of 5-10 U.  Since effect lasts 6 h or 
less, use in chronic treatment is limited.  
• Desmopresin:  DDAVP (synthetic vasopressin) in a dose of 0.05-0.2ml applied to 
the upper respiratory mucous membrane twice daily by nasal cannula or nasal 
spray.  
The effect lasts 12-24 h, can be given intranasally, SC or IV and it is a preparation of choice for both adults and children.  
2. Nonhormonal therapy:  to reduce polyuria 
• Chlorpropamide (an oral hypogycemic agent) may increase endogenous ADH 
in patients who have partial ADH deficiency.  Dose: 250-500 mg PO makes patients asymptomatic daily 3-5 mg/kg PO. 
• Thiazide diuretics : have paradoxical effect on decreasing urine output in 
patients with DI.  They are the preferred drugs for treating nephrogenic DI.  Thiazides are only partially effective, decreasing the urine volume by 30%-50 %. 
• Restricting salt intake may be helpful.  
• Prostaglandin inhibitors such as indom ethacin (1.5-3 mg/kg/d PO in divided 
doses) may be effective.  
• Treatment of underlying causes of DI , if treatable.  
 
References  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Disorders of the anterior Pituitary and the neurohypophysis, pages 2076- 2103. 
2) Myers R. Allen , National Medical Series for independent Study ( NMS ) 3rd edition 
Medicine, Diseases of the pituitary gland, pages 75-78


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Internal Medicine 
 
 491CHAPTER EIGHT 
DISEASE OF THE NERVOUS SYSTEM 
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Understand   the epidemiologic significance of Headaches. 
2. Understand the classification of common headaches. 
3. Identify the clinical manifestation of common headaches. 4. Manage patients with acute common headache and prevention of recurrent attacks.  
 
1. Headache 
• Headache is one of the commonest complaints in medical practice.  As many as 90% of 
individuals have at least one episode of headache per year.  Severe disabling headache is reported to occur at least annually by 40% of individuals worldwide. 
• It results from distention, stretching, inflammation or destruction of pain sensitive cranial 
structures.  These pain sensitive structures are the scalp, dura, sinuses, falx cerebri, 
middle meningeal arteries, proximal segments of  large pial arteries and cranial nerves 5, 
9 and 10.  Brain parenchyma is not pain sensitive.   
• A pain (sensory stimuli) from these structures is conveyed to the brain either via 
trigeminal nerve or first three cervical nerves. 
Classification of headaches 
Headache can be clarified pathophysiologically as: 
1. Vascular headache 
• Migraine headache 
• Cluster headache 
• Miscellaneous (orgasmic, Hangover)  
2. Cranial Neuralgias 3. Tension headache 
4. Traction –inflammation headache 
• Cranial arteritis 
• Meningitis 
• Brain tumor 
• Increased /Decreased ICP


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Internal Medicine 
 
 4925. Extra cranial lesions 
• Paranasal sinusitis 
• Dental problems 
• Ear problems 
• Ocular problems 
• Cervical problem 
Evaluation of patients presenting with Headache 
When evaluating a patient with headache, the goal is to: 
• Distinguish serious headache from benign headache syndrome  
• Give appropriate treatment. 
Appropriate History  is critical in evaluating a patient with headache. 
• Characterize the headache:  the quality, location, duration, time course, the conditions 
that produce, exacerbate or relieve it should be reviewed.  
• Look also for associated symptoms, medication history and psychiatric history. 
Physical Examination:  is important to search for underlying serious illnesses.  It should include 
• Vital signs  (Blood pressure, temperature)    
• Head and neck examination : scalp tenderness, sinus tenderness, examination of the 
oral cavity and tempromandibular joint. 
• Ophthalmologic evaluation including  : fundoscopic examination pupillary size, 
corneal clouding 
• Systematic evaluation of other systems  (Glands, chest, CVS, abdomen, GUS, MSS, 
and Integumentary system) 
• Neurological examination  including change in mental status, focal neurological deficit, 
neck stiffness and other meningeal signs 
Investigation 
• Diagnosis of common primary headache syndromes  is clinical. No specific test is 
available. 
• Occasionally investigations including N euro-imaging studies are important if the


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neck stiffness and other meningeal signs 
Investigation 
• Diagnosis of common primary headache syndromes  is clinical. No specific test is 
available. 
• Occasionally investigations including N euro-imaging studies are important if the 
headache is atypical or it is associated with abnormalities on physical examination. 
After appropriate evaluation of the headache the following clinical features should be considered as indicators of serious underlying disease. 
1. First severe headache ever described as the worst type of headache in the patient’s life  
may suggest subarachnoid hemorrhage


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Internal Medicine 
 
 4932. Subacute worsening over days or weeks (tumor) 
3. Disturbs sleep or present immediately upon awakening (tumor) 4. Abnormal neurological exam (space occupying lesions) 
5. Fever or other unexplained systemic signs (meningitis) 
6. Vomiting precedes headache  
7. Headache induced by bending, lifting or  cough 8. Known systemic illnesses 
9. Onset of headache in patients older than 55 yrs.  
 
Common Headache syndromes 
1. Vascular headache 
• Vascular headaches refers to a group of headache syndromes, of unknown cause ,in 
which pain results from dilation of one or more of branches of carotid arteries.   
• Migraine headache and cluster headache account for the majority of the cases. 
 
A)  Migraine Headache 
• Definition:  migraine headache is a benign and episodic disease, characterized by 
headache, nausea, vomiting and/ or other symptoms of neurological dysfunction. 
• It is the most common cause of vascular headache. It approximately affects 15% of 
women and 6% men. 
• It usually begins in childhood or young adult life. 
Etiology : the cause of migraine is often unknown, but several common precipitants have been 
observed.  
1) Family history  of migraine present in nearly 2/3 of patients. 
2) Environmental, dietary and psychological factors. 
• Emotional stress , depression  
• Altered sleep pattern or sleep deprivation 
• Menses , Oral contraceptives 
• Alcohol intake especially red wine  
• Caffeine withdrawal


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2) Environmental, dietary and psychological factors. 
• Emotional stress , depression  
• Altered sleep pattern or sleep deprivation 
• Menses , Oral contraceptives 
• Alcohol intake especially red wine  
• Caffeine withdrawal  
• Various food staffs ( e.g. . chocolates, nuts, aged , cheese , meals containing 
nitrates


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Internal Medicine 
 
 494• Perfumes 
3) It may develop after seemingly minor head injury. 
 
Pathogenesis:  different hypothesis are proposed including: 
1) Vascular theory:  in this theory it is said that migraine and neurological symptoms are 
results of extracranial vasodilatation and intracranial vasoconstriction. 
2) Neuronal theory : a slowly spreading neuronal depolarization is considered as a cause. 
3) Trigeminovascular system abnormality : this theory says dysfunction of trigeminal 
nucleus caudalis leads to release of vasoactive neuropeptides resulting in migraine. 
 
Clinical feature 
Migraine may be precipitated by some of the factors mentioned above. It is relieved by sleep 
and exhilaration, Sumatriptan and pregnancy. 
The syndrome of Classical migraine has five phases: 
• Prodromal phase : characterized by lassitude, irritability difficulty in concentrating 
• Aura phase: patients with aura often report visual complaints, vertigo, aphasia or other 
neurological deficit before the onset of the headache  
• Headache phase  – characteristic migraine headache 
• Headache termination  – usually occurs within 24 hours 
• Post headache phase  – feeling of fatigue.  Sleepiness and irritability 
Characteristic Migraine head ache is:  
 Moderate to severe head pain , pulsating quality often unilateral ( affecting half part of 
the head )  
 It is exacerbation by physical activity and relived by sleeping


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Characteristic Migraine head ache is:  
 Moderate to severe head pain , pulsating quality often unilateral ( affecting half part of 
the head )  
 It is exacerbation by physical activity and relived by sleeping  
 It is often associated with Nausea and/or vomiting, photophobia, phonophobia/ 
sonophobia (dislike ad avoidance of laud sounds or noises).  
 Multiple attacks may occur, each lasting 4 – 72 hrs. 
There are different variants of Migraine  Common migraine 
• This is the commonest variation of migraine headache 
• No focal neurological disturbance precedes the recurrent headache


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Internal Medicine 
 
 495Classic migraine 
• It is associated with characteristic premonitory  sensory, motor or visual symptoms.  Most 
common symptoms reported are visual which include scotomas and/or hallucinations. 
Complicated migraine 
• Migraine associated with dramatic transient neurological deficit, or a migraine attack that 
leaves a persisting residual neurological deficit. 
 
Treatment  
Therapy should first involve removal of inciting agents when possible. 
1.  Acute/abortive tr eatment of migraine 
These are lists of drugs effective for acute management of migraine attack  
a) NSAIDS (Nonsteroidal antinflamatory agents): such as  ASA, paracetamol, Ibuprofen, 
Diclofenac may reduce the severity and duration of migraine attack. These drugs are 
effective for mild to moderate attack s and are most effective when taken early. 
Side effects:  Dyspepsia and GI irritation are common side effects. 
b)  5-Hydroxytryptophan-1 Agonists: is a serotonin agonist that decreases substance P 
release at the trigeminovascular junction.  
i. Nonselective (Ergot preparations: Ergotamine and dihydro-ergotamine)  
o Widely used for relief of acute attacks 
o Has oral, sublingual, rectal, nasal and parentral preparation.  Parentral forms are 
used for rapid relief of the attack. 
o Usually prepared combined with caffeine which potentiates the effect by 
improving absorption. 
o Dose: Initial  dose: 1 – 2 mg oral /SL/ rectal and repeat every hour if there is no


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used for rapid relief of the attack. 
o Usually prepared combined with caffeine which potentiates the effect by 
improving absorption. 
o Dose: Initial  dose: 1 – 2 mg oral /SL/ rectal and repeat every hour if there is no 
relief of headache to a maximum of 6 – 8 mg over 24 hrs 
o Side effects: are nausea, vomiting, myalgias, chest discomfort, peripheral 
ischemia and even angina. Excess use may lead to rebound headache and dependency  
o Contraindication: patients  with vascular diseases like coronary heart disease 
ii. Selective - Triptans including (Naratriptan, Ritatriptan, Sumatriptan, and 
Zolmitriptan): are new drugs in management of migraine. 
o Sumatriptan –  single 6 mg SC dose is effective in 70 – 80% of patients 
c) Dopamine agonists: are used as adjunctive therapy.


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Internal Medicine 
 
 4962. Prophylactic Treatment: includes drug regimens and changes in patients behavior  
Medical therapy:  
• These are drugs that have capacity to stabilize migraine. Prophylactic treatment is 
indicated if the patient has three or more attacks per month. 
• Drugs used for this purpose include β-blockers (propranolol), Tricyclic 
antidepressants (amitriptyline), and Calcium channel blockers (Verapamil), Valproic 
acid. 
• Start with low dose and gradually increase if there is no adequate response. 
        Biofeedback therapy 
• It is simple and cost effective. It lessens migraine attacks by helping patients deal more 
effectively with stress 
 
B)  Cluster Headache  
• Cluster head ache is a vascular headache syndrome, characterized by severe, acute 
headache that occurs in clusters lasting several weeks followed by pain free intervals that averages a year. 
• Common in men than women.  Male: Female ratio is 8:1 
• Usually begins 3
rd to 6th decades 
• Cluster headache is periorbital less commonly temporal.  It has rapid onset without 
warning.  It is also severe and explosive in quality lasting 30 min to 2hrs, subsiding abruptly. 
• Clusters characteristically occur in the spring and fall several times a day particularly at 
night and stay for 3 – 8 weeks 
• During attack patients often have associated nasal stiffness, lacrimation and redness of 
the eye ipsilateral to the headache. 
• Alcohol provokes attacks in about 70% of patients 
 
Treatment


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night and stay for 3 – 8 weeks 
• During attack patients often have associated nasal stiffness, lacrimation and redness of 
the eye ipsilateral to the headache. 
• Alcohol provokes attacks in about 70% of patients 
 
Treatment 
Acute attack /abortive therapy (Treatment) 
• Inhalation of 100% oxygen and 
• Sumatriptan 6 mg S.C. stat said to be helpful and ergotamine or other analgesics may 
also be used. 
Preventions/prophylactic therapy: clusters attacks can be prevented effectively by:


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Internal Medicine 
 
 497• Prednisolone , Lithium, Methysergide, Ergotamine, Sodium valproate and verapamil 
 
C) Tension headache (Tension type headache ) 
• Most common cause of headache in adults 
• Common in women than men 
• Can occur at any age, but onset during adolescence or young adulthood is common. 
 
Etiology: various precipitating factors may cause tension headache in susceptible individual 
including.  
• Stress – usually occurs in the afternoon after long stressful work hours 
• Sleep deprivation 
• Uncomfortable stressful position and/or bad posture 
• Hunger (Irregular meal time) 
• Eye strain resulting from continuous TV watching, working on computer screen for a long 
time. 
Clinical feature  
• Tension headache is characterized by mild or  moderate, bilateral pain.  Headache is a 
constant, tight, pressing or band like sensation in the frontal, temporal, occipital or 
parietal area. 
• Usually lasts less than 24 hrs but can persist for days or weeks. 
• Prodromal symptoms are absent some patients have neck, jaw or tempromandibular 
joint discomfort. 
• On examination some patients may have tender spots in the pericranial or cervical 
muscles. 
 
Treatment:  management of tension headache consists:-  
1. Pharmacotherapy 
• Abortive therapy/acute treatment  
o Stop or reduce severity of individual attacks 
o This can be done with simple analgesics like paracetamol, ASA, Ibuprofen, and


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Treatment:  management of tension headache consists:-  
1. Pharmacotherapy 
• Abortive therapy/acute treatment  
o Stop or reduce severity of individual attacks 
o This can be done with simple analgesics like paracetamol, ASA, Ibuprofen, and 
Diclofenac.  If treatment is unsatisfactory addition of caffeine or other analgesic is 
beneficial.


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Internal Medicine 
 
 498• Long term preventive therapy 
o Main form of therapy for chronic form of tension headache 
o This kind of treatment is indicated if the headache is : 
 Frequent (> 2 attacks / week ),  
 Of long duration (> 3hrs)  
 Severe (cause significant disability)  
 Associated with overuse of abortive medication 
o Commonly used drug for long term treatment is Amitryptilline. 
2. Physical Therapy:  different techniques can be used including  
 Hot or cold application 
 Positioning 
 Stretching exercises 
 Traction 
 Massage 
3. Psychological Therapy 
• Includes reassurance, Counseling, relaxation, stress management programs and 
biofeedback techniques reduce both the frequency and severity of chronic headache. 
 
D)  Headache Associated with Brain Tumor 
• About 30% of patients with brain tumor present with headache. 
• Brain tumor can affect all ages and both sexes.  Headache of brain tumor is usually 
intermittent dull aching, moderate intensity which worsens with time.  It disturbs sleep 
in about 10% of patients, exacerbated by exertion and postural changes.  With time 
patients can develop nausea and vomiting. 
• Upon examination focal neurological deficit may be detected. 
E) Temporal Arteritis 
• It is also called giant cell arteritis.  It is an inflammatory disorder of the carotid artery 
and its branches. 
• It is common in elderly, and women account for 65% of cases. 
           Clinical feature


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E) Temporal Arteritis 
• It is also called giant cell arteritis.  It is an inflammatory disorder of the carotid artery 
and its branches. 
• It is common in elderly, and women account for 65% of cases. 
           Clinical feature 
• Typical presenting symptom includes headache, polymyalgia rheumatica, jaw 
claudication, fever and weight loss.


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Internal Medicine 
 
 499• Headache is located to temporal or occipital area, described as dull and boring. It is 
usually worse at night and is often aggravated by exposure to cold. 
• Scalp tenderness is often found over temporal artery. 
• 50% of patients with untreated temporal arteritis develop blindness due to 
involvement of ophthalmic artery and its branches. 
  Diagnosis 
• ESR is often elevated. 
• Biopsy of temporal artery confirms the diagnosis. 
         Treatment 
• Prednisolone 80 mg /day for 4 – 6 weeks 
 
F) Lumbar Puncture headache 
• Occurs in 10 – 30% of patients having LP 
• Usually begins within 1 – 2 days and persists for 3 – 4 days. 
• Headache of lumbar puncture is usually bifrontal or occipital, dull aching 
aggravated by sitting or standing, head shaking, jugular vein compression and 
disappears in prone or supine position. 
• Treatment:  simple analgesics and lie the patient supine. 
  
References:  
3) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Headache,      pages 85-93. 
4) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Headache, pages 61—613.


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Internal Medicine 
 
 5002. Diseases of the Spinal cord 
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Identify the characteristic features of diseases of the spinal cord. 2. Describe the Etiologies of diseases of the spinal cord. 3. Identify the clinical manifestation of common diseases of the spinal cord. 
4.  Understand the diagnostic wok up for common diseases of the spinal cord. 
5. Understand the management of common diseases of the spinal cord. 
 
• Spinal Cord is part of the central nervous system contained in the spinal canal.   The adult 
spinal cord is 18 cm long, oval or round in shape in cross section. It has two parts, white 
matter and gray matter, with central canal at the center. The white matter contains ascending sensory and descending motor fibers and gray matter contains nerve cell bodies. Spinal cord is organized into 31 somatotropic segments, i.e.  8 cervical, 12 thoracic, 5 Lumbar, 5 sacral 
and 1 coccygeal segments. 
• Diseases of the spinal cord are frequently devastating, because the spinal cord contains, in a 
small cross-sectional area, almost the entire motor output and sensory input of the trunk and 
the limbs. 
 Generally diseases of spinal cord are characterized by:  
• The presence of a level below which motor/sensory and/or autonomic function is 
disturbed.   
1. Motor disturbance causes weakness (paraplegia, quadriplegia), spasticity,


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the limbs. 
 Generally diseases of spinal cord are characterized by:  
• The presence of a level below which motor/sensory and/or autonomic function is 
disturbed.   
1. Motor disturbance causes weakness (paraplegia, quadriplegia), spasticity, 
hypereflexia and extensor plantar response, which is due to disruption of descending   corticospinal fibers.   
2. Impaired sensation  results from disordered func tion of ascending spinothalamic 
and dorsal column pathways.   
3. Autonomic disturbance  leads to disturbed sweating, bladder, bowel and sexual 
dysfunction.


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Internal Medicine 
 
 501Some causes of spinal cord diseases 
1) Compressive : lesions may be epidural, intradural or intramedullary  
i) TB spodylitis    
ii) Neoplasms    
iii) Epidural abscess   
iv) Epidural hemorrhage v) Cervical spondylosis vi) Herniated disc /disc prolapse 
vii) Fractured / displaced vertebral body 
2) Vascular 
i) AV – malformation 
ii) Spinal artery thrombosis or embolization 
3) Inflammatory 
i) Transverse myelitis, Borrelia, Syphilis  ii) MS (multiple sclerosis) iii) Vasculitis 
4) Infections 
i) Viral : Varicella zoster virus , HSV-1 and HSV-2 , CMV , HIV  ii) Bacterial : Myocobaterial ,  iii) Parasitic : Schistosomaisis , Toxoplasmosis  
5) Developmental :  syringomyelia , meningomyelocel 
6) Metabolic 
i) V-B 12 deficiency ii) Neurolathrism: that is a spastic parapares is resulting from consumption of “Guaya”, 
which grows in the northern part of Ethiopia. This cereal has neurotoxin which causes paraparesis when consumed in large amount for relatively long period of 
time. 
 
Common Spinal Cord Diseases  
A. Neoplastic spinal cord compression 
May be classified as: 
1) Extramedullary:  tumor outside the spinal cord. 
i) Epidural:  outside the dural layer


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Internal Medicine 
 
 502 Commonest cause of neoplastic compression of spinal cord in adults. Usually 
results from metastasis to adjacent vertebral bone or direct compression of the 
spinal cord. 
 Commonest neoplasm  include: breast, lung, prostate, kidneys, lymphoma and 
multiple myeloma 
 Most frequently involved site is thoracic cord 
ii) Intradural:  inside the dural layer 
 These are slowly growing benign tumors like meningioma, neuroblastoma, 
lipoma   
2) Intra medullary:  tumors within the spinal cord. 
 These are uncommon tumors , including ependymoma, hemangioblastoma low 
grade astrocytoma 
Clinical feature 
• Initial symptom is backache, which is localized, and which worsens with movement, coughing or sneezing.  The pain may radiate to the legs, trunk or following dermatomal distribution. 
• The pain may be sever and awaken the patient at night. 
• As compression progresses patient devel ops progressive weakness, sensory 
abnormalities and autonomic disturbances change in bladder function and constipation. 
Physical findings include: 
• Weakness, spasticity, hyperreflexia 
• Loss of or decreased sensations to pinprick in the lower extremities 
• Extensor plantar response , and loss of abdominal reflexes and anal sphincter tone 
• Urinary retention  
Investigations 
• Check for primary tumor sites 
• Plain X-ray of the spine 
• Myelography  
• Radionuclide bone scan 
• CT/MRI 
• Biopsy 
Æ usually unnecessary in patients with known pre-existing cancer.


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• Urinary retention  
Investigations 
• Check for primary tumor sites 
• Plain X-ray of the spine 
• Myelography  
• Radionuclide bone scan 
• CT/MRI 
• Biopsy 
Æ usually unnecessary in patients with known pre-existing cancer. 
Therapy: depends on site and type of tumor. 
Treatment modalities include


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Internal Medicine 
 
 503Steroids : help to reduce the interstitial edema 
 Should be started immediately with in the first 12 hrs of occurrence of symptoms 
Prednisolone 40 mg PO BID ,  or Dexamethason 12 mg IV followed by 4 mg IV QID may 
be used 
Radiotherapy. 
 Is effective even for classically radio-resistant tumors   
 Prevents new weakness and may give recovery of function 
Surgery: decompression or vertebral body resection 
 Useful especially for intradural and intramedullary tumors 
Note: Treatment should be started as soon as possible (with in 12 hrs). Fixed motor deficits 
(paraplegia or quadriplegia), once established for > 12 hrs, do not usually improve, and beyond 
48 hrs the prognosis for substantial motor recovery is poor. 
 
B. Tuberculosis of the spine (Pott’s disease) 
• One of commonest causes of myelopathy in  developing countries where Tuberculosis is 
endemic, Ethiopia. 
• Often Involves two or more adjacent vertebral bodies 
• Commonest site is lower thoracic and upper lumbar vertebrae 
Clinical features 
• Patients present with insidious on set of back pain, which progressively get worse. 
• Gibus deformity (kyphotic swelling over the back) 
• Numbness and loss of sensation with a sensory level 
• Weakness of the lower limbs, often spastic in nature, with exaggerated deep tendon 
reflexes and up going plantar (Babinisky’s sign)  
• Bladder and /bowel dysfunction (Urinary retention with overflow incontinence, constipation or fecal incontinence)


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reflexes and up going plantar (Babinisky’s sign)  
• Bladder and /bowel dysfunction (Urinary retention with overflow incontinence, constipation or fecal incontinence)  
• In about 65% of cases evidences of extra spinal tuberculosis is present  
Diagnostic workup:  
1. Imaging studies 
• Plain radiograph show characteristically destructive process of the vertebrae, 
involvement of disc space with deformity. 
• CT/MRI may show the lesion more clearly


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Internal Medicine 
 
 504Treatment  
• Medical Therapy 
o DOTS: short course anti tuberculosis chemotherapy  is mainstay of therapy.  
o Steroids  can be added it there is neurological deficit  
• Surgery:  is indicated if there is spinal instability or deformity and unresponsiveness to 
medical treatment. 
 
C. Prolapse of intervertebral disc 
• It occurs due to trauma, sudden severe strain or degenerative changes. 
• Commonest site of for disc prolapsed is the lumbar region. 
Clinical feature 
Localized back pain aggravated by straining with or without 
• Radiculopathy 
• Segmental sensory loss 
• Changes in deep tendon reflexes (asymmetrical) 
Straight leg raising sign is positive:  the patient will have back pain, when stretched leg is 
raised / flexed at the hip joint. 
Diagnostic workup 
• Myelography: may help to localize the site of prolapse  
• CT/MRI: can easily demonstrate the prolapsed disk  
Therapy:  
Medical therapy : is often supportive ad include 
Bed rest, adequate analgesics and physical therapy 
Supporting belts or corsets 
Surgery : is the definitive treatment for disk prolapse. 
 
D. Transverse Myelitis   
It is an acute or sub acute inflammatory disorder of the spinal cord.  
It occurs   associated with; 
• Antecedent infection ( either viral or Mycoplasmal .)  
• Recent vaccination 
• Multiple sclerosis 
• Collagen vascular disease (SLE)


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Internal Medicine 
 
 505Clinical feature 
• Initial symptom is localized back or neck pain or radicular pain followed by various 
combinations of paresthesia, sensory loss, motor weakness and sphincter disturbances, 
which can evolve within hours to several days. 
Investigation 
• CSF: may be normal or show pleocytosis and increased protein. 
Treatment 
• Steroids can be used in moderate to severe cases. 
 
E. Metabolic and toxic myelopathies  
 
i) Subacute combined dege neration of spinal cord 
• Neurologic disease mainly affecting the spinal cord, resulting from severe Vit-B 12 
deficiency. 
• Vit-B 12 deficiency results abnormalities on myelin basic protein leading to swelling of 
myelin sheath followed by demyeliniation and gliosis.  
• These changes mainly affect the posterior and lateral columns of spinal cord. 
Clinical Feature: patients present with;- 
• Paresthesia in the hands and feet. 
• Early loss of position and vibration senses (loss of propioreceptor sensations). 
• Progressive spastic and ataxic weakness 
• Some patients may develop optic atrophy and encephalopathy 
Treatment 
    Vitamin B 12:  1000μg IM/d for 5 – 10 days, followed by   
1000 μg IM/week for 1 month, and then 
1000 μg IM month lifelong. 
 
iii) Neurolathrism 
• Neurolathrism is syndrome that affects the nervous system of man due to consumption 
of peas of the lathyrus species (“Guaya” seeds) that contains neurotoxic amino acid.


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1000 μg IM month lifelong. 
 
iii) Neurolathrism 
• Neurolathrism is syndrome that affects the nervous system of man due to consumption 
of peas of the lathyrus species (“Guaya” seeds) that contains neurotoxic amino acid. 
Excessive consumption of these (Guaya) seeds occurs during times of food shortage, in Northern parts of Ethiopia (Gondar, Tigray, Wello and part of Gojam).


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Internal Medicine 
 
 506• It affects predominantly young men. 
 
Clinical feature 
Onset can be acute /subacute usually precipitated by manual labour, febrile illness or diarrhea 
then the patients will develop weakness, spastici ty and rigidity progressively preventing them 
from walking. Usually no sensory abnormality is seen. Some of severely affected cases may 
develop incontinence and impotence. Investigation 
• No specific laboratory test required.   
• Diagnosis of neurolathrism is by exclusion of other causes and taking proper dietary 
history and understanding the geographic distribution of the diseases.  
 
Treatment 
• No cure once established 
Prevention 
• Banning cultivation and consumption of the seed (" Guaya”).  
• Breeding of nontoxic variant if possible. 
• Use of certain preparation methods (Cooking or soaking in excess water) makes the 
seed less toxic. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Diseases 
of the Spinal cord, pages 2438-2446. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Myelopathy and other spinal cord disorders, pages 635-637.


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Internal Medicine 
 
 5073. Cerebrovascular diseases  
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define cerebrovascular diseases/stroke. 2. Understand   the epidemiologic significance of stroke. 3. Understand the classification of stroke and the etiologies. 
4. Identify the clinical manifestation of different types of stroke. 
5. Understand the diagnostic approach of patients with stroke. 6.  Understand the principles of management of patients with stroke.  
7. Understand the preventive strategies for stroke.  
 Definition : Syndrome of an abrupt onset of nonconvulsive, focal neurologic deficit resulting 
from sudden interruption of the blood supply to parts of the brain, lasting 24 hours or longer. 
 
Classification of stroke  
I. Etiologic classification  
1) Ischemic   -stroke accounts for 80 – 90% of all stroke in developed countries 
a) Embolic 
b) Thrombotic 
i) Large vessel disease: resulting from narrowing of cerebral arteries doe to 
atherosclerosis. 
ii) Small vessel disease (Lacunar infarct) iii) Miscellaneous: E.g. Vasculitis resulting thrombus formation  
2) Hemorrhagic Stroke: accounts for 10-20 % of cerebrovascualr accidents in developed 
nations. It is a much more commoner cause of stoke in developing countries , mainly associated with unrecognized or poorly controlled hypertension  
a) Primary Intracerebral Hemorrhage (PICH) b) Subarachnoid Hemorrhage (SAH) 
II. Classification based on the duration of stroke


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a) Primary Intracerebral Hemorrhage (PICH) b) Subarachnoid Hemorrhage (SAH) 
II. Classification based on the duration of stroke  
1) Transient Ischemic attack:  TIAs are   focal neuralgic deficit lasting < 24 hrs confined to 
an area of brain perfused by specific artery , and neurologic deficit resolves in less than 24 hours


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 5082) Reversible Ischemic neurologic deficit:  sudden onset focal neurologic deficit which 
lasts for more than 24 hours, but the neurologic deficit recovers / resolves /. 
3) Stroke in evolution:  a focal neurologic deficit, the degree of which is progressing over 
a couple of hours or days. 
4) Complete stroke:  sudden onset of focal neurologic deficit, in which the deficit neither 
improves nor gets worse over time. It is oft en associated with infarction of part of the 
brain. 
 
Epidemiology and risk factor  
Stroke is prevalent all over the worldwide. It is third commonest cause of death in developed 
world following Coronary heart diseases and cancer. It is a leading cause of disability. The prevalence and incidence of stroke is also on the rise in developing countries. 
Major risk factors associated with stroke include 
• Incidence is higher in men and old age 
• Hypertension 
• Smoking 
• Diabetic mellitus 
• Hyperlipidemia 
• Atrial fibrillation 
• Myocardial infarction 
• Congestive heart failure 
• Acute alcohol abuse 
Approach to a patient with stroke: 
Goals /Steps  
1. Assessment and maintenance of vital functions  
2. Determination of presumptive diagnosis of stroke subtype 
3. Confirmation of stroke subtype 
4. Management of a patients with stroke  
 
1. Initial Assessment and maintenance of vital functions/stabilizing the patient


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2. Determination of presumptive diagnosis of stroke subtype 
3. Confirmation of stroke subtype 
4. Management of a patients with stroke  
 
1. Initial Assessment and maintenance of vital functions/stabilizing the patient  
Stroke should be considered as medical emergency, as it affects vital functions of an individual.  For this reason the initial step in management of patients with acute stroke should be rapid 
assessment and maintenance of vital functions. This includes:


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Internal Medicine 
 
 509a) Maintenance of air way and ventilation 
b) Control of blood pressure 
 Acute stroke alters autoregulation of cerebral blood flow, compromising the blood 
supply to an already damaged brain. Close monitoring of blood pressure and correction of both hypotension and hypertension reduces this risk. 
 If the patient is hypertensive treatment is recommend only when the DBP ≥120 and 
SBP 
≥ 200 mmHg.  Short acting antihypertensive drugs are preferred. 
 If the patient is hypotensive, it should be corrected by fluid administration and 
treatment of the underlying cause for the hypotension.  
c) Control of body temperature. 
 Fever occurs in 44% of patients with acute stroke.  The fever may be due to stoke or 
infections.  Because fever worsens the prognosis of stroke body temperature should be controlled appropriately. 
d) Fluid management 
 Maintenance of euvolumic state and establishment of IV access using normal saline 
(rather than glucose solutions) is also important. Glucose is said to be neurotoxic and it is better avoided in patients with stroke. 
N.B Exclude causes of brain dysfunction, which mimic stroke like states like syncope, migraine, hysteria and trauma. 
 
2. Determine Presumptive Di agnosis of Stroke Subtype 
Numbers of clinical features are useful in determining the type of stroke. A good history taking, 
and proper physical examination may suggest the possible cause of the stroke. 
Important historical information includes:


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Numbers of clinical features are useful in determining the type of stroke. A good history taking, 
and proper physical examination may suggest the possible cause of the stroke. 
Important historical information includes: 
• Mode of onset and pattern of progression 
o Embolisms usually occur suddenly when the patient is awake, most often early in 
the morning, giving maximum deficit at onset. 
o Hemorrhagic stokes also occur suddenly while the patient is awake, any may be 
physically active or straining, and progresses within minutes to hours. 
o Thrombosis often occurs during sleep hour or present upon arising from bed 
progressing in a stepwise fashion. 
• Prior history of TIA  (transient ischemic attacks). These are often associated with 
thrombotic (atherosclerotic) vascular disease.


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Internal Medicine 
 
 510• Associated symptoms 
o Headache, vomiting, reduced alertness suggest hemorrhagic stroke than 
ischemic stroke. Very severe headache with altered consciousness without major 
neurologic deficit may suggest subarachnoid hemorrhage. 
o If patient is having fever raises suspicion of infective endocarditis.   
o Seizure is common in embolic stroke. 
• Look for risk factors for stroke  
• Looking for other medical conditions  associated with stroke such as hypertension, 
diabetes, smoking and use of drugs like OCP* may suggest the diagnosis. 
 
Physical Examination 
• Physical Findings may give clue to the type of stroke the patient is suffering from. 
• Absent/reduced peripheral pulses suggest atherosclerosis or embolism  
• Presence of neck bruit suggests extra cranial occlusion of carotid arteries  
• Cardiac abnormalities: such as atrial fibrillation, murmurs or cardiac enlargement may 
suggest embolic stroke, the embolus originating from the heart. 
• Fever raises concern for infectious etiologies 
• Ophthalmoscopic examination: papilledma or retinal hemorrhage may suggest 
subarachnoid hemorrhage or increased intracranial pressure. 
 
Table VIII-3-1.  Characteristic features of different types of stroke   
 
 Embolic 
stroke  Intracerebral hemorrhage Large vessel thrombosis  Lacunar 
infarctions  Subarachnoid 
hemorrhage 
Onset 
  
 
 Sudden onset with maximum deficit at 
onset  Sudden (deficit  
Progresses over minutes to 
hours)


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Embolic 
stroke  Intracerebral hemorrhage Large vessel thrombosis  Lacunar 
infarctions  Subarachnoid 
hemorrhage 
Onset 
  
 
 Sudden onset with maximum deficit at 
onset  Sudden (deficit  
Progresses over minutes to 
hours) 
  Sudden,  Gradual, stepwise, or 
Stuttering Sudden, 
Gradual, Stepwise 
or 
Stuttering  Sudden,  Usually few or not focal signs 
 
 
Time of 
occurrence When the 
patient is  
Awake 
 When the patient is  
Awake and 
active When the patient is  
Asleep or 
inactive When the patient is  
Asleep or  
inactive When the patient is 
Awake and  
active


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Internal Medicine 
 
 511  
  
Warning 
signs (TIA) None  
 None 
 
 Usually 
 
 Variable, 
TIA’s  
may occur None 
 
 
Associated symptoms 
(Headache 
Vomiting ) 
 Sometimes 
 
 Usually 
 
 Sometimes 
 
 No 
 
 Always (stiff  
neck) 
CT 
scan  
 Decreased 
density  
 Increased density
 
 
 Decreased  
density  
 Usually 
normal  
 
 Usually  
abnormal  
 
LP Usually clear  Usually bloody  
 Clear  Clear  Invariably 
blood  
 
These characterizations are generally accepted principles regarding stroke; however, it is good 
to remember that stroke can present atypically. 
3. Confirmation of Diagnosis:  different investigations are needed to confirm the 
diagnosis. 
• Imaging studies (CT or MRI): are the most important initial diagnostic tests in patients 
with stroke (if available and affordable by the patient).  CT can identify or excludes hemorrhagic stroke and other conditions which simulate stroke (like Neoplasm and abscesses).  Complete Infarction is usually seen after 24 hours. MRI is more sensitive than CT for early diagnosis of brain infarction. 
• Other Tests are:   
Lumbar puncture  – may be needed to make a diagnosis of small SAH which can be 
missed by CT or MRI. 
o Carotid Doppler studies : to look for carotid artery narrowing  
o Angiography : to identify the exact location and the specific artery blocked  
o Echocardiography : to look for cardiac sources of embolization  
o ECG: to look for arrhythmias such as atrial fibrillation


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Internal Medicine 
 
 512o CBC, ESR, VDRL 
o Tests for HIV infection : stroke associated with vasculitis is common in HIV positive 
patients  
o FBS, Lipid profile : to look for diabetes and hyperlipidemia 9 risk factors for stroke  
o Coagulation profile: to look bleeding tendencies. 
 
4. Management of specific stroke  
Goal of Treatment  
• Interruption of further brain damage 
• Prevention and management of complication  
A. General Measures 
• Admit the patients where close follow up can be given 
• Continue follow up and maintenance of vital functions. 
o Airway and ventilation 
o Controlling of blood pressure 
o Controlling body temperature 
o Fluid administration /Hydration 
• If the patient is comatose or has impaired mental status 
o Changing the patients position every 2 hrs and avoid the occurrence of bed sores 
o Bladder and bowel care: if the patient has incontinence – catheterize 
• Infections such as aspiration pneumonia should be treated with antibiotics 
 
B. Management of Specific Etiologies 
1) Atherosclerotic stroke (Thrombotic stroke  )  
i) Thrombolytic therapy: in developed coun tries thrombolytic therapy with 
medications such as rt-PA (plaminogen activator), to patients who present within 
3 hrs of onset of stroke, helps to lyse the thrombus and restore perfusion to the affected brain. 
Contraindications:  
• Extensive infarct on CT,  
• Recent surgery, Head trauma 
• GI or urinary hemorrhage, bleeding disorders, Anticoagulation with


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3 hrs of onset of stroke, helps to lyse the thrombus and restore perfusion to the affected brain. 
Contraindications:  
• Extensive infarct on CT,  
• Recent surgery, Head trauma 
• GI or urinary hemorrhage, bleeding disorders, Anticoagulation with 
prolonged PT/PT


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Internal Medicine 
 
 513• Seizure at stroke onset 
• Severe uncontrolled hypertension.   
ii) Anticoagulants: use of Heparin and Warfarin is controversial. Low dose heparin 
can be given for prevention of thromboembolism. 
iii) Anti-platelet aggregation agents: 
Aspirin reduces the incidence of stroke and vascular mortality. General 
recommendation is to give 325 mg of ASA once daily. It may not help to resolve the already formed thrombus, but ASA prevents recurrence of stroke. 
2) Embolic stroke: (Cardiogenic embolus) 
• Anticoagulation is indicated to prevent recurrent embolic stroke. Anticoagulation 
with heparin should be initiated when the acute phase of stroke is over. Care should be taken to avoid hemorrhagic transformation of infarct. Warfarin is used for chronic anticoagulation. 
3) Intracerebral hemorrhage 
• Continue supportive measures 
• Control very high blood pressure  
• Surgical consultation is indicated for removing cerebellar hematoma, as it may 
compress vital centers in the brainstem. 
4) Subarachnoid Hemorrhage 
Medical therapy:  
(a) Supportive measures include bed rest, sedatives, analgesic, laxative,  
(b) Control of hypertension and  
(c) Nimodipin (calcium channel blocker) is given to prevent neurologic deterioration 
due to vasospasm.   
Surgical therapy : Saccular aneurysms are treated surgically 
 
C. Prevention of further stroke:  
• Control of hypertension 
• Control blood sugar in diabetics 
• Ceasation of  smoking


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due to vasospasm.   
Surgical therapy : Saccular aneurysms are treated surgically 
 
C. Prevention of further stroke:  
• Control of hypertension 
• Control blood sugar in diabetics 
• Ceasation of  smoking 
• Physical activity and weight reduction  
• Anticoagulation for atrial fibrillation 
• ASA 75 mg Po daily in individuals older than 50 and have history of TIA


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Internal Medicine 
 
 514• Surgery (Endarterioactomy): if a narrowed artery is detected  
D. Rehabilitation:  is a very important part of management, and it shall be started early and 
include:- 
• Physiotherapy  
• Occupational and speech therapy. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, 
Cerebrovascular diseases, pages 2372-2392. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edtion Medicine, 
Stroke, pages 619-625.


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Internal Medicine 
 
 5154. Impairment of consciousness and Coma 
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define different levels of Impairment of consciousness and Coma. 2. List the etiologies of Impairment of consciousness and Coma. 3. Understand the diagnostic approach of Impairment of consciousness and Coma. 
4. List differential diagnosis to Impairment of consciousness and Coma.  
5. Understand the principles of management of patients with coma.  
 
Introduction 
Maintenance of conscious state requires proper functioning of the cerebral hemispheres, 
reticular activating system found in brain stem and corticothalmic connections.  If there is structural, metabolic or toxic insult of diffuse nature to these structures results in alteration of 
conscious level of different degree. 
• Coma  is severe degree of reduced consciousness (alertness and responsiveness) from 
which the patient cannot be aroused. 
• Stupor  is a sleep like unarousability, from which the patient can be awakened by vigorous 
stimuli. 
• Drowsiness:  is a state of reduced consciousness characterized by easy arousal that can be 
maintained only for brief period of time. 
• Vegetative state:  is characterized by the patient’s unawareness of self or external stimuli. 
Autonomic functions are relatively well maintained, and a sleep-wake cycle exists. The


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maintained only for brief period of time. 
• Vegetative state:  is characterized by the patient’s unawareness of self or external stimuli. 
Autonomic functions are relatively well maintained, and a sleep-wake cycle exists. The 
patient cannot interact with others in a meaning full fashion. The patient can survive with medical and nursing support.  
• Brain death:  This is a state in which there has been cessation of cerebral blood flow; as  a 
result there is  global loss of brain function while respiration is maintained by artificial means and the heart continues to pump.  
Etiologies  
1. Diseases that cause no focal neurologic deficit or lateralizing neurologic signs . The 
loss of consciousness in such patients is diff use bilateral hemispheric impairment, and such 
patients have normal brainstem function. Some of the causes include :-


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Internal Medicine 
 
 516• Metabolic disturbances such as :  hepatic encephalopathy ,uremic encephalopathy 
,hypoglycemia, diabetic ketoacidosis. Electrolyte imbalance (hyponatremia, 
hypernatremia, Hyperkalemia, Hypoca lcaemia), Hypoxia, Hypercapnia etc 
• Intoxications:  alcohol, sedative drugs, opiates 
• Sever systemic or CNS infections  : meningitis, encephalitis, cerebral malaria, 
cerebral abscess 
• Post seizure state  : status epilepticus  
• Hypertensive encephalopathy , eclampsia 
• Sever hyperthermia or hypothermia  
• Head trauma:  brain concussion  
2. Diseases that cause focal neurologic deficit: these disorders cause coma by affecting 
the reticular activating system. They are classified in to two depending on the location of the lesion.    
a) Supratentorial ( hemispheric) lesions  
• Epidural or subdural hematoma 
• Intraparenchymal hemorrhage (hemispherical hemorrhage) 
• Large ischemic infarction 
• Tumor , Abscess , Trauma  
b) Infratentorial lesions  
• Pontine or cerebellar hematoma 
• Basilar artery thrombosis 
• Ischemic cerebellar infarction  
• Tumor , abscess 
Approach to a patient in Coma 
Complete and rapid assessment of the patient is critical for optimal care. 
A. Assessment and maintenance of vi tal function is the initial step 
• Maintain the air ways and ensure adequate  breathing ( ABC of life )  
• Maintain circulation  
B. Establishment of cause of coma : is done by taking a careful history, doing rapid but


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• Maintain the air ways and ensure adequate  breathing ( ABC of life )  
• Maintain circulation  
B. Establishment of cause of coma : is done by taking a careful history, doing rapid but 
through physical examination and investigations. 
Patient History:  
Past medical history:  looking for disease like diabetes, hypertension, cirrhosis, chronic renal 
disease, malignancies and other diseases.


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Internal Medicine 
 
 517• History of medications: legal or illicit dr ugs (sedatives, hypnotics, narcotics ) and history 
of drug abuse 
• Circumstances and rapidity with which change in mental status developed (sudden 
onset indicating vascular causes, gradual onset indicating metabolic and infectious 
causes  fluctuations suggest subdural hematoma) 
• Recent patient complaints preceding loss of consciousness: medical and neurologic 
symptoms (fever suggesting infections, polyuria and polydypsia indicating DKA) 
• Details regarding the site where the patient was found ( e.g. the presence of empty drug 
vials or evidence of fall or trauma 
Physical examination should be through. 
• Vital signs : Extremes of BP, pulse or temperature and abnormal pattern of breathing. 
o Fever suggests systemic or CNS infections or Neurogenic fever 
o Tachypnea – in pulmonary infections or acidosis 
o Hypertension – hypertensive encephalopathy 
• Head and neck : evidence of trauma and the presence of meningismus  
• Skin:  look for signs of trauma or injection.     
• General systemic examination: looking for evidences of systemic illnesses like 
cirrhosis, chronic renal, failure, meningococcemia etc. 
Neurologic examination: is the cornerstone of assessment of comatose patient. It should be 
descriptive and systematic.   
1. Level of consciousness : can be assessed semi quantitatively using the Glasgow 
coma Scale .  
 
Table VIII-4-1 Glasgow coma Scale: 
Eye opening     Score


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descriptive and systematic.   
1. Level of consciousness : can be assessed semi quantitatively using the Glasgow 
coma Scale .  
 
Table VIII-4-1 Glasgow coma Scale: 
Eye opening     Score  
Spontaneous   To verbal stimulus       
To painful stimulus 
None  4 3 
2 
1 
Best verbal response  
Oriented   Confused   5 4


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Internal Medicine 
 
 518 
 
 
 
  
  
 
   
 Points are given for best response in each category and are added giving a score between 3 
(deep coma) and 15(normal)  
 
2. Brain stem reflexes  
Assessment of brainstem functions helps to localize the cause of coma. This can be done using brain stem reflexes including, pupillary light response, ocular movements, corneal reflex and the 
respiratory pattern.  If the brainstem functions are normal, coma must be ascribed to bilateral 
hemispherical disease.  
a) Pupillary light response 
Pupillary reactions are examined with a bright, diffuse light. During examination size, shape, 
symmetry and reaction to light should be noted on both eyes.  
o Normally reactive and round pupils of midsize (2.5 to 5 mm) essentially exclude 
midbrain damage. 
o Enlarged (>6mm) and unreactive pupil on one side signifies a compression or 
stretching of the third nerve from the effects of a mass above. 
o Bilaterally dilated and unreactive pupils, indicates severe midbrain damage, 
usually from compression by a mass. 
o Bilaterally small (1 to 2.5 mm) and reactive pupils (not pinpoint) are seen in 
metabolic encephalopathies or in deep bilateral hemispheral lesions such as hydrocephalus or thalamic hemorrhage. 
o Very small but reactive pupils (< 1 mm)/pinpoint pupils, characterize narcotic or 
barbiturate overdoses but also occur with extensive pontine hemorrhage the thalamus. Inappropriate words  Unintelligible words  None  3 2 1


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o Very small but reactive pupils (< 1 mm)/pinpoint pupils, characterize narcotic or 
barbiturate overdoses but also occur with extensive pontine hemorrhage the thalamus. Inappropriate words  Unintelligible words  None  3 2 1 
Best  motor response  
Obeys commands  Localizes pain   Withdrawal from pain   
Extensor response  
Flexor response  None  6 5 4 
3 
2 1


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Internal Medicine 
 
 519b) Ocular Movements 
Before maneuvers the eyes are observed by  elevating the lids and noting the resting 
position and spontaneous movements of the eyeballs. 
o Lid tone is tested by lifting the eyelids and noting their resistance to opening and 
the speed of closure. Resistance to opening the eye lids may suggest hysteric 
conversion. Easy eyelid opening with slow closure indicates sever coma. 
o Midline deviation suggests frontal/pontine damage. 
o Dysconjugate gaze (abduction or adduction) suggests cranial nerve 
abnormalities. 
o Spontaneous eye movements roving, dipping, bobbing suggest damages being 
at different sites. 
o The eyes look towards a hemispheric lesion and away from a brainstem lesion. 
i. Occulocephalic reflex 
Oculocephalic reflex is elicited by moving the head from side to side or vertically with eyes held open. In comatose patient with intact brainstem  
o If the eyeballs move to the opposite direction of the head movement Æintact 
brainstem function (“doll’s eyes” movement is positive.) 
o If the eyeballs move to the same direction of the head movement Æ Brainstem 
dysfunction. 
ii. Caloric (occulovestibular) reflex 
o This test is performed by irrigating the ear with ice (cold) to stimulate the 
vestibular apparatus. In patients with intact brain stem the eyes move to the irrigated ear. 
c)  Corneal reflex   
o This test assesses the integrity of dorsal midbrain and pontine. It is lost if the


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vestibular apparatus. In patients with intact brain stem the eyes move to the irrigated ear. 
c)  Corneal reflex   
o This test assesses the integrity of dorsal midbrain and pontine. It is lost if the 
reflex connections between the fifth (afferent) and the seventh (efferent) cranial nerves within the pons are damaged. 
d) Respiration:  
• Abnormalities of respiratory pattern can help in coma diagnosis but are of less localizing 
value in comparison to other brainstem signs. 
o Shallow, slow, but regular breathing  suggests metabolic or drug depression. 
o Cheyne-Stokes respiration  signifies bihemispherical damage or metabolic 
suppression, and commonly accompanies light coma.


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Internal Medicine 
 
 520o Rapid, deep (Kussmaul) breathing  usually implies metabolic acidosis but may 
also occur with pontomesenephalic lesions and severe pneumonia. 
o Agonal gasps  reflect bilateral lower brainstem damage and are indicators of 
severe brain damage and a near death situation. 
3. Motor function /response 
Posture of the patient : 
o Quadriparesis and flaccidity : suggest pontine or medullary damage  
o Decorticate posturing: flexion of the elbows and the wrists with supination of the 
arms, and extension of the legs, suggests severe bilateral or unilateral 
hemispheric or diencephalic lesion (damage above the midbrain.) 
o Decerebrate posturing  (extension of elbows and the wrist with pronation of the 
forearm and extension of the legs) indicates damage to the brainstem( midbrain or pontine compromise )    
o Spontaneous activities  – if the patient is yawning, swallowing, coughing or 
moaning the coma is not deep. 
o Abnormal body movements  – seizure, myoclonus may suggest the cause of 
the coma is status epelepticus, uremia etc.  
o Assess tone, response to painful stimuli and presence of asterixes. Asymmetric 
motor responses have localizing value. 
Differential Diagnosis: 
Psychogenic Coma (hysteric coma):  patient often has history of psychiatric illness, and non 
physiologic response on physical examination. 
o Resistance to having the eyelids opened (the patient resists eyelid opening when the 
examiner tries to open it)


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physiologic response on physical examination. 
o Resistance to having the eyelids opened (the patient resists eyelid opening when the 
examiner tries to open it)  
o Failure of the patient’s arm, when held by the examiner over the patent’s face, to fall 
up on the face when released by the examiner. 
o Nystagmus when the ear is irrigated with cold water 
o Adversive head and eye movements  
 
Laboratory investigations 
• Blood film, CBC, urine analysis 
• Measurements of serum glucose level, renal and liver function test.


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Internal Medicine 
 
 521• Lumbar puncture and CSF examination  should be done as soon as possible unless 
increased intracranial pressure is suspected to exclude infections and subarachnoid 
hemorrhage. 
• Measurements of serum electrolytes, cultur es, toxicological analysis, arterial blood gas 
analysis, EEG and imaging studies are also helpful in diagnosis of coma if available.   
Management 
Ideally the, care of comatose patient is started together with the initial assessment to identify the etiology. 
a) 
Initial therapy  : Maintaining an adequate airway, optimal ventilation and 
maintaining adequate perfusion ( blood pressure) 
o If there is possibility of cervical fracture, immobilization of the neck is 
essential 
o Endothracheal intubation is often indicated to protect the airways  
o Blood samples for CBC, electrolyte glucose, RFT, LFT etc should be 
obtained. 
o Intravenous thiamine: 100 mg IV with 50 % glucose solution is given. This 
treatment is given if hypoglycemia is even remote possibility, and thiamine is 
given with glucose in order to avoid eliciting Wernicke disease in malnourished 
o Naloxone(0.4mg ) is administered in case of opiate intoxication 
o Flumazenil can be given if benzodiazepine or hepatic coma is suspected  
o Correct any associated problem  like hypertension, hypoglycemia 
hyperthermia and hypoxia 
b) Give care of comatose patient: 
• Monitor vital signs 
• Provide adequate ventilation and oxygenation.


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o Correct any associated problem  like hypertension, hypoglycemia 
hyperthermia and hypoxia 
b) Give care of comatose patient: 
• Monitor vital signs 
• Provide adequate ventilation and oxygenation. 
• Maintain appropriate position and change position frequently 
• Catheterize and insert  nasogastric tube 
c)    Manage the primary cause of coma.


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Internal Medicine 
 
 522References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Acute 
confusional state and Coma, pages 1624-1630. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edtion Medicine, 
Loss of consciousness, pages 600-605.


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Internal Medicine 
 
 5235. Seizure and Epilepsy 
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define Seizure and epilepsy. 2. Describe the international classification of Seizure. 3. Understand   the epidemiology of Seizure and epilepsy. 
4. List the etiologies or risk factors for Seizure disorder. 
5. Identify the clinical manifestation of different types of Seizure disorders. 6. Understand the Evaluation and diagnostic approach to Seizure. 7.  Identify complications of Seizure. 8. List differential diagnosis for Seizure. 
9. Manage patients with Seizure or epilepsy.  
10. Understand status epileptics and its management. 
 
Definition: Seizure  is a paroxysmal event due to abnormal excessive discharge of cerebral 
neurons. The paroxysmal event may be subtle or dramatic. Depending on the distribution of the 
discharge, the manifestations may be: 
• Motor 
• Sensory 
• Autonomic or 
• Psychiatric manifestation.  
Epilepsy –  is a syndrome characterized by recurrent  (two or more) unprovoked seizure attacks, 
due to a chronic, underlying process in the brain. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy. 
International classification of seizures: 
Epileptic seizures can be classified in many different ways. Commonly used classification is the 
one developed by International League against Epilepsy.


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International classification of seizures: 
Epileptic seizures can be classified in many different ways. Commonly used classification is the 
one developed by International League against Epilepsy.  
1) Partial seizures: beginning locally 
a) Simple partial seizure: (with motor, somatosensory, autonomic or psychiatric symptoms  
b) Complex partial seizure   
c) Partial seizures with secondarily generalization


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Internal Medicine 
 
 5242) Generalized seizures  
a) Absence seizures ( petit mal ) 
b) Tonic – clinical seizures ( grand mal ) 
c) Myoclonic seizures  
d) Clonic seizures  e) Tonic Seizures  f) Atonic seizures  
3) Unclassified  
a) Neonatal seizures  b) Infantile spasm  
The basis for this classification is manifestations during seizure attack and EEG feature between attacks. This classification is useful in understanding underlying etiology, selecting 
appropriate treatment and understanding the prognosis of seizure type.  Epidemiology 
• Epilepsy is estimated to affect 0.5-4% of the population around the world.  
• The prevalence is said to be higher in developing countries.  
• Grand mal seizure account for 40 to 80 %of all types of epileptic seizures.  
• It is estimated that 5-10 % of the population will have at least one seizure attack in 
their life time, with the highest incidence occurring in early childhood and late adulthood. 
• In Ethiopia based on a study done by Teklehaymanot R
. the prevalence of active 
epilepsy is estimated to be 5.2/1000. Analysis of 468 epileptics seen in neurology clinics of Addis Ababa showed highest incidence in males aged 11-20 years. The 
commonest type of seizure was found to be grand mal seizure accounting for 60% of all cases.  
Etiology of seizure or risk factors:  The causes of epilepsy/seizure are vary greatly in different age groups and across different regions of the world


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commonest type of seizure was found to be grand mal seizure accounting for 60% of all cases.  
Etiology of seizure or risk factors:  The causes of epilepsy/seizure are vary greatly in different age groups and across different regions of the world 
• Idiopathic or cryptogenic : in which the cause is unknown,  accounts for the majority.   
• Genetic factor  (Family History)  
• Perinatal causes : perinatal asphyxia, birth trauma, perinatal infection  
• CNS infections : encephalitis, toxoplasmosis, cerebral malaria,


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Internal Medicine 
 
 525• Head trauma: penetrating head injury, depressed skull fracture, intracranial hemorrhage 
and prolonged post traumatic coma are associated with increased risk of having seizure 
disorder. 
• Neoplasms : metastatic or primary brain tumors  
• Vascular causes : Infarction or stroke, vascular malformations   
• Metabolic abnormalities : hyponatremia, hypo or hyperglycemia, Uremia  
• Inflammatory causes : Systemic lupus erythromatus  
• Degenerative diseases:  Alzheimer’s disease  
• Drugs:  Thephylline, Cocaine, Lidocaine  
 
Clinical features   
I. Partial Seizures:  these are seizures, which arise from localized region of the brain.  
a) Simple partial/focal seizures  
• These are seizure activities in which consciousness is not impaired.  
• Manifestation can be motor, sensory, autonomic or psychiatric.  
• Motor manifestation is usually focal clonic or tonic movement of angle of mouth, finger or 
thumbs. This seizure activity may spread ov er one side of the body (Jacksonian march) 
to involve larger body part. (E.g. the convulsive activity can start in the face, move to 
ipsilateral arm, and then to the leg) 
• The rest of manifestations include transient sensory abnormalities, flushing and sweating 
or odd feelings.  
b) Complex partial seizure  
• These are focal seizures activities accompanied by impairment of the patient’s ability to


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• The rest of manifestations include transient sensory abnormalities, flushing and sweating 
or odd feelings.  
b) Complex partial seizure  
• These are focal seizures activities accompanied by impairment of the patient’s ability to 
maintain normal contact with the environment. The patient is unable to respond appropriately to visual or verbal commands during the seizure, and has impaired recollection or awareness of ictal phase. 
• The seizure frequently begins with an aura , which may  manifest with hallucination ( e.g. 
Olfactory . visual , auditory or gustatory ) and complex illusions ( e.g. having experienced a new event ) 
• The start of the ictal phase is often a sudden behavioral arrest or motionless stare, which 
is often accompanied by automatism, which is involuntary automatic behavior (repeated complex activities like chewing, lip smoki ng, “picking movement” of the hands  , and 
display of emotions).


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Internal Medicine 
 
 526• They have also post-ictal confusion and transition to full recovery may take minutes to 
hours.  
 
c)  Partial seizure with secondary generalization 
• These are focal seizures, which evolve into a generalized seizure. These are usually 
tonic-clonic type and difficult to different iate from primary generalized tonic-clonic 
seizure.  
 
II. Generalized seizures  
There are seizure disorders which arise from bo th cerebral hemispheres simultaneously, with 
without any detectable focal onset.  
a) Absence seizure  : 
• It is characterized by sudden and brief lapses of consciousness without loss of postural 
control.  
• The seizure typically lasts for only few sec onds, consciousness returns as sudden as it 
was lost. 
• It usually manifests with blank stari ng and they may have also subtle motor 
manifestations like blinking of the eyes, chewing movements.  
• There is no post-ictal confusion.  
• The seizure may occur as many as hundreds of times per day  
• It is usually detected by unexplained daydr eaming and decline in school performance.  
• It usually begins in childhood (4- 8 yrs ) , and it often has a good prognosis, with 60-70 5 
of such patients will have spontaneous remission during adolescence.  
b) Generalized tonic clonic seizure (Grand mal) 
• Is the most common seizure type. 
• The seizure usually begins abruptly without warning (no aura or focal manifestations.)


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of such patients will have spontaneous remission during adolescence.  
b) Generalized tonic clonic seizure (Grand mal) 
• Is the most common seizure type. 
• The seizure usually begins abruptly without warning (no aura or focal manifestations.) 
• The ictal phase  is begins with tonic contraction of muscles throughout the body , which 
is responsible for loud moan or cry (due tonic contraction of the muscles of respiration and the larynx), tonic posturing, respiration is impaired and the patient falls  to the 
ground, and there may be  tongue biting due to tonic contraction of the jaw muscles. 
After 10 – 20 seconds the tonic phase evolves to clonic phase characterized by bilateral 
jerking clonic movement involving the whole body. This lasts for another 1 minute.


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Internal Medicine 
 
 527• The post-ictal phase  is characterized by unres ponsiveness, muscle flaccidity, 
excessive salivation and frothing of saliva which may cause stridorous breathing and 
partial airway obstruction. Bladder or bowel incontinence may occur at this point.  Patients gradually regain consciousness over mi nutes to hours, and during this transition 
there is typically a period of postictal confusion, headache, muscle ache and fatigue that can last for many hours.  
c) Atonic Seizures :  
• Are characterized by sudden loss of postural muscle tone, lasting 1 to 2 seconds.  
• Consciousness is briefly impaired. 
• It usually manifest as a head drop or nodding movement, while a longer seizure may 
cause the patient to collapse  
d) Myoclonic  seizure  :  
• Is characterized by a sudden and brief muscle contraction that may involve one part of 
the body or the entire body.  
• A normal common physiologic form of myoclonus is sudden jerking movement observed 
while falling asleep. 
• Pathologic myoclonus is most commonly seen with metabolic disorders, degenerative 
diseases of the CNS or anoxic brain injury .  
 
Complications 
• Status epilepticus  
• Accidents 
• Hypoxic brain damage  
• Mental retardation and impairment of intellectual function  
• Sudden death  
• Psychosocial (Social stigma).  
Diagnostic approach/Evaluation


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Complications 
• Status epilepticus  
• Accidents 
• Hypoxic brain damage  
• Mental retardation and impairment of intellectual function  
• Sudden death  
• Psychosocial (Social stigma).  
Diagnostic approach/Evaluation  
Patient’s history and physical examination can aid in the determination of whether or not a seizure or some other transient event was responsible for the patient’s symptoms  
History should include: - 
History of the event  
• Presence of any prodromal symptoms  
• Description of seizure by reliable observer


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Internal Medicine 
 
 528• Post ictal symptoms  
• Urinary incontinence, myalgia and tongue bite or oral lacerations are clues to the 
proper diagnosis. 
History   of suggesting cause and risk factors  
• Febrile convulsion (history of high grade fever )  
• CNS infections (current /Previous)  
• Head injury  
• Stroke  
• Developmental abnormality 
• Family history  
• Social history (like alcohol abuse)  
Physical examination:  features that should be looked for include  
• Skin for evidence of Neurofibromatosis  
• Organomegaly: Metabolic storage diseases  
• CVS/ carotid artery - stroke  
• Complete neurological exam. 
Investigations  
• EEG (Electroencephalography)  is most useful test in diagnosis of seizure disorder. 
It should be performed while the patient is asleep and awake. Abnormal EEG 
supports the diagnosis of seizure and may give information about the type of seizure. However abnormal EEG is not adequate for diagnosis of seizure and normal EEG 
can be found in epileptics.  
• Neuroimaging preferably MRI  : may help to see any space occupying lesion in the 
brain 
• Other routine laboratory assessment  may be required in management of patients 
with epilepsy (CBC. Urinalysis, serum glucos e, liver function test, renal function test 
electrolytes, toxicological screening).  
Differential Diagnosis for Seizure  
• Syncope 
• Psychogenic seizure (hysteric conversion)  
• Transient Ischemic attack 
• Migraine


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Internal Medicine 
 
 529Management:  
Goal of therapy: 
• Complete control of seizure  
• Prevent development of complications and socioeconomic consequences.  
Treatment of seizure includes:-  
1. Treatment of underlying condition  
• Metabolic disorders such as hypoglycemia , hyponatremia or drug intoxication should 
be corrected   
• Structural CNS lesion lie tumors may be removed surgically.   
2. Avoidance of precipitating factor  
• Maintain normal sleep schedule  
• Avoid taking  excess alcohol  
• Reduce stresses using  , physical Exercise , meditation or counseling  
3. Suppression or control of recurrent seizure  
Antiepileptic drug therapy (AEDT)   
• The Goal of antiepileptic therapy is to achieve complete control of seizure with no or 
minimal side effects, preferably using single agent and easy dosing schedule  
When do we start anti epileptic drugs?  
• Recurrent seizure of unknown cause or a known cause that cannot be 
reversed  
• Single seizure due to  : 
o Identified CNS lesion (tumor, infection, trauma)  
o With abnormal neurologic exam  
o Presenting as status epilepticus  
o With post-ictal Todd’s paralysis 
o With strong family history of seizure disorder 
o With abnormal EEG


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Internal Medicine 
 
 530• Note:  anticonvulsant therapy is not often initiated in patients with a single, 
unprovoked convulsion, a normal neurologic examination, and a normal 
neuroimaging study and EEG unless they  experience a second seizure. 
General principles :  
• An attempt is usually made to prevent subsequent seizure using a single agent , in order 
to limit side effects.  
• The drugs should be administered in progressive dose until seizure control has been 
achieved or until drug toxicity occurs.  
• Only if monotherpay fails should a second drug be added to the patient’s regimen. If 
control is achieved, then the first agent might be carefully withdrawn. 
• A number of drugs are available for treatment of epilepsy and the choice of medication is 
based on the seizure type   
 Table VIII-5-1 Selection of antiepileptic drugs  
 Primary GTCS  Partial  Absence  Atypical absence 
, myoclonic, 
Atonic  
First line  Valproic acid  
Lamotrigine Carbamazepine  
Phenytoin 
Valproic acid  Valproic acid  
Ethusuximide Valproic acid   
Second line  
  
 Phenytoin 
Carbamazepine  Phenobarbitone  Topiramate  Phenobarbitone Lamotrigin Clonazepam Lamotrigin Clonazepam Topiramate  
i. Phenobarbitone  
• In developing countries, Phenobarbitone is the drug of choice for the control of partial 
and GTC seizures, due to the wide availability and cheaper cost of the drug.  
• Its efficacy is quite acceptable in comparison to most of the AEDS, but it has some side


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and GTC seizures, due to the wide availability and cheaper cost of the drug.  
• Its efficacy is quite acceptable in comparison to most of the AEDS, but it has some side 
effects that might interfere with compliance. These side effects have to be explained to 
the patient and his family early on.  
•  This drug is available in the following dosage forms: 15, 30, 60 and 100 mg tablets.


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Internal Medicine 
 
 531Dosage:  
• The usual starting dose for adults is 60 PO daily. If seizure is not controlled the dosage 
may be increased gradually at intervals of no less than 2-3 weeks to a maximum dose of 
200 mg PO BID.  
Common side effects of Phenobarbitone  
• Fatigue , Listlessness , depression  
• Insomnia (especially in children)  
• Distractibility and short attention span (especially in children) and Hyperkinesia , 
Irritability  
• Poor memory  
• Decreased libido  
In cases of treatment failure or poor control with maximum tolerable doses of drug, a second AEDS is often added to the regimen. The addition of a second drug is associated with worsening of adverse effects; hence care should be taken, before one decides to add a second drug to the original regimen. 
ii. Phenytoin: is the usual prescribed as a second line drug in resource limited settings like 
ours mainly because of its availability and cost.  
Dosage :  
• 100 mg PO BID or TID , which may be gradually increased to a maximum of 200 mg PO 
TID ( i.e. 600 mg daily ) 
Side effects: 
• CNS : nystagmus , ataxia  
• Gingival hyperplasia  
• Coarsening of facial feature 
• Toxic hepatitis and liver damage  
iii. Carbamazepine : is also available in Ethiopia. It is often given for the treatment of partial 
seizure  
Dosage:  a low initial dosage with gradual increase is advised. 
• 200 mg Po BID and gradually increase the dos age by 2OO mg every week until the best


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seizure  
Dosage:  a low initial dosage with gradual increase is advised. 
• 200 mg Po BID and gradually increase the dos age by 2OO mg every week until the best 
response is achieved or maximum dose of 1600 mg daily. 
Side effects  
• Aplastic anemia 
• Dizziness drowsiness


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Internal Medicine 
 
 532• Skin rash  
• Transient diplopia 
When to stop antiepileptic drugs? 
• It is common practice to continue treatment until the patient has been seizure free for at 
least 3 years.  
• Thereafter, consideration of drug withdrawal is based on a number of factors like:-  
o The ease with which control was achieved starting from the time of AED drug 
initiation.  
o The type of seizure  
o The presence of other neurological co-morbidity e.g. mental retardation, focal 
neurological deficit.  
• The probability of relapse after stopping treatment is somewhere around 10-40%  
• It is not known whether remissions for 3 or more years consist of “cure” or “ control” and 
so drug withdrawals have to be gradual, over a period of months to minimize the risks of 
relapse.  
• Most relapses occur within a year of discontinuing of medications. The more severe and 
long lasting a patient’s active epilepsy before remission, the greater the risk of relapse.  
When to refer patients to a neurologist or tertiary level hospital   
• Failure to respond to treatment  
• Recurrence of previously controlled seizure  
• Change in clinical pattern of seizure  
• Appearance of previously absent symptoms/sign  
• Development of side effects of a drug  
4. Managing psychosocial issues  
• Social stigma  : avoid misconceptions in the public through health education 
• Psychiatric problems  : depression , psychosis  ,anxiety should be treated


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• Development of side effects of a drug  
4. Managing psychosocial issues  
• Social stigma  : avoid misconceptions in the public through health education 
• Psychiatric problems  : depression , psychosis  ,anxiety should be treated  
• Social problems  (education, employment, marriage): encourage patients to go 
school /work to get married and establish family. 
• Educate Patients and families:  about the diseases and what precautions patient 
should take.  
 Seizure /epilepsy can be controlled by drugs  
 Drug discontinuation creates problem and follow up is important  
  Advice Patients to avoid


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Internal Medicine 
 
 533¾ Alcohol/ other drugs or substances like “Chat”                                                         
¾ Heights  
¾ Cooking with open fire 
¾ Machineries that may cause  injury  
¾ Swimming  
¾ Driving  
 What should families or attendants do during active seizure  
¾ No traditional treatment is beneficial  
¾ To be calm  
¾ Loosen patient’s clothing 
¾ Keep from injury  
¾ Turn head to side  
¾ Do not insert anything into  the month  
 
Surgical Therapy: Patient’s refractory to medical control of seizure may benefit from surgery 
to control the epilepsy. Surgical interventions include  
• Temporal lobe resection 
• Corpus callosum sectioning   
Status epilepticus  
• A condition characterized by continuous or repetitive discrete seizure with 
impairment of consciousness during interictal period, which lasts for more than 30 
minutes. It is a medical emergency  
It can be caused or precipitated by  
• Non compliance with AED  
• CNS infections  
• Metabolic derangement  
• Tumors  
• Trauma  
• Stroke 
• Refractory epilepsy


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Internal Medicine 
 
 534Clinical features: 
Generalized status epilepticus is obvious when t he patient is having over convulsion, however 
after 30-35 min of uninterrupted seizure, the signs may become increasingly subtle. Patients 
may have mild clonic movement of only the fingers, or fine, rapid movement of the eyes. Complications of Status epilepticus: 
• Aspiration  
• Hypoxia  
• Metabolic acidosis  
• Hypotension 
• Hyperthermia 
• Rhabdomyolysis and associated myoglobinuria  
• Multiple physical injures including vertebral bone fracture 
• Irreversible neuronal injury   
 
Management  
1. Emergency supportive measures  
Keep Airway patent and maintain breathing  
Secure IV line and take blood for laboratory investigation 
Give glucose IV with Thiamine   
2. Control the seizure  with anticonvulsant  
1
st step: Lorazepam 0.1 mg/kg IC at a rate of 2mg/min or Give diazepam IV 5- 10 mg IV  
2nd step: Phenytoin 20 mg/kg IV at a rate of 50 mg /min if seizure continues  
3rd step: Phenobarbital 20 mg/kg IV at a rate of 50 -75 mg/min, if seizure still continues  
4th Step: General anesthesia with Medazolam, Pr opofol or pentobarbitol, if seizure becomes 
refractory  
In resource limited setting Diazepam 5-10 mg IV is given 2-3 times, and if the seizure is not 
controlled Phenytion 1000 mg PO is given through NG tube. Phenobarbitone can also be used. 
3. Treat the precipitating cause (metabolic abnormalities or infections)


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controlled Phenytion 1000 mg PO is given through NG tube. Phenobarbitone can also be used. 
3. Treat the precipitating cause (metabolic abnormalities or infections)  
4.  Give maintenance antiepileptic drug: after the acute condition is controlled.


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Internal Medicine 
 
 535References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Seizure 
and Epilepsy, pages 2357-2371. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Seizure, pages 626-628.


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Internal Medicine 
 
 5366. Parkinson’s Diseases and other movement disorders  
 
Learning objectives: at the end of this lesson the student will be able to : 
1. Define Parkinsonism and Parkinson’s disease. 2. List the etiologies or Parkinsonism. 3. Understand   the epidemiology and risk factors for Parkinsonism. 
4. Describe the clinical manifestation of Parkinson’s diseases. 
5. Understand the principles of management of Parkinson’s diseases.  
6. Understand the basic clinical features of other movement disorders.  
 
Parkinsonism:  
Definitio n: Parkinsonism is a clinical syndrome characterized by :- 
• Bradykineisa : slowness and paucity of movement   
• Tremor:  This occurs at rest  
• Rigidity  
• Snuffling gate and  
• Flexed posture  
 Etiologies: 
1. Parkinson’s Diseases: It is sporadic and idiopathic with unknown etiology.  
• Is the commonest cause of Parkinsonism accounting for 75 % of all cases?  
• It is characterized by degeneration of cells in the substantia nigra,  which causes 
deficiency of dopamine (a neurotransmitter) in the CNS, leading to a series of changes in motor control pathways. These degenerative changes are believed to be due to accumulation of the presynaptic protein α-synuclien. 
2. Other known causes : account for 25 % of all cases   
a) Familial ( primary Parkinson’s diseases ) 
b) Other neurodegenerative diseases 
• Shy-Drager  syndrome 
• Motor neuron disease with PD features  
• Dementia with Lewy bodies


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2. Other known causes : account for 25 % of all cases   
a) Familial ( primary Parkinson’s diseases ) 
b) Other neurodegenerative diseases 
• Shy-Drager  syndrome 
• Motor neuron disease with PD features  
• Dementia with Lewy bodies 
• Progressive supranuclear palsy 
• Wilson’s disease


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Internal Medicine 
 
 537• Huntington’s diseases 
c) Miscellaneous acquired conditions 
• Vascular parkinsonism ( stroke affecting the extrapyramidal structures) 
• Normal pressure hydrocephalus  
• Cerebral palsy 
• Repeated trauma:“ dementia puglistica” with parkisonian features ( e.g. seen in 
professional boxers like Mohamed Ali ) 
• Infectious : post encephalitis PD , Neurosyphilis 
• Hypothyroidism or pseydohypoparathyriodism 
• Drugs:  
• Neroleptics ( antipsychotics e.g. Haloperidol ,Chlorpromazine  
o Antiemetics : metoclopromide ,  
o Methyldopa 
o Valproic acid  
• Toxins : Cyanide , Methanol , Carbon monoxide, manganese  
 Epidemiology: 
• PD affect > 1 million people in US ( 1 % of those > 55 years ) 
• The peak age of onset is the 60s ( range is 35-85 years  )  
• Familial PD tend to have an earlier age of ons et ( typically before the age of 50 year) 
 
Risk factors for Parkinsonism include  
• Positive family history  
• Male gender,  
• Head injury  
• Exposure to pesticides  
• Consumption of well water  
• Rural living  
Clinical Features  
A diagnosis of PD can be made with some confidence in patients with some confidence in 
patients who present with at least 2 of the three cardinal signs –rest tremor, rigidity and 
bradykinesia


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Internal Medicine 
 
 538Motor Features  
Resting tremor:   
• It is present in 85 % of patients with true PD, and a diagnosis of PD is difficult when 
tremor is absent. 
• It starts unilaterally and has a gradual onset, affecting first distally involving the digits 
and wrist where it may present with “pill –rolling” character.  
• Tremor usually spreads prox imally, ipsilaterally and occasionally to the leg, before 
crossing to other side after a year or two. 
• It may appear later in the lips, tongue, and jaw but spears the head. 
Bradykinesia/akinesia:  
• It is the most disabling feature which interferes with all aspects of daily living. Patients 
have trouble in walking, rising from seated posit ion, turning over in bed, dressing etc.  
• Fine motor movement is also impaired as  evidenced by decreas ed manual dexterity and 
hand writing ( micrographia ) 
• Soft speech (hypophonia) is the other of bradykinesia. 
• Masked face , decreased eye blinking 
Rigidity: 
• Is felt as a uniform resistance to a passive movement about a joint throughout the full 
range of motion. Brief regular interruption of resistance during passive movement may 
give rise to“cogwheels rigidity. 
Gait disturbance:  
• Patients have shuffling short steps,  and a tendency to turn en bolc ,  
• Festinating gait,  a typical feature of Parkinsonism, result from a combination of flexed


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give rise to“cogwheels rigidity. 
Gait disturbance:  
• Patients have shuffling short steps,  and a tendency to turn en bolc ,  
• Festinating gait,  a typical feature of Parkinsonism, result from a combination of flexed 
posture and loss of postural reflux, which causes the patient to accelerate in an effort to catch up with the body’s centre of gravity. 
• Freezing of gait :  is a feature of more advanced PD, occurs commonly at the onset of 
locomotion (start hesitation), when attempting to change direction to turn around and upon entering narrow space such as a doorway. 
• Abnormalities of balance and posturing:  tends to increase as the disease progress 
• Stooped posture : flexion of the head, stooping and tilting of the upper trunk, and 
tendency to hold the arm in flexed posture while waking is common.  
• In advanced diseases postural instability may lead to frequent falls and injuries.


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Internal Medicine 
 
 539Non motor features: 
• Loss of sense of smell  (anosmia) 
• Sensory abnormalities  often manifest as distressing sensation of inner restlessness  
and aching pain in the muscles of the extremities which often develops as anti 
Parkinson’s medications are wearing  off. 
• Sleep disorders  are common in PD, which may manifest as day time drowsiness 
frequent napping. This may result from disrupted sleep from night time worsening of symptoms and difficulty of turning over in bed  
• Autonomic dysfunction: may manifest with orthostatic hypotension, constipation 
urinary urgency and frequency , excessive sweating  
Neuropsychiatric System  
• Depression  affects approximately half of patents  
• Anxiety  disorders  
• Cognitive abnormalities : affect many patients and it may manifest with difficulty of 
doing complex tasks, long term planning, and memorizing or retrieving new information. 
Dementia is 6X more common in PD patients than their age matched controls. 
• Psychotic symptoms : affect 6 – 40 % of patients with PD, visual hallucination are 
common symptoms, and depression and dement ia are risk factors for developing 
psychiatric symptoms. 
Treatment  
• The goal of therapy in PD is to maintain function and quality of life and to avoid drug 
induced complications  
• Parkinson’s disease is a progressive di sease, therefore management protocols vary 
depending on the patient symptoms and the extent of functional impairment.


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induced complications  
• Parkinson’s disease is a progressive di sease, therefore management protocols vary 
depending on the patient symptoms and the extent of functional impairment. 
1. Pharmacotherapy of motor symptoms: 
• Therapy to control motor symptoms should be initiated as soon as the patient’s 
symptoms begin to interfere with the quality of life.  
Early Parkinson’s disease:  
a) Selegilline  is selective and irreversible mono aminoxide (MAO) inhibitor.  
• It may slow the clinical progression of Parkinson’s diseases and delay the need 
for other medication. This drug has minimal effect on symptoms when used as monotherapy or as an adjuvant to Carbidopa/levodopa.


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Internal Medicine 
 
 540• Selegilline is used as an initial therapy or added to alleviate tremor of 
Carbidopa/levodopa associated wearing effect  
Dose:   5 mg PO with breakfast and lunch  
b) Dopamine agonists :  have direct post synaptic effect on do dopamine receptors. 
• Dopamine agonist monotherpay is well tole rated and significantly reduced the risk of 
later treatment –related complications such as motor fluctuation and dyskinesia 
associated with Carbidopa/levodopa treatment. 
Non Ergot alkaloids: 
o Rupinirole:  Initial dose 0.25 mg Po TID  to maximum target dose as 
monotherapy is 12-24 mg/day 
o Parmipexole  ; Initial dose 0.125 mg PO TID maximum target dose as 
monotherapy is 1.5-4.5 mg /day 
Ergot alkaloids  
o Pergolide ; Initial dose 0.05 mg PO TID to maximum dose 1.5-6 mg /day 
o Bromocriptine : Initial dose 1.25 mg Po BID or TID, to maximum target 
dose as monotherapy 7.5-15 mg/day 
• When dopamine agonists are used as monotherapy, higher doses are required to control 
symptom. However the dose should be titrated gradually.  
• Most patients require the addition of levodopa or another agent, within 1-3 yrs of 
initiating dopamine agonists 
• Older patients and those with akinetic rigidity have a low risk of motor complications and 
dyskinesia, and may be satisfactorily treated with levodopa as an initial therapy. 
Advanced Therapy 
c) Levodopa/Carbidopa Formulation (Sinemet®, Atamet®)


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dyskinesia, and may be satisfactorily treated with levodopa as an initial therapy. 
Advanced Therapy 
c) Levodopa/Carbidopa Formulation (Sinemet®, Atamet®) 
• Levodopa : is converted to dopamine by presynaptic neuron and therefore increase the 
amount of neurotransmitter available to the post synaptic dopamine receptor. 
• Carbidopa:  blocks systemic/peripheral conver sion of levodopa to dopamine, thereby 
decreasing the undesirable systemic effects of levodopa such as nausea and orthostatic hypotension. 
Dose:  
• Carbidopa/levodopa  IR 25/100 mg Initial dose: t/2 tab PO TID, to maximum target 
dose of 3-6 25/100 mg tabs /day (i.e.  1 -2 tabs PO TID)  
• Carbidopa/levodopa  CR 50/200 mg tabs : dose 1tab BID or TID


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Internal Medicine 
 
 541The dosage of these drags should be escalated gradually 
Wearing- off effects:  management of Parkinson’s disease becomes increasingly difficult 
as the disease progresses. Late treatment related complications include.  
• Dsykineisa:  refers to choreiform and dytonic movements that occur as a peak 
dose effect or at the beginning or end of the dose.  
• Motor fluctuation:  (on and off phenomenon) these are wide random swings in 
the patient’s mobility or exaggerated ebb and flow of Parkinsonian signs, experienced by many patients between doses of anti-Parkinson medication. 
More than 50 % of patients with PD treated over five years with levodopa will develop 
these complications  
d) Levodopa Augmentation :  
i) Catechol O-methytransferase (COMT) inhibitors  
• Estacapone and tolcapone offer augmentation of the effect of levodopa by 
blocking enzymatic degradation of levodopa and dopamine. 
• These drugs are used in conjunction with Carbidopa/levodopa  , they alleviate the 
wearing off symptoms  
ii) Anti-cholinergics  :are given as adjuncts to  dopaminomimetic therapy 
• They are useful in controlling resting tremor and dystonia  
• Bezhexol is a drug which is available and commonly used 
iii)  Amantadine  : has anti-cholinergic and dopaminomimetic properties  
• It helps to reduce drug induced dyskinesia  
• Can be effective early in the course of the diseases, or as an adjunct therapy later


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iii)  Amantadine  : has anti-cholinergic and dopaminomimetic properties  
• It helps to reduce drug induced dyskinesia  
• Can be effective early in the course of the diseases, or as an adjunct therapy later 
in the diseases course  to help “ smooth out “ motor function  
 
2. Neuroprotective therapy  
Reducing the progression of PD through neuroprotective or restorative therapy is a major focus 
of research. Some of the neuroprotecitve treatment trails arte  
• Non steroidal anti-inflammatory agents  
• Estrogens replacement therapy   in post menopausal women  
• Selegilline therap y delays the need for levodopa therapy by 9 -12 months in newly 
diagnosed patients. Studies demonstrated that patients who remain on Selegilline for 7 yrs experienced slower motor decline.


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Internal Medicine 
 
 5423. Therapy of non motor symptoms  
• Insomnia due to nocturnal akinesia  : treated with night time supplemental dose of 
Carbidopa /levodopa 
• Depression :  Responds to anti depressants like Amitriptyline  
• Psychotic patients : first remove anticholinergics and amantadine if the patient is taking. 
Reduce the dose of dopaminomimetic if the patient is not responding. If still the patient 
has psychotic symptoms and signs, start antip sychotics with minimal extrapyramidal side 
effects. 
• Dietary manipulation  : limiting  protein intake during the day  may improve levodopa’s 
efficacy 
• Physical therapy  and an exercise program help to optimize mobility. 
 Surgical therapy 
• Pallidotomy , and thelamothomy  ; may be a therapeutic option for refractory 
Parkinson’s diseases 
• Neurotransplantation : Transplantation of fetal substantia nigra tissue or cells. 
 
Other movement disorders  
Hyperkinetic disorders: these are disorders associated with increased movement.  
1. Tremor  
a) Benign essential tremor is characterized by  posture related 5-9 Hz oscillation of hands 
and forearms that impairs performance of fine motor tasks. 
• This type of tremor is familial and may be accompanied by titubation (head 
tremor/bobbing  ) 
• Consumption of alcohol may temporarily suppress the tremor: stress , caffeine or 
sleep deprivation may exacerbation the condition  
• β-adrenergic blocking agents are effective in controlling tremor.


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tremor/bobbing  ) 
• Consumption of alcohol may temporarily suppress the tremor: stress , caffeine or 
sleep deprivation may exacerbation the condition  
• β-adrenergic blocking agents are effective in controlling tremor. 
a) An Action (kinetic) tremor is evident when the patient moves his or her arms; there may 
be a relatively mild accompanying postural and intention component.  • Clonazepam treatment can be useful. 
2. Myoclonus 
Definition:  a brief, lightning-like contraction of a muscle or group of muscles.


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Internal Medicine 
 
 543Etiology: 
• Metabolic derangements (e.g. uremia) 
• Degenerative diseases (e.g. Alzheimer’s) 
• Slow virus infections (Creuzfeldt-Jakob disease, subactue sclerosing panencephalitis) 
• Severe closed head trauma 
• Hypoxic-ischemic brain injury 
Signs and symptoms:   
• Myoclonus may occur normally as a pers on falls asleep (nocturnal myoclonus).  
• Common hiccup (singultus) is a form of myoclonus affecting the diaphragmatic muscles. 
• Action myoclonus: is a myoclonus that increases with intended movements, It occurs  
typically after brain injury;  
• Palatal myoclonus is a continuous, rhythmic contraction of posterior pharyngeal 
muscles. 
 
Treatment:   
• Correct underlying metabolic abnormalities.  
• Clonazepam 0.5-2 mg PO. TID or valproate may be effective. 
 
3. Tics 
• Brief, rapid, simple or complex involuntary movements, which are stereotypical and 
repetitive, but not rhythmic .  
• Simple motor tics  (e.g. blinking) often begin as nervous mannerisms in childhood or 
later, and disappear spontaneously.  
• Complex motor tics often resemble fragments of normal behaviour such as touching, 
smelling and jumping. 
• Simple phonic tics  include throat clearing, sniffing and grunting and complex phonic 
tics include the repetition of words and coprolalia. 
• Tourette’s syndrome : a complex type of tics disorder characterized by multiple motor 
and one or more phonic tics that may occur many times a day, nearly every day for more than 1 year.


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tics include the repetition of words and coprolalia. 
• Tourette’s syndrome : a complex type of tics disorder characterized by multiple motor 
and one or more phonic tics that may occur many times a day, nearly every day for more than 1 year. 
Treatment  
• Education of patients and their family 
• Drugs: Clonidine, Haloperidol


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Internal Medicine 
 
 5443. Chorea and Athetosis 
Definition:  
• Chorea:  is brief, purposeless involuntary movements of the distal extremities and face, 
which may merge imperceptibly into purposeful or semi purposeful acts that mask the 
involuntary motion. 
• Athetosis:  is writhing movements, often with alternating postures of the proximal limbs 
that blend continuously into a flowing stream of movement. Both often occur together (choreoathetosis). 
Etiology:  
• Huntington’s disease (see below) 
• Thyrotoxicosis 
• SLE 
• Drugs (antipsychotics) 
4. Chorea gravidarum   
• It is choreiform movement occurring during pregnancy, often in patients with a history of 
rheumatic fever.  
• Chorea usually begins during the first trimes ter and resolves spontaneously by or after 
delivery. Rarely, a similar disorder occurs  in women taking oral contraceptives.  
• Treatment consists of sedation with barbiturates, because other drugs may harm the 
fetus. 
5. Hemiballismus   
• It is violent, continuous proximal limb flinging movements confined to one side of the 
body, usually affecting the arm more than the leg.  
• It is caused by a lesion, usually an infarct, in the region of the contralateral sub-thalamic 
nucleus of Luys.  
• Differential diagnosis includes acute hemichorea, usually due to tumor or infarct of the 
caudate nucleus, and focal seizures. Although disabling, hemiballismus is usually self-
limited, lasting 6 to 8 wk.


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nucleus of Luys.  
• Differential diagnosis includes acute hemichorea, usually due to tumor or infarct of the 
caudate nucleus, and focal seizures. Although disabling, hemiballismus is usually self-
limited, lasting 6 to 8 wk.  
• Treatment with antipsychotics is often effective. 
6. Huntington’s Disease 
Definition:  also called Huntington’s chorea, chronic progressive chorea or hereditary chorea. 
It is an autosomal dominant disorder characterized by choreiform movements and progressive 
intellectual deterioration, usually beginning in middle age.


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Internal Medicine 
 
 545Etiology:  Genetically determined.  
 
Signs and symptoms:  Develop insidiously.  
• Dementia or psychiatric disturbances may precede the disease or develop during the 
course (anhedonia, asocial behaviour).  
• Motor manifestations: flicking movements of the extremities, a lilting gait, motor 
impersistence (inability to sustain a motor act, such as tongue protrusion), facial grimacing, ataxia, and dystonia. Disorder is always progressive; patients ultimately lose physical and mental abilities to care for themselves. 
Treatment:   
• No treatment for the underlying cause.  
• Antipsychotics may control behaviour problems (e.g. chlorpromazine 100-900 mg/d PO 
or haloperidol 10-90 mg/d PO). 
 
7. Dystonia 
Definition:  Sustained abnormal posture and disruptions of ongoing movement, resulting from 
alterations in muscle tone; it is classified as generalized, focal or segmental: 
Generalized dystonia (dystonia musculorum deformans)   
• It is a rare progressive syndrome characterized by movements that result in sustained, 
often bizarre postures.  
• Symptoms usually begin in childhood with inversion and plantar fixation of the foot while 
walking.  
• Generalized dystonia is often hereditary.  
• In its most severe form, the disorder can be relentlessly progressive. Severely affected 
patients may become twisted into grotesque fixed postures.  
• Mental function is usually preserved.


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• Generalized dystonia is often hereditary.  
• In its most severe form, the disorder can be relentlessly progressive. Severely affected 
patients may become twisted into grotesque fixed postures.  
• Mental function is usually preserved. 
 
Focal dystonia  affects a single body region. Rarely, dystonic movements spread to an adjacent 
region (segmental dystonia),  and even more rarely, the process generalizes.


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Internal Medicine 
 
 546Treatment:   
Treatment is often unsatisfactory. 
• For generalized dystonia,  high-dose anticholinergics and/or the dopamine-depleting 
drug reserpine 0.1-0.6 mg/d PO are most often used. Levodopa and carbamazepine 
benefit a few patients.  
• For focal or segmental dystonias  or for generalized dystonia that severely affects 
specific body regions, local injection of purified botulinum a toxin is the treatment of choice. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, 
Parkinson’s diseases and other movement disorders, pages 2406-2417. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edtion Medicine, 
Movement disorders, pages 629-633.


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Internal Medicine 
 
 5477. Peripheral neuropathy 
 
Definition:  A general term indicating peripheral nerve disorder of any cause.  
 Classification of neuropathies  
Neuropathies may be classified based on: 
1. The type of symptoms and signs  : Sensory , Motor , Autonomic , Or any combination  
2. Distribution  
• Mononeuropathy:  single nerve affected  
• Multiple mononeuropathy( mononeuritis multiplex) : two or more nerves in separate 
areas affected 
• Polyneuropathy:  many nerves simultaneously affected 
3. Course : ( acute , subacute or chronic )  
4. Nerve conduction test (NCT ):  Axonal or Myelin sheath  
 Etiology: 
Table VIII-7-1 Etiologies of neuropathies based the predominant symptoms or signs    
 Causes  
Neuropathy  Acute  Subacute of Chronic  
  Sensory neuropathy   
 
   
Diabetes mellitus         Leprosy 
Uremia 
Alcohol abuse 
Vitamin deficiency: Vit B1, B6, B12 
HIV 
Hereditary neuropathies  
Drugs : Cisplatin , Phenytoin 
Paraneoplatic syndrome       
 
Motor neuropathy     Guillain-Barre syndrome Porphyria  Critical illness Poliomyelitis  Chronic inflammatory demyelinating polyneuropathy ( CIDP ) Lead intoxication


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Internal Medicine 
 
 548Sensorimotor 
neuropathy  
 
    
Diabetes mellitus  
Uremia 
Vasculitis  
Hypothyroidism  
Paraprotinemias 
CIDP 
Drugs  
Toxins  
 
Autonomic neuropathy   Guillain-Barre syndrome Porphyria  
 Diabetes mellitus  
Amyloidosis Familial dysautonomia  
 Etilogoies based on distribution  
1. Mononeuropathy:  
• Trauma : most common cause of localized injury to single nerve 
• Focal neuropathy : violent muscular activity, forcible overextension of joint, repeated 
small traumas 
• Pressure or entrapment paralysis:  affects superficial nerves at bony prominences or 
at narrow canals; also from tumors, bony hyperostosis, casts, crutches, prolonged 
cramped postures. 
• Haemorrhage  into a nerve, exposure to cold or radiation 
• Tumor invasion 
Multiple mononeuropathy ( mononeuritis multiplex) : 
• Collagen vascular disorders  (polyarteritis nodosa, SLE, Sjörgen’s, RA) 
• Sarcoidosis 
• Metabolic diseases  (diabetes, amyloidosis) 
• Infectious diseases  (e.g. HIV, leprosy) 
Polyneuropathy:  
• Acute febrile diseases: from toxin (e.g. diphtheria), autoimmune reaction (Guillain-Barré 
syndrome) 
• Immunization 
• Toxic agents: barbital, phenytoin, heavy metals, carbon monoxide etc.


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 549• Nutritional deficiencies, metabolic disorders: B vitamin deficiency, hypothyroidism, 
porphyria, sarcoidosis, amyloidosis, uremia, diabetes mellitus. 
• Malignancy 
 
Signs and symptoms : 
Specific mononeuropathies: 
Are characterized by pain, weakness and paresthesias in distribution of affected nerve; multiple mononeuropathy is asymmetric; nerves may be involved all at once or progressively. 
Ulnar nerve palsy:   
• Often caused by trauma to nerve in the ulnar groove of the elbow, or due to compression 
at cubital tunnel;  
• Paresthesia and sensory deficit in 5
th and medial half of the 4th fingers is a common 
finding.  
• Thumb adductor, 5th finger abductor and interossei muscles are weak and atrophied.  
• Claw hand deformity may occur. 
Carpal tunnel syndrome:   
• Is compression of median nerve in volar aspect of wrist, may be unilateral or bilateral.  
• Paresthesia in radial-palmar aspect of hand and pain over the wrist and palm; pain may 
be more severe at night.  
• Sensory deficit in palmar aspect of first three fingers may follow; thumb abduction and 
opposition may become weak and muscles atrophied. 
• For all, conservative treatment should be tried first, with surgical exploration taking place 
if no success or worsening of symptoms occurs. 
Radial nerve palsy:  
• Is due to compression of nerve against humerus;  
• Weakness of wrist and finger extensors (wrist drop),  
• Sensory loss over dorsal aspect of 1st finger.


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if no success or worsening of symptoms occurs. 
Radial nerve palsy:  
• Is due to compression of nerve against humerus;  
• Weakness of wrist and finger extensors (wrist drop),  
• Sensory loss over dorsal aspect of 1st finger. 
Peroneal nerve palsy:   
• It is usually caused by compression of nerve against fibular neck.  
• Weakness of foot dorsiflexion and eversion (foot drop) occurs;  
• Sensory deficit over anterolateral aspect of lower leg and dorsum of foot or web space 
between 1st and 2nd metatarsals can occur.


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Internal Medicine 
 
 550Specific polyneuropathies:   
• Are relatively symmetric, often affecting sensory, motor, and vasomotor fibers 
simultaneously.  
• They may affect the axon cylinder or the myelin sheath and, in either form, may be acute 
(e.g. Guillain-Barré syndrome) or chronic (e.g., renal failure). 
Diabetic neuropathy   
Sensory polyneuropathy  
• Develops slowly over months or years.  
• Sensory abnormalities are common, usually starting in the lower extremities, more 
severe distally than proximally. 
• Peripheral tingling, numbness, burning pain, or deficiencies in joint proprioception and 
vibratory sensation are often prominent.  
• Pain is often worse at night and may be aggravated by touching the affected area or by 
temperature changes.  
• In severe cases, there are objective signs of sensory loss, typically with stocking-and-
glove distribution.  
• Achilles and other deep tendon reflexes are diminished or absent.  
• Painless ulcers on the digits or Charcot's joints may develop when sensory loss is 
profound. Sensory or proprioceptive deficits may lead to gait abnormalities.  
Motor neuropathy : results in distal muscle weakness and atrophy.  
Autonomic neuropathy : Autonomic nervous system may be additionally or selectively 
involved, leading to: 
• Nocturnal diarrhoea 
• Urinary and faecal incontinence and impotence (erectile dysfunction)  
• Postural hypotension.  
• Vasomotor symptoms vary. The skin may be paler and drier than normal, sometimes


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involved, leading to: 
• Nocturnal diarrhoea 
• Urinary and faecal incontinence and impotence (erectile dysfunction)  
• Postural hypotension.  
• Vasomotor symptoms vary. The skin may be paler and drier than normal, sometimes 
with dusky discoloration; sweating may be excessive.  
• Trophic changes (smooth and shiny skin, pitted or ridged nails, and osteoporosis) are 
common in severe, prolonged cases.  
Polyneuropathy due to nutritional deficiencies:   
• Is commonly seen among alcoholics and the malnourished patients.  
• Wasting and symmetric weakness of the distal  extremities is usually insidious but can 
progress rapidly, sometimes accompanied by sensory loss, paresthesia, and pain.


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Internal Medicine 
 
 551• Aching, cramping, coldness, burning, and numbness in the calves and feet may be 
worsened by touch.  
• Multiple vitamins may be given when etiology is obscure, but they have no proven 
benefit.  
Diagnostic approach to neuropathies  
• History and physical examination  
• CBC:  e.g. megaloblasts in pernicious anaem ia may suggest Vit-B12 deficiency or 
stippled RBCs indicate lead poisoning. 
• LFT, AP,  
• Renal function test: creatinine to assess for renal function test   
• glucose  
• Urine analysis  
• Serum protein and electrophoresis  (e.g. multiple myeloma) 
• TFT if suspicion of thyroid dysfunction 
• Electromyography, nerve conduction velocity tests  
• Muscle biopsy, sural nerve biopsy  as needed 
Treatment:   
• Treatment of the underlying cause or system ic disorder; recovery is usually slow 
• Traumatic lesions with complete transection of nerve require surgery.  
• Entrapment neuropathies may require corticosteroid injections or surgical 
decompression. Physical therapy and splints  reduce the likelihood or severity of 
contractures. 
• If impaired sensation renders the patient prone to injury, protective measures should be 
taken. 
• Autonomic insufficiency is difficult to manage ; orthostatic hypotension can be treated 
with agents that expand blood volume ( e.g. fludrocortisone ) and increase vascular tone 
( epinephrine and yohimbine ) 
• Tricyclic antidepressants, carbamazepine, phenytoin and capsaicin can help patients


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with agents that expand blood volume ( e.g. fludrocortisone ) and increase vascular tone 
( epinephrine and yohimbine ) 
• Tricyclic antidepressants, carbamazepine, phenytoin and capsaicin can help patients 
suffering room pain.   
 
Guillain-Barré syndrome 
Definition:  also called Landry’s ascending paralysis 
• It is an acute inflammatory demyelinating polyradiculoneuropathy.


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Internal Medicine 
 
 552• It is predominantly motor neuropathy charac terized by muscular weakness and arflexia 
(loss of deep tendon reflexes) 
• It has an acute onset and it is usually rapidly progressive in nature.  
• There may be also mild distal sensory loss. 
 
Etiology and pathogenesis:  
The etiology is not known but it is believed to be due to  autoimmune damage to the myelin 
sheath of peripheral nerves.  
In about 2/3 of cases, the disease begins 5 days to 3 wk following an antecedent event such as: 
• Non specific viral syndrome 
• May be associated with HIV infection  
• Campylobacter jejuni infection 
• Hepatitis , infectious mononucleosis  
• Mycoplasma pneumonae infection 
• Vaccination 
• Surgery 
• Lymphoma or  
• SLE 
It is the most common acquired demyelinating neuropathy. 
Signs and symptoms:   
• Relatively symmetric weakness with pares thesia usually begins in the legs and 
progresses to the arms. 
• Weakness typically evolves over hours to a few days, and for 90% of patients, weakness 
is maximal at 3 wk after which the patent reaches a plateau, and further progression is 
unlikely.   
• Weakness is always more prominent than sensory abnormalities and legs are usually 
more affected than the arms.  
• Deep tendon reflexes are lost.  
• Sphincters (both bladder and bowel) are usually spared.  
• More than 50% of patients with severe disease have weakness of facial muscles 
(diaparesis).


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more affected than the arms.  
• Deep tendon reflexes are lost.  
• Sphincters (both bladder and bowel) are usually spared.  
• More than 50% of patients with severe disease have weakness of facial muscles 
(diaparesis).  
• The lower cranial nerves are also frequently involved, causing bulbar weakness and 
difficulty of swallowing difficulty of handling secretions and maintaining the airways.


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Internal Medicine 
 
 553• Most patients need hospitalization, and almost 30 % require ventilator assistance at 
some time during their illness due to possible respiratory failure. 
• Autonomic dysfunction: wide fluctuation in BP, postural hypotension, and inappropriate 
ADH secretion, cardiac arrhythmias and pupillary changes occur in severe cases. These 
complications need close monitoring as they may be fatal. 
• Pain is another common feature of GBS. The usual type of pain is deep aching pain in 
the weakened muscles. Back pain involving the entire spine may also be felt. 
• Respiratory paralysis and autonomic dysfunction may be life-threatening. 
• About 5% of patients die. 
Diagnosis:   
• Presumptive diagnosis is made based on history and physical examination.  
• CSF analysis:  elevated protein but few (<50 mononuclear cells) or no cells not cells 
(albumino-cytologic dissociation). 
• Nerve conduction test (NCT):  slow nerve conduction velocity, evidence of conduction 
block, and prolonged distal latencies, which suggest demyelination is the usual finding. 
Differential diagnosis:   
• Toxins (organic phosphate, botulism),  
• Acute poliomyelitis. 
Treatment: 
Guillain-Barré syndrome is a medical emergency,  requiring constant monitoring and support of 
vital functions.  
General supportive measures: 
• The airway must be kept clear, and vital capacity should be measured frequently, so that 
respiration can be assisted if necessary.


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vital functions.  
General supportive measures: 
• The airway must be kept clear, and vital capacity should be measured frequently, so that 
respiration can be assisted if necessary.  
• Fluid intake should be sufficient to maintain a urine volume of at least 1 to 1.5 L/d.  
• Extremities should be protected from trauma and from the pressure of bed rest.  
• Heat helps relieve pain, making early physical therapy possible.  
• Immobilization, which may cause ankylosis, should be avoided. Passive full-range joint 
movement should be started immediately and active exercises begun when acute 
symptoms subside.  
• Heparin 5000 U SC BID may help to avoid thromboembolism in bedridden patients.


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Internal Medicine 
 
 554Immunotherapy:  
• Plasmapheresis:  can shorten the length of time that the patient is dependent on 
respirator and unable to ambulate. Criteria to initiate plamapheresis include the inability 
of the patient to walk or rapid progression of the diseases. 
• Immunoglobulin treatment:  it is also effective and decreases morbidity and hastens 
recovery. Plasmapheresis and immunoglobulin treatment may be given in combination  
• Steroids are not effective in GBS , but in chronic relapsing Polyneuropathy, 
corticosteroids improve weakness and may be needed for a long time. Immunosuppressive drugs (azathioprine) and plasmapheresis benefit some patients. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  Nerve 
and muscle dioders, pages 2500-2540. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Neuropathy: pages 638-640.


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Internal Medicine 
 
 5558. CNS infections  
 
I. Pyogenic (bacterial) meningitis 
 
Learning Objective :  At the end of this unit the student will be able to  
1. Define Bacterial meningitis.   
2. List the etiologies of Bacterial meningitis.   
3. Describe the mode of transmission Bacterial meningitis.     
4. Describe the epidemiology of Bacterial meningitis.   
5. Identify the clinical features of Bacterial meningitis.   
6. List the common complications of Bacterial meningitis.   
7. Describe the most commonly used tests for the diagnosis of Bacterial meningitis.   
8. Make an accurate diagnosis of Bacterial meningitis.   
9. Understand the management of Bacterial meningitis.   
10. Understand methods of prevention Bacterial meningitis.   
 
Definition:  is an inflammation of the arachnoid layer of the meninges and the fluid that 
circulates, in the ventricles and sub-arachnoid space (CSF), caused by bacterial infection 
 
Etiologic agents:   the causes of bacterial meningitis vary with age: 
• Infants (< 1 year) : E. coli, group-B streptococcus, Listeria monocytogenous  are the 
commonest causative agents. 
• Young children/toddlers (age 1- 6 years ) : Haemophilus influenza, Meningococcus  
account for > 50 % of cases 
• Adolescents and Adults:  Meningococcus, Pneumococcus  are the commonest 
etiologies 
• In immunocompromised hosts and cancer patients : Listeria, Staphylococcus, 
Pseudomonas aeruginosa  etc. 
Rout of infection:


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account for > 50 % of cases 
• Adolescents and Adults:  Meningococcus, Pneumococcus  are the commonest 
etiologies 
• In immunocompromised hosts and cancer patients : Listeria, Staphylococcus, 
Pseudomonas aeruginosa  etc. 
Rout of infection: 
• Droplet infection through the upper airways:  E.g. In Meningococcus meningitis,  with 
possibly epidemic spread 
• Haematogenous spread:  e.g. in Pneumococcus pneumonia 
• Contagious spread from adjacent sites :  e.g. in otitis media , sinusitis


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Internal Medicine 
 
 556• Direct:  e.g. in open head injury 
Epidemiology: 
• Bacterial meningitis is the most common form of suppurative CNS infection. 
• In the West due to the availability of vaccines for N. meningitidis  and H. influenza,  S. 
pneumonae  has become the leading cause of bacterial meningitis. 
• However, in African and most developing countries, N. meningitidis is still the leading 
cause of bacterial meningitis in adolescents and adults. An outbreak of meningitis 
epidemic has been documented to occur every 7- 10 years in the meningitis belt in African, which includes our country Ethiopia. 
Clinical presentation; 
• Incubation period:   the incubation period for Meningococcal meningitis may range from 
1-10 days, but mostly the clinical manifestations occur within in  2-4 days 
• Meningitis may manifest as an acute fulminant illness that progress rapidly in few hours  
or as a subacute infection that progressively worsens over several days. 
• The classic clinical triad of meningitis is fever, headache and nuchal rigidity (neck 
stiffness) , which are seen in > 90 % of patients . 
• Alteration in metal status can occur in > 75 % of patients and can vary from lethargy to 
comma.  
• Nausea and vomiting are common symptoms. 
• Avoiding light (photophobia) is seen in some patients. 
• Seizure occurs as part of the initial presentation of bacterial meningitis, or during the 
course of the illness in 20-40 % of patients


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• Nausea and vomiting are common symptoms. 
• Avoiding light (photophobia) is seen in some patients. 
• Seizure occurs as part of the initial presentation of bacterial meningitis, or during the 
course of the illness in 20-40 % of patients  
• In Meningococcal meningitis of sudden onset with severe course, patients develop 
diffuse erythromatus maculopapular rash which rapidly becomes petechial, purpural or bullos lesions. The petichiae are found on the trunk, lower extremities, in the mucous 
membrane and the conjunctiva, and occasionally on the palms and soles.   
• In older and debilitated patients the symptoms of meningitis may be subtle. 
Meningeal signs  are clinical signs often sound in patients with meningitis  
• Neck stiffness  when head is flexed passively 
• Kerning’s sign : when one leg which is flexed at the hip and knee joints, is passively 
extended at the knee joint, the other leg flexes at the knee.  
• Brudzinski’s sign:   Upon passively flexing the head, one notices flexion of both legs at 
the knees


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 557Note:  These classic meningeal signs may not be seen in infants, old persons and patients in 
coma. 
Complications:   
• Brain edema,  
• Hydrocephalus 
• Brain abscess, 
• Septic vein thrombosis 
• Hearing impairment  
• Fulminant meningococcal sepsis: Waterhouse-Friedrichsen syndrome is a clinical 
condition resulting from hemorrhagic necrosis of the adrenal gland, with multi-organ 
failure. Patients are hypotensive or in sho ck.  Disseminated intravascular coagulation 
(DIC) with skin and mucosal purpura and bleedings are commonly seen associated features.  
Diagnostic approach  
• History, physical examination,  
• Search for possible source of infection(pneumonia , otitis media , sinusitis , head injury)  
• CSF analysis  
• Identify the organism from CSF and blood (culture, PCR etc.) 
• Serologic antibody test : latex agglutination test  
 
Laboratory findings: 
General signs of inflammation: leukocytosis, CRP and ESR ↑ 
CSF analysis: 
• Gross appearance and opening pressure : CSF looks turbid and the opening pressure is 
increased ( due to raised intra cranial pressure ) 
• Cell count and differential : polymorphonuclear leukocytosis 
• Biochemical tests : glucose is decreases and  protein in the CSF is elevated   
• Gram stain Culture and sensitivity  
o Meningococcus are seen as gram negative intracellular diplococcic


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 558Table VIII-8-1, CSF analysis findings in different types of meningitis  . 
 Bacterial meningitis  Viral meningitis  Tuberculous 
meningitis  
Appearance  Turbid  Clear  Cob-web appearance
 
Cell count/µl  Several thousand  Several hundreds  Several hundreds  
Cell type  Granulocytes(PMNLs)  Lymphocytes  Lympho-, monocytes  
Glucose  ↓ (< 30 mg/dl)  Normal  ↓ (< 30 mg/dl)  
Protein  ↑ (> 120 mg/dl)  Normal  ↑ (> 120 mg/dl)  
Lactate dehydrogenase  ( LDH)
 > 3.5 mmol/L  < 3.5 mmol/l  > 3.5 mmol/l  
Differential diagnosis:   
• Virally caused meningoencephalitis (Coxsackie- , Echo-, Mumps-virus, HIV, measles, 
CMV, VZV, HSV) 
• Chronic meningitis : Tuberculous meningitis , Cryptococcal meningitis  
• Subarachnoid hemorrhage  
Treatment:   
A. Antibiotic Therapy  
1. Empirical antibiotic therapy :  
Bacterial meningitis is a medical emergency and antibiotics should be initiated immediately before the results of the CSF gram stain and culture are known. Antibiotics should be given intravenously, at higher doses  
• In adults without underlying disease: Ceftria xone 2 gm IV BID plus Ampicilline 2 gm IV 
QID for 2 weeks. 
• Crystalline Penicillin 3-4 million IU, IV ever y 4 hours plus Choramphnicole 1gm IV QID  
are alternative antibiotics for a resource limited setting . 
• Patients with ENT infection or head injury: Ceftriaxone 2 gm IV BID and Vancomycin 1 
gm IV BID + treatment of the underlying cause.


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are alternative antibiotics for a resource limited setting . 
• Patients with ENT infection or head injury: Ceftriaxone 2 gm IV BID and Vancomycin 1 
gm IV BID + treatment of the underlying cause. 
• If suspected hospital-acquired infection: Ceftriaxone 2 gm IV BID plus Vancomycin 1 gm 
IV BID plus Gentamycin (80 mg TID) 
• In immunodeficient patients: Ceftriaxone 2 gm IV BID plus Vancomycin 1 gm IV BID plus 
Ampicillin (2g IV QID)


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 5592. Specific antibiotic therapy : is given when the specific etiologic agent is identified 
through gram stain or culture  
• N. meningitidis  : Even though Ceftriaxone or Cefotaxim provide adequate empirical 
coverage  , Penicillin G remains the drug of choice for N. Meningitides 
Crystalline Penicillin 3-4 million IU, IV every 4 hours for 7 -10 days may be adequate.  
• Pneumococcal meningitis :  Antibiotic therapy in initiated with Cephalosporins plus 
Vancomycine  
Ceftriaxone 2 gm IV BID and Vancomycin 1 gm IV BID for 2 weeks  
• H. influenza  : Ceftriaxone 2 gm IV BID for 1- 14 days may be enough  
Choramphnicole 1gm IV QID may be an alternative antibiotic, for patients who may not afford Ceftriaxone. 
B. Symptomatic and adjunctive Therapy 
• Steroids:  
o Dexamethason  when initiated before antibiotic therapy reduces the number of 
unfavourable outcomes, including death and neurologic complications. It is mainly advantageous in children, predominantly with meningitis due to H. 
Influenza and S. Pneumoniae.  
Dose : Dexamethason10 mg IV 15-20 minutes before the first dose of antibiotics 
and 4 mg IV QID for 4 days   
• Treat increased intracranial pressure : 
o Elevation of the patients head to  30-45o  
o Intubation and hyperventilation  ( till PaCO 2 is lowered to 25-30 mmHg ) 
o Mannitol IV infusion  
• Regulate water and electrolyte balance,  
• Thromboembolism prophylaxis 
• Patients with meningococcal meningitis should be isolated .


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o Intubation and hyperventilation  ( till PaCO 2 is lowered to 25-30 mmHg ) 
o Mannitol IV infusion  
• Regulate water and electrolyte balance,  
• Thromboembolism prophylaxis 
• Patients with meningococcal meningitis should be isolated . 
Chemoprophylaxis:  In case of N. Meningitides, all close contact to the patient should be given 
chemoprophylaxis with:- 
• Rifampicin 600 mg PO BID for 2 days in adults and 10mg/kg PO BID for children > 1 yr. 
• Ciprofloxacin 750 mg PO stat can be given as an alternative for adults.


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 560II. Viral encephalitis  
 
Learning Objective :  At the end of this unit the student will be able to  
1. Define viral encephalitis.  
2. List the etiologies of viral encephalitis.   3. Identify the clinical features of viral encephalitis.     
4. Describe the most commonly used tests for the diagnosis of viral encephalitis.     
5. Understand the management of viral encephalitis.     
 
Definition:  Inflammation of the brain parenchyma, with or without involvement of the meninges, 
caused by virus. The spinal cord and/or nerve roots may also involved rarely.  
 Signs and symptoms:   
• Acute febrile illness with evidence of meningeal involvement (meningeal signs) 
• Altered level of consciousness (ranging from lethargy to coma) 
• Abnormal mental state (hallucinations, agitation, personality change, behavioural 
disorder, psychosis) 
• Evidence of either focal or diffuse neurologic signs or symptoms.  
• Focal or generalized seizures occur in > 50 % of cases.  
• Most common focal findings are aphasia, ataxia, hemiparesis (with hyperactive tendon 
reflexes), involuntary movements and cranial nerve deficits. 
 
Organisms:  Viruses causing encephalitis 
 
Common
 Less common  Rare 
Arboviruses, enteroviruses, HSV-1, 
mumps
 CMV, EBV, HIV, 
measles, VZV  Adenoviruses, CTFV, influenza A, LCMV, 
parainfluenza, rabies, 
rubella


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 561Laboratory findings: 
 CSF examination:  check for increased intracranial pressure first. Characteristic profile 
is undistinguishable from viral meningitis and consists of lympocytic pleocytosis, 
elevated protein, normal glucose level 
 CSF PCR, if available 
 CSF culture, usually negative (esp. in HSV-1 infections) 
 Serologic studies and antigen detection, if available 
 MRI, CT, and EEG: if available, done to exclude alternative diagnoses, and assist in 
differentiation between focal and diffuse encephalitic process (e.g. 90 % of patients with 
HSV-1 infection have abnormalities in the temporal lobe on MRI). 
 Brain biopsy:  reserved for patients with unclear diagnosis, lack of response to therapy 
and who have abnormalities on imaging techniques. 
 
Treatment: 
Supportive therapy (usually in ICU):  
• Check vital signs, restrict fluid, and give antipyretics.  
• Treat seizures and/or give prophylactic therapy (high risk for seizures!). 
Medication: 
• Acyclovir 10 mg/kg TID for at least 14 days (adult dose). 
• Gancyclovir (5 mg/kg BID) or Foscarnet (60 mg/kg TID) are especially 
recommended for CMV infections. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Meningitis  
and Encephalitis , pages 2471-2489. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
CNS infections, pages 644-645.


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 562CHAPTER NINE 
CONNECTIVE TISSUE DISORDERS AND DISEASES OF THE 
JOINTS  
 
Overview:   
These are a group of medical disorders resulting from immunologic damage to the connective 
tissue of the body. 
They overlap with each other, may affect many organ systems, and often respond to 
immunosuppressives. Their pathologies vary. The following are some of connective tissue disorders:  
1. Systemic lupus erythematosus (SLE),  
2. Rheumatoid arthritis  
3. Systemic sclerosis ( Scleroderma )  4. Polymyositis  5. Mixed connective tissue Disorder  
6. Primary Sjörgen’s syndrome 
7. Behçet’s disease.  
 
1. Systemic lupus erythematosus (SLE) 
 
Definition:  SLE is a chronic immune disorder characterized by multisystem involvement and 
clinical exacerbations and remission.  
Circulating immune complexes and autoantibodi es cause tissue damage and organ dysfunction. 
Epidemiology:  
• The prevalence of SLE is approximately 15-5- cases per 100, 000 population 
• The prevalence in young women of child bearing age is 8- 10X that of men (F: M ratio is 
8:1 – 10:1) 
• More common in black women than white women , more common in pregnancy 
• SLE has familial tendency and the concordance rate among identical twins is 50 % 
Etiology:  No single cause identified for SLE, it results from complex interaction of 
environmental, genetic factors and hormonal influences


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 5631) Environmental factors: virus and drugs or toxins. It may be induced by drugs (isoniazid, 
hydralazine, chlorpromazine etc.) 
2) Genetic factors : there is genetic predisposition to SLE 
3) Autoimmunity : loss of tolerance to autoantigens  is central to the pathogenesis 
4) Hormonal influence : as the disease is more common in women of child bearing age , 
estrogen may play a role in the pathogenesis  
Clinical features : Signs and symptoms: 
a) Systemic symptoms:  Fatigue , weight loss and fever are prominent systemic 
complaints  
b) Skin:   
• Photosensitive malar butterfly rash( facial erythema over the cheeks and nose ) ,  
• The chronic potential scarring discoid lesions, alopecia,  
• Livedo reticularis, Raynaud’s phenomena, purpura, oral ulcers, urticaria, 
conjunctivitis, bullae.  
c) Musculoskeletal:   
• Joint/muscle pain, non-erosive polyarthritis 
• Myositis, proximal myopathy,   
• Aseptic bone necrosis 
d) Renal:  SLE cause diffrent types glomerulonephritis which may manifest with  
proteinuria, casts, edema, and later on to Cronic renal failure ( uremia)  
e) CNS:  Focal or diffuse neurologic disordrs occur in approximatly 50 % of pateints  
• Generalized manifestations  : Severe headache, reactive depression, 
psychosis, seizure , and cognitive disturbance 
• Focal:  focal seizure, hemiparesis, paraparesis, cranial nerve lesions, ataxia, 
chorea may also be seen. 
• Peripheral nerves : some pateints may have sensory or senorimotor


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psychosis, seizure , and cognitive disturbance 
• Focal:  focal seizure, hemiparesis, paraparesis, cranial nerve lesions, ataxia, 
chorea may also be seen. 
• Peripheral nerves : some pateints may have sensory or senorimotor 
neuropathies   
f) Lung:   
• Pleurisy,  
• Lupus pneumonitis,  
• Fibrosing alveolitis 
g) CVS:   
• Hypertension from renal involvment


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 564• Pericarditis,  
• Non infective endocarditis 
• Myocarditis 
• Coronaty vessle Vasculitis    
h) Blood:  anemia, leukopenia, lymphopenia, thrombocytopenia, increased ESR 
i) Gastrointestinal tract:  intestinal vasculitis , Pancreatitis  
j) Other:  fever, splenomegaly, lymphadenopathy, recurrent abortion 
Diagnosis: 
1) Hematology: Anemia, elevated ESR, decreased platelet count  
2) Urinalysis:  proteinuria, hematuria   
3) Renal function test : BUN and creatinin may be elevated  
4) Serology  
• ANA (antinuclear antibodies) nearly 99 % of patients with SLE have ANAs 
• Antibodies against double-strand DNA 
• Low complement components ( C3 and C4 ) 
 
Treatment:   
1) If the SLE is believed to be due to be drug-induced, stop the drug.  
2) Give sun-block creams or  sunscreens  
3) NSAIDs  are used in full anti inflammatory dose for fever, joint complaints and serositis. 
4) Hydroxychloroquine if joint/skin symptoms are not controlled by NSAIDs, e.g. 400 mg/d PO for 6 mo, then 200 mg/d. 
5) Corticosteroids :  
• High-dose predenisolone in life-threatening conditions, 1 mg/kg/d for 6 wks, then 
taper. May be combined with other immunosuppressives. 
• Low-dose predenisolone is of value in chronic disease. 
6) Cytotoxic drugs: (E.g. azathioprine, cyclophsphamide) sometimes are employed to treat severe refractory features of SLE, particularly renal diseases. 
Prognosis  
• Early diagnosis and treatment decreases morbidity and mortality


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6) Cytotoxic drugs: (E.g. azathioprine, cyclophsphamide) sometimes are employed to treat severe refractory features of SLE, particularly renal diseases. 
Prognosis  
• Early diagnosis and treatment decreases morbidity and mortality  
• Renal diseases and infectious complications are the major causes of death 
• CNS diseases can lead to severe disability


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 565References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  Asthma,     
pages 1508-1515 
2) Myers R. Allen , National Medical Series for independent Study ( NMS ) 3rd edition 
Medicine, Asthma, pages 75-78


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 5662. Rheumatoid Arthritis ( RA ) 
 
Learning objectives:  at the end of this lesson the student will be able to: 
1) Define Rheumatoid arthritis  
2) Describe the etiology and pathogenesis of Rheumatoid arthritis  3) Identify the clinical features of Rheumatoid arthritis 
4) Understand the diagnostic approach and investigations for Rheumatoid arthritis  
5) Understand the management principles of Rheumatoid arthritis  6) Describe prognostic factors for Rheumatoid arthritis  
 
Definition:  it is a chronic multisystemic inflammatory disease of unknown cause, characterized 
by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical 
distribution.  The potential of the synovial inflammation to cause cartilage damage and bone erosion and subsequent changes in joint integrity is the hall mark of the diseases.  
Epidemiology 
• The prevalence of RA is approximately 0.8 in the population. 
• Women are more affected than men with F: M ratio of 3:1 
• The prevalence increases with age and, and the sex difference diminishes in the older 
age group. 
Etiology:  
Te cause of RA remains unknown. It is suggested that RA may be a manifestation of a 
response to an infectious agent in a genetically susceptible host.  
1) Genetic factors  : genetic susceptibility to altered immune response may play a role 
• The concordance rate among monozygotic twins is 4X, and first degree relatives


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response to an infectious agent in a genetically susceptible host.  
1) Genetic factors  : genetic susceptibility to altered immune response may play a role 
• The concordance rate among monozygotic twins is 4X, and first degree relatives 
of patients with RA have a very high chance of developing RA 
• The presence of HLA-DR4 allogen is associated with high incidence of RA.  
2) Infectious agent : may play a role in triggering an autoimmune reaction. Infectious 
agents such as rubella, Mycoplasma, CMV  and EBV virus may play a role in the pathogenesis  
Clinical Features  
Onset: 
• Insidious onset : in about 2/3 of patients the RA begins insidiously with prodromal 
nonspecific symptoms such as fatigue, weight loss, anorexia, generalized body


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 567weakness and vague musculoskeletal symptoms, for weeks or months before the 
occurrence of specific joint symptoms. 
• Acute onset:  in about 10 % of patients RA has an acute onset, with rapid development 
of polyarthritis, associated with constitutional symptoms, including fever, lymphadenopathy and splenomegaly. 
1) 
Articular ( joint )  manifestations:  result from persistent inflammatory  synovitis  
• Pain , swelling and tenderness of involved joints , aggravated by movement 
• Generalized joint stiffness is often seen after a period of inactivity. Morning stiffness 
which lasts greater than 1 hr, which is a feature of inflammatory arthritis is a common complaint. 
• Bilateral, symmetrical small joint involvement is typical for RA 
Commonly affected joints are:- 
• Wrist joints, Metacarpo phalangal joints (MPJ) and proximal interphalangal PIP) 
joints  are often involved but distal interphal angal (DIP) joints are often spared. The 
elbow joint , and keen joints are also affected by RA.  
• Wrist joint :  synovitis of wrist joint is very comm on is RA , and may lead to limitation of 
movement , deformity and median nerve entrapment ( Carpal tunnel syndrome) 
• Elbow joint  involvement may lead to flexion contracture 
• Keen joint  is commonly involved with synov ial hypertrophy, chronic effusion and 
frequent ligamentous laxity. Pain and swelling behind the knee may be caused by


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• Elbow joint  involvement may lead to flexion contracture 
• Keen joint  is commonly involved with synov ial hypertrophy, chronic effusion and 
frequent ligamentous laxity. Pain and swelling behind the knee may be caused by 
extension of inflamed synovium in to poplitial space ( Baker’s cyst ) 
• Arthritis of the forefoot, ankles and subtalar joints  can produce sever pain with 
ambulation and as well as a number of deformities. 
• Axial involvement is limited to cervical spines  ;  Atlantoaxial ligament involvement , 
in the cervical spine can lead to instability between  C1 and C2 vertebrae and potential neurologic complaints 
Joint deformities:  with persistent inflammation, a variety of characteristic joint changes 
develop due to damage or weakening of ligaments, tendons and joint capsule. These deformities include:- 
• Z- deformity:  radial deviation at the wrist with ulnar deviation of the digits 
• Swan neck deformity : hyperextension of the PIP joints, with compensatory flexion of 
DIP joints 
• Boutonier deformity : Flexion contracture of PIP joints and extension of DIP joints


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 5682) Extraarticular features  : RA is a systemic diseases with a variety of extraarticular 
manifestation  
• Although these occur frequently, not all of them has clinical significance. However, 
occasionally they may be the major evidence of disease activity and source of morbidity. 
• More often, these manifestation occur in patients who have high titer of rheumatoid 
factor and patients who have more severe and established diseases 
a) Rheumatoid nodules:  are the most common features of extraarticular diseases and are 
found in 20-25 % of patients.  
These firm subcutaneous masses typically are found in areas on periarticular structures and on areas exposed to of repetitive trauma (e.g. extensor surface of the forearm, the 
olecranion at the elbow, proximal ulna, Achilles tendon and the occipit).  
In some patients rheumatoid nodules may be found on the viscera (e.g. lungs, meningitis) 
b) Rheumatoid vasculitis : This can affect nearly any organ system and is seen in patients 
with severe RA, and high titer of circulating Rheumatoid factor. 
• Peripheral nerves  : Distal sensory neuropathy or Mononuritis multiplex 
• Skin:  cutanous ulceration  , dermal necrosis  
• Digital gangrene  
• Visceral infarction  : Myocardial infarction , vasculitis involving the lungs , bowel 
, liver, spleen, pancreas ,kidneys etc 
c) Eye involvement : 
• Keratoconjuctivitis sicca is seen  in 10% -15 % of rheumatoid arthritis patients


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• Visceral infarction  : Myocardial infarction , vasculitis involving the lungs , bowel 
, liver, spleen, pancreas ,kidneys etc 
c) Eye involvement : 
• Keratoconjuctivitis sicca is seen  in 10% -15 % of rheumatoid arthritis patients 
who have a secondary form of Sjogren syndrome  
• Scleritis or episcleritis  occur less common 
d) Lungs  
• Pleuritis and pleural effusion may be seen is some patients. The pleural fluid 
typically has low glucose concentration. 
• Intestinal fibrosis 
• Rheumatoid nodules  may appear on the lung, single or multiple. 
e) Heart  
• Asymptomatic Pericardits  is fund in 50% of patients on autopsy. It is often 
associated pleural effusion.  
• Myocarditis and Valvular dysfunctio n are rare findings


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 569f) Neurologic manifestations  : the CNS is not directly affected   
• Peripheral nerves are affected  through Entrapment (carpal tunnel syndrome) or 
Vasculitis related mononuritis multiplex 
• Atlantoaxial sublaxation  : may lead to compression of spinal cord  
g) Hematologic features  
• Anemia of chronic diseases 
• Thrombocytosis  
• Felty’s syndrome: chronic RA with splenomegaly and neutropenia, with an 
occasional thrombocytopenia and anemia. ,  
Constitutional symptoms : like weight loss, fever anorexia and fatigue are common complaints 
and may be severe in patients with extraarticular manifestations  
Diagnostic approach for RA  1) Proper history  taking  and Physical examination  play a crucial role in making the  
diagnosis of RA 
2) Laboratory findings  
a) Hematology: CBC may show normocytic, normoch romic anemia, leukocytosis and 
thorombocytosis. ESR is often raised indicating chronic inflammation 
b) Rheumatoid factor: It is autoantibodies against the Fc component of IgG. It is typically 
present in 60 % of patients in the first year and 80% of patients with long standing diseases. Note that 30 -40 % of patients with rheumatoid arthritis may be sero-negative for Rheumatoid factor. 
3) Radiographic findings :  
• Early  characteristic changes include soft tissue swelling and loss of bone in periarticular 
areas (periarticular osteopenia). 
• Late: sustained inflammation leads to loss of bones at joint margins (erosion) and joint


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• Early  characteristic changes include soft tissue swelling and loss of bone in periarticular 
areas (periarticular osteopenia). 
• Late: sustained inflammation leads to loss of bones at joint margins (erosion) and joint 
space narrowing as a result of cartilage loss and joint deformity. 
Revised American revised Criteria for classification of RA 
1) Morning stiffness: lasting > 1 hr 
2) Arthritis of three or more joint areas:  
3) Arthritis of hand joints: wrist, MCP and PIP 
4) Symmetrical athirst  
5) Rheumatoid nodules: subcutaneous nodules over bony prominences 
6) Serum rheumatoid factor


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 5707) Radiologic changes : periarticular bony erosion and other fndigs  
 
Interpretation: 
• Four of seven criteria are required to clas sify a patient as having Rheumatoid arthritis 
• Patients with two or more criteria, the clinical diagnosis of RA is not excluded. 
Therapy  
Goals of therapy: 
1. Short term  : Controlling pain and reducing inflammation without causing undesired side 
effects 
2. Long term : Preservation of joint function and the ability to maintain life-style.  
A) Pharmacotherapy  
1) First line Treatment:  NSAIDs ( Non steroidal anti-inflammatory drugs ):  are the first line 
drugs.  
• They are used to control symptoms and signs of local inflammatory process.  
• These agents are rapidly effective in alleviating pain and symptoms , but there effect on long term disease progression is minimal. 
• Aspirin, Ibuprofen, diclofenac, indometacin may be used  
 
Dose: Aspirine 900 mg PO TID, Ibuprofen 400 mg PO BID or Diclofenac 50 mg PO BID or 
TID 
Side effects : Dyspepsia, PUD, Renal dysfunction, bone marrow toxicity. 
2) Second line treatment:  low dose oral Corticosteroids have potent  anti-inflammatory effect  
, but they have equally predictable unwanted side effects. 
• Systemic administration:  are given in sever progressive articular diseases and extra 
articular involvement  
Dose:  start 5-10 mg once daily in the morning. If patients improve, attempt should be 
made to taper the dose.


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• Systemic administration:  are given in sever progressive articular diseases and extra 
articular involvement  
Dose:  start 5-10 mg once daily in the morning. If patients improve, attempt should be 
made to taper the dose. 
• Local injection:  steroids may be injected occasional ly to joints which are severely 
affected  
3) Third line: Disease modifying antirheumatic drugs- or slow acting antirheumatic drugs 
(DMARD) 
•  This group of agents include Methotrexate , gold compounds , D-penicillamine , 
antimalarials and sulfasalazine


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 571• These are drugs which have no analgesic effect and generally require weeks to months 
before anti-inflammatory effects are evident. Hence, NSAIDs should continue during the 
administration of DMARDs. 
• They have the capacity to alter the course of RA. 
• They are used in patients with rheumatoid arthritis, who are not responding to NSAIDs 
(with or without steroid).  
• These drugs may be used singly mostly, but they may be prescribed in combinations in 
patients with bad prognosis or refractory diseases. 
• The disease progression is delayed with these drugs and acute phase reactants such as 
ESR and C-reactive proteins frequently decline. 
Methotrexate  is the most frequently DMARD used, which is relatively rapidly acting  
Dose:  given in an intermittent low dose:  7.5-30 mg once weekly 
Side effects : GI upset, oral ulcer, liver function abnormalities and insidious liver fibrosis. 
Administration of folic acid or folinic acid may diminish the frequency of some side effects,  
4) Fourth line: Anti cytokine agents:  this are biological agents that bind and neutralize TNF. 
These drugs are effective in controlling signs and symptoms of RA in patients who ailed to respond with DMARDs.  
5) Fifth line : immunosuppressive therapy : 
These include drugs such as Azathiopri ne, cyclsosporine, and cyclophosphamide.


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These drugs are effective in controlling signs and symptoms of RA in patients who ailed to respond with DMARDs.  
5) Fifth line : immunosuppressive therapy : 
These include drugs such as Azathiopri ne, cyclsosporine, and cyclophosphamide. 
They have the same therapeutic effect as DMARDs, but they are not more effective than DMARDs They are prescribed to patients who fail to respond to DMARDs 
B) Non pharmacologic therapy  
1) Patient education:;  
• Description of the illness : the chronicity of the diseases  
• Rest and exercise  a. Patients should be advised to rest or splint acutely involved joints  b. Exersise is advised to srenghten muscle surrounding  involved joints , when the 
arthritis is resolved  
2) Physiotherapy and occupational therapy  to reduce disability


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 572Assessment of response: 
• Resolution of symptoms : reduction or disappearance of joint pain, stiffness and 
swelling  
• Functional status:  ability of the patient to perfo rm daily activities and living  
• Laboratory:  anemia may be corrected and ESR  declines 
 
Surgical therapy:  
• Early:  synovectomy may decrease the inflammato ry process in joints or tendon sheaths 
that remain inflamed despite drug therapy 
• Late:  artheroplasy or total joint replacement may be appropriate to relive pain or help 
restore function in structurally deformed joints.  
Prognostic factors: poor prognostic factors include  
• Many persistently inflamed joints  
• Poor functional status  
• Low educational status of the patient         
• Rheumatoid factor positivity  
• HLA-DR4 positivity 
• Extra-articular diseases 
• Persistently elevated acute phase reactants ( ESR, C-reactive protein ) 
• Radiologic evidence of erosion 
 
 
 
References:  
3) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  Asthma,     
pages 1508-1515 
4) Myers R. Allen , National Medical Series for independent Study ( NMS ) 3rd edition 
Medicine, Asthma, pages 75-78


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 5733. Other connective tissue diseases  
3.1. Systemic sclerosis (Scleroderma)  
It is defined as a connective tissue characterized by widespread small vessel obliteration 
disease and fibrois of the skin and multiple internal organs. 
Classification: 
• Limited cutaneous systemic sclerosis:  formerly called CREST syndrome ( calcinosis, 
Raynaud’s, esophageal motility disorder, sclerodactyly and telangeictasia). 
• Diffuse cutaneous systemic sclerosis  with skin, renal and gut involvement; associated 
with malignant hypertension, Raynaud’s and myocardial disease. No effective treatment 
known. 
• Localized (morphea=localized scleroderma):  localized skin sclerosis, progresses rarely. 
Characteristic antibodies: topoisomerase, RNA polymerase, centromeres. 
 
3.2. Primary Sjörgen’s syndrome 
 
Definition:  Association of a connective tissue disease (in 50 % rheumatoid arthritis) with 
keratoconjunctivitis sicca (dry eyes) or xero stomia (dry mouth) due to lymphocyte and plasma 
cell infiltration into secretory glands. 
 
Signs and symptoms: 
• Dry eyes, mouth 
• Dyspareunia 
• Dry skin 
• Dysphagia 
• Otitis media 
• Pneumonia 
• Other: neuropathy, renal involvement, hepat osplenomegaly, drug reactions, lymphoma, 
decreased well-being (headaches, GI symptoms, decreased concentration). 
Diagnosis: 
• History and physical examination 
• Schirmer’s test to quantify tear production 
• Biopsy of salivary glands


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 574Treatment:  artificial tears, occlusion of punctum which drains tears. Xerostomia may respond to 
frequent cool drinks or artificial saliva spray. 
 
3.3. Idiopathic myopathies: pol ymyositis and dermatomyositis 
 
Definition:  polymyositis is an idiopathic inflammatory muscle diseases characterized by 
insidious, symmetrical, prominent proxim al muscle weakness resulting from muscle 
inflammation, elevated muscle enzymes and characteristic EMG finding.  
• Signs and symptoms:   
• Skin : The rash of dermatomyositis consists of erythematous paths which sometimes are 
scaling or atrophic and distributed over the face and, neck and upper chest and extensor surfaces. Rash on cheeks, eyelids and light-exposed areas may be seen. 
• Lung:  Chronic interstitial lung diseases 
• Joint:  mild symmetrical inflammatory arthritis   
• Muscles : most patients have gradual but steady progression of muscle weakness. 
Some patients may have fulminant course that acute respiratory failure or myoglobinurin 
acute renal failure can ensue. 
• Pharyngeal muscle weakness  can lead to a problem in swallowing and aspiration and 
respiratory muscle dysfunction. Patients may have also dysphonia, facial edema.  
• Other features :  retinitis and myocardial involvement may occur. 
 Diagnosis:   
• Muscle enzyme (CK)is elevated  
• EMG (electromyography) shoe characteristic features  
• Muscle biopsy.


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• Other features :  retinitis and myocardial involvement may occur. 
 Diagnosis:   
• Muscle enzyme (CK)is elevated  
• EMG (electromyography) shoe characteristic features  
• Muscle biopsy. 
 Treatment:  Rest, prednisolone (start with 1 mg/kg/d PO), other immunosuppressives. 
 
3.4. Mixed connective tissue disease 
• MCTD combines features of SLE, system ic sclerosis and polymyositis. Renal or CNS 
involvement is rare.  
• Antibodies against ribonuclear protein are present.


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 575• Treat with immunosuppressives including steroids. 
 
3.5. Relapsing polychondritis 
• Relapsing polychondritis attacks pinna, nasal septum and larynx, the last causing stridor.  
• It is associated with aortic valve disease, arthritis and vasculitis.  
• Treat with steroids. 
 
3.6. Behçet’s disease 
Definition:  A multiorgan disease associated with certain HLA-types and thromboses.  
More common in men M:f=2:1. 
Signs and symptoms:  
• Joints:  arthritis 
• Eyes:  pain, decreased vision, floaters, iritis, retinal vein occlusion 
• Mouth, scrotum, labia : painful ulcers, heal by scarring 
• Gut: colitis 
• CNS:  meningoencephalitis, increased intracranial pressure, brainstem signs, dementia, 
myelopathy, encephalopathy, cerebral vein thrombosis. 
 Treatment:  Colchicine, steroids (topical and oral), other immunosuppressives. 
 
References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition,  
Connective tissue diseases , pages 1979-2015. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine,  
pages 570-581.


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Internal Medicine 
 
 5764. Gout  
Learning objectives:  at the end of this lesson the student will be able to: 
1) Define Gout   
2) Describe the etiology and pathogenesis of Gout  
3) Identify the clinical features of Gout 
4) Understand the diagnostic approach and investigations for Gout   5) Understand the management principles of different types Gout   
Definition:  A group of disorders of purine metabolism that are characterized by serum uric acid 
elevation (hyperuricemia), urate deposits in articular or extraarticular tissues. 
Elevation of serum uric acid alone is not sufficient for the diagnosis of gout; only 10 % of patients with hyperuricemia develop gout. Some unknown factors predisposes some patients to 
urate deposition and articular inflammation, in the setting of sustained hyperuricemia 
Etiologic classification of Hyperuricemia 
All gout syndromes are characterized by either epis odic or constant elevation of serum uric acid 
concentration above 7 mg/dl. Patients with elevated serum uric acid are mainly due to  1) Overproduction: account for 10 % of patients. These patients synthesize greater than 
normal amount of uric acid de novo. The urin ary excretion of urate is >1000mg/day (they 
have normal urinary excretion of uric acid). The defect causing uric acid overproduction may be :- a) Primary : purine pathway enzyme defect  
b) Secondary :  increased cell turn over or cellular destruction associated with alcohol use,


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have normal urinary excretion of uric acid). The defect causing uric acid overproduction may be :- a) Primary : purine pathway enzyme defect  
b) Secondary :  increased cell turn over or cellular destruction associated with alcohol use, 
hematologic malignancies , chronic Hemolysis , or cancer chemotherapy 
2) Under secretion of Uric acid : account for 90 % of patients. Decreased renal excretion of 
uric acid is the underlying reason for hyperuricemia (urinary excretion of uric acid is < 700mg/dl ) a) Drugs:  Diuretics , alcohol , Aspirin interfere with tubular handling of urate 
b) Renal diseases  ; chronic renal failure , lead nephropathy , inherited disorders  
Conditions associated with Gout  
• Obesity:  serum uric acid level rises with body weight 
• Diabetes mellitus : more common in gout 576 patients 
• Hypertension:  is more common in gout patients  
• Hyperlipidemia 
• Atherosclerosis


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 577Clinical Stages of gout  
a) Asymptomatic hyperuricemia  : is characterized by an increased serum uric acid level 
in the absence of clinical evidences of deposition diseases (i.e. arthritis , tophi , 
nephropathy or uric acid stones) 
• These patients have an increased risk of having nephrolithiasis  or acute obstructive 
uropathy  
b) Acute gouty arthritis :  is the second and primary manifestation of gout – is an 
extremely painful , acute onset arthritis • Most patients (80-90 %) are middle aged or elderly men who have had sustained 
asymptomatic hyperuricemia for 20-30 yrs before the first attack. 
• Premenopausal women are not affected by gouty arthritis, perhaps due to the effect 
of estrogen on uric acid clearance.  However gout may be seen in postmenopausal 
elderly women who have mostly associated hypertension. 
• Onset of acute gouty arthritis in teens or 20s is unusual, and when it occurs it is often 
associated with primary or secondary causes of uric acid overproduction. 
• Several events may precipitate acute gouty arthritis including: dietary excess, 
trauma, surgery, excessive alcohol ingesti on, ACTH or glucocorticoid withdrawal, 
hypouricemic therapy and serious medical illn esses like myocardial infarction and 
stroke . 
• Presentation:  an acute onset of severe, painful and tender joint swelling, affecting


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hypouricemic therapy and serious medical illn esses like myocardial infarction and 
stroke . 
• Presentation:  an acute onset of severe, painful and tender joint swelling, affecting 
the first Metatarsoplalangal joint (called podagra). Other joints also may be affected including tarsal joints, ankle and knee. The fingers joints may be inflamed in elderly patients. 
• Many attacks occur suddenly at night with rapid evolution of joints with erythema, 
swelling, tenderness and warmth. Intense joint inflammation can extend in to the soft tissue and mimic cellulitis or phlebitis. Fever can occur in sever attacks. 
• Polyarticular involvement can occur in so me cases, and typically progression from 
monoarticular to polyarticular involvement occurs by extension to adjacent joints. 
• Course:  acute attacks usually resolve spontaneously in few days 9 3-10 days), 
although some can extend over several weeks. The affected joint usually returns to normal between attacks and patients do not have residual symptoms until the next episode.


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 578c) Intercritical gout: The third stage of gout is an asymptomatic period after the initial 
attack. Recurrence of new attacks may occur during this stage. 
• Recurrence of monoarticular attacks: about 7% of patients never experience a new 
attack of acute gouty arthritis after the first attack. However 62% experience a 
recurrence of gouty arthritis with in 1 yr. 
• Typically the patient is asymptomatic between attacks, but attacks become more 
frequent and abate more gradually if urate deposition remains untreated. 
• Diseases progression:  Attacks tend to become polyarticular and more sever over 
time. Some patients develop a chronic inflammatory arthritis without asymptomatic intervals leading to a condition which may resemble rheumatoid arthritis.   
d) Chronic tophaceous gout:  develop in untreated patients and is the final stage of gout. 
The tophus is a collection of urate crystal masses surrounded by inflammatory cells and fibrosis. 
• Typical locations for tophaceous deposits are   
o The pinna of the ear  
o The surfaces of chronically involved joints and subchondral bone as well as 
extensor surface of the forearm, olecranon , and the intrapatellar and Achilles 
tendons 
e) Renal complications : may arise at any stage of gout, but nephrolithiasis is the only


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extensor surface of the forearm, olecranon , and the intrapatellar and Achilles 
tendons 
e) Renal complications : may arise at any stage of gout, but nephrolithiasis is the only 
common clinical presentation of renal involvement. Proteinuria and impaired ability to concentrate urine related to urate deposition in the renal interstitium have been described in gout patients. 
Diagnostic work up 
A) Acute gouty arthritis  ; 
• Laboratory findings  
(1) Serum uric acid  value often is not helpful in the clinical diagnosis of acute gout. 
Serum uric acid concentration is normal in at least 10 % of patients at the time of 
an acute attack and an elevated serum uric acid is nonspecific for acute gout. It can be used to assess the effectiveness of hypouricemic therapy. 
(2) Synovial fluid analysis : The demonstration of urate crystals, especial 
intracellular crystals, in synovial fluid is diagnostic. Synovial fluid WBC of 10,000- 
60,000 /µl with predominant neutrophils are common in acute attacks.


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 579B) Chronic tophaceous gout: 
• Physical appearance ; tophi are firm movable and superficial located. If they 
ulcerate a chalky material extrudes. 
• Radiologic findings : tophaceous deposits appear as well defined large erosions 
(punched out erosions) of the sbchondral bone. These erosions are more common at 
the first Metatarso phalangal joint (MTP), and at the base of the heads of phalanges: however any joint area can be affected. Typically gouty erosions have an overhanging edge of subchondral new bone formation  
• Aspiration : tophi can be aspirated an crystals can be demonstrated  
 
Therapy  
1) Asymptomatic hyperuricemia : no need for treatment, other than correction of the 
underlying causes. 
2) Acute gouty arthritis : drug treatment of acute  gouty arthritis is most effective  when 
started early after the symptoms begin 
a) Colchicine  has anti-inflammatory effect, and if it  is given early, it is effective in 
85 % of patients. 
Dose:   Colchicine 0.6 mg is given every hr until the relief of symptoms or 
gastrointestinal toxicity occurs. It may also be given intravenously during acute attack in patients who cannot take PO medication. 
b) NSAID:  are used in high but quickly tapered dose. Drugs like Aspirin that affect 
uric acid clearance should be avoided. Indomethacine:  25-50 mg PO TID,  
Ibuprofen: 800 mg Po TID 
Diclofenac: 25-50 mg PO TID   
c) Corticosteroids :


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b) NSAID:  are used in high but quickly tapered dose. Drugs like Aspirin that affect 
uric acid clearance should be avoided. Indomethacine:  25-50 mg PO TID,  
Ibuprofen: 800 mg Po TID 
Diclofenac: 25-50 mg PO TID   
c) Corticosteroids :  
Oral glucocorticoids:  Prednisolone, 30-50 mg/day as the initial dose and 
tapered over 5-7 days. Intraarticular injections  of steroids can be used to treat acute gout of single 
joint, particularly when the use of other agents is contraindicated. 
d) Drugs that alter serum uric acid concentration  (e.g. allopurinol, probenicide) 
should be avoided during acute attack, because of lowering of serum uric acid


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 580level induces the release of crystals in to joint space and prolong the acute 
attack. 
3) Intercritical gout : Prophylactic treatment with small dose of colchicines (0.6 mg once or 
2X per day) or small doses of a NSAID can be used to prevent new attacks. 
4) Chronic tophaceous gout  : the aim of therapy is to control hyperuricemia( i.e. to reduce 
serum urate level to < 5 mg/dl ) 
a) Uricosuric agents  (E.g. probenicide, Sulfinpyrazone). This drugs facilitate the renal 
excretion of uric acid. It can be used in patients who excrete less than 700 mg of uric acid daily, who have normal renal function, and who have no history of urinary stones. Dose: Probenicide 200 mg PO Bid increased gradually as needed up to 2 gm 
b) Xanthine Oxide inhibitors:  include allopurinol; this drug competitively inhibits 
xanthine oxidase. This drug is preferred in patients with urate excretion greater than 1000 mg/day, creatinin clearance < 30 ml/min, tophaceous gout or history of nephrolithiasis. Dose: 300 mg single morning dose initially and may be increased up to 800 mg if 
needed.  Dosage is reduced in the presence of renal failure to avoid toxicity. 
 
 References:  
1) Kasper L., Braunwald E., Harrison’s principles of Internal medicine, 16th Edition, Gout,     
pages 2046-2050. 
2) Myers R. Allen, National Medical Series for independent Study (NMS) 3rd edition Medicine, 
Gout, pages 727-532.


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Abhishek Joshi  
Corinne Ryan  
Sabe Sabesan  
Suresh Varma  
Zulfiquer Otty  
 
 
DEPARTMENT OF MEDICAL ONCOLOGY  
TOWNSVILLE CANCER CENTRE  
TOWNSVILLE UNIVERSITY HOSPITAL  
TOWNSVILLE , AUSTRALIA  
 
  
 
 
 
 
 
 
 
MEDICAL ONCOLOGY HANDBOOK  
FOR JUNIOR MEDICAL OFFICERS


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Medical Oncology Handbook for Junior Medical Officers  
5th Edition June 2020, 
Townsville, Australia.  
 
Townsville Cancer Centre is a teaching partner of the James Cook University and 
research partner of the Australian Institute of Tropical Health &Medicine,  
Townsville, Queensland, Australia .


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1 
  
INTRODUCTION:  
Welcome to the Department o f Medical Oncology at the Townsville Cancer Centre. By 
the end of the term, you should be able to identify and manage common side effects of 
chemotherapy and radiotherapy in the areas  of general practice, emergency departments 
and rural hospitals and general medical wards. Y ou will also have some understanding of 
treatment principles and aims of cancer therapy for common malignancies. This 
handbook is meant for the use of resident medical officers and basic physician trainees. 
It may also be useful to advanced trainees in the ir first few months of training. We hope 
that this experience will give you the skills to deal with cancer patients with positive and 
empathetic approach.  
If you are encountering emotional difficulties when dealing with poor prognosis, please 
talk to one o f us earlier in the term to learn ways to deal with it effectively.  
 
Enjoy the medical oncology rotation.  
 
 
Regards,  
 
CONSULTANT MEDICAL ONCOLOGISTS


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2 
 TABLE OF CONTENTS   
ORIENTATION TO MEDIC AL ONCOLOGY DEPARTME NT ............................  3 
PRINCIPLES OF MANAGE MENT OF PATIENTS ON SYSTEMIC THERAPY  9 
Common side effects of systemic therapeutic agents  ................................ ................  13 
Chemotherapy related emesis  ................................ ................................ ....................  16 
PRINCIPLES OF TARGET ED THERAPY  ................................ ..............................  19 
PRINCIPLES OF CANCER  IMMUNOTHERAPY  ................................ .................  21 
Medical Oncology Emergencies  ................................ ................................ ................  32 
SUMMARY OF MANAGEMEN T OF COMMON CANCERS   ............................  33 
BREAST CANCER  ................................ ................................ ................................ .... 33 
Cancers of the Gas tro-Intestinal Tract  ................................ ................................ ..... 37 
GBM  ................................ ................................ ................................ ...........................  41 
GERM CELL TUMOURS  ................................ ................................ .........................  41 
HEAD AND NECK CANCER  ................................ ................................ ...................  43


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GERM CELL TUMOURS  ................................ ................................ .........................  41 
HEAD AND NECK CANCER  ................................ ................................ ...................  43 
LUNG CANCER  ................................ ................................ ................................ ........  43 
MELANOMA  ................................ ................................ ................................ .............  45 
GYNAECOLOGICAL CANCER  ................................ ................................ ...............  47 
CANCERS OF GENITO URINAR Y SYSTEM  ................................ ........................  48


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3 
 ORIENTATION TO MEDICAL ONCOLOGY DEPARTMENT  
Junior medical officers play an important role in the day-to-day care of patients in 
Medical Oncology Department . It is critical that you work in c lose collaboration with 
senior medical, nursing and allied health staff , along with our administrative support 
officers.  
We have outlined some useful practice poi nts will help you to settle into our department 
smoothly.  
Educational and training resources  
Electronic medical records  
Townsville Cancer Centre uses MOSAIQ as its EMR. Please become familiar with 
MOSAIQ by contacting the CNC for MOSAIQ on 32888 or through  our administrative 
support officers 44331671 prior to commencement. We assume that you are familiar with 
the ieMR, the THHS -wide EMR.  
Chemotherapy protocol  
eviQ is a very useful website to learn chemotherapy protocols and side -effects. It also 
contains in formati on about managing extravasation (www.eviq.org.au ). 
NB: RMOs and interns are not expected to write chemotherapy orders. When 
writing oral chemotherapy, targeted agents and colony stimulating factors, please 
exercise caution and follow the advice of your registrars and consultants.  
Medication prescribing  
Quality of inpatient medication prescribing can be improved by adhering to the THHS 
guide for inpatient medication prescription . 
End of life care bedside tutorial and introduction to telehealth


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Medication prescribing  
Quality of inpatient medication prescribing can be improved by adhering to the THHS 
guide for inpatient medication prescription . 
End of life care bedside tutorial and introduction to telehealth  
These two topics are available on YouTube  (searchable using the titles)  and are useful 
resources for developing mental frameworks for approaching these topics.  
Basic principles of oncology  
Clinical oncology for medical students is a useful resource for learning basic principles 
of oncology care.  
 
http://wiki.cancer.org.au/oncologyformedicalstudents/Clinical_Oncology_for_Medical_
Students


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4 
 Documentation  
Since funding for operations of medical departments are linked  to their clinical activities, 
it is important to use coding terminologies during documentation  of patient notes . 
Issues with central venous access devices  
We use central lines commonly in oncology and therefore, it is prudent to be aware of 
managing comp lications. As a rule , when it is difficult to draw blood from lines or inject 
fluids, it is important to use imaging (including chest -Xray and linogram) for checking 
the position and viability before using the lines. Please seek advice when infection and 
thrombosis are  suspected /proven . We can rarely save lines using antibiotics   
Self-care  
Please maintain physical, emotional, mental and spiritual health. Take  regular  breaks  as 
much as possible and maintain effective work -life balance  (This doesn’t mean work is 
bad and life is good; it is about having a balance that suits your needs) . Please seek help 
if you think you need help including emotional support and guidance.  
Day unit  
• Orientate with the Day -unit staff and introduce yourself t o senior nursing 
staff and establish working relationships  with them .   
• You are the first point of call for any issues in day unit and therefore, please 
make sure that you are always available during rostered hours.  Day unit relies 
on effective discharge o f patients to maintain flow. A delay due to one issue


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• You are the first point of call for any issues in day unit and therefore, please 
make sure that you are always available during rostered hours.  Day unit relies 
on effective discharge o f patients to maintain flow. A delay due to one issue 
could delay the whole day’s operation and care of other patients.  
• Infusion reactions are medical emergencies: You should always attend to a 
patient having a reaction, leaving everything else. If you are  not available, 
please make sure another doctor can attend the patient immediately.  
Clinics  
• Being “On Time” is important! Clinics start on time so that patients can 
receive their chemotherapy in day unit without delays.  
• If a patient is seen by the consulta nt in clinic, please ask them to sign the blue 
form.  
Dealing with consultants and registrars  
Please don’t hesitate to seek help from senior medical staff. All changes in management 
should be discussed. Harass them even if they are busy!


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5 
 Dealing with nurses and other health professionals  
• Advice from nursing staff is an important resource for patient care.  
• When chemotherapy changes, delays or cancellation occur, it is prudent to 
inform the nursing and pharmacy staff. 
Dealing with patients on chemothera py and chemotherapy orders  
• When you see a patient for chemotherapy review, please prepare the care 
plans for the next cycle.  
• Dose reduction: After consultation with senior medical staff, please document 
dose reductions and make changes on MOSAIQ scripts. I f there is  a dose 
increase, it is possible only from the next cycle.  
• All chemotherapy booking s are done through administration officers and day 
unit schedulers . 
• Initial c hemotherapy orders should be counter -signed by a consultant.  
• Please be familiar with i mportant practice points for common medications as 
described in this hand book.  
Admitted patients  
• Make sure they are seen by consultants within 24 hours of admission and on a 
regular basis;  
• Have an expected date of discharge and do the discharge planning , including 
timely completion of high -quality discharge summaries; ideally on the day 
of discharge, using the national guide for discharge summaries . 
• If a patient undergoing chemotherapy is admitted with complications, inform 
the day -unit and the treating consultant of any changes in treatment. It will 
also be important to document this episode on MOSAIQ for continuity of


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• If a patient undergoing chemotherapy is admitted with complications, inform 
the day -unit and the treating consultant of any changes in treatment. It will 
also be important to document this episode on MOSAIQ for continuity of 
care and future planning includ ing dose changes and addition of GCSF.  
• If any oncology patient is admitted in another department or another hospital 
with complications, inform the treating consultant and document on 
MOSAIQ.  
• In-patient consults from other departments need to be seen on th e same day, 
discussed with or seen by the consultant on call and documented on 
MOSAIQ.  
• It is important to i nform the consultant on call of any patients admitted to 
medical oncology.  
Remember to use telehealth for appointments via our teleoncology coordinator. Telehealth is 
appropriate for  most rural &  selected metro patients


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6 
  
CONSULTANT MEDICAL O NCOLOGISTS/ SENIOR M EDICAL 
OFFICERS  
Professor Sabe  Sabesan  
BMBS (Flinders) , PhD, FRACP  
Senior  Staff Specialist  
Clinical Dean, James Cook University &  
Townville Hospital and Health Services  
 
Dr Suresh Varma  
MBBS , MD, DM, FRACP  
Senior Staff Specialist and senior lecturer  
 
Dr Abhishek Joshi  
MBBS,  MD, DM, FRACP  
Senior Staff Specialist and senior lecturer  
 
Dr Zulfiquer Otty  
MBBS, MD, MRCP, FRACP  
Staff specia list and senior lecturer  
 
Dr Corinne Ryan  
MBBS (Hons), B  Appl  Sci, FRACP  
Staff specialist and senior lecturer  
 
Dr Christine Mitchell  
MBBS (Adelaide), FRACGP  
Senior Medical Officer Medical Oncology


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7 
 WEEKLY TIMETABLE  
Time  Mon day Tues day Wed nesday  Thurs day Friday 
0745 -0830  GI MDT  
(0800 -0900)   Breast MDT  
Gynae MDT 
every three 
weeks  
  Colorectal  
MDT  
(0800 -0900)  
0900 -1200  Clinics  
SV, ZO, 
CR Clinic  
SV, ZO 
H&N MDT  Clinic  
CM, SV,  AJ Clinic  
CM, CR, AJ, 
ZO Clinic  
SV, ZO, AJ, 
1230 -1330  Grand rounds  
(RDA)  Clinic  
SS 
 Radiology  
(Weekly) /  
Uro MDT 
(fortnightly)  Clinical 
Reasoning  
(RDA)   
1330 - Clinic 
Spill -over Clinic  
AJ/SV  Skin MDT  
(1300 -1400)   
1400 -1500  Journal Club  
Reg training 
M&M   
1500 -1600  
1600 -1700   Neuro -MDT 
(monthly ) Lung MDT   
Educational aims for this rotation:  
• Management of complications of systemic therapy . 
• Familiarity with common systemic therapy  regimens . 
• Management of medical emergencies . 
• Management of quality of life issues . 
• Understanding of psychosocial issues related to cancer patients - discussing  
prognosis, breaking bad news, family meetings etc. 
• Understanding of curative vs palliative intent therapy . 
• Familiarity  with the management of common maligna ncies including 
multidisciplinary approach . 
 1430 -1530  
Long case 
practice for 
BPT, RMO 
and Interns


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8 
 Routine t asks:  
• Managing inpatients – routine inpatient care, ward consultations, weekend 
roster (it is the responsibility of the registrars to do this roster).  
o Prior to consultant ward rounds, results should be available for imaging 
studies, histology and blood tests.  
o (For interns, all the procedures except IV cannulation need to be initially 
supervised by registrars or consultants).  
• Review of day unit patients . 
• Review of clinic patients . 
• Phone consults  from GPs, other staff and the patients . 
• Participation in a long case practice session each Tuesdays (taking turn 
among BPT, RMO and Interns)  and other education sessions listed in the 
time- table  
• Participation in departmental Research and/or Quality Impro vement projects  
 
Day unit and clinic patient review:  
• To assess fitness for systemic therapy . 
• To assess symptoms and side effects of treatment.  
• To address new concerns .  
• To assess for treatment response -  
o tumour markers , 
o scans - performed after 2 -3 cycles .    
• To update systemic therapy  scripts .


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9 
 PRINCIPLES OF MANAGE MENT OF PATIENTS ON 
SYSTEMIC THERAPY  
Assessing fitness for systemic therapy  
Fitness for systemic therapy  depends on many  factors:  
• performance status , 
• the type and severity of side effects from pr evious cycles or doses , 
• blood parameters , 
• co-morbidities  and 
• Patient choice  
If cure is the aim, it is usual to accept mild -to-moderate, non -life-threatening toxicities 
and continue treatment without delaying or reducing the dosage to minimise side effects. 
Sometimes it is prudent to use supportive therapy such as  G-CSF to maintain  dose 
intensity. However, in patients with incurable metastatic disease where quality of life is 
paramount, dose delays or dose reductions are necessary.  
Performance status  
This is graded using the Eastern Cooperative Oncology Group (ECOG) scale.  
 
Grade  ECOG performance status  
0 Fully active, able to carry on all pre -disease performance without 
restriction . 
1 Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work  
2 Ambulatory and capable of all selfcare but unable to carry out any 
work activities. Up and about more than 50% of waking hours  
3 Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours  
4 Completely disabled , cannot carry on any self -care, totally confined 
to bed or chair


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work activities. Up and about more than 50% of waking hours  
3 Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours  
4 Completely disabled , cannot carry on any self -care, totally confined 
to bed or chair  
 
Usually, patients with ECOG grade > 2 are not fit for chemotherapy. The exception is 
chemotherapy -sensitive cancers such as lymphoma and small cell lung cancers. The 
decision to offer chemotherapy must be individualised , depending upon factors such as  
age of the patient, & comorbidities.  For example, a young patient with metastatic breast


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10 
 cancer with poor performance status could still be offered systemic treatments. Targeted 
agents and  endocrine therapy are usually tolerated better than chemotherapy.  
 
Toxicity from previous cycles of systemic therapy  
Clinicians must assess whether a side effect is affecting QOL, performance status  or is 
life threatening:  
First, determine the type and se verity of side effects.  
For example, in patients with early breast cancers undergoing taxane chemotherapy, mild 
peripheral neuropathy is acceptable. However, in patients undergoing fluorouracil -based 
therapy, ongoing or severe diarrhoea necessitates a dose  delay and dose reduction of 
subsequent cycles.  
Mid-cycle neutropenic fever usually requires dose reduction of the subsequent cycle 
unless the cancer is curable. If the cancer is curable or a substantial duration of remission 
is expected, prophylactic colo ny stimulating factors such as pegfilgrastim (neulasta) 
and/or antibiotics can reduce the risk of subsequent and opportunistic infection s. 
 
Next, determine the effects on important organs, such as:  
• Fertility. Discuss semen cryopreservation with men. Option s for women 
should also be discussed, particularly in young women of child -bearing 
potential and where curative intention treatment is planned.  Options include  
preservation of egg, embryo and a piece of ovary is offered by some fertility 
groups. Women who  wish to discuss this option should be referred to a


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potential and where curative intention treatment is planned.  Options include  
preservation of egg, embryo and a piece of ovary is offered by some fertility 
groups. Women who  wish to discuss this option should be referred to a 
fertility specialist.  
• Renal function, liver functions.  
• Cardiac function. This may affect the dosage of anthracyclines (check 
ejection fraction before treatment begins and after every 2 –3 cycles) and 
trastuzumab (check ejection fraction before treatment begins and every 3 
months during therapy).  
Toxicity is graded according to NCI common terminolo gy criteria for adverse events1. 
1. Blood parameters:  
a. Requires haematological and non-haematological parameters.  
 
1 National cancer institute common toxicity criteria (CTCAE, version 4.03, June 
2010 ), National Institutes of Health, National Cancer Institute  . 
http://ctep.cancer.gov .


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11 
 For most regimens, a neutrophil count >1.5 x 109/L and platelet count > 100 x 
109/L are needed for safe administration of chemotherapy. For some regimens, 
lower levels may be acceptable.  
Single agent bleomycin and vincristine  are not myelotoxic and administration is 
not affected by blood counts.  
Renal function is important for cisplatin and carboplatin and liver function for 
docetaxel , Magnesium levels especially  for cisplatin  and Calcium levels for 
denosumab.  
Action  - withhold treatment until recovery, then dose delay and/or dose reduction  
after discussion with senior staff . 
b. Pregnancy test: For women of child bearing potential, perform beta HCG 
before initiating treatment.  
2. Non-haematological toxicity  
(Also see the summa ry of common side effects for selected drugs on page 25). 
a. Diarrhoea – mainly 5FU based, Irinotecan, Oxaliplatin, docetaxel . 
Action  - low threshold for withholding therapy if diarrhoea the day before , or 
moderate diarrhoea for longer than expected duration , or nocturnal diarrhoea.  
b. Mucositis/mouth care . 
c. Emesis . 
   Action  - (see anti -emetics) change class, change route, add another agent , or  
   reduction of chemotherapy dose.  
d. Skin Rash . 
e. Neuropathy - Cisplatin, Oxaliplatin, Taxanes and Vinca alkaloids . 
               Doses are delayed , reduced or omitted if neuropathy persists or interferes with  
               function.  
f. Autotoxicity - Cisplatin . 
g. Renal impairment - Cisplatin.


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Doses are delayed , reduced or omitted if neuropathy persists or interferes with  
               function.  
f. Autotoxicity - Cisplatin . 
g. Renal impairment - Cisplatin.  
Action - prior to most agents, need to check creatinine especially if they are renally 
cleared  and Carboplatin  dose adjusted based on creatinine.  
h. Pulmonary toxicity - bleomycin, methotrexate . 
3. Physical  examination -Routine exam and oral cavity, central lines and IV site 
infections, lymph nodes and signs of recurrence and side effects.


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12 
 Symptom control  
Discussion or shared care with palliative care is helpful.  However, basic principles are as 
follow s: 
(Also refer to the Guide for inp atient medication prescription)  
1. Pain:    Always find out the cause of the pain before prescribing analgesics . 
Total daily morphine requirement will guide the required daily slow release dose. 
When prescribing breakthrough, the dose is 1/6th of the daily do se. So, if you are 
increasing the daily dose, break through need s to increase as well. If oral intake is 
difficult —patches or infusional morphine are options.  
4. Dyspnoea:    Again, find out the cause, for cancer related dyspnoea —nebulised 
morphine and anxioly tics could be helpful.  
When to stop cancer treatment  
A decision to stop treatment prematurely depends on the aim of the treatment.  
For curable cancers, it is acceptable to continue treatment with dose modifications. 
However, life threatening or severe dose  limiting toxicities usually necessitate cessation 
of treatment (eg. moderate to severe peripheral neuropathy with taxanes and oxaliplatin, 
severe enteritis from fluorouracil). Alternative regimens are sometimes available.  
If the cancer is incurable and th e toxicities severely interfere with the activities of daily 
living, treatment may have to be stopped.  
Deteriorating performance status and organ function usually require cessation of 
treatment. Ongoing neutropenia or thrombocytopenia typically means the p atient is not


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living, treatment may have to be stopped.  
Deteriorating performance status and organ function usually require cessation of 
treatment. Ongoing neutropenia or thrombocytopenia typically means the p atient is not 
going to handle further chemotherapy.  
In case of patients with metastatic disease, palliative care team referral is done even when 
they are on active treatment, to improve symptom management and supportive care.


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13 
 Common side effects of systemic therapeutic agents  
• Adriamycin/ Epirubicin    
Be aware of cumulative dose, p erform cardiac function every 2-3cycles.  
• Bleomycin -  
Lung functions every 3 weeks  (consider, discuss with consultant)  
• Cisplatin  
Renal function, Mg levels, peripheral neuropathy, hearing loss/tinnitus.  
• Carboplatin  
Adjust dose based on renal function; Dose  = AUC x (GFR+25).  
• 5-FU 
Diarrhoea -In severe cases, it can be life threatening.  
Before proceeding with treatment, please make sure no diarrhoea on the day an d 
on the previous day of chemotherapy. When diarrhoea has been moderate to 
severe, consider dose reduction or cessation.  
5FU could also cause coronary artery spasm.  
In severe 5FU enteritis, admission for bowel rest +/ -TPN along with 
aggressive anti diarrh oeal and antibiotics may be required.  
• Gemcitabine  
Pneumonitis, peripheral edema.  
• Irinotecan - Normal bilirubin is required.  
Diarrhoea and flushing: acute symptoms related to parasympathetic system could 
settle with atropine with chemotherapy.   
For chron ic symptoms, dose reduction may necessary.  
• Taxol/ Paclitaxel  
Peripheral neuropathy, flu like symptoms .


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 • Taxotere/Docetaxel  
Adequate liver function, peripheral edema, neuropathy, rash.  
• Oxaliplatin  
Cold induced paresthesia ( acceptable), but signs of peripher al Neuropathy may be 
dose limiting.  Laryngo spasm (cold induced) and bronchospasm are other acute 
side effects.  
• Cyclophosphamide/ Ifosfamide  
Renal function, hydration, confusion from encephalopathy.  
• Capecitabine  
Mucositis, hand foot syndrome, rash, angina , diarrhoea.  
• Trastuzumab  
Cardiac function every 3 months.  
• Cetuximab/Panitumumab  
Acneform rash.   
• Methotrexate  
Folinic acid rescue  for higher doses only . 
• Caelyx/ Liposomal doxorubicin  
Rash, hand foot syndrome, cardiac function.  
• Avastin /Bevacizumab  
Hypertension and proteinuria.  
• Denosumab  
Prolonged hypocalcaemia  (require calcium suppliments).  
• Dabrafenib  (b-Raf inhibitor)  
Pyrexia, rash, s quamous cell carcinomas of skin.  
• Mekinist – MEK inhibitor  
Usually  combined with Dabrafenib to reduce in cidence of skin squamous cell 
carcinoma  
• Zolendronic acid  
Renal function, hypocalcaemia, requires dose reduction for renal impairment.  
Need calcium supplements .


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 • Check point inh ibitors (Ipilumumab, nivolumab , Pembrolizumab ) 
Autoimmune complications such as  colitis, pneumonitis, hepatitis and 
inflammation  of pituitary gland leading to Addison’s crisis require urgent medical 
attention.  
• Alopecia  
This does not occur with every medication.  
Common with breast, ovarian, sarcoma, small cell, lung (Carbo/Taxol) canc er and 
testicular regimens  
Common chemotherapy abbreviations  
Breast Cancer   
TAC  Docetaxel, Adriamycin, Cyclophosphamide  
FEC  5Fluorouracil, Epirubicin, Cyclophosphamide  
AC (inc DD) Adriamycin, Cyclophosphamide (DD for dose dense)  
TC Docetaxel, Cyclophosphamide  
Colo -rectal Cancer   
FOLFOX  Oxaliplatin, Continious infusion 5Fluorouracil and 
Leucovorin  
XELOX  Oxaliplatin, Capecitabine  
FOLFIRI  Irinotecan, Continious infusion 5 Fluorouracil and 
Leucovirin  
XELIRI  Irinotecan, Capecitabine  
Gastric/Lower Oesophageal   
ECF  Epirubicin, Cisplatin, 5 Fluorouracil  
EOX Epirubicin, Oxaliplatin , Capecitabine  
FLOT  5FU, Leucovorin , Oxaliplatin, Docetaxel  
Head and Neck Cancer   
TPF  Docetaxel, Cisplatin, 5 Fluorouracil  
Testicular Cancer   
BEP  Bleomycin, Etoposide, Cisplatin  
TIP Paclitaxel, Ifosfamide, Cisplatin


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 Chemotherapy related emesis  
Causes of nausea and vomiting in patients receiving chemotherapy:  
• Chemotherapy related . 
• Other causes such as  gastro -oesophageal reflux disease or medications 
related.  
Pathways by which chemotherapeutic agents may produce an emetic 
response 2 
 
 
Chemotherapy -induced emesis  results from stimulation of a multistep reflex pathway that 
is controlled by the brain and triggered by afferent impulses to the vomiting centre  from 
the chemoreceptor trigger zone, gastrointestinal tract (by way of vagal affere nt fibres ), 
and possibly, the cerebral cortex.   
 
2 Hesketh, P. J. (2008). "Chemotherapy -induced nausea and vomiting." New England 
Journal of Medicine  358(23): 2482 -2494.


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17 
 Emetogenic potential of chemotherapy agents  
 
High  
(>90%)  Moderate  
(60-90%)  Moderate  
(30-60%)  Low  
(10-30%)  Minimal  
Cisplatin 
>50mg/m2  Carboplatin  Cyclophos 
<750mg/m2  Xeloda/5FU  Bleomycin  
Dacarbazine  
 Cisplatin  
<50mg/m2  cabazitaxel  Docetaxel  Herceptin  
Cyclophos>  
1.5g/m2  Doxorubicin  
>60mg/m2  Doxorubicin  
20-60mg/m2  Caelyx  Cetuximab  
 Epirubicin  
>90mg/m2  Epirubicin 
<90mg/m2  Taxol  Vincristine  
  Irinotecan,  
Oxaliplatin  Gemzar,  Vinorelbine  
*Acute or early nausea and vomiting - within 24 hours of chemotherapy.  
*Delayed/late – after 24 hours of chemotherapy. .  
For Cisplatin, emesis reaches its maximal intensity 48 -72 hours after chemotherapy and 
can last up  to 6-7 days.  
*Anticipatory nausea and vomiting - Nausea before chemotherapy  
Five neurotransmitter receptor sites are of primary importance in the vomiting reflex: M1 
– muscarinic, D2 – dopamine, H1 – histamine, 5 -hydroxytryptamine (HT) -3 – serotonin, 
Neurokinin 1 (NK1) receptor – substance P  
Antiemetics  
• Neurokinin 1 receptor antagonist - Aprepitant (emend), fosaprepitant  
(Only for prophylaxis ). 
• 5HT3 antagonists: ondansetron (zofran), granisetron & palonosetron  (aloxi) . 
• Dopamine antagonists: 1.  Phenothiazines - prochlorperazine, 2. Benzamides: 
Metoclopromide.  3.  Butyrophenons -haloperidol . 
• Glucocorticoids: active in early and delayed nausea.  
• Anti-histamines: Promethazine .


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• Dopamine antagonists: 1.  Phenothiazines - prochlorperazine, 2. Benzamides: 
Metoclopromide.  3.  Butyrophenons -haloperidol . 
• Glucocorticoids: active in early and delayed nausea.  
• Anti-histamines: Promethazine . 
• Benzodiazepins: Lorazepam (useful for anticipatory emesis) .


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18 
 High emetogenic drugs and anthracycline containing regime ns for breast 
cancer3  
• NK1 inhibitors: eg Emend (Aprepitant)  
Day 1: 165 mg pre chemotherapy with no subsequent doses . 
Plus 
• 5HT3 antagonists: eg Aloxi (Palonosetron)  250 mcg IV on  Day 1 only or 
Ondansetron 8mg twice daily for 2 -3 days starting the night of chemotherapy.  
Plus 
• Dexamethasone  
8-12 mg IV pre -chemo and 8mg oral mane for 2 -3 days.  
NB- for patients who ex perience sudden decline in well -being when steroids are 
stopped, a weaning off regimen might be useful.  
• Metoclopramide  
10 mg Q6H PRN.  
NB: 5HT antagonists can be constipating  - so warn patients about prevention of 
constipation. No need to prescribe take -home 5HT antagonists after Palonosetron.  
Moderately emetogenic drugs or combination of drugs:  
• 5HT3 antagonist : eg Aloxi (Palonosetron)  250 mcg IV on day 1 Plus. 
• Dexamethasone  8 mg IV pre -chemo and 8mg oral mane 2 -3 days . 
NK1 inhibitors  can be added to the above regimen if the patients experience 
nausea & vomiting after moderately emetogenic chemotherapy.  
Mildly emetogenic drugs:  
Usually premedication with metoclopramide 10 mg Q6H PRN would be adequate. 
If nausea is not controlled, we may have to treat it like moderate drugs after 
excluding other causes of nausea such as gastroesophageal  reflux and 
ulcers/gastritis.  
If nausea persi sts, consider other causes.  
Addition of lorazepam 1 mg Q6H PRN may be useful especially for anxious


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excluding other causes of nausea such as gastroesophageal  reflux and 
ulcers/gastritis.  
If nausea persi sts, consider other causes.  
Addition of lorazepam 1 mg Q6H PRN may be useful especially for anxious 
patients . 
 
3 Roila, F., J. Herrstedt, et al. (2010). "Guideline update for MASCC and ESMO in 
the prevention of chemotherapy - and radiotherapy -induced nausea and vomiting: 
results of the Perugi a consensus conference." Annals of Oncology  21 Suppl 5 : v232 -
243.


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19 
 PRINCIPLES  OF TARGETED THERAPY   
  
 
If we use analogy of pesticides : empiric chemotherapy would be “Raid” while targeted 
therapy is “R oach Hotel”.   
Dr David Gandara  
It is like using a “smart”  bomb versus a “cluster” bomb.  
Dr Nevin Murray  
 
The figure below d epicts typical targets for anti -cancer drugs which could be pathways, 
processes and physiology which are uniquely dis rupted in cancer cells: receptors, genes, 
angiogenesis, tumour pH etc.


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20 
  
Table 1 below depicts some targ ets and commonly available anti -cancer drugs in common 
solid tumours . 
 
Table 1 Targets and examples of treatments for common solid tumours.  
Disease  Target  Treatment  
Adenocarcinoma of lung  EGFR exon 9, 11 mutation  Erlotinib, Gefitinib , Afatinib  
 T 790M  Osemertinib  
 ALK -EML4 fusion gene  Crizotinib /Alectinib  
Melanoma  BRAF  Dabrafenib, Vemurafinib  
 MEK  Mekinist  
Colon Cancer  RAS  Cetuximab, Panitimumab  
Breast Cancer  Her 2 neu amplification  Trastuzumab , Pertuzumab, 
Lapatinib  
 ER and PR  Tamoxifen, Aromatase 
Inhibitors  
Prostate Cancer  AR receptor  Enzalutamide, Abiraterone  
GIST  CD 117 (c -kit) Imatinib Mesylate


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21 
 PRINCIPLES OF CANCER  IMMUNOTHERAPY  
 
 
 
(CTLA4 outcompetes CD28 for CD80 and CD86, and the costimulatory signal ceases as 
the target is eliminated, reducing the release of pro -effector cytokines such as IL -12 and 
cytotoxic enzymes such as perforin and granzyme B. Homeostasis is restored.)  
 
In a state of chronic antigen presentation, such as malignancy, the chronic presence of 
antigen or pro -inflammatory cytokines (IL -12, IFN  gamma, etc) can upregulate PD -1 
expression on the T cell; tumour  clones can also select for PD -L1 expre ssion. With PD -
1-PD-L1 binding, even in the presence of the costimulatory molecule, "peripheral 
exhaustion" can occur.  
 
 
 
 
The anti -CTLA -4 antibody, ipilimumab  was the first immune checkpoint inhibitor to be 
approved based upon its ability to prolong survival in patients with metastatic mel anoma.  
Programmed cell death 1 (PD -1) is a trans -membrane protein expressed on T cells, B 
cells, and NK cells . It is an inhibitory molecule that binds to PD -ligand 1 (PD -L1; also 
known as B7 -H1) and PD -L2 (B7 -H2). PD -L1 is expressed on the surface of multiple 
tissue types, including many tumour  cells, as well as hematopoietic cells; The IgG4 
subclass PD -1 inhibiti ng antibodies  like nivolumab  and pembrolizumab  prolonged 
overall survival in randomized trials in various cancers, including metastatic melanoma ,


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22 
 clear cell renal carcinoma, bladder cancer, head and neck cancer  and non-small cell lung 
cancer.  
Immune Response Criteria : The patt erns of response to treatment with these 
immunotherapy agents differ from those with molecularly -targeted agents or cytotoxic 
chemotherapy in several important respects . 
Toxicities associated with checkpoint inhibitor immunotherapy  
Checkpoint inhibition is  associated with a unique spectrum of side effects termed 
immune -related adverse events (irAEs) or, occasionally, adv erse events of special 
interest . IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less 
common inflammatory event s4. 
In general, treatment of moderate or severe irAEs requires interruption of the checkpoint 
inhibitor and the use of corticosteroid immunosuppression. Treatment is based upon the 
severity of the observed toxicity:  
• For patients with grade 2 (moderate) imm une-mediated toxicities, treatment 
with the checkpoint inhibitor should be withheld and should not be resumed 
until symptoms or toxicity is grade 1 or less. Corticosteroids should be started 
if symptoms do not resolve quickly . 
• For patients experiencing gra de 3 or 4 (severe or life -threatening) immune -
mediated toxicities, treatment with the checkpoint inhibitor should be 
permanently discontinued. High doses of corticosteroids ( prednisone  1 to 2 
mg/kg/day or equivalent) should be given. When symptoms subside to grade


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mediated toxicities, treatment with the checkpoint inhibitor should be 
permanently discontinued. High doses of corticosteroids ( prednisone  1 to 2 
mg/kg/day or equivalent) should be given. When symptoms subside to grade 
1 or less, steroids can be gradually tapered over at least one month.  
• Patients who will benefit from corticosteroids generally do s o within days. If 
symptoms do not clearly improve, particularly after approximately three days 
with intravenous steroids, our approach is to administer infliximab  (5 mg/kg) 
rather than continue with a prolonged course of high -dose IV corticosteroids. 
If symptoms persist after the first infliximab dose, a second dose of 
infliximab (5 mg/kg) can be repeated two weeks after the initial dose.  
 
 
Detailed management of various toxicities is covered by Cancer Institute of NSW’s 
eviQ:Cancer Treatments Online site . Free registration is required for login.
 
4 Naidoo J et al.(2015) Toxicities of the anti -PD-1 and anti -PD-L1 immune checkpoint 
antibodies. Annals of Oncology 2015;26(12):2375


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23 
 Common side effects of oncology medications  
 Myelosuppression  Mucositis  Enteritis  Alopecia  Cardiac  Renal  Neuropathy  Liver  Rash  Lung 
Anthracyclines  ++ +  ++ +   +   
Capecitabine  + ++ ++  angina     +HFS   
Carboplatin  ++      +    
Cisplatin  +     ++ ++    
Cyclophosphamide  +   +  +  +   
5FU  ++ ++  angina     +  
Gemcitabine  +  +       + 
Irinotecan  +  ++ +    +   
Oxaliplatin   + + +    ++    
Paclitaxel  +   ++   ++    
Docetaxel  +  + ++   ++ + +  
Permetexed  +  +        
 
Examples of Monoclonal antibodies and small molecules  
 Infusion reactions  cardiac  rash  thyroid  Proteinuria  diarrhea  Hypertension  
Trastuzumab  + 
+ 
+ +      
Bevaczuzumab     +  ++ 
Cetuximab/panitumab   ++     
Sunitinib   ++ + + + +


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24 
 FEBRILE NEUTROPENIA  
Neutropenic Fever 5 6 
It is a medical emergency. It is the responsibility of the MO to ensure prompt 
antibiotic administration.  
With diarrhoea and neutropenia, even if afebrile, it is advisable to use the 
same protocol.  
Definitions  
• A single oral temperature of 38.3  C.  
• A temperature ≥ 38  C on two occasions over 1 hour . 
• ANC ≤ 500 or less ≤ 1000/µl with predicted rapid decline to less than 500/µl . 
Septic Work -Up 
• Physical examination . 
• Blood cultures x 2 sets (venipuncture and indwelling venous catheter if 
present), urine C&S, cultures from any  suspected sites, CXR ). 
Treatment of Neutropenic Fever 7 
Antibiotics (early involvement of anti -microbial stewardship service is  
beneficial) . 
• Anti pseudomonal penicillins (Piperacillin/tazobactam & Ticarcillin) and 
cephalosporins (Cefepime) are used as single agents.  
In patients with hypersensitivity to pen icillins, seek expert advice.   
Modifications  
• Aminoglycosides may be added  if patient is unstable to cover resistant 
pseudomonal bacteremia.  
 
5 Freifeld, A. G., E. J. Bow, et al. (2011). "Clinical practice guideline for the use of 
antimicrobial agents in neutropenic  patients with cancer: 2010 Update by the 
Infectious Diseases Society of America." Clinical Infectious Diseases 52(4): 427 -
431. 
6 National Comprehensive Cancer Network (NCCN) Clinical P ractice Guidelines in


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antimicrobial agents in neutropenic  patients with cancer: 2010 Update by the 
Infectious Diseases Society of America." Clinical Infectious Diseases 52(4): 427 -
431. 
6 National Comprehensive Cancer Network (NCCN) Clinical P ractice Guidelines in 
Oncology, Prevention and treatmen t of cancer -related infections, Version 2.2011.  
www.nccn.org  . 
7 Therapeutic guidelines. online -tg-org-au.cknservices.dotsec.com


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25 
 • Add Vancomycin if clinically unstable, gram positive blood cultures before 
antibiotics, severe mucositis present, already on Quinolone prophylaxis, a 
catheter associated cellulitis or tunnel  infection, past history, high prevalence 
or carrier of Methicillin -resistant staph aureus.  
• Metronidazole for abdominal symptoms or suspected C. difficile infection.  
• Persistent neutropenic fever on D5 – add antifungal therapy (Amphotericin B 
0.5mg/kg /day o r Fluconazole 400mg/day) . 
Discuss with consultants first.  
Duration of Antibiotics (variable)  
• Low risk patient (clinically well, stable signs, no mucositis, ANC >100/µL, 
rising ANC, afebrile within 2 -3 days of starting antibiotics, negative cultures) 
consid er early discharge on oral Ciprofloxacin and Augmentin for 5 days or 
cease antibiotics altogether when ANC >500/µL . 
• High risk patients,  who become afebrile within 3 days, should continue 
parenteral antibiotics, targeted to the specific pathogen, until reso lution of 
neutropenia .  
• Specific pathogens need to be treated according to therapeutic guidelines 
while continuing broad coverage.


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26 
 Patients with any of the following characteristics are considered to be  at 
high risk for serious complications during episodes of neutropenic fever  
• Neutropenia (absolute neutrophil count <500 cells/microL) anticipated to last 
>7 days*   
Presence of any comorbid medical problems, including, but not limited to:  
• Hemodynamic instability  
• Oral or gastrointestinal mucositis that interferes with swallowing or causes 
severe diarrhoea   
• Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, 
or diarrhoea   
• Neurologic or mental status changes of new onset   
• Intravascular catheter infection, especially catheter tunnel infection  
• New pulmonary infiltrate or hypoxemia  
• Underlying chronic lung disease  
• Complex infection at the time of presentation : 
Inpatient status at the time of development of fever  
Uncontroll ed or progressive cancer  
Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times 
normal values) or renal insufficiency (defined as a creatinine clearance of <30 
mL/min)  
Multinational Association for Supportive Care in Cancer (MASCC) risk index 
score <21


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27 
 Guide to Febrile Neutropenia  
 
 
 
Colony stimulating factors (GCSF)  are generally not recommended in management of 
febrile neutropaenia, with some exceptions.


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28 
 Catheter -related infections  
Catheter removal is recommended in addition to antibiotic therapy for at least 14 days. 
But, if the infection is caused by coagulase -negative staphylococci and is important to 
save the line, catheter could be retained using systemic antibiotics.  
Extravasation of Chemotherapy  Drugs  8 
If it d oes occur, proper documentation should include the time, site of line insertion, 
needle size, estimated amount of extravasated medication, technique used to manage the 
extravasation, appearance of site, photograph, patient ’s comments, and notification of 
physician.  
Management  
 
Stop infusion.  Before removing cannula attempt to aspirate some of extravasated fluid.  
If antidote exists give it both IV through cannula and by SC infiltration see Table 2 below.  
 
Intermittent local cooling is recommended, except for vinca alkaloids (warming packs).  
Rest and elevate the affected site for 48 hours.  Telephone contact daily and assess need 
for plastic surgery.  
 
Day unit nurses have protocols for managing extravasatio n and their input will be 
important for developing management plans.  
 
8 Albanell, Joan, and Jose Baselga. "Systemic therapy emergencies." Seminars in 
oncology . Vol.  27. No. 3. 2000.


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29 
 Table 2 Example of Antidotes for Vesicant and Irritant Drugs  
 
Chemotherapy 
agent  Pharmacologic  
antidote  Nonpharmacologic  
Antidote  Method of  
Administration  
• Mechlorethamine  
(nitrogen 
mustard)  
• Cisplatin  
(large 
extravasation)  Sodium  
thiosulfate  None  Prepare 1/6 molar solution: if 
10%Na thiosulfate solution,  
mix 4 mL with 6 mL sterile 
water for injection.  
Through existing IV line, 
inject 2 mL for every 1 mg 
extravasated.  Inject SC if 
needle is removed.  
• Vincristine  
• Vinblastine  
• Vindesine  
• Etoposide  
• Vinorelbine  Hyaluronidase  Warm packs. 15 -20 
minutes at least 
four times/day for 
the first 24 -48 
hours and elevate  Prepare hyaluronidase, 150 
units/mL with 1 -3 mL saline.  
Inject through existing IV 
line, 1 mL for each 1 mL 
infiltrated.  Inject SC if needle 
is removed.  
• Doxorubicin  
(Adriamycin)  
• Daunorubicin  
• Idarubicin  
• Mitomycin C  DMSO  Ice packs  Apply cold pad with 
circulating ice water pack or 
cryogel pack for 15 -20 
minutes at least four times/day 
for first 24 -48 hours.  Some 
benefit of 99% dimethyl 
sulfoxide (DMSO) 1 -2 mL 
applied to site every 6 hours.  
• Paclitaxel  
• Docetaxel  Hyaluronidase  Ice pac ks As for Vinca alkaloids.  
• Mechlorethamine  
(nitrogen 
mustard)  
• Cisplatin  
(large 
extravasation)  Sodium  
thiosulfate  None  Prepare 1/6 molar solution: if 
10%Na thiosulfate solution, 
mix 4 mL with 6 mL sterile 
water for injection.  
Through existing IV line,


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• Mechlorethamine  
(nitrogen 
mustard)  
• Cisplatin  
(large 
extravasation)  Sodium  
thiosulfate  None  Prepare 1/6 molar solution: if 
10%Na thiosulfate solution, 
mix 4 mL with 6 mL sterile 
water for injection.  
Through existing IV line, 
inject 2 mL for every 1 mg 
extravasated.  Inject SC if 
needle is removed.  
• Paclitaxel  
• Docetaxel  Hyaluronidase  Ice packs  As for Vinca alkaloids.


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30 
 PREMEDICATIONS TO PR EVENT ALLERGIC REACT IONS  
Paclitaxel Premedications  
• Recommended schedule:  
Dexamethasone 20 mg oral, 12 hours and 6 hours before Paclitaxel (in practice 
the night before and the morning of treatment).  
Promethazine 25 mg IV 30 -60 minutes before therapy.  
Ranitidine 50 mg IV 30 -60 minutes before therapy.  
Additional Dexamethasone IV as antiemetic depending if Paclitaxel given alone 
(4mg IV) or in combination with other drugs.  
 
• Modified regimen (in cases where the patient forgets to take premedication, 
or 2nd and subsequent cycles where no hypersensitivity reaction occurred 
with 1st tr eatment an d steroids are not appropriate) . 9 10 11 
o Dexamethasone IV 20 mg 30 minutes before Paclitaxel.  
o Promethazine IV 25 mg IV 30 -60 minutes before therapy.  
o Ranitidine 50 mg IV 30 -60 minutes before therapy.  
 
• Modified schedule for weekly regimen (where ster oids are not appropriate):  
o  1st Treatment   
▪  Dexamethasone 12 mg IV . 
▪ Promethazine 25mg IV . 
▪ Ranitidine 50mg IV . 
If no hypersensitivity reaction, subsequent treatments may be given without 
premedications.12 
Docetaxel Premedications13 
• Recommende d schedule for 3 weekly regimen . 14 
Dexamethasone 8mg BD oral x 6 doses (starting night before treatment) . 
 
9 Product Information, 2001  
10 Markman M. J Clin Oncol  15(12): 3517, 1997  
11 Kintzel PE. Ann Pharmacother  35:1114 -7, 2001  
12 Quock J. Proc ASCO  18 abstr 635, 1999


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Dexamethasone 8mg BD oral x 6 doses (starting night before treatment) . 
 
9 Product Information, 2001  
10 Markman M. J Clin Oncol  15(12): 3517, 1997  
11 Kintzel PE. Ann Pharmacother  35:1114 -7, 2001  
12 Quock J. Proc ASCO  18 abstr 635, 1999  
13 Product Information, 2001  
14 Jackisch C. Proc ASCO  19 abstr 417, 2000


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 Additional Dexamethasone IV as antiemetic depending if Docetaxel used alone 
(4mg IV) or in combination with other drugs.  
• Schedule for weekly regimen:  
Dexamethasone 8mg oral BD x 3 doses (starting night before treatment) . 
Monoclonal Antibodies  
• Trastuzumab (Herceptin) may cause fever and chills, chest tightness and 
tachycardia with 1st infusion.  
• Rituximab (Mabthera) may cause asthenia, chills, bronchospas m, 
hypotension, angioedema.  Premedicate with Paracetamol 1 g QID, 
Promethazine 25 mg IV and Hydrocortisone 200 mg IV 30 -60 minutes prior 
to drug.  
• Cetuximab requires phenergan 12.5mg or 25 mg prior to infusion.


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 Medical Oncology Emergencies  
(Management of Neutropaenic fever is discussed above. ) 
Spinal Cord -compression  
Neurological symptoms and signs consistent with spinal cord compression necessitates .  
• Urgent review and MRI of spine.  
• Urgent neurosurgical and or radiotherapy referral . 
• Start Dexamethasone 8mg IV stat , followed by 16 -24 mg daily in divided 
doses.  
SVC Obstruction:  
• If the patient presents with st ridor or respiratory compromise , emergency 
treatment with endovascular stent and Radiotherapy is required.  
• In other cases: a histologica l diagnosis is required prior to initiating specific 
treatment.  
• In chemotherapy -sensitive malignancies like small –cell lung cancer, germ 
cell tumour or lymphoma, systemic chemotherapy is usually t he treatment. In 
most other tum ours, including non -small c ell lung cancer, Radiotherapy is the 
preferred treatment.  
• Endovascular stenting could achieve rapid relief of symptoms.  
Hypercalcemia:  
• Saline hydration, IV zelodronic acid, IV frusemide after adequate hydration . 
• Steroids useful in hypercalcaemia due to lym phoma . 
• s/c calcitonin may be useful in resistant hypercalcemia . 
Infusion reactions and other acute reactions  
• Mild to moderate infusion reactions with no features of anaphylaxis -  
• IV hydrocortisone and phenergan. Stop infusion till reaction subsides and 
restart at a lower rate, with close monitoring.


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Infusion reactions and other acute reactions  
• Mild to moderate infusion reactions with no features of anaphylaxis -  
• IV hydrocortisone and phenergan. Stop infusion till reaction subsides and 
restart at a lower rate, with close monitoring.  
Severe infusion reactions and anaphylaxis (hypotension, angioedema,  
bronchospasm, generalised urticaria)  - Resuscitation  with epinephrine, 
hydrocortisone,  phenergan ranitidine and fluids.  
DO NOT RE -CHALLENGE.


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33 
 SUMMARY OF MANAGEMEN T OF COMMON CANCERS  15 16 
This section outlines the principles behind the management of common cancers.  
For metastatic cancers, enrolment into a clinical trial is the best treatment option.  
Summaries provided below are developed using eviQ and NCCN guidelines as practical 
guidance.  
 
 
BREAST CANCER  
Early breast cancers:  
(Includes axillary node positive disease .) 
• Mostly curative intent therapy.  
Post-operative systemic treatment depends on oestr ogen and/ or progestogen 
receptor status, Her 2 st atus and the estimated risk of systemic relapse.  
• Prognostic factors.  
Size, age, grade, axillary nodes, receptor status and lympho -vascular invasion.  
 
 Low risk  Average risk  High risk  
Size <1cm  1-2 cm  >2 cm 
Age   <35 
Nodes  Negative   Positive  
Grade  Grade 1  Grade2  Grade3  
ER/PR  Positive   Negative  
Her2  Negative   Positive  
LVI Absent  present   
 
• Low risk  - Hormonal manipulation or nil.  
• Average  - Hormonal +/ - chemotherapy for ER/PR positive disease,  
 
15 www.nccn.org . 
16 www.eviq.org.au


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  Chemotherapy for ER/PR negative disease.  
• High risk - Chemotherapy + hormonal manipulation for ER positiv e disease.  
Chemotherapy for ER/PR negative disease.  
• For Her-2 positive disease , Herceptin is given with chemotherapy for total of 
52 weeks (3 weekly).  
• Hormonal manipulation -  
In premenopausal women; Tamoxifen alone may be an option . In patients who 
remain premenopausal after che motherapy  and have high risk disease , ovarian  
suppression with LHRH agonists or bilateral oophorectom y with exemestane or 
Tamoxifen is better than Tamoxifen alone.  Aromatase Inhibitors are not used 
alone in premenopausal women.  
Consider 10 years of tamoxifen over 5 years of treatment, particularly f or patients 
at highest baseline risk eg where chemotherapy was indicated.  
In post -menopausal women  - Aromatase inhibitors are the preferred endocrine 
treatment unless contraindicated. In patients who cannot tolerate AI or where it is 
contraindicated, Tamox ifen is used.   
In post -menopausal patients who start treatment with tamoxifen, switching to AI 
after 2 -3 years is recommended.  
5-10 additional years of aromatase inhibitors after 5 years of tamoxifen improves 
survival in high -risk patients.  
For patients on AIs and documented osteopaenia addition of bisphosphonates  
decreases the risk of decline in bone density.  They are also encouraged to take 
regular calcium and vitamin D tablets.  DEXA scans are done yearly to two yearly


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For patients on AIs and documented osteopaenia addition of bisphosphonates  
decreases the risk of decline in bone density.  They are also encouraged to take 
regular calcium and vitamin D tablets.  DEXA scans are done yearly to two yearly 
for monitoring bone  health in patients on aromatase inhibitors.  
Chemotherapy regimens - 
• Lower risk/Average risk - 4x TC,  
• High risk - 3x FEC - 3x D OR  AC-weekly Taxol  OR AC - dd Taxol . AC may 
be given in dose dense fashion (preferred if possible).  
• In Her-2 positive disease , Trast uzumab  is combined with Taxanes and not 
with anthracyclines because of risk of cardiac toxicity. Eg FEC -D Herceptin 
or AC -Taxol Trastuzumab .  Pertuzumab may be added in treatment given 
neoadjuvantly.  
• In Her2 positive disea se, a non -anthracycline regimen , eg TCarboH is an  
alternative .17 
 
17 Slamon, D., W. Eiermann, et al. (2011). "Adjuvant trastuzumab in HER2 -positive 
breast cancer." New England Journal of Medicin e 365(14): 1273 -1283


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 • G-CSF prophylaxis - If severe neutropenia, cycles delayed because of 
neutropenia or complicated by neutropenic fever, add neulasta  (most of these 
protocols now have upfront G -CSF)    
Neoadjuvant chemotherapy:  
• Chemotherapy regim ens are similar to adjuvant regimens.  
• More effective in triple negative or Her -2 positive disease.  
• May be used to achieve breast conservation in some cases, large primary 
tumour sizes, clinical nodal involvement (locally advanced disease) or if 
surgical c oncerns for upfront surgery.  
• Patients with residual cancer after neoadjuvant chemotherapy may require 
further chemotherapy treatment or a change in agent (eg capecitabine if triple 
negative, TDMI (trastuzumab emtansine) if HER2 positive).  
Post -operative  radiotherapy:  
• After lumpectomy, radiotherapy decreases local recurrence rates.  
• After mastectomy, indications include (but not limited to):  
o close or positive margins  
o >/=4 axillary nodes involved  
o tumour size >5 cm  
• Extensive lymphovascular inva sion.  
Radiotherapy is given after the chemotherapy is completed, but can occur 
concurrently with Herceptin in Her2 positive disease  
Locally advanced and inflammatory breast cancers  
• The cure rate is lower than with early breast cancers.  
• Chemotherapy is giv en before surgery to reduce the size of the primary and 
eradicate micrometastases (see above for regimens).  
• Radiotherapy is given after surgery.  
Metastatic breast cancer


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• Chemotherapy is giv en before surgery to reduce the size of the primary and 
eradicate micrometastases (see above for regimens).  
• Radiotherapy is given after surgery.  
Metastatic breast cancer  
• First line ER/PR + HER2 - bone only metastases - Endocrine therapy +/ - CDK 
4/6 inhibitor (eg palbociclib or ribociclib) . 
• Patients with bone metastases also benefit from monthly Bisphosphonates or 
Denosumab to reduce pain, skeletal events and hypercalcemia.  
• First line chemotherapy is  usually Taxane or Anthracycline based (depending 
upon chemotherapy exposure in adjuvant setting) with combination therapies


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 generally reserved for patients with high volume disease (including visceral 
disease) or suggestion of aggressive clinical course . 
Later lines of therapy can include taxanes, gemcitabine, capecitabine, 
vinorelbine and eribulin.  Choices may be influenced by patient and physician 
preferences, previous chemotherapy exposure and patient fitness.  For further 
detailed information on these  protocols , visit eviQ website.  
• In Her 2 positive disease, Taxanes can be combined with Trastuzumab  and 
Pertuzumab as initial treatment.  
Second line treatment may include TDM1 (Trastuzumab emtansine ). If 
progression on TDM -1, use Lapatanib/capecitabine a nd Herceptin/ 
chemotherapy .


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 Cancers of the Gastro -Intestinal Trac t 
Anal Cancer  
 
Majority of patients are treated with concurrent chemo -radiation. This requires PICC 
insertion and CADD pump for delivery of continuous infusion 5 - Fluorouracil.  
 
Regimen:  
Mitomycin C on Day 1 and 5 -Fluorouracil on Days 1 to 4 and 29 to 32 along 
with radiation for 5 -6 weeks  (standard of care).  
 
Mitomycin C can be substituted with Cisplatin  (if patient has hypersensitivity to 
mitomycin or has any coagulation or bleeding disorders or thrombocytopenia).  
If patient cannot have PICC for some reason 5 -Fluorouracil can be substituted 
with Capecitabine.  
 
Metastatic Anal Cancer: Different chemother apies can be used such as, 
Carboplatin & Paclitaxel (weekly/three weekly), 5Fu & Cisplatin, FOLCIS 
(5Fu, leucovorin & Cisplatin), mFOLFOX, mDCF.  
 
Gastro -Oesophageal and Gastric Cancer  
 
Definitive Concurrent Chemo -Radiation  
 
For those not suitable for surgery:  
Cisplatin and 5 -Fluoruracil along with radiation (2 cycles)  
 
Neo-adjuvant  chemoradiation : 
 
Weekly Carboplatin and Taxol  
Alternatively, Cisplatin and 5 -Fluorouracil with radiation.  
 
Peri-operative chemotherapy : 
 
For aden ocarcinoma of lower oesophagus, gastro -oesophageal junction and stomach.  
4 cycles FLOT pre and post resection.  
or, 3 cycles of ECF / EOX  pre and post resection . 
or 2 x cis/5fu pre & post resection.  
 
Advanced or Metastatic Carcinoma of Gastro -oesophageal J unction/Stomach:


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4 cycles FLOT pre and post resection.  
or, 3 cycles of ECF / EOX  pre and post resection . 
or 2 x cis/5fu pre & post resection.  
 
Advanced or Metastatic Carcinoma of Gastro -oesophageal J unction/Stomach:  
 
Different single agent/combination regimens can be used depending on existing co -
morbidities. Many regimens can be used for both adenocarcino and squamous cell 
carcinoma.  
Combination : FOLFOX 6  or XELOX  
Single agents:  Docetaxel, paclitaxel, irinotecan  
 
For HER -2 positive adenocarcinoma – Add Trastuzumab (Herceptin).


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CERS OF THE GASTRO -INTESTINAL TRAC  
Biliary and Gall Bladder  
Outcome is usually poor in patients with multiple co -morbidities and poor performance 
status. In these cases, omitting chemotherapy from management plans may be prudent.  
• Adjuvant therapy for node positive disease – fluoropyrimidine or Gemcitabine 
based chemotherapy (eg: Cisplatin or Carboplatin /Gem citabine).  
Consider chemoradiati on for margin -positive or node positive cancer.  
• Metastatic/inoperable – Same regimens as adjuvant therapy.  
Hepatocellular carcinoma  
• Limited disease: Operable or locoregional therapy available  
• Inoperable  or not suitable for locoregional therapy:  Lenvatinib  or Sorafenib  
in Child -Pugh A patients) . Role of systemic chemotherapy is not established.  
 
Metastatic Neuro -endocrine Tumours of Gastro -intestinal Tract  
• Grade I/II – Sandostatin/Lanreotide . On progression capecitabine and 
temozolomide.  
      Everolimus or sunitinib can be used for pancreatic Grade I/II tumours.  
• Grade III – Carboplatin and etoposide or cisplatin and etoposide .  
Adeno -carcinoma of Pancreas  
Role of neoadjuvant therapy contin ues to evolve, and this is usually not standard practice 
outside of clinical trial settings except where an MDT strongly recommends this 
approach. Outcome is usually poor in patients with multiple co -morbidities and poor 
performance status. In these cases,  omitting chemotherapy from management plans may 
be prudent.


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approach. Outcome is usually poor in patients with multiple co -morbidities and poor 
performance status. In these cases,  omitting chemotherapy from management plans may 
be prudent.  
 
• Adjuvant – modified FOLFORINOX x 6 months or Capecitabine + 
Gemcitabine . 
• Advanced/metastatic – If disease recurrence occurs after 6 months of 
completing adjuvant therapy, same regimen could be c onsidered. In good 
performance patients with minimal co -morbidities, m FOLFIRINOX or 
Gemcitabine and nab -Paclitaxel.  After 4 -6 months, less intensive components 
could be maintained.


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 In poor performance patients, BSC alone or single agent  regimens such as 
gemcitabine  may be appropriate.  
 
 
 Colon Cancer  
Stage I and II surgery alone.  
Stage II with adverse features is  treated as stage III with adjuvant chemotherapy. 
Adverse features are – poorly differentiated histology, lympho -vascular invasion, 
bowel obstruction, perforation, fewer than 12 lymph nodes in the resected 
specimen, perineural invasion, close or positive m argins.  
Adjuvant chemotherapy  is for six months. However, in low risk patients (T1 -3 
N1) shorter duration (three months) of adjuvant XELOX (CAPOX) is equivalent 
to six months of XELOX in efficacy with less neurotoxicity . If using mFOLFOX 
recommendation is for six months of treatment. For High risk features, 
recommendation is for six months of treatment.  
Regimens : Different schedules of calcium leucovorin and 5 fluorouracil, 
Capecitabine, FOLFOX  & XELOX . 
Metastatic cancer : Any adjuvant regimen can be used in metastatic setting. Other 
regimens are Irinotecan, FOLFIRI, FOLFOXIRI, XELIRI.  
Assess patients with imaging after 3 cycles of chemotherapy for respectability  of 
lesions. Discuss  in GI multi -disciplinary meetings. Some of the patients with few 
metastases ma y eventually be curable.  
Bevacizumab is usually combined to different chemotherapy regimens in 
metastatic setting unless contra -indicated.  
Patients with KRAS wild type tumours have additional option of having


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metastases ma y eventually be curable.  
Bevacizumab is usually combined to different chemotherapy regimens in 
metastatic setting unless contra -indicated.  
Patients with KRAS wild type tumours have additional option of having 
Cetuximab/ Panitumumab added  to chemotherapy re gimen.  
 
Rectal Cancer  
Most of the patient s are treated with neo -adjuvant concurrent chemo -radiotherapy.  
Chemotherapy consists of continuous infusion 5 -Fluorouracil through PICC line or oral 
capecitabine. If the patient did not receive neo -adjuvant treatmen t it may be given post -
operatively for T3/T4 or node positive tumours.


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 For those who had neo -adjuvant treatment further adjuvant chemotherapy is offered post -
operatively in the form of leucovorin -5-Fluorouracil/capecitabine  to complete six months 
of perio perative chemotherapy.  
FOLFOX is currently not approved for rectal cancer.  
 
Metastatic rectal cancer  
All the regimens used in colonic cancer can be used in metastatic rectal cancer including 
Bevacizumab, cetuximab and panitumumab.  
Assess patients with imag ing after 3 cycles of chemotherapy for res ectability of 
lesions. Discuss  in GI multi -disciplinary meetings. Some of the patients with few 
metastases may eventually be curable.  
 
Gastro-Intestinal Stromal Tumours (GIST)  
• Adjuvant  – for those with high risk features – Imatinib for 3 years . 
High Risk Features are : Primary GIST greater than 5 cm with a mitotic count of 
greater than 5/50 high power fields (HPF); or  
Primary GIST greater than 10 cm with any mitotic rate; or  
Primary GIST with a mitotic count of greater than 10/50 HPF  
• Metastatic  -   Imatinib. Sunitinib can be used when progress on Imatinib.


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 GBM  
• Surgery is for resectable disease.  
• For resected GBM, Temazolamide with RT and 4 weeks later, 5days per 
month for 6 m onths of Temazolamide improves survival.   
Temazolamide:  
• With RT - 75mg/m2/day M -F. 
• After RT or on its own for palliation - 150-200 mg/m2/day for 5 days a 
month.  
Check platelets mid cycle as a caution.  
Unresectable and incurable GBM - options include Temazolam ide & Avastin 
based combinations.  
GERM CELL TUMOURS   
Stage 1 -   
• Normally for stage 1 seminoma  (make sure serum AFP normal)  - Single 
dose carbo platin AUC 7.  Check counts every week for 2 weeks post  
chemotherapy . 
Discuss sperm banking  with patient prior to g iving chemotherapy. However , 
fertility is unlikely to be affected  with one cycle of carboplatin.  
• For stage 1 non -seminoma - wait and watch (6 weekly markers and 3 
monthly CTs first 2 years and later relax to 6 monthly scans and 3 monthly 
bloods for another 3 years).  
or 2 cycles of BEP for patients who are not reliable for follow up  or who move 
around different towns . 
Stage 2 onwards -  
This includes patients with normal scans but have the markers eleva ted few weeks 
post orchidectomy.  
Seminoma:  
• Stage 2 or stage 3: 
Good prognosis - 3 cycles of BEP . 
Intermediate prognosis - 4x cycles of BEP ( only first 3 cycles are with Bleomycin).  
• Non seminoma   
Good prognosis - 3 x cycles of BEP,


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 Intermediate or poor prognosis - 4x cycles of BEP.  
Residual disease /mass  after optimal chemotherapy needs to be resected.  
Pre BEP treatment:  
• History of renal, auditory,  neuropathy and vascular issues,  
• Lung function test - DLCO and lung volumes,  
• Sperm banking  (Semen cryopreservation: In Townsville, this is performed by 
QFG) , ELFTS, FBC, LDH and markers.  
(Please discourage smoking ). 
• Recurrent GCTs can still be cured by TIP or VIP chemotherapy.  
Prognostic groups:  Seminoma:  
 
 Good prognosis  Intermediate prognosis  
Primary site  any any 
Presence of non 
pulmonary met astasis no yes 
Markers  (not AFP)  any any 
 
If serum  AFP  is elevated, it is treated as non -seminoma.  
Non -Seminoma:  
 
 Good  Intermediate  Poor  
Primary site  Non mediastinal  Non mediastinal  mediastinal  
Non pulmonary 
metastasis no no yes 
Markers   
AFP <1000  1000 -10000  >10000  
B HCG  <5000  5000 -50000  >50000  
LDH  <1.5 x ULN  1.5-10 x ULN  >10 x ULN


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HEAD AND NECK CANCER  
• Resectable disease - Surgery.  
For high risk disease, post op radiotherapy with chemotherapy improves survival.  
• Unresectable  disease or organ preservation -  
Induction chemotherapy followed by chemoradiotherapy.  
Induction chemotherapy - 2 -3 cycles of T PF. 
Chemoradiotherapy - weekly cisplatin 40mg/m2.  
• *If not fit for weekly cisplatin , abnormal renal function or cardiac issues -  
Cetuximab ( Erbitux ) Loading dose 400mg/m2 one week prior to RT and then 
weekly 250mg/m2 weekly  (Discuss with Radiation oncologists for their 
preference ). 
They need Phenergan 12.5mg or 25mg as premed ications .  
• Metastatic H&N cancer - (Cisplatin or Carboplatin) and 5FU / Capecitabine  
Second -line -PDL1 antibody Nivolumab.  
LUNG CANCER  
• Non Small Cell Lung cancers:  
*Stage I to III - Surg ical resection  offers the best chance of cure.  
• For resected stage 1b, II or III  -  
Adjuvant chemotherapy with cisplatin  & vinorelbine x 4 cycles to improve 
survival in fit and <70 years.  Carboplatin & paclitaxel  is other alternative.  
• *Stage III - 
For patients who are unresectable, chemo -radiation can improve survival.  
• concurrent with radia tion-  
Cisplatin with Etoposide is the preferred regimen. Other alternativ es are used in 
patients who are unfit for Cisplatin (elderly, renal impairment etc) . 
Eg - Carbo platin (AUC 2) and Paclitaxel (50mg.m2) weekly with radiation.   
Post CRT immunotherapy improves outcomes.


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patients who are unfit for Cisplatin (elderly, renal impairment etc) . 
Eg - Carbo platin (AUC 2) and Paclitaxel (50mg.m2) weekly with radiation.   
Post CRT immunotherapy improves outcomes.  
 
Non metastatic pan coast tumours  - chemo -radiotherapy followed by surgery.  
• *Stage IV or incurable stage III b-  
Always test for oncogenic mutations like EGFR , ALK  and ROS -1 in Non 
Squamous  NSCLC. If either is positive, treat with EGFR inhibitor ( Afatinib is


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 preferred or Erlotinib or Gefitinib) or ALK inhibitor (Alectinib is preferred or 
Crizotinib ).  
• All NSCLCs (non squamous or squamous) should also be tested for PDL -1 by 
IHC (to check for eligibility of using immunotherapy alone as first line treatment). 
If PDL -1 expression >50%  and there is no actionable mutation , then single agent 
Pembrolizumab (anti PDL -1) can be offered as upfront treatment (without 
chemotherapy).  
• For NSCLC patients with PDL -1 expression less than 50% and  with no actionable 
mutation, consider offering combination of immunotherapy (anti PDL -1) along 
with platinum doublet chemotherapy if performance status is reasonable (ECOG 
<=2) . 
• Maintenance Pemetrexed  chemotherapy can be considered in patients with Non 
Squamous  NSCLC who have not progressed after first line combination 
treatment.  
• All these patients with incurable disease should be considered for clinical trial if 
one is available.  
• In select  patient  groups (e.g elderly with good PS, or patients who have 
contraindication for immunotherapy like significant autoimmune disorder), single  
agent chemotherapy alone is a reasonable option  
Once first line treatment with chemotherapy fails – consider treatment with  anti 
PDL -1 antibody  (e.g Nivolumab) for 2nd line treatment.  
• Palliative best supportive care is reasonable for patients with poor (ECOG>2) PS. 
Consider early referral to palliative care for all stage IV lung cancer patients


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PDL -1 antibody  (e.g Nivolumab) for 2nd line treatment.  
• Palliative best supportive care is reasonable for patients with poor (ECOG>2) PS. 
Consider early referral to palliative care for all stage IV lung cancer patients 
undergoing active treatment as this has shown to improve survival.  
Small cell lung cancer  
• Limited stage -  
Cisplati n and etoposide x 4 cycles and radiation as early as possible or Carboplatin 
and etoposide for 6 cycles and radiation.  
At the end of the treatment, if no brain mets - Prophy lactic cranial irradiation to 
add another 5% survival benefit.  
• Extensive stage - 
Carboplatin and etoposide with immunotherapy for 6 cycles. If complete response 
that last for 6 -12 months, could have re treated.  
• Urgent chemotherapy (with or without  tumour ly sis prophylaxis ) for patients 
presenting with bulky disease and oncology emergency (e.g SVC obstruction).


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 Mesothelioma  
Surgical decortication can be useful in selected patients.  
Otherwise, Carbo AUC 5 or Cisplatin and Pemetrex ed every 3 weeks.  
Important - 1 week before Pemetrex ed - start VitB12 1000mcg IM every 9 
weeks and folic acid 0.5 mg daily until Pemetrex ed is stopped.  
Consider Clinical trial for these patients if available.  
 
 
 
 
MELANOMA  
• Stage I to III - resection of the primary +/ - sentine l node biopsy and node 
dissection for node positive disease.  
o Stage IB or II can be considered for clinical trial with adjuvant 
treatment if available otherwise ongoing surveillance.  
• For stage III disease : 
o Stage IIIA disease: consider imaging and BRAF muta tion testing. 
Consider systemic treatment on clinical trial, otherwise surveillance.  
o Resected stage IIIB/C/D disease: imaging to confirm staging and 
BRAF mutation testing. Immunotherapy  (anti PD -1) for BRAF WT 
disease, or Dabrafenib (BRAFi) and Trametinib (MEKi) for patients 
with BRAF V600 mutation. Observation is also an option. Treatment 
subject to ECOG 1 or less.  
o Unresectable stage III disease: treat as unresectable stage IV disease.  
o Consider adjuvant radiotherapy in patients with involved surgical 
margi ns. 
• Stage IV disease  
o Limited/oligometastatic (resectable) disease. Imaging to confirm 
staging. BRAF mutation testing. LDH. Systemic treatment followed 
by imaging and resection OR resection followed by systemic 
treatment.


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margi ns. 
• Stage IV disease  
o Limited/oligometastatic (resectable) disease. Imaging to confirm 
staging. BRAF mutation testing. LDH. Systemic treatment followed 
by imaging and resection OR resection followed by systemic 
treatment.  
▪ Systemic treatment depending on BR AF and performance 
status.  
▪ Systemic options are the same as resected stage III disease


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 o Disseminated (unresectable) disease.  
▪ In patients without brain metastasis: systemic therapy as 
above, intralesional T -VEC, palliative resection or RT. Best 
supportive care.  
▪ With brain metastasis: Primary RT , Palliative resection with or 
without adjuvant RT , Followed by systemic therapy as above  
or combination immunotherapy in low volume cases .


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 GYNAECOLOGICAL CANCER  
• Ovarian cancer  
Stage 1 - Surgery  (adjuvant chemotherapy for high risk patients such as with 
tumour rupture or positive peritoneal washings) . 
Stage >/= 2 Debulking surgery, BSO/TAH.  
Post debulking su rgery - Carbo AUC 5/6 and Taxol weekly or three weekly  (three 
weekly generally prefe rred) .   
Patients who are unfit for surgery can be given neo adjuvant chemotherapy first 
and receive surgery after several cycles of chemotherapy (interval debulking) with 
subsequent adjuvant chemotherapy.  This approach may reduce surgical morbidity 
of de bulking procedures without compromising outcomes.  
Intraperitoneal chemotherapy may be used in selected stage3 disease, after 
optimal debulking surgery.  
In patients who have metastatic disease (stage 4) or those who do not achieve 
optimal debulking (residua l disease >1cm), bevacizumab for one year may be 
used on the PBS.   
 
• Relapsed Disease  
Choice of agent may depend upon interval since last exposure to platinum (ie 
platinum sensitive versus resistant).  
Newer agents such as PARP inhibitors may be used depending upon BRCA 
mutation status . 
Protocols include carboplatin/caelyx, carboplatin/gemcitabine and topotecan . 
Cervical cancer  
• Early disease - surgery  
• Locally advanced - chemoradiotherapy with weekly cispla tin, 
• Metastatic - Platinum/ Taxol / Bevacizumab , Taxol/Topotecan , Gemcitabine .


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48 
 CANCERS OF GENITO URINARY SYSTEM  
PROSTATE CANCER  
Treatment depends on disease stage and hormone sensitivity.  
 
• Early stage disease  is treat ed with surgery, radiotherapy ( externa l beam and/ 
or brachytherapy) or observation. Treatment modality is individualised based 
on several factors: age and co morbidities of the patient, serum PSA level, 
Gleeson score, clinical stage and patient preference based on benefits and 
side effects of therapy.  
For example, a patient with clinically non apparent tumour with Gleason score of 
<6 who has a life expectancy of <10 years coul d be actively observed without any 
impact on survival.  
For locally advanced inoperable disease, radical radiotherapy cou ld lead to cure. 
Androgen deprivation therapy is sometimes used for short periods  (4-6 months) 
before/concomitantly/ after radiotherapy in selected high-risk patients.  
 
Metastatic disease  is incurable and the aims are to prolong survival and improve 
quali ty of life.  
 
Hormone Sensitive disease:  
• All Hormone sensitive tumours are treated with a GnRH agonist  (eg- 
goserelin,  leuprorelin). To prevent flare, antiandrogens  (eg- flutamide,  are 
started 1-2 weeks before the injection  and continued for a total of 3-4 weeks ). 
Whether anti - androge ns are continued beyond that is  controversial.  
• Chemotherapy wi th Docetaxel 75 mg/m2 x 6 doses , can be added to 
hormonal therapy  in fit patients with high volume (presence of visceral mets


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Whether anti - androge ns are continued beyond that is  controversial.  
• Chemotherapy wi th Docetaxel 75 mg/m2 x 6 doses , can be added to 
hormonal therapy  in fit patients with high volume (presence of visceral mets 
or >= 4 bony mets)  metas tatic disease, as it improves survival significantly 
(CHAARTED, STAMPEDE trials).  
Hormone Refractory disease:  
• Hormone refractory disease includes patients where the disease has 
progressed despite hormonal manipulation.  GnRH agonists are usually 
continued.    
• Chemotherapy improves median survival by up to 3 months and maintains 
improvement in quality of life.   
• Bone metastases are treated with intravenous bisphosphonates  (eg-zoledronic 
acid) or RANK -ligand inhibitor Denosumab monthly.  For asymptomatic and 
low volume disease, chemotherapy is usually delayed.


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49 
 • Symptomatic metastases or rapid rise in PSA (doubling time of <3 months) 
may be treated with docetaxel  (75mg/m2)  and prednisone  5 mg BD.  On 
progression after doc etaxel, newer androgen inhibitors (below) are effective.  
Palliative care is another option.  
• Localised bone pain responds to external beam radiotherapy very well. Men 
with multifocal painful bone metastases and those with persistent or recurrent 
pain despite receiving EBRT to maximal normal tissue tolerance may achieve 
palliation of their symptoms by treatment with bone -targeted radi oisotopes 
such as strontium -89. 
Disease progression after chemotherapy : Abiraterone , an andr ogen biosynthesis 
inhibitor or Enz alutamide an androgen receptor signalling inhibitor are effective . Median 
progression free survival and overall survival are better compared to placebo.  
Renal Cell Carcinoma  
• Metastatic renal cell carcino ma with clear cell  histology is  treated based on 
risk stratification  (example IMDC criteria) . 
• Low risk disease can be treated with tyrosine kinase inhibitors Sunitinib  or 
Pazopanib. Cabozantinib or Sorafenib can be used after failure of these. 
Sorefenib can also be used for  papillary carcinoma. Everolimus and axitinib 
are other second line options available.  
• Intermediate and high -risk disease is treated with combination 
immunotherapy Ipilimumab (anti CTLA4) and Nivolumab (anti PDL -1).


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are other second line options available.  
• Intermediate and high -risk disease is treated with combination 
immunotherapy Ipilimumab (anti CTLA4) and Nivolumab (anti PDL -1). 
• Once progressed on first like VEGF TKI, immunotherapy is drug of choice 
for second line treatment. Vice versa if disease progresses on immunotherapy 
then VEGF TKI such as Cabozantinib or Sunitinib or Pazopanib can be used.  
Urinary Bladder Cancer  
• Non-muscle invasive disease is treated with surger y and adjuvan t intravesical 
therapies (eg.  BCG  or Mitomycin ). 
• Muscle invasive disease is treated with surgery. Pre -op Cisplatin based (neo-
adjuvant) chemotherapy improves survival.  
• Adjuvant Cisplatin based Chemotherapy is considered for those at high ris k 
of recurrence such as T3/T4 tumours, lympho -vascular invasion or positive 
nodes  if neo -adjuvant therapy was not given .  
 
Inoperable disease may be managed with:  
• Radiotherapy with or without radio -sensitising chemotherapy with weekly 
cisplatin or mitomyci n and infusional 5 -Fluorourcil.


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50 
 • Chemotherapy alone (platinum and gemcitabine), or a  
• Palliative care alone.  
 
Metastatic disease  is managed with chemotherapy , immunotherapy  or palliative care 
alone.  
Platinum based chemotherapy is usually  the first line palliative treatment. One such 
regimen is Carboplatin and Gemcitabine.   
 
Immunotherapy with Pembrolizumab is used as second line treatment after failure of 
platinum -based  chemotherapy.


