document: lennox - gastaut syndrome ( lgs ) , one of the catastrophic epilepsies of childhood , is classified by the international league against epilepsy as a symptomatic generalized epilepsy syndrome . originally described in 1966 , this 
   tonic seizures ( especially during sleep ) , atonic ( astatic or drop attacks ) seizures , and atypical absence seizures are most commonly observed ; some patients also develop myoclonic , generalized tonic - clonic , or partial seizures . 
   the second feature required by the definition is an interictal awake electroencephalogram ( eeg ) pattern consisting of slow spike wave discharges ( less than 3 hz ) , usually with a generalized distribution . 
   another characteristic eeg feature is paroxysms of low voltage fast activity at about 10 hz during sleep . 
   the third component of the definition of lgs is cognitive impairment involving moderate to severe mental retardation and behavioral disorders including aggression and autistic features . over 75% of children with lgs 
   these include numerous congenital or acquired etiologies , such as cortical maldevelopment , perinatal hypoxia - ischemia , cns infection , or neurometabolic disorders . 
   about 20% of children with lgs have prior infantile spasms ( west syndrome ) and evolve into lgs with age . 
   the typical age of onset of lgs is between 2 and 5 years ; boys are affected about 5 times more often than girls.5 the prognosis of lgs is poor , with regard to both seizures and cognitive outcome . 
   risk factors for a poor cognitive prognosis include symptomatic etiology , history of nonconvulsive status epilepticus , prior infantile spasms , and early age of seizure onset.6 due to the encephalopathic nature and multiple seizure types , lgs is notoriously difficult to treat.7 many drugs reduce seizures initially , only to lose effectiveness over time . 
   children often end up on polypharmacy with numerous anticonvulsants , which adds to the cumulative side effects and drug 
   drug interactions.3 furthermore , the seizures themselves are thought to contribute to the cognitive impairment and behavioral comorbidities . 
   difficulties in diagnosing lgs are discussed in detail in a recent review.4 sometimes the classic clinical and eeg features are not present at the onset of the syndrome . due to the heterogeneous causes , 
   for example , it can be difficult to differentiate between spasms and tonic seizures and to identify and quantify atypical absence seizures accurately . 
   systematic difficulties complicate performance of drug trials in lgs , including the very frequent occurrence ( often nearly uncountable ) of atypical absence seizures , the inaccuracy of parental reports of seizure semiology and frequency , the wide range of etiologies , and the evolution of seizure types over time . 
   a few randomized , double blind , placebo - controlled trials of single agents have been performed in lgs.5,7 felbamate,8 lamotrigine,9 and topiramate10 reduced the occurrence of atonic and tonic - clonic seizures in children with lgs . 
   all of these studies entailed addition of the study drug to other medications , and the studies varied considerably in their experimental design and patient selection criteria . 
   no head - to - head trial comparing more than one drug has been published . 
   even with the new generation of anticonvulsants , valproic acid is considered the most useful initial medication of choice for drop attacks , atypical absences and myoclonic seizures in lgs.5,11,12 although there are no controlled studies , valproic acid is reportedly effective against multiple lgs seizure types including atypical absence , myoclonic , and other situations in which slow spike - wave discharges are found on eeg . 
   caution must be exercised in using valproic acid in children under the age of 2 years , especially if they are receiving several other anticonvulsants , because of the risk of hepatotoxicity . in that age group , it has been recommended to try topiramate or lamotrigine first.11 felbamate could also be considered as an alternative to valproic acid , because felbamate lacks the sedative side effect seen with other anticonvulsants ( eg , topiramate , benzodiazepines ) , which exacerbates seizure occurrence . 
   owing to the risk of aplastic anemia and hepatoxicity with felbamate use , this medication must be used with caution and appropriate patient monitoring of blood levels , liver function , and hematologic indices . 
   a recent study showed that clobazam significantly reduced both drop and non - drop seizures in a dose - dependent manner in patients with lgs.13 clobazam reportedly has less sedative effects than other benzodiazepines , making it an attractive potential adjunctive treatment for lgs . 
   an animal model of lgs does not exist , hampering progress in design of therapeutics . 
   it is not surprising that there is no experimental model , since lgs comprises so many distinct seizure types and lacks a consistent underlying etiology . 
   treatment of rats with a cholesterol synthesis blocker produces atypical absence seizures with slow spike waves , providing an opportunity to study the mechanism of this specific seizure type , which appears to involve gabab receptors.14 these observations have not yet been exploited therapeutically . 
   some general treatment considerations include recommendations to use as few anticonvulsants concurrently as possible to avoid side effects from polytherapy , avoid excessive drowsiness which exacerbates several of the seizure types in this syndrome , and consider the cognitive and psychological comorbidities which result from both lgs and its treatment . 
   clearly , a multidisciplinary approach is required to address the medical and psychosocial aspects of lgs . at present , authorities recommend valproic acid as the first line medication , followed by one or two of the second - line agents ( lamotrigine , rufinamide , topiramate , clobazam , felbamate , 
   levetiracetam).5,12 if those therapies fail to achieve treatment goals , zonisamide , the ketogenic diet , vagus nerve stimulation , or corpus callosotomy can be tried ( the latter targeting drop attacks ) . of note 
   , carbamazepine and gabapentin can exacerbate some of the seizure types in lgs.11,15 the role of newer anticonvulsants such as vigabatrin and zonisamide remain undetermined in lgs . 
   rufinamide [ 1-(2,6-difluoro - phenyl)methyl-1h-1,2,3-triazole-4-carboxamide ] is a triazole derivative granted orphan drug status for the adjunctive treatment of lgs in the united states in 2004 . 
   , rufinamide was approved by the united states food and drug administration for treatment of lgs in children 4 years of age and older . 
   it is also approved for adjunctive treatment of partial seizures in adults and adolescents.16 rufinamide is structurally unrelated to other anticonvulsants . 
   its mechanism of action reportedly involves decreased firing of high frequency sodium - dependent action potentials and prolongation of sodium channel inactivation.17 enhancing sodium channel inactivation would prevent a neuron from generating subsequent bursts of high frequency action potentials . 
   however , data implicating an effect of rufinamide on sodium channels is presently published only in abstract form and , given the preclinical profile , other mechanisms of action are likely to operate.18 rufinamide has a wide spectrum of anticonvulsant effectiveness in animals including the maximal electroshock model ( for generalized tonic - clonic and partial seizures ) and the subcutaneous pentylenetetrazol model ( for clonic seizures).19 in support of the hypothesized action of rufinamide on sodium channels , seizure protection in those in vivo models is also afforded by other anticonvulsants that block sodium channel function . 
   rufinamide also blocks seizures induced by subcutaneous strychnine , bicuculline , and picrotoxin.20 rufinamide has an excellent safety profile in animals and lacks obvious cognitive side effects and behavioral toxicity at clinically relevant doses . on the rotorod test of motor coordination 
   , rufinamide had a higher safety index than phenytoin , phenobarbital , and ethosuximide.19 the drug also appears to be relatively devoid of cognitive side effects in humans . in a multicenter study of 189 adolescent and adult patients with partial seizures , 12 weeks of treatment with 
   rufinamide failed to cause deficits ( compared to placebo ) in several measures of cognitive function , including psychomotor speed and alertness , processing speed , and working memory.21 taken orally , rufinamide is well absorbed ( 85% after an oral dose).22 the absorption rate is slow and the extent of absorption decreases as the dose is increased . 
   after a single 400 mg oral dose in healthy adults , the time to maximum plasma concentration ranges from 1.5 to 10 hours with an average of about 6 hours , with a mean maximum plasma concentration ( cmax ) of 3.03 g / ml.23 rufinamide has low protein binding ( 34% ) and food does not affect the time to maximum plasma concentration or peak plasma concentration.22 the plasma half life is 6 to 10 hours and is unaffected by renal disease . 
   rufinamide is eliminated primarily via metabolism , the principal metabolite being a carboxylic acid derivative . 
   this metabolite primarily appears in the urine , and only about 2% of rufinamide occurs in the urine unchanged . 
   the low plasma binding rate of rufinamide suggests that drug  drug interactions are likely to be minimal . 
   however , in conditions like lgs , in which polypharmacy is usual , careful elucidation of drug  drug interactions is necessary . in all of the clinical trials with rufinamide , 
   , there were no significant effects of rufinamide on the plasma concentrations of valproic acid , lamotrigine , or topiramate.24 there is no study of the effects of rufinamide on felbamate concentration . at average steady state concentrations of rufinamide , 
   this comparison includes population pharmacokinetic analyses of carbamazepine , lamotrigine , phenobarbital , phenytoin , and valproic acid . 
   however , phenytoin clearance was decreased at average steady state levels of rufinamide up to 21% , suggesting that phenytoin levels should be closely monitored in patients on concurrent rufinamide . 
   the clearance of rufinamide is not significantly affected by several other anticonvulsants including carbamazepine , phenytoin , primidone , and phenobarbital . 
   however , rufinamide clearance was decreased by valproic acid with elevated rufinamide levels of up to 70%.20 therefore , valproic acid therapy should be introduced cautiously and at relatively low doses in children already on rufinamide . 
   early sponsored studies , including open label extensions , provided data that rufinamide had a beneficial effect as add - on therapy for partial seizures in adolescents and adults . for lgs , a single double - blind randomized placebo controlled trial has been published.24 this study involved 138 patients between the ages of 4 and 30 years who had lgs diagnoses for a median of 7.5 years . 
   study subjects were randomized to either oral rufinamide ( titrated up to 45 mg / kg / day over 14 days ) ( n = 74 ) or placebo ( n = 64 ) in addition to their other antiepileptic drugs . 
   this study involved a 28-day baseline followed by an 84-day parallel group treatment ( 14 days titration , 70 days maintenance ) . 
   primary end points were the percent change in seizure frequency and the parent / guardian ratings of seizure severity . 
   the investigators found a significant decrease in total seizures compared with placebo ( 32.7% vs 11.7% : p = 0.0015 ) , and tonic - atonic seizures compared with placebo ( 42.5% vs + 1.4% : p < 0.0001 ) . 
   the patients on rufinamide also had a greater improvement in seizure severity and a higher 50% responder rate compared with placebo for both total seizures and tonic - atonic seizures . 
   adverse effects in this study were modest , with 24% of treated patients experiencing sedation and 21% experiencing vomiting . eight percent of the rufinamide group withdrew because of adverse side effects . 
   cognitive or psychiatric adverse events were less common among rufinamide - treated patients than in the placebo group . 
   it was concluded that rufinamide is well tolerated and efficacious for seizures in lgs . a 3-year open - label followup study , published in abstract form only 
   , reports continued rufinamide effectiveness.25 that study included 124 patients treated for a median of 432 days at a dose of 10 to 45 mg / kg / day . 
   compared to the placebo group , there was a decrease in total seizures at all time points assessed up to 3 years , ranging from 42.6% to 79.3% . 
   furthermore , rufinamide was well tolerated over the long term , with only 12 patients discontinuing the drug because of adverse side effects ( most commonly vomiting , pyrexia , and somnolence ) . a recently published study from europe , using observational retrospective data from multiple centers , examined the effectiveness of rufinamide in children and adults with refractory epilepsy , including lgs.26 in the subgroup with lgs , 17 of 31 patients ( 55% ) had a response rate with greater than 50% reduction in countable seizures . 
   investigators found fatigue , vomiting , anorexia in 10% to 20% of patients but no serious adverse effects . 
   again , this study concludes that rufinamide is effective and well tolerated in patients with refractory epilepsy , including lgs . 
   although promising as a novel anticonvulsant in lgs , several caveats arise regarding rufinamide . in part , issues relate to the study populations . 
   as discussed above , patients with lgs are notoriously difficult to treat , are often treated with multiple anticonvulsant medications , and seizures are of several different types and difficult to monitor and count . therefore , the question arises as to what place rufinamide will hold in overall treatment algorithm for lgs . 
   however , a larger number of patients must be treated with this medication to establish its role in the treatment armamentarium . 
   the role of this new medication in relationship to prior drugs with some reported effectiveness in lgs needs to be further defined . 
   taken orally , rufinamide is well absorbed ( 85% after an oral dose).22 the absorption rate is slow and the extent of absorption decreases as the dose is increased . 
   after a single 400 mg oral dose in healthy adults , the time to maximum plasma concentration ranges from 1.5 to 10 hours with an average of about 6 hours , with a mean maximum plasma concentration ( cmax ) of 3.03 g / ml.23 rufinamide has low protein binding ( 34% ) and food does not affect the time to maximum plasma concentration or peak plasma concentration.22 the plasma half life is 6 to 10 hours and is unaffected by renal disease . 
   rufinamide is eliminated primarily via metabolism , the principal metabolite being a carboxylic acid derivative . 
   this metabolite primarily appears in the urine , and only about 2% of rufinamide occurs in the urine unchanged . 
   the low plasma binding rate of rufinamide suggests that drug  drug interactions are likely to be minimal . 
   however , in conditions like lgs , in which polypharmacy is usual , careful elucidation of drug  drug interactions is necessary . in all of the clinical trials with rufinamide , 
   , there were no significant effects of rufinamide on the plasma concentrations of valproic acid , lamotrigine , or topiramate.24 there is no study of the effects of rufinamide on felbamate concentration . at average steady state concentrations of rufinamide , 
   this comparison includes population pharmacokinetic analyses of carbamazepine , lamotrigine , phenobarbital , phenytoin , and valproic acid . 
   however , phenytoin clearance was decreased at average steady state levels of rufinamide up to 21% , suggesting that phenytoin levels should be closely monitored in patients on concurrent rufinamide . 
   the clearance of rufinamide is not significantly affected by several other anticonvulsants including carbamazepine , phenytoin , primidone , and phenobarbital . 
   however , rufinamide clearance was decreased by valproic acid with elevated rufinamide levels of up to 70%.20 therefore , valproic acid therapy should be introduced cautiously and at relatively low doses in children already on rufinamide . 
   results from randomized controlled clinical trials of rufinamide are just appearing . early sponsored studies , including open label extensions , provided data that rufinamide had a beneficial effect as add - on therapy for partial seizures in adolescents and adults . for lgs , a single double - blind randomized placebo controlled trial has been published.24 this study involved 138 patients between the ages of 4 and 30 years who had lgs diagnoses for a median of 7.5 years . 
   study subjects were randomized to either oral rufinamide ( titrated up to 45 mg / kg / day over 14 days ) ( n = 74 ) or placebo ( n = 64 ) in addition to their other antiepileptic drugs . 
   this study involved a 28-day baseline followed by an 84-day parallel group treatment ( 14 days titration , 70 days maintenance ) . 
   primary end points were the percent change in seizure frequency and the parent / guardian ratings of seizure severity . 
   the investigators found a significant decrease in total seizures compared with placebo ( 32.7% vs 11.7% : p = 0.0015 ) , and tonic - atonic seizures compared with placebo ( 42.5% vs + 1.4% : p < 0.0001 ) . 
   the patients on rufinamide also had a greater improvement in seizure severity and a higher 50% responder rate compared with placebo for both total seizures and tonic - atonic seizures . 
   adverse effects in this study were modest , with 24% of treated patients experiencing sedation and 21% experiencing vomiting . 
   cognitive or psychiatric adverse events were less common among rufinamide - treated patients than in the placebo group . 
   it was concluded that rufinamide is well tolerated and efficacious for seizures in lgs . a 3-year open - label followup study , published in abstract form only 
   , reports continued rufinamide effectiveness.25 that study included 124 patients treated for a median of 432 days at a dose of 10 to 45 mg / kg / day . 
   compared to the placebo group , there was a decrease in total seizures at all time points assessed up to 3 years , ranging from 42.6% to 79.3% . 
   furthermore , rufinamide was well tolerated over the long term , with only 12 patients discontinuing the drug because of adverse side effects ( most commonly vomiting , pyrexia , and somnolence ) . a recently published study from europe , using observational retrospective data from multiple centers , examined the effectiveness of rufinamide in children and adults with refractory epilepsy , including lgs.26 in the subgroup with lgs , 17 of 31 patients ( 55% ) had a response rate with greater than 50% reduction in countable seizures . 
   investigators found fatigue , vomiting , anorexia in 10% to 20% of patients but no serious adverse effects . 
   again , this study concludes that rufinamide is effective and well tolerated in patients with refractory epilepsy , including lgs . 
   although promising as a novel anticonvulsant in lgs , several caveats arise regarding rufinamide . in part , issues relate to the study populations . 
   as discussed above , patients with lgs are notoriously difficult to treat , are often treated with multiple anticonvulsant medications , and seizures are of several different types and difficult to monitor and count . therefore , the question arises as to what place rufinamide will hold in overall treatment algorithm for lgs . 
   however , a larger number of patients must be treated with this medication to establish its role in the treatment armamentarium . 
   the role of this new medication in relationship to prior drugs with some reported effectiveness in lgs needs to be further defined . 
   rufinamide is a novel , broad - spectrum anticonvulsant drug with promising potential for treatment of many seizure types . in particular 
   , the multiple seizure types seen in patients with lgs may be amenable to treatment with rufinamide . 
   rufinamide appears to have a good safety profile and is well tolerated with minimal expected side effects . 
   some of the most common side effects ( eg , somnolence , vomiting ) could perhaps be ameliorated by slow titration . 
   patient and caretaker satisfaction data need to be obtained . given the devastating nature of the seizures and cognitive impairments in lgs , any treatment with an even modest benefit is a welcome addition to the therapeutic armamentarium .
summary: objective : this review summarizes the treatment of lennox - gastaut syndrome , an intractable epileptic encephalopathy of early childhood . in particular , the review focuses on rufinamide , a recently released anticonvulsant medication with reported effectiveness in this epilepsy syndrome.methods:a systematic literature search ( pubmed ) was performed to review the existing literature pertaining to the treatment of lennox - gastaut syndrome as well as studies involving rufinamide as an anticonvulsant medication.results:the published literature to date documents a beneficial effect of rufinamide on children over 4 years old with lennox - gastaut syndrome . 
   studies indicate a significant decrease in tonic and atonic seizure frequency as well as total seizure frequency compared to placebo - treated children . 
   rufinamide appears to be well tolerated and a safe medication , somnolence and vomiting being the most common side effects.conclusions:rufinamide is a promising adjunctive therapy for lennox - gastaut syndrome , an intractable childhood epilepsy . to ensure its optimal effectiveness 
   , clinicians must be familiar with the medication s clinical response profile and potential for adverse effects .