MYOCLONUS TREATMENT STRATEGIES 29
routine use for developing highly specific antimyoclonicdrugs.Economicforcescontinuetodrivethedevelopmentof AEDs for partial seizures, with subsequent adoption of some AEDs to treat myoclonic seizures based on clinicalexperience.No controlled clinical trials have solely evaluated theefficacy of treatment for myoclonic seizures; rather, theyhave evaluated the effect of treatment on epilepsy syn-dromes that may include myoclonus. This practice hasresulted from the difficulty in accurately quantifying my-oclonic seizures before and after treatment in controlledclinicaltrials.Thislimitationmustbeacknowledgedwhenevaluatingdrugtreatmentstrategiesformyoclonicepilep-sies. In this review of treatment options, the AmericanAcademy of Neurology Quality Standards Subcommit-tee practice guidelines (29) are used to classify the levelsof evidence for each treatment. These recommendationsare based on the following levels of evidence for thera-peutic modalities: (a) class I
controlled clinical trials;(b) class II
case-controlled and cohort studies; and (c)class III
evidence provided by case series, case reports,and expert opinions. For most epilepsy syndromes withmyoclonic seizures, the controlled trial data (class I evi-dence)onlyappliestotheoveralltreatmentoftheepilepsysyndrome, not specifically to the myoclonic component.As a result, most information presented in this article isbased on class II or class III evidence for the treatment of myoclonic seizures. Additionally, all the information pre-sented herein regarding therapies that may cause exacer-bationofmyoclonicseizuresisbasedonclassIIIevidence(typically case series).
EPILEPSY SYNDROMESWITH MYOCLONIC SEIZURESSyndromes of infancy and early childhood
Myoclonic seizures that begin in infancy are typi-cally associated with both poor response to treatment andpoor ultimate prognosis (3). Included in this category areearly myoclonic encephalopathy (neonatal myoclonic en-cephalopathy), infantile spasms, and severe myoclonicepilepsyininfancy(Dravetsyndrome).Benignmyoclonicepilepsy of infancy is an exception in that it can have agood response to treatment and a favorable prognosis. Forinfants and young children, there are few conditions thatfall between these two ends of the spectrum.Massiveoraxialbilateralmyocloniasarethemyoclonicfeaturesofearlymyoclonicencephalopathy.Thisraresyn-drome has onset during the first month of life and is oftenfatal by 1 year of age. The electroencephalogram (EEG)in patients with this condition reveals a burst-suppressionpatternandmayevolvetowardtypicalhypsarrhythmia.Nocontrolledclinicaltrialshaveinvestigatedthetreatmentof earlymyoclonicencephalopathy.Treatmentoptionsareallbasedonanecdotalreports,andalthoughdrugtherapyhasdemonstrated some efficacy, response to treatment is typ-ically poor and seizure freedom is rarely achieved. Noneof the conventional AEDs, adrenocorticotropic hormone(ACTH) gel, prednisone, or pyridoxine has been effec-tiveintreatingthissyndrome(30).Themyocloniasofthissyndrome gradually decrease with age.Thetreatmentofinfantilespasmsisbasedontheunder-lying etiology of the spasms (31,32). With respect to bothseizure control and developmental outcome, infants whohave underlying focal cortical dysplasia, porencephaliccysts, or (rarely) a brain tumor may show the best re-sponse to epilepsy surgery. Anecdotal and controlled trialdata indicate that VGB is the treatment of choice for in-fantilespasmsassociatedwithtuberoussclerosiscomplex(33
37).Childrenwithcryptogenicinfantilespasmsshowthe best response to ACTH in clinical trials (32,38). Useof VGB (32
35,39) and nitrazepam (NTZ) (40) to treatcryptogenic infantile spasms has also been evaluated inclinical trials. In Japan, pyridoxine is typically admin-istered as initial therapy for infantile spasms but has alow response rate (41
43). Other treatment options thathavebeenpursuedincaseseriesincludeVPA,prednisone,FBM, LTG, TPM, and zonisamide (ZNS) (38,39,44,45).The ketogenic diet has recently shown success in childrenwith refractory infantile spasms (cryptogenic and symp-tomatic etiologies) (46). Children with symptomatic eti-ologiesareoftentreatedwiththesamemedications,buttheresponse rate is much lower than in children with a cryp-togenic etiology (32,38,39,44). As such, in patients withsymptomaticetiologies,arisk/benefitassessmentmustbemade for each therapeutic option and discussed with thechild
s parents.Severe myoclonic epilepsy in infancy (Dravet syn-drome) begins with partial or generalized, often pro-longed, febrile seizures in normal infants before 1 yearof age. Myoclonus occurs between the ages of 1 and 4years, typically upon awakening. Children progress to ex-periencemultipleseizuretypes,andtheirpsychomotorde-velopment becomes retarded after the second year of life.Photoparoxysmal effects are common in this syndrome.Recent placebo-controlled, multicenter studies have eval-uated the efficacy of stiripentol in the treatment of severemyoclonicepilepsyininfancy(Dravetsyndrome)(47,48).In one study by Chiron et al. (47), children were typicallytreated with VPA and clobazam during the baseline phase(Fig. 2). They were then randomized to treatment with
Stiripentol (n=21)Valproate, clobazamPlacebo (n=20)8 weeks50 to 100 mg/kg/dStiripentol0 to 4 weeksBaseline
Severe myoclonic epilepsy in infancy (47) study design.
Epilepsia, Vol. 44, Suppl. 11, 2003