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Myoconic Seizures

Myoconic Seizures

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Published by Rohit Vishal Kumar
Myoclonic Seizures are a special type of epileptic seizures which occur in Infants between 5 to 12 months of Age. It is also known as "Salaam Seizures" because the seizures the oriental salaam procedure. It can be a potential life threatening problem for the young infant

Some articles are provided here with in the hope the some parents will benefit from the material
Myoclonic Seizures are a special type of epileptic seizures which occur in Infants between 5 to 12 months of Age. It is also known as "Salaam Seizures" because the seizures the oriental salaam procedure. It can be a potential life threatening problem for the young infant

Some articles are provided here with in the hope the some parents will benefit from the material

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Published by: Rohit Vishal Kumar on Sep 29, 2008
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(Suppl. 11):27–37, 2003Blackwell Publishing, Inc.
International League Against Epilepsy
Treatment Strategies for Myoclonic Seizures and EpilepsySyndromes with Myoclonic Seizures
James W. Wheless and
Raman Sankar
 Department of Neurology and Pediatrics, Texas Comprehensive Epilepsy Program,University of Texas – Houston, Houston, Texas;and †Department of Neurology and Pediatrics, Mattel Children’s Hospital at UCLA,University of California – Los Angeles, Los Angeles, California, U.S.A.
Despite the availability of numerous treatment op-tions, the diagnosis and treatment of myoclonic seizures con-tinue to be challenging. Based on clinical experience, valproateand benzodiazepines have historically been used to treat my-oclonic seizures. However, many more treatment options existtoday, and the clinician must match the appropriate treatmentwith the patient’s epilepsy syndrome and its underlying etiol-ogy. Comorbidities and other medications must also be consid-ered when making decisions regarding treatment. Rarely, someantiepileptic drugs may exacerbate myoclonic seizures. Mostepileptic myoclonus can be treated pharmacologically, but somecasesrespondbettertosurgery,theketogenicdiet,orvagusnervestimulation.Becausemyoclonicseizurescanbedifficulttotreat,clinicians should be flexible in their approach and tailor therapyto each patient.
Key Words:
Myoclonic seizures—Epilepsy—Antiepileptic drug therapy.
Single myoclonic jerks in patients with epilepsy havelong been recognized. Myoclonus comes from the Greek 
meaningturmoil.Whilethis term was used by the Greeks to describe the erraticmovement often seen with myoclonic jerks, it aptly de-scribes the current state of therapy for myoclonic seizuresand myoclonic epilepsies. Jeavons addressed the prob-lem of nosology of the myoclonic epilepsies in 1977 (1),suggesting that myoclonic epilepsies were as difficult toclassifyastheyweretotreat.Myoclonushasbecomeade-scription for many semiologically and nosologically dif-ferent conditions. The treatment of myoclonic epilepsiesis still problematic 25 years later (2–7).One task for clinicians is to establish whether or notthe paroxysmal episodes that the patient is experiencingconstitute epilepsy. The first step in this process is todetermine if a reversible etiology is present. The physi-cian is then confronted with a clinical conundrum. My-oclonus may only be one part of an epilepsy syndrome,and several problems regarding its treatment exist: (a) notall antimyoclonic drugs are antiepileptic, (b) only someantiepilepsy drugs (AEDs) are antimyoclonic, (c) manymyoclonic epilepsies are refractory to treatment, and(d)someAEDs may exacerbatemyoclonus orinducemy-
Address correspondence and reprint requests to Dr. J. W. Wheless atTexas Comprehensive Epilepsy Program, University of Texas – Hous-ton, 6431 Fannin St., Suite 7044, Houston, TX 77030, U.S.A. E-mail:James.W.Wheless@uth.tmc.edu
oclonic seizures. If no reversible etiology is found, themyoclonus, which is one component of an epilepsy syn-drome, can be treated along with the syndrome. Accuratedefinitionofapatient’sepilepsysyndromeisanimportantfactor in treatment. Comorbidities and other medicationsmustalsobeconsideredwhenmakingdecisionsregardingtreatment.Historically, valproate (VPA) and clonazepam (CZP)have been used to treat myoclonic seizures based onclinical experience. Both drugs work by promoting
-aminobutyric acid (GABA) action in the brain. However,many more options are available today, and cliniciansmust match the appropriate treatment with the epilepsysyndrome and its underlying etiology. Most epileptic my-oclonus is treated medically, but some cases may respondto surgery, the ketogenic diet, or vagus nerve stimulation.Animal models of myoclonic seizures have played arole in evaluating the possible efficacy of drug therapy fortreatment of human myoclonic seizures. Animal modelscanbeclassified as thoseinvolving provokedseizuresandthose involving genetic models. Provocation of seizuresin the former is commonly accomplished by chemicalor electrical means, although other means, such as hy-poxia and intermittent light stimulation, have also beenused. Classic pharmacologic screening involving rodents,as used by the Anticonvulsant Screening Project of theNationalInstituteofNeurologicDisordersandStroke,hasproduced inconsistent information for predicting the effi-cacy of potential therapeutic agents against myoclonus.
With earlier-generation AEDs, models were only some-what predictive of efficacy. Only CZP and VPA havedemonstrated efficacy in animal models for protectionagainst all three seizure provocations involving subcuta-neous pentylenetetrazol, bicuculline, and picrotoxin (8).Ethosuximide (ESM), which was only marginally ac-tive against bicuculline, has been shown not to be auseful antimyoclonic AED (8,9). Phenytoin (PHT) andcarbamazepine (CBZ) clearly distinguished themselvesas agents that were mainly active in the maximal elec-troshock model (10). Among new-generation AEDs, fel-bamate (FBM) has shown clinical utility in a varietyof myoclonic seizures and was also active in protect-ing rats against subcutaneous pentylenetetrazol, subcu-taneous bicuculline, and subcutaneous picrotoxin (11).Gabapentin (GBP), the next agent to arrive on the UnitedStates market, has been shown to be ineffective in sub-cutaneous bicuculline and picrotoxin provocations in therodent(12)andappearstobeclinicallyusefulonlyforpar-tial and secondarily generalized seizures (13). Vigabatrin(VGB),likeGBP,hasnotdemonstratedsignificantactivityagainst subcutaneous bicuculline or picrotoxin challenge,and is not a clinically useful agent for most syndromesinvolving myoclonic seizures (14). Experience with GBPhighlights another difficulty in the use of animal mod-els for screening compounds to treat myoclonus. Kan-thasamy et al. (15) found GBP to be antimyoclonic in aposthypoxicrodentmodel,butnotformyoclonusinducedby administration of 
-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane).Experience with other new-generation AEDs has alsorevealedmanyinconsistencies.Lamotrigine(LTG),whichhas an animal testing profile resembling that of PHT (16),hasdemonstratedclinicalutilityfortreatingsomepatientswith juvenile myoclonic epilepsy (JME) (17). Paradox-ically, LTG is also known to exacerbate myoclonus insome patients (18
20). Topiramate (TPM), another new-generation agent, has been shown to be ineffective inblocking chemically induced seizures (21). Nevertheless,this medication may be of value in treating a variety of syndromes that involve myoclonus, as is discussed laterin this article.The most extensively described genetic model of epilepsy involves
Papio papio
, the photosensitive baboon(Fig. 1A). Killiam et al. (22) first reported that when theseanimals were subjected to intermittent light stimulation,paroxysmal discharges in the form of spikes and wavesor polyspikes and waves resulted (Fig. 1B). Behaviorally,bilateral and synchronous myoclonic jerks appeared andwerefollowedbygeneralizedconvulsiveseizures.Thein-volvementoftheGABAergicsysteminthismodelwasde-scribedindetailbyMeldrumandWilkins(23).Thismodelcorrectly predicted GBP
s lack of efficacy in human my-oclonic epilepsies (24). However, VGB was shown to beeffective in blocking photically induced epileptic activity
FIG. 1. A:
Baboon in the primate chair for EEG recording.
EEG demonstrating a photomyoclonic response in
Papio hamadryas anubis 
, cynocephalus, an animal model for photosen-sitiveepilepsy.(FigurecourtesyofDr.C.AkosSzabo,UniversityofTexasHealthSciencesCenter,SanAntonio,TX,U.S.A.,reprintedwith permission.)
in the baboon (25), suggesting that the baboon model alsohas limitations in its ability to predict the clinical utilityof test AEDs. This model is apparently not routinely usedin screening, and many of the new-generation AEDs haveno published literature describing their use in this model.Another well-characterized genetic model involves thetottering mouse. The
locus causes a delayed-onset re-cessive neurological disorder in the mouse, featuring astereotyped triad of ataxia, intermittent focal myoclonicseizures,andburstsofgeneralized6-to7-Hzspikewaves.This model has not been routinely used in screening forAEDs; hence, its reliability for this purpose is unknown.Other genetic models of inherited myoclonus include adisorder of the inhibitory glycine receptor that results inspontaneous and stimulus-sensitive myoclonus in PolledHereford calves (26) and spontaneous and photically in-duced myoclonus in a mutant strain of Fayoumi chickens(27). The possible importance of the glycine receptor insome myoclonic disorders is highlighted by the recent de-velopmentofatransgenicmousemodelofhyperekplexia,which involves a mutation in the gene for the
sub-unit of the glycine receptor (28). However, the cost andinconsistent availability of these animals precludes their
 Epilepsia, Vol. 44, Suppl. 11, 2003
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
FIG. 2.
Severe myoclonic epilepsy in infancy (47) study design.
 Epilepsia, Vol. 44, Suppl. 11, 2003

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