Introduction. Clinical manifestations

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1 Juvenile myoclonic epilepsy Fernando Cendes MD PhD (Dr. Cendes of the University of Campinas - UNICAMP has no relevant financial relationships to disclose.) Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.) Originally released October 18, 1993; last updated December 30, 2016; expires December 30, 2019 Introduction This article includes discussion of juvenile myoclonic epilepsy, benign juvenile myoclonic epilepsy, Herpin-Rabot-Janz syndrome, impulsive petit mal, jerk epilepsy, JME, juvenile myoclonic epilepsy of Janz, myoclonic epilepsy of adolescence, and myoclonic petit mal. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview In this updated article, the author discusses evidence concerning brain network damage and dysfunction, genetic factors, as well as prognosis and antiepileptic drug treatment in juvenile myoclonic epilepsy. Key points Juvenile myoclonic epilepsy is a form of generalized epilepsy with a strong genetic component characterized by (a) myoclonic jerks (cardinal symptom) that are most frequent in the early morning and (b) generalized tonic-clonic seizures. Typical absence seizures may also occur, but these are infrequent and short, and are often ignored by the patient. The differential diagnosis includes other types of idiopathic generalized epilepsies, juvenile absence epilepsy, and generalized epilepsy with generalized tonic-clonic seizures on awakening. Although juvenile myoclonic epilepsy has been considered a long-lasting condition, with frequent seizure relapses after withdrawal of medication, studies have shown that a significant proportion of patients become seizure free off medication. Sodium valproate is the most effective AED; however, the high risk of fetal malformations and other side effects limit its use in young women. Lamotrigine and levetiracetam are good alternatives, but lamotrigine may exacerbate myoclonus. Topiramate and zonisamide are also good alternatives. Benzodiazepines may have an adjunctive role for short periods. Lifestyle advice is an integral part of the treatment of juvenile myoclonic epilepsy. Patients should avoid sleep deprivation and drinking alcohol. Historical note and terminology Juvenile myoclonic epilepsy was first reported in France by Herpin (Herpin 1867). The terminology was variable until Janz and his colleagues in Germany reported 47 cases and proposed the name "impulsive petit mal" as a clinically definable epileptic syndrome (Janz and Matthes 1955; Janz and Christian 1957). The syndrome was later called juvenile myoclonic epilepsy (of Janz) in the English-speaking world (Asconape and Penry 1984; Delgado-Escueta and Enrile- Bacsal 1984). The International League Against Epilepsy suggested the equivalent terms "juvenile myoclonic epilepsy" and "impulsive petit mal" (Commission on Classification and Terminology of the International League Against Epilepsy 1989). A report of the ILAE Commission on Classification and Terminology suggests that juvenile myoclonic epilepsy should be classified as an electroclinical syndrome and to avoid the term idiopathic (Berg et al 2010). Clinical manifestations Presentation and course

2 Juvenile myoclonic epilepsy typically appears in the second decade. The age of onset ranges from 8 to 24 years, with peak onset between 12 and 18 years (Delgado-Escueta and Enrile-Bacsal 1984). It is characterized by myoclonic seizures, associated at times with generalized tonic-clonic seizures or absence seizures. The cardinal seizure type is that of myoclonic jerks characterized by sudden, brief, bilaterally symmetrical and synchronous muscle contractions. The intermittent and involuntary shocklike contractions ("secousse") affect mainly the shoulder and upper extremities; much less commonly, the lower extremities or the entire body may also be involved. Myoclonic seizures may occur either singly or in clusters (Asconape and Penry 1984; Janz 1985). Objects may be thrown as a result of jerks, or, rarely, patients may fall. Consciousness remains unimpaired during myoclonic seizures, even if they occur in series or in myoclonic status epilepticus (Janz 1989). Generalized tonic-clonic seizures appear after the onset of myoclonic seizures in the majority of cases (Asconape and Penry 1984). The average interval between the first myoclonic seizures and the beginning of tonic-clonic seizures is 3.3 years (Janz 1985). A convulsive seizure may begin with a series of myoclonic jerks of increasing intensity, followed by generalized myoclonus and then by generalized tonic-clonic seizures. This characteristic picture has been described as "myoclonic grand mal," "impulsive grand mal," and "clonic-tonic-clonic seizures" (Janz 1985). Both the myoclonic seizures and generalized tonic-clonic seizures have a special circadian pattern, ie, they occur almost exclusively on or soon after awakening, either from all-night sleep or from a nap (Asconape and Penry 1984). The myoclonic and generalized tonic-clonic seizures are frequently precipitated by early awakening, sleep deprivation, emotional stress, alcohol consumption, recreational drug use, or photic provocation (Dreifuss 1989; Janz 1989). Occasionally, they may also occur sporadically during the daytime, or when the patients are tired and relaxed. Photosensitivity occurs in approximately one third of the patients (Asconape and Penry 1984; Dreifuss 1989). Seizure precipitation by complex neuropsychological tasks, especially when they require some kind of motor action ("praxisinduction"), has been shown to be associated with juvenile myoclonic epilepsy in up to half of the patients (Matsuoka et al 2000). As peri-oral reflex myoclonias elicited by talking and reading are also frequent in this syndrome (Mayer et al 2001), the presence of some reflex epileptic traits seems to be one of its characteristics (Berg et al 2010; Thomas et al 2012). Absence seizures, usually of typical variants, occur in 15% to 30% of afflicted patients and begin at a mean age of 11.5 years (Asconape and Penry 1984; Delgado-Escueta and Enrile-Bacsal 1984), although these are infrequent and shorter than in childhood absence epilepsy or in juvenile absence epilepsy, and frequently go unnoticed by patients and family members (Thomas et al 2012). Intelligence usually remains normal in patients with juvenile myoclonic epilepsy (Janz 1985). However, associated immature personality, emotional instability, and inadequate social adjustment have been reported (Bech et al 1976; Wandschneider et al 2012). Together with higher seizure frequency, impulsive behavior correlates with worse social adjustment (Moschetta and Valente 2013). In 1 study, praxis-induced seizures were more common in males and patients with reflex traits presented higher rates of persistent myoclonia and more frequent psychiatric comorbidities (Carvalho et al 2016). Prognosis and complications Juvenile myoclonic epilepsy does not often remit spontaneously. A relapse rate as high as 90% after discontinuation of AEDs has been reported (Janz 1985; Schmidt 2000). Although lifelong therapy and lifestyle monitoring have been considered necessary, studies show that this is not the case for all patients (Penry et al 1989). A long-term follow-up study showed that early complete remission of generalized tonic-clonic seizures under AEDs significantly increased the chance for complete seizure freedom, and the occurrence of EEG photoparoxysmal responses significantly increases the risk of seizure recurrence after AED discontinuation (Geithner et al 2012). A population-based study showed that one third of patients did not require AED treatment 25 years after onset of seizures, with 17% being free of all seizure types and 13% with only myoclonus (Camfield and Camfield 2009). Another study showed that after a mean follow up of 45 years, 59% of patients were seizure free for 5 years or more, and 28% of those were off medication (Senf et al 2013). These authors also observed that the presence of absence seizures was an independent predictor of poorer outcome (Senf et al 2013). Hofler and colleagues showed that after a period of up to 36 years, 62% of patients with juvenile myoclonic epilepsy were seizure free of all types of seizures for more than 1 year, 53% for more than 2 years with AED, and 9% of patients were seizure free for more than 2 years without medication (Hofler et al 2014). They also found that absences in the first year of epilepsy, along with myoclonic and convulsive seizures, were associated with

3 poorer prognosis (Hofler et al 2014). Patients with psychiatric comorbidities also had a poorer prognosis (Brodie 2016). Further long-term studies with larger number of patients are necessary to determine the true risks of seizure recurrence and prognostic factors in patients with juvenile myoclonic epilepsy. It appears that patients with predominantly myoclonic seizures during adolescence and a few isolated tonic-clonic seizures have the best chance of complete control (Baykan et al 2013). Clinical vignette A 35-year-old woman was referred for consultation in the epilepsy clinic. She had a history of generalized tonic-clonic seizures since the age of 14. Seizures occurred mostly soon after awakening or after stressful moments, particularly when she was very tired or had lack of sleep. She brought a couple of normal EEGs and a normal MRI and said that her previous doctors, including a neurologist, did not know what she had because all the exams were normal. She was using carbamazepine and had taken phenytoin and phenobarbital in the past without good seizure control. Her neurologic exam was normal, and during the interview she confirmed that she had had myoclonic jerks in the morning, but she never thought that this was relevant. Doctors never asked her about these jerks, which did not bother her much. She was told that her diagnosis was juvenile myoclonic epilepsy. An EEG after partial sleep deprivation showed typical 4-Hz generalized spike and polyspike-and-slow waves with predominance over the frontal regions. Because she was overweight and the myoclonic jerks were not very frequent, she was prescribed lamotrigine, with a very slow titration up to 300 mg a day. She has been free of generalized tonic-clonic seizures and has had rare early morning myoclonus. This is a typical history, and it is easy to make a diagnosis of juvenile myoclonic epilepsy. It is still often misdiagnosed and mistreated by many physicians, even though it is one of the most common forms of epilepsy in young adults. Early morning myoclonic jerks is one of the most important features and should always be asked of patients with a history of generalized tonic-clonic seizures. Biological basis Etiology and pathogenesis Juvenile myoclonic epilepsy is an electroclinical epilepsy syndrome with a strong genetic component (Winawer et al 2003; Thomas et al 2012; Johannesen et al 2016). Not a single case associated with organic brain pathology has been reported, although a history of febrile or isolated seizures in childhood can be obtained in a minority of cases (Janz 1985; Janz 1989). However, functional and structural neuroimaging data have shown subtle, but consistent, abnormalities in patients with juvenile myoclonic epilepsies (Vollmar et al 2012; Wandschneider et al 2012; de Oliveira et al 2013; Focke et al 2014; Ekmekci et al 2016). Fifty percent of patients have first- and second-degree relatives with epileptic seizures (Delgado-Escueta et al 1989); 80% of symptomatic and 6% of asymptomatic siblings have diffuse 4- to 6-Hz polyspike-and-wave complexes in their EEG. Twelve percent of asymptomatic siblings also have diffuse, nonspecific EEG abnormalities. The concordance rate for monozygotic twins is 0.7 to 1.0, whereas that for dizygotic twins is the same as in siblings (Greenberg et al 1988). Despite long and intense genetic research, the genetics of the syndrome are not fully clarified. A polygenic mode of inheritance is the more likely cause as the different reflex epileptic traits that are frequent parts of the phenotype are also genetically determined. Evidence indicates that one gene involved in juvenile myoclonic epilepsy may be located on the short arm of chromosome 6 (Durner et al 1992), but it was not found in all investigated families (Elmslie et al 1996). Another candidate locus was found on chromosome 15q (Elmslie et al 1997) but, again, could not be found ubiquitously (Sander et al 1999). A relationship appears to exist between juvenile myoclonic epilepsy and other idiopathic age-related generalized epilepsies such as childhood absence epilepsy, epilepsy with grand mal seizures, and early childhood myoclonic epilepsy because more than one phenotype may exist in the same family (Winawer et al 2003). A number of genes predisposing to juvenile myoclonic epilepsy have been identified over the last decade, although

4 results are not always replicated in different studies indicating a high genetic heterogeneity (EPICURE Consortium 2012; Heinzen et al 2012). Among these genes, mutations in genes encoding for subunits of the γ-aminobutyric acid (GABA)A receptor and also in the Myoclonin1/EFHC1 gene appear to be relevant for juvenile myoclonic epilepsy (Cossette 2010; de Nijs et al 2012; Johannesen et al 2016). No specific pathophysiology has been identified for this idiopathic syndrome; however, there has been increased interest in the basic mechanisms of generalized epilepsies (Avoli et al 1990). There has been growing neuroimaging evidence for a thalamic-cortico-frontal network dysfunction in juvenile myoclonic epilepsies (Vollmar et al 2012; de Oliveira et al 2013; Focke et al 2014; Ekmekci et al 2016). These abnormalities do not appear to be secondary to seizures and may be genetically determined (Liu et al 2011; Wandschneider et al 2012). Indeed, unaffected siblings of juvenile myoclonic epilepsy patients showed abnormal fmri co-activation in the primary motor cortex and supplementary motor area, as well as abnormal functional connectivity between motor and prefrontal cognitive networks, similarly as in juvenile myoclonic epilepsy patients (Wandschneider et al 2014). Microstructural white matter and gray matter abnormalities were present in patients with new-onset juvenile myoclonic epilepsy using diffusion tensor imaging (DTI), indicating these abnormalities exist since the beginning of the disease (Ekmekci et al 2016). In addition, there is evidence for a network dysfunction, with hyperconnectivity involving primary motor, parietal, and subcortical regions that correlate with cognitive task performance (Caeyenberghs et al 2014). Epidemiology" The reported incidence of juvenile myoclonic patients among all epilepsies has increased from 2.7% in 1957, to 5.4% in 1977, and to 11.9% in 1984, as awareness of this disease has increased (Janz 1985; Delgado-Escueta et al 1989). Today, it is estimated that the prevalence of juvenile myoclonic patients is around 5% to 10% of all patients with epilepsy, with a clear predominance of women (Camfield et al 2013). Diagnosis may still be commonly missed, largely because patients fail to report their myoclonic jerks, and physicians fail to specifically ask about them. In one study, definitive diagnosis of a series of patients referred to an epilepsy center was delayed by a mean of 14.5 years (Grunewald et al 1992). The point prevalence was estimated at 5.6 out of 10,000 among people with less than 30 years of age in Norway. Juvenile myoclonic epilepsy constituted 9.3% of all epilepsies in that age group (Syvertsen et al 2017). Differential diagnosis The myoclonic seizures of juvenile myoclonic epilepsy are massive and bilaterally synchronous. They can be easily distinguished from other forms of nonepileptic myoclonus, which are characteristically focal and sporadic, as seen with the progressive myoclonus epilepsies (where there is coexistence of both nonepileptic myoclonus and epilepsy), certain lipid storage disorders, and postanoxic myoclonus. Myoclonic seizures occur in patients with other idiopathic generalized epilepsies such as the absence epilepsies, and epilepsy with grand mal seizures on awakening, but are not the most prominent features of these syndromes. The Lennox-Gastaut syndrome, epilepsy with myoclonic-astatic seizures, and epilepsy with myoclonic absences begin in childhood rather than adolescence and are associated with more frequent seizures and mental impairment. In the latter two, the myoclonic seizures usually involve the face and are associated with absences, whereas consciousness is not impaired during the myoclonic seizures of juvenile myoclonic epilepsy. Elicitation of the typical clinical features of juvenile myoclonic epilepsy (which requires the physician to ask specifically about jerks early in the morning) in association with the characteristic EEG pattern makes it difficult to miss this diagnosis. Diagnostic workup Because the jerks in juvenile myoclonic epilepsy are brief, without loss of consciousness, and take place in the morning soon after awakening, they are often interpreted as "nervousness" or "clumsiness" until generalized convulsions occur (Dreifuss 1989). Many patients ignore mild events and are unaware that they are abnormal (Thomas et al 2012). The EEG background activity is normal during wakefulness and sleep, except in case of antiepileptic drug (AED) intoxication or inadequate treatment. Seventy-four percent of patients have epileptiform interictal EEG patterns (Obeid and Panayiotopoulos 1988). Typical

5 interictal abnormalities consist of brief (1 to 3 seconds) 3- to 6-Hz generalized discharges of spike and polyspike-an- -slow waves that are usually asymptomatic, and sometimes may appear asymmetrical or with pseudo focalities (Lombroso 1997). Focal EEG features are relatively common and may contribute to misdiagnosis of juvenile myoclonic epilepsy as focal epilepsy; however, these focalities do not influence treatment response (Seneviratne et al 2014; Japaridze et al 2016). Classical 3-Hz spike-and-wave complexes or 3-Hz polyspike-and-wave complexes characteristic of typical absence seizures may occur in some teenagers. The ictal EEG is characterized by 10- to 16-Hz medium-high amplitude spikes followed by irregular slow waves. The number of spikes ranges from 5 to 20 per episode and correlates with the intensity rather than the duration of each seizure (Janz and Christian 1957). Provocative measures, such as photic stimulation and sleep deprivation, can help elicit the characteristic EEG abnormalities. Recording during the process of awakening may be necessary for the diagnosis (Janz 1985). Sleep deprivation is very effective in precipitating seizures. Praxis-induction is found by neuropsychological testing during EEG (Matsuoka et al 2000), and perioral reflex myoclonias, unless observed during the interview with the patient, require a video-eeg investigation that includes reading aloud and free talking (Mayer et al 2001). Polyspike-and-wave discharges are seen more frequently after nocturnal awakening than after morning awakening (Janz 1985). The incidence of photosensitivity has been reported to be as high as 30.5% (Janz 1985). Neurologic examination and neuroimaging studies are normal in this syndrome, although 1 study showed unrelated or nonspecific MRI abnormalities in up to 24% of juvenile myoclonic epilepsy patients (Betting et al 2006). There was a higher proportion of EEG focalities in patients with abnormal MRI, which were in most part concordant with the location of the MRI findings. Management Both medical treatment and counseling are important in the management of juvenile myoclonic epilepsy. Monotherapy with sodium valproate is the most effective in controlling myoclonic, generalized tonic-clonic, and absence seizures; however, the high risk of fetal malformations and other side effects limit its use, particularly in young women (Tomson et al 2016). Due to its reduced serum fluctuations and single daily dosage, divalproex sodium extended-release formulation may significantly improve tremor, weight gain, and gastrointestinal complaints while maintaining similar seizure control as valproate traditional formulation (Leppik and Hovinga 2013). Low doses of valproate (500 to 1000 mg) may be sufficient for initial treatment in juvenile myoclonic epilepsy (Hernández-Vanegas et al 2016). Lamotrigine is a good alternative for treating patients with juvenile myoclonic epilepsy, but it may exacerbate myoclonus (Mantoan and Walker 2011). Clonazepam is a useful add-on therapy for myoclonus and can be used in combination with lamotrigine to avoid its promyoclonic effects. The combination of lamotrigine and valproate may be an alternative for patients who fail seizure control with monotherapy. Levetiracetam is also a good alternative, in particular when lamotrigine exacerbates myoclonus. One study showed lower retention rate for levetiracetam than valproate due to poorer seizure control during long-term follow-up (Sala- Padró et al 2016). However, patients with levetiracetam achieved more myoclonic seizure freedom than those with valproate. Topiramate and zonisamide may be an alternative for some patients who do not tolerate valproate, particularly patients with severe weight gain due to valproate (Park et al 2013; Brodie 2016). Benzodiazepines may have an adjunctive effect for short periods and are sometimes good for intermittent use in specific stressful situations. Clonazepam may be beneficial for controlling myoclonic seizures but not the generalized tonic-clonic seizures. Complete elimination of myoclonic seizures could cause additional disability by depriving patients of the warning jerks that herald the onset of generalized tonic-clonic seizures (Obeid and Panayiotopoulos 1989). Seizures are usually precipitated by fatigue, noncompliance, stress, sleep deprivation, and alcohol consumption. Successful treatment is contingent on acceptance of appropriate limitations on lifestyle. Special considerations

6 Pregnancy A major concern is the high risk of valproate causing major congenital malformations. A study comparing carbamazepine, phenobarbital, valproic acid, and lamotrigine confirmed particularly higher malformation rates in women taking valproic acid at doses higher than 1500 mg per day, whereas lamotrigine at a dose of less than 300 mg per day had the lowest rate of malformations (Tomson et al 2011). However, lamotrigine at doses higher than 300 mg per day was no safer than valproic acid at doses lower than 700 mg per day, demonstrating that both the type and dose of AED are important to consider in women of childbearing potential. References cited Asconape J, Penry JK. Some clinical and EEG aspects of benign juvenile myoclonic epilepsy. Epilepsia 1984;25: PMID Avoli M, Gloor P, Kostopoulos G, Naquet R, editors. Generalized epilepsy; neurobiological approaches. Boston: Birkhäuser, 1990:481. Baykan B, Martínez-Juárez IE, Altindag EA, Camfield CS, Camfield PR. Lifetime prognosis of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28 Suppl 1:S PMID Bech P, Kjaersgard Pedersen K, Simonsen N, Lund M. Personality in epilepsy. A multidimensional study of personality traits. Acta Neurol Scand 1976;54: PMID Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, Epilepsia 2010;51(4): PMID Betting LE, Mory SB, Lopes-Cendes I, et al. MRI reveals structural abnormalities in patients with idiopathic generalized epilepsy. Neurology 2006;67(5): PMID Brodie MJ. Modern management of juvenile myoclonic epilepsy. Expert Rev Neurother 2016;16(6): PMID Caeyenberghs K, Powell HW, Thomas RH, et al. Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis. Neuroimage Clin 2014;7: PMID Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73(13): PMID Camfield CS, Striano P, Camfield PR. Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28 Suppl 1:S15-7. PMID Carvalho KC, Uchida CG, Guaranha MS, Guilhoto LM, Wolf P, Yacubian EM. Cognitive performance in juvenile myoclonic epilepsy patients with specific endophenotypes. Seizure 2016;40: PMID Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30: Cossette P. Channelopathies and juvenile myoclonic epilepsy. Epilepsia 2010;51 Suppl 1:30-2. PMID Delgado-Escueta AV, Enrile-Bacsal F. Juvenile myoclonic epilepsy of Janz. Neurology 1984;34: PMID Delgado-Escueta AV, Greenberg DA, et al. Mapping the gene for juvenile myoclonic epilepsy. Epilepsia 1989;30:S8-18. PMID de Nijs L, Wolkoff N, Coumans B, Delgado-Escueta AV, Grisar T, Lakaye B. Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development. Hum Mol Genet 2012;21(23): PMID de Oliveira MS, Betting LE, Mory SB, Cendes F, Castellano G. Texture analysis of magnetic resonance images of

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9 the missing link. Neurology 2012;78(20): PMID Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014;137(Pt 9): PMID Wandschneider B, Thompson PJ, Vollmar C, Koepp MJ. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 2012;53(12): PMID Winawer MR, Rabinowitz D, Pedley TA, Hauser WA, Ottman R. Genetic influences on myoclonic and absence seizures. Neurology 2003;61(11): PMID **References especially recommended by the author or editor for general reading. Former authors Jerome Engel MD PhD (original author) and Peter Wolf MD ICD and OMIM codes ICD codes ICD-9: Juvenile myoclonic epilepsy: ICD-10: Juvenile myoclonic epilepsy: G40.3 OMIM numbers Juvenile myoclonic epilepsy: # Profile Age range of presentation years years Sex preponderance Female > male Family history family history may be obtained Heredity heredity may be a factor heredity typical complex pattern of inheritance Population groups selectively affected none selectively affected Occupation groups selectively affected none selectively affected

10 Differential diagnosis list progressive myoclonus epilepsies lipid storage disorders postanoxic myoclonus absence epilepsies epilepsy with grand mal seizures on awakening Lennox-Gastaut syndrome epilepsy with myoclonic-astatic seizures epilepsy with myoclonic absences juvenile absence epilepsy Associated disorders Infantile spasms West syndrome Myoclonic absence Lennox-Gastaut syndrome Other topics to consider Epilepsy Generalized onset tonic-clonic seizures Juvenile absence epilepsy Lamotrigine Levetiracetam Myoclonus Sleep disorders Topiramate Copyright MedLink Corporation. All rights reserved.