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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282XOn-line version ISSN 1678-4227

Arq. Neuro-Psiquiatr. vol.65 no.4b São Paulo Dec. 2007

http://dx.doi.org/10.1590/S0004-282X2007000700036 

VIEWS AND REVIEWS

 

Juvenile myoclonic epilepsy

 

Epilepsia mioclônica juvenil

 

 

Isabel AlfradiqueI; Marcio Moacyr VasconcelosII

INeurology Intern at HUAP-UFF
IIPhD in Neurology at UFF, Associate Professor of Pediatrics and Neurology at UFF, Mother-Infant Department, Chairman, Former-Fellow in Child Neurology at Children’s Hospital, George Washington University, Washington, DC, USA

 

 


ABSTRACT

Juvenile myoclonus epilepsy (JME) is a common epileptic syndrome, the etiology of which is genetically determined. Its onset occurs from 6 through 22 years of age, and affected patients present with myoclonic jerks, often associated with generalized tonic-clonic seizures - the most common association - and absence seizures. JME is non-progressive, and there are no abnormalities on clinical examination or intellectual deficits. Psychiatric disorders may coexist. Generalized polyspike-and-waves are the most characteristic electroencephalographic pattern. Usual neuroimaging studies show no abnormalities. Atypical presentations should be entertained, as they are likely to induce misdiagnosis. Prevention of precipitating factors and therapy with valproic acid (VPA) are able to control seizures in the great majority of patients. Whenever VPA is judged to be inappropriate, other antiepileptic drugs such as lamotrigine may be considered. Treatment should not be withdrawn, otherwise recurrences are frequent.

Key words: juvenile myoclonic epilepsy, diagnosis, etiology, treatment.


RESUMO

A epilepsia mioclônica juvenil é uma síndrome epiléptica comum, cuja etiologia é fundamentada na genética. Inicia-se entre 6 e 22 anos e os indivíduos apresentam mioclonias, que podem ser acompanhadas por crises tônico-clônicas generalizadas - associação mais comum - e crises de ausência. A doença não é progressiva, e não há alterações detectáveis no exame físico ou déficits intelectuais. Distúrbios psiquiátricos podem coexistir. Polipontas-ondas lentas generalizadas constituem o padrão eletrencefalográfico ictal típico. Não há anormalidades em exames de imagem convencionais. Apresentações atípicas devem ser consideradas, pois predispõem a erros de diagnóstico. A prevenção de fatores desencadeantes e o uso de ácido valpróico (VPA) controlam as crises epilépticas na grande maioria dos casos. Quando o VPA é inapropriado, outras drogas como a lamotrigina podem ser utilizadas. O tratamento não deve ser interrompido, visto que as recidivas são freqüentes.

Palavras-chave: epilepsia mioclônica juvenil, diagnóstico, etiologia, tratamento.


 

 

The first description of juvenile myoclonic epilepsy (JME) mounts to the 19th century1. During the 1950’s, JME gained a wider projection with Janz, who called it " Impulsiv Petit Mal" 2. Other terms have been used to define it, such as " myoclonic epilepsy of adolescence" , " benign myoclonic juvenile epilepsy" , and " Janz syndrome" 2. The International League against Epilepsy (ILAE) currently classifies JME within the group of Idiopathic Generalized Epilepsies (IGE) with variable phenotypes3.

Our goal is to review JME, including its clinical presentation and electroencephalography (EEG), and to underline the primary factors that contribute to frequent errors or delay in diagnosis4. Major advances in genetics and the most recent findings in neuroimaging studies are described as well. References for this review were identified by searches of Medline with the terms " juvenile myoclonic epilepsy" and " myoclonic epilepsy" , limited to articles published in English since 2001. In another search, the authors utilized the terms " epilepsy" , " practice guidelines" , and " treatment" to select pertinent articles on treatment guidelines. In addition, an effort was made to search for studies on the Brazilian population through the online library SciELO, and a few references were also identified from relevant articles and books.

 

EPIDEMIOLOGY

JME is said to represent 5-11% of all epilepsy cases4. Its incidence has been estimated at approximately 1 per 100,000 population, while its prevalence varies from 10 to 20 per 100,0005.

JME makes its clinical appearance between 6 and 22 years of age, but 50% of cases present at ages 13-16 years2. Myoclonic seizures are present in all patients (appearing at 12-18 years) and are associated with generalized tonic-clonic seizures (GTCS) in 80-97%, the average age of onset the latter being 16-18 years, and with absence seizures (AS) in 12-54% of patients6.

JME affects both male and female patients equally7, although a female predominance has been described2. Early onset of AS is more common in girls, while boys present with them at a later age, and in boys there is a predominance of asymptomatic AS, that is, a typical EEG not accompanied by symptoms7. A family history of epilepsy was present in 65.9% of 41 studied families, and 36% had at least two family members affected by JME7.

JME patients have no intellectual or neurologic deficits, and the disease follows a non-progressive course2. In a study of 170 patients, overall mortality rate due to sudden death was estimated to be 0.9 per 1000 patient-years, and associated psychiatric disorders were considered to be risk factors for unexpected death8.

In Brazil, a retrospective study was performed and showed results that were similar to those in the literature9. JME accounted for 2.8% of all epilepsy cases. There was a female predominance (73.1%), with age of onset between 7 and 18 years (average 13 years). All patients manifested myoclonic jerks, while 92.3% had GTCS and 19.2% had AS. A positive family history of epilepsy was present in 53.8%9.

 

ETIOLOGY

JME etiology stems from genetics2. Its inheritance mode is unclear, as there have been reports of autosomal dominant, autosomal recessive modes, and multifactorial and complex models10. Although JME cases are genetically heterogeneous, patients within those various groups are not clinically distinguished by the current diagnostic methods11.

Many studies tried to identify genes associated with JME. It was suggested that polymorphism of gene KCNQ3 (8q24), responsible for the voltage-dependent potassium channel, may be an important predisposing factor for JME in Indian probands11. KCNQ3 is expressed late, what might explain disease presentation during adolescence11. This potassium channel is implicated in the slow inhibitory post-synaptic potential and regulates the fast repolarization phase12. So, decreased activity of this potassium channel delays the repolarizing action potential and lowers the amount of excitation needed to produce subsequent action potentials, predisposing to undesirable discharges12.

Another identified gene is CLCN2 (3q26), responsible for the synthesis of voltage-gated chloride channel ClC-2, which is specially expressed in neurons inhibited by gamma-aminobutyric acid (GABA) and serves to maintain low intracellular concentrations of chloride, essential to the gabaergic inhibitory response10,11,13,14. The recognized mutation is a premature stop codon (M200fs x 231) and is associated with loss of function of channel ClC-2, resulting in chloride intracellular accumulation and, therefore, decrease in response to GABA or even inversion to an excitatory response10,13.

Some studies demonstrated one locus in chromosome 6p that predisposes to JME10. An additional study extended these findings and detected five mutations of gene EFHC1 (6p12)10,11, whose protein interacts with type R voltage-dependent calcium channel (CaV2.3), inducing an increase in its current13. While mutations in this gene may suggest neuronal membrane electrical destabilization, another possibility was advanced13. A pro-apoptotic effect was attributed to gene EFHC1, mediated by the action of its protein on Cav2.3, interfering with intracellular calcium influx13. So, the presence of mutations in this topography might impair apoptosis during the process of central nervous system maturation, producing an increased density of neurons under deficient calcium control and consequently hyperexcitable circuits11.

Some French-Canadian families exhibited autosomal dominant JME10,11. Those individuals were heterozygous for missense mutation Ala322Asp in gene GABRA1 (5q34), responsible for the synthesis of alpha1 subunit of receptor GABAA11. This receptor produces fast synaptic inhibition, and its dysfunction has long been suspected in epilepsy pathogenesis10. However, this mutation was not found among 83 patients with IGE, including JME patients10.

Other genetic sites have also been studied, but their contribution to JME pathogenesis is incompletely understood1. While the list of genes implicated in epilepsy is ever growing, most researchers presume that several genes linked to epilepsy exert a modest effect, producing only a small functional change in their gene products, which is not detected by current analyses14. JME manifestation depends most likely on the interaction of one or more of the various identified genes with other genetic, epigenetic, or environmental factors15.

The neuropathologic finding described in JME patients is microdysgenesis11,16, a mild malformation of cortical development whose role in epileptogenesis has not yet been clarified17. Recently, controversies were raised regarding the relationship of this cortical malformation with the epilepsies, as it has also been found within other entities, and universal diagnostic criteria have not been established for microscopic analysis, making it difficult to compare studies in the literature17.

 

DIAGNOSIS

JME diagnosis is based upon clinical criteria and typical electroencephalographic findings, such as: 1) presence of myoclonic jerks, AS, and GTCS with an age-dependent onset and well defined precipitating factors; 2) normal neurologic examination and head computerized tomography; 3) a generalized EEG pattern of spikes and/or polyspikes-and- waves; 4) complete remission of seizures in 80% of patients during valproic acid (VPA) therapy4.

This clinical presentation is quite characteristic, but misdiagnosis and its attendant treatment delay are frequent4,6,18,19. In a study, the correct diagnosis was delayed by 8.3±5.5 years, and even in a tertiary center, patients were followed for 17.7±10.4 months until the diagnosis was established, corresponding to 6±4 clinic visits4. Sousa et al.19 assessed 41 patients and detected a mean diagnostic delay of 8.2 years after onset of epileptic seizures; among the individuals whose epilepsy presented with myoclonias, mean delay was 6.1 years and among those who presented with AS and/or GTCS, 10.8 years.

The most common incorrect diagnosis was GTCS, followed by partial epilepsies4,18. There are a few factors contributing to these error rates, which may have a clinical or electroencephalographic substrate19.

The primary clinical factor is the failure to detect myoclonic jerks4,18,19. Most patients do not complain of myoclonias4, because either they find them to be unimportant or are ashamed by their occurrence, or else because myoclonic seizures are uncommon and not perceived as abnormal19. Patients interpret them in different ways, and many believe they are part of a GTCS19. In addition, clinicians frequently fail to ask about the occurrence of myoclonias during medical interview, a fact that was present in 14 out of 22 patients4. JME still appears to be a disease with which most physicians have no familiarity, therefore they interpret myoclonic jerks as stress or partial epileptic seizures19.

Asymmetric myoclonias and the occurrence of GTCS at nighttime or as the first epileptic seizure have also been implicated as confounding factors4,19.

Electroencephalographic factors include the presence of findings that are atypical but do not exclude JME4,18,19. Focal abnormalities deviated diagnosis toward partial seizures, particularly when AS are not recognized (misinterpreted as complex partial seizures) or when myoclonic jerks are predominantly unilateral (mistaken for motor partial seizures)4. Focal abnormalities on the EEG were found in 19.7-29.3% of patients18,19. Asymmetry of the recording amplitude with a generalized pattern also contributed to diagnostic error and was present in 38 out of 76 patients18.

Finally, a normal recording was obtained on the initial EEG of 41% of patients, and 73.2% had at least one normal EEG recording during work-up19. Normal recordings were attributed to drug therapy, indicating that EEG should be performed before treatment onset19. Serial EEGs seem to be fundamental to confirm diagnosis: 3 recordings identified 84% of cases, and this figure increases to 94% when 4 to 8 recordings are obtained, but there is no significant increase with more than 8 recordings19.

A correct diagnosis of JME has an important impact on treatment and outcome of patients4. Delay in disease identification hampers seizure control and may lead to status epilepticus, nonreversible brain damage, decreased school performance, social difficulties, and even death4.

 

CLINICAL PRESENTATION

Identification of myoclonic jerks is critical to JME diagnosis16. They are characterized by single or repetitive, bilateral, abrupt, symmetric, arrhythmic, involuntary movements, predominantly involving the shoulders and arms; however, they can be unilateral16,20. One study showed involvement of upper extremities in 97.7% of patients and of lower extremities, trunk, and face in 46.5%, 23.3%, and 14%, respectively21. The most typical myoclonus is likely to be shoulder elevation with elbow flexion20. A myoclonic jerk is brief, but a duration of up to one second was described in association with an even slower relaxation phase20. The amplitude varies from violent movements to minimal twitchings, with the latter being called minipolymyoclonus20. At times, however, there are no visible movements, and the patient reports only a subjective electric shock sensation inside the body16.

During myoclonic jerks, consciousness is well preserved16. Most myoclonias occur when awakening from a night of sleep or a nap, a fact that was found in 62.8-87.5% of cases7,21.

Only 3-5% of JME patients have just myoclonic jerks16. GTCS are present in 80-97% of patients6 and appear months or years after onset of myoclonias2. They are often preceded by generalized mild to moderate myoclonic jerks of increasing frequency and intensity, which last a few minutes16. GTCS are characterized by absent sensory aura, violent movements, and a long duration of the tonic phase16. They occur most commonly after awakening, and this feature was observed in 53.7% of cases21 and in 11 out of 16 patients7.

Absence seizures are present in a lower frequency, varying from 12 to 54%6. Age at onset is around 10.5 years (±3.4 years)7. Among 72 patients with AS followed throughout one year, 15% developed myoclonic seizures, leading to JME diagnosis22. Predictors of progression to JME were lack of response to antiepileptic drugs (AEDs) within the first year of treatment, absence status, family history of generalized seizures in first-degree relatives, and slowed background on initial EEG22. AS may occur several times a day, without any circadian variation, and are not associated with automatisms16. When AS appeared before 10 years of age, they were associated with a severe change in consciousness, a feature that was detected in 12.1% of patients7.

Fig 1 shows a chronologic sequence of the three epileptic seizure types in JME.

 

 

Precipitating factors of epileptic seizures are varied, and the most often one is sleep deprivation, reported in 58.3-89.5% of cases6,7. Other triggers that have been identified include fatigue (73.7%), photosensitivity (36.8%), menses (24.1%), mental concentration (22.8%), and stress, excitement, or frustration (12.3%)7. Alcohol ingestion was also found to be a precipitating factor in 51.2% of cases21.

 

PSYCHIATRIC EVALUATION

In a study23, 49% of JME patients were diagnosed with psychiatric disorders. Anxiety (46.9%) and mood (38,7%) disorders were most frequently observed, and generalized anxiety and major depression were the most common in each group, respectively. Personality disorders were detected in 20 patients and included, in decreasing order of frequency, histrionic, passive-aggressive, borderline, dependent, and obsessive-compulsive personalities. On the other hand, it is important to acknowledge the potential contribution of AEDs in patients with a predisposition to psychiatric disorders23.

 

ELECTROENCEPHALOGRAPHY

Patients with JME typically present with an EEG that has a background rhythm within the limits of normal2. However, the presence of moderately excessive theta activity and/or alpha rhythm slowness have been described in 28 individuals7. Interictal findings include bursts of generalized and irregular spike-and-waves and polyspike-and-waves, in a frequency of 3-5 Hz and frontocentral dominance24 (Fig 2). The polyspikes are not necessarily followed by slow waves. These bursts may be fragmentary and are usually confined to the frontal regions24.

 

 

The typical ictal EEG of a myoclonic seizure displays the pattern of polyspike-and-wave, which consists of a group of 5 to 20 generalized, almost always symmetrical and high frequency (10-16 Hz) spikes, usually followed by slow waves in a frequency of 2,5-5 Hz2,24,25. The onset and maximal voltage are seen in the frontocentral regions, then spreading to the parietal, temporal, and occipital regions2. This finding may be present in 22.2% to 51.4% of patients6,19,21.

The myoclonic jerk occurs simultaneously with the polyspike-and-wave pattern, but the latter continues beyond the termination of the jerk, and may persist for several seconds24. There appears to be a correlation between the number of spikes in a given complex and the severity of the associated myoclonic seizure2.

However, other patterns may be observed in ictal EEGs. The main alternative pattern is generalized and irregular spike-and-wave (3-5 Hz), reported among 25.2-78.4% of cases6,19. In addition, the clinician may find slow sharp waves, bursts of slow waves, groups of sharp waves, groups of spikes, and a fast rhythm25.

Focal discharges were more frequent in the frontal regions19,25. They may be isolated spikes, sharp waves, slow waves, or spike-and-wave complexes7,16,21. Asymmetry of the recording was found in 9.8-33.3% of cases1,19,21, and its frequency was increased in EEGs with sleep deprivation25.

Hyperventilation made the EEG abnormalities more obvious in all patients that were analyzed by Panayiotopoulos et al7. Besides, photic stimulation produced a paroxysmal response in 30-40% of patients1. Sousa et al25 assessed the effect of sleep deprivation, which increased the EEG sensitivity in 73.3%, increased three-fold the global index of discharges, and prolonged their duration.

 

NEUROIMAGING STUDIES

JME usually causes no abnormalities in neuroimaging studies4,6,26. However, recently developed neuroimaging techniques have detected structural abnormalities. An increase in cortical gray matter was identified in mesial frontal lobes16,26, frontobasal regions, and anterior portion of the thalamus26. Magnetic resonance spectroscopy found a reduced N-acetylaspartate in the temporal lobe16.

 

DIFFERENTIAL DIAGNOSIS

Epilepsy with generalized tonic-clonic seizures on awakening and juvenile absence epilepsy rank high in the list of differential diagnoses2. Both may present all three seizure types that are common in JME, however in different proportions, which may disguise the correct diagnosis2. Other epilepsies that should be considered are absences with eyelid myoclonias and epilepsy with myoclonic absences1.

Although rare, the progressive myoclonic epilepsies, such as Unverricht-Lundborg disease and Lafora disease, should be ruled out. They usually affect patients in a similar age range, but they also include neurologic deficits, worsening of myoclonic seizures, and a slow background rhythm in the EEG2.

Other causes of myoclonias should be included in JME’s differential diagnosis, such as hypnagogic myoclonia - a normal phenomenon16 - and acquired forms of myoclonic jerks, which may be associated with post-anoxia and lipid storage disease1.

 

TREATMENT

JME treatment is based on AEDs and control of precipitating factors1. As JME is a lifelong disorder, its treatment should be continued indefinitely, otherwise recurrences are rather frequent, occurring within a variable period of months to years after AED discontinuation2; seizure recurrence may even lead to status epilepticus1.

Given JME high prevalence, it is surprising that there is no randomized controlled clinical trial assessing its initial monotherapy27. Based on anecdotal clinical experience and case series, VPA was established as the first-choice AED27. It controls all three seizure types in 85% of cases2. A good therapeutic response occurs even in patients who have a significant family history28. Some studies reported a favorable response in adult patients that were treated with VPA dosages as low as 500 mg per day, and a double-blind crossover study found no significant difference in seizure frequency between 1000 mg or 2000 mg daily of VPA29. A reasonable approach may be to start with a single daily dosage after dinner of 500 mg with an extended-release VPA formulation and then adjusting it to response, but increasing daily dosage to 2000 mg does not improve seizure control1,32. VPA therapy may be limited by adverse effects or by drug interactions, as VPA inhibits uridine diphosphate-glucuronosyltransferase and cytochrome P450 isoenzymes1. In addition, a subgroup of patients that are refractory to VPA has been identified30. Independent clinical factors thought to be involved in inadequate control of epileptic seizures were the coexistence of all three seizure types and the presence of psychiatric disorders30.

When a patient does not respond to VPA, the 2004 National Institute for Health and Clinical Excellence (NICE) guidelines suggest lamotrigine (LTG) as the first choice. Second choice AEDs include clobazam, levetiracetam, and topiramate31.

LTG may be able to accomplish remission of epileptic seizures, however there are also reports of worsening of myoclonic seizures and GTCS1,32, primarily at higher doses31. Combination therapy with VPA+LTG appears to have a synergistic effect, but one should be aware of the possibility of the patient developing a severe skin rash32.

Clobazam has long been used in the treatment of partial and generalized epilepsies31. Among 16 female patients that had intolerable adverse effects to VPA, substitution of clobazam for VPA as monotherapy gained control of epileptic seizures in nine (56.3%), yet clobazam is more frequently prescribed as adjunctive therapy33.

Levetiracetam is an alternative to VPA due to its low incidence of adverse effects and lack of known drug interactions1. Response rate for myoclonias was 58.3% versus 23.3% for placebo, and 80% of cases were reported to be free of epileptic seizures32.

Topiramate therapy during one year was able to control GTCS in 62.5% of patients and myoclonic jerks in 68.8%, although 13.6% had an increase in frequency of absence seizures34.

Clonazepam may also be utilized4, as it helps to control myoclonic jerks in association with VPA, although it has a lesser effect on GTCS1,32. It is considered to be a sound option as an add-on medication during epileptic seizure exacerbations, however its prolonged use is inappropriate in the long run given its sedative effect and tachyphylaxis1.

Carbamazepine and phenytoin may worsen myoclonic seizures1. Other AEDs that should no be used include gabapentin, tiagabine, and vigabatrin1,32.

 

CONCLUSION

JME is a common yet underdiagnosed epileptic syndrome. The clinician should inquire a patient suspected with epilepsy regarding the occurrence of myoclonic jerks and, in addition, he or she should consider atypical presentations, otherwise JME diagnosis might be omitted. Its etiology is still surrounded by many unsolved issues, however recent advances in genetic and neuroimaging studies will be helpful to clarify JME’s physiopathogenesis.

 

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Received 12 June 2007, received in final form 10 August 2007. Accepted 5 September 2007.

 

 

Dr. Marcio Moacyr Vasconcelos - Avenida das Américas 700 / bloco 6 / sala 229. 22640-100 Rio de Janeiro RJ - Brasil. E-mail: mmvascon@centroin.com.br
Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói RJ, Brazil

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