Refractory juvenile myoclonic epilepsy: a meta-analysis of prevalence and risk factors.

BACKGROUND AND PURPOSE: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME. METHODS: We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random-effects meta-analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well-controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta-analysis of risk factors for refractoriness. RESULTS: Overall, 35% (95% confidence interval, 29-41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52-94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta-analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis-induced seizures. CONCLUSION: One-third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME.

West syndrome followed by juvenile myoclonic epilepsy: a coincidental occurrence?

BACKGROUND: West syndrome is an age-dependent epilepsy with onset peak in the first year of life whose aetiology may be symptomatic or cryptogenic. Long-term cognitive and neurological prognosis is usually poor and seizure outcome is also variable. Over the past two decades a few patients with favourable cognitive outcome and with total recovery from seizures were identified among the cryptogenic group suggesting an idiopathic aetiology. Recent research has described two children with idiopathic WS who later developed a childhood absence epilepsy. CASE PRESENTATION: We reviewed the medical records of patients with West syndrome admitted to the our Child Neuropsychiatry Unit in the last 15 years in order to know the clinical evolution of infantile spasms.We report a child with West syndrome with onset at 8 months of age followed by some clusters of bilateral, arrhythmic myoclonic jerks of the upper limbs, mainly on awakening, synchronous with the generalized discharges of 4 Hz spike-wave occurring at 12 years of age and by co-occurrence of a later generalized tonic-clonic seizure at 14 years and four months, both sensitive to Levetiracetam suggesting a juvenile myoclonic epilepsy. CONCLUSIONS: This unusual evolution, never previously reported, suggests that both electroclinical features mentioned above may share some pathophysiological processes genetically determined which produce a susceptibility to seizure and emphasizes that the transition between different age-related epileptic phenotypes may involve also the West syndrome.

Chronodependency and provocative factors in juvenile myoclonic epilepsy.

In juvenile myoclonic epilepsy (JME), occurrence of seizures and epileptiform EEG discharges is influenced by internal and external factors. The most important internal factor is the chronodependency: the occurrence of myoclonic jerks in the early morning is one of the hallmarks of JME. Approximately two-thirds of the patients with JME report that seizures are provoked by a variety of general factors like stress, fatigue, fever, and sleep and more specific precipitants like flashing sunlight, music, reading, thinking, and excess alcohol. The prevalence rate of photosensitivity (photoparoxysmal EEG response) in patients with JME ranges from 8 to 90%; it is seen more often in females and adolescents and depends on drug use. Since both JME and photosensitivity are connected with generalized types of epilepsy and myoclonus, the two traits are comorbid for that reason. Epileptiform EEG discharges can be provoked by other activation methods: sleep, hyperventilation, and specific cognitive tasks. Attention seems to have a non-specific, inhibitory effect of the epileptiform discharges. Hyperventilation can induce absence seizures in patients with JME, while cognitive tasks are efficient in precipitating myoclonic seizures. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy.

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.

[Juvenile myoclonic epilepsy]. / Juvenil myoklonusepilepsi.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is a generalised epilepsy with seizure onset in youth. The aim of this review is to present updated knowledge about the etiology, diagnosis and treatment of JME. MATERIAL AND METHOD: The review is based on a judicious selection of original English language articles, meta-analyses, and reviews found in PubMed, and the authors' own experience with the patient group. RESULTS: Seizure onset occurs in adolescence. All have myoclonias, about 90 % have generalized tonic-clonic seizures, and one third have absences. Myoclonic jerks are frequently the debut symptom, while tonic-clonic seizures appear later on. Patients are particularly susceptible to seizures shortly after waking. It is important to ask specifically about myoclonias as most patients do not report jerks spontaneously. The electroencephalograms of 44-81 % of the patients show discharges of 4-6 Hz polyspike waves. Focal EEG abnormalities may be seen in about 30 %. When patients are treated with valproate and seizure-precipitating factors are avoided, especially sleep deprivation, about 80 % become seizure-free. Lamotrigine and levetiracetam are alternative therapies for women of childbearing age. Attempts to taper off the medication after several years of seizure freedom entail a high risk of seizure relapse. INTERPRETATION: As there may be features of focal epilepsy in the seizure semiology and/or the EEGs, it may be difficult to diagnose JME. Thus, many patients are misdiagnosed as having a focal epilepsy and are given antiepileptic drugs that may aggravate the tendency to seizures.

Sex-specific disease modifiers in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

Perceptions of fever and fever management practices in parents of children with Dravet syndrome.

OBJECTIVE: The first seizure in Dravet syndrome is often considered a febrile seizure (FS), but shortly thereafter, both FSs and seizures without fever occur, leading to diagnosis. Fever remains a factor that easily precipitates seizures. We studied the perception and management of fever of parents of children with Dravet syndrome. METHODS: We conducted this survey using an anonymous, self-administered questionnaire. RESULTS: A total of 20 parents returned the questionnaire. Fever remains a trigger of seizures in 90% of patients. All parents have an accurate knowledge of fever and its management. The familial and socioprofessional impact of fever attacks appears to be very strong. CONCLUSION: Fever represents a significant concern of parents of children with Dravet syndrome. The level of parental anxiety is high in case of fever. The anxiety seems related to fear of seizure recurrence leading to significant modification of parental behavior.

"Benign" myoclonic epilepsy of infancy as the initial presentation of glucose transporter-1 deficiency.

We report the case of a young boy carrying a de novo missense mutation (c.1199G>T; p.R400L) in the SLC2A1 gene who presented initially with benign myoclonic epilepsy of infancy. Eventually, he had a poor outcome with refractory generalised tonic-clonic, myoclonic and absence seizures, ataxia, significant mental impairment and slowing of head growth. He responded poorly to ketogenic diet. This case extends the phenotype of GLUT1-related syndromes and also sheds light on the genetic basis of myoclonic epilepsies of infancy suggesting that variable outcome may depend on genetic factors. [Published with video sequences].

Myoclonic status epilepticus in juvenile myoclonic epilepsy.

BACKGROUND: Myoclonic status epilepticus (MSE) is rarely found in juvenile myoclonic epilepsy (JME) and its clinical features are not well described. We aimed to analyze MSE incidence, precipitating factors and clinical course by studying patients with JME from a large outpatient epilepsy clinic. METHODS: We retrospectively screened all patients with JME treated at the Department of Neurology, Medical University of Innsbruck, Austria between 1970 and 2007 for a history of MSE. We analyzed age, sex, age at seizure onset, seizure types, EEG, MRI/CT findings and response to antiepileptic drugs. RESULTS: Seven patients (five women, two men; median age at time of MSE 31 years; range 17-73) with MSE out of a total of 247 patients with JME were identified. The median follow-up time was seven years (range 0-35), the incidence was 3.2/1,000 patient years. Median duration of epilepsy before MSE was 26 years (range 10-58). We identified three subtypes: 1) MSE with myoclonic seizures only in two patients, 2) MSE with generalized tonic clonic seizures in three, and 3) generalized tonic clonic seizures with myoclonic absence status in two patients. All patients responded promptly to benzodiazepines. One patient had repeated episodes of MSE. Precipitating events were identified in all but one patient. Drug withdrawal was identified in four patients, one of whom had additional sleep deprivation and alcohol intake. Two patients received inappropriate treatment (carbamazepine, phenytoin). CONCLUSIONS: MSE is a rare event in JME. Precipitating factors are commonly identified and for such cases the treatment response and outcome are excellent, in contrast to other cases with unknown causes.

Childhood Absence Epilepsy evolving to Eyelid Myoclonia with Absence Epilepsy.

PURPOSE: Children with Childhood Absence Epilepsy (CAE) may develop generalized tonic-clonic seizure or juvenile myoclonic epilepsy. A possible evolution to Eyelid Myoclonia with Absence Epilepsy (EMA) hasn't been documented yet. We report the electroclinical features of a case series of children with CAE that evolved to EMA after therapy withdrawal. METHOD: Of 108 patients with CAE referred at our Epilepsy Center in the last ten years, 5 satisfied the inclusion criteria: CAE diagnosis, a minimum of 3 years follow-up, a progression to EMA after therapy withdrawal. RESULTS: All the six subjects were females. CAE was characterized by typical absences induced by hyperventilation; intermittent photic stimulation (IPS) was negative. All subjects were treated successfully with valproate. After drug withdrawal, all the six girls presented EMA. EMA was characterized by eyelid myoclonia with or without brief absences related to generalized spike/polyspike-waves discharges induced by IPS and less frequently by eye-closure. CONCLUSIONS: Our study documented another possible evolution of CAE into EMA. These results support the hypothesis that these two epileptic conditions are dynamic processes evolving into one another. CAE and EMA could be considered "system epilepsy" characterized by a high susceptibility to changes in the brain networks during specific life periods such as childhood and puberty.

Juvenile myoclonic epilepsy.

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.

Comparison of valporic acid efficacy in familial versus sporadic cases of juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy is a heterogeneous syndrome, both in genetic and clinical aspects. AIMS: This study was conducted to compare the efficacy of valproic acid in familial versus sporadic cases of this syndrome. SETTINGS AND DESIGN: Seventy patients with JME were identified; 24 patients (34.3%) had positive history of JME in their first degree relatives (group I) and 46 patients (65.7%) were sporadic (group II). MATERIALS AND METHODS: Valproic acid was started for the patients with upward titration. The cases were followed for one year after final titration of the drug with regular blood monitoring. Patients, who had no myoclonic, absence and grand mal seizures within one year, were considered excellent responders. STATISTICAL ANALYSIS: We used Student T-test and Fisher's exact test for quantitative and qualitative variables respectively. Logistic Regression test was used to evaluate the predictive factors for final treatment outcomes. RESULTS: Mean dosage of valproic acid was 800 mg/d in both groups (13 mg/kg and 12.4 mg/kg respectively). Mean therapeutic levels of the drug in group I and II were 74 microg/ml and 78.4 microg/ml respectively. Excellent responders' rate was 66.7% in group I and 76.1% in group II. History of absences and older age at the onset of grand mal seizures decreased excellent responders' rate in both groups. CONCLUSIONS: Considering response to valproic acid, there is no significant difference in familial versus sporadic cases of JME, whereas history of absences and older age at the onset of grandmal seizures, decrease the probability of being excellent responders in this syndrome.

Language- and praxis-induced jerks in patients with juvenile myoclonic epilepsy.

Reflex traits have been described in patients with idiopathic generalized epilepsy. We report on four patients with juvenile myoclonic epilepsy in whom the coexistence of praxis- and language-induced jerks was documented in video-polygraphic EEG recordings.[Published with video sequences].

Absence of GABRA1 Ala322Asp mutation in juvenile myoclonic epilepsy families from India.

An Ala322Asp mutation in the GABRA1 gene was recently reported to be responsible for causing the autosomal dominant (AD) form of juvenile myoclonic epilepsy (JME) in a French-Canadian family. To study if JME families from India exhibiting the AD mode of inheritance carry the Ala322Asp mutation, we examined 35 unrelated JME-affected individuals from such families for the Ala322Asp mutation in GABRA1. Ala322Asp mutation was not observed in any of these JME-affected individuals, suggesting that this mutation is unlikely to be a predominant mutation involved in causation of epilepsy. To evaluate the possibility of other mutation(s) in and around GABRA1 that may predispose to JME, we compared the allele frequencies at two marker loci, D5S2118 and D5S422, flanking GABRA1, in probands and 100 matched population controls. One of the allele frequencies at D5S422 shows a significant difference between the cases and controls (chi-square = 11.44, d.f. = 1, P = 0.0007), suggesting genetic association between JME and genes located in the proximity of the DNA marker.

The new patient with a first seizure.

BACKGROUND: First seizures are common, with one in 20 people suffering a seizure at some time in their life. OBJECTIVE: This article aims to outline the assessment of patients with a first seizure, including making an accurate diagnosis of both seizure type and an epilepsy syndrome, if present. DISCUSSION: Seizures are classified into generalised and partial (arising from a focal region in the brain) based on clinical and electroencephalogram findings. However, as a partial seizure may proceed to a tonic clonic phase, differentiation may be difficult. Inquiring directly about 'minor' epileptic symptoms before the episode such as absences, myoclonic jerks, visual or auditory hallucinations or feelings of déjà vu, is needed to attempt to make a epilepsy syndrome diagnosis, as this has practical implications for treatment, prognosis and genetic counselling. Generalised epilepsies should be treated initially with valproate, while partial epilepsies should be treated with carbamazepine and switched to newer agents if intolerance occurs.

Ophthalmoplegic migraine with isolated third cranial nerve palsy in a known case of juvenile myoclonic epilepsy.

Among the various forms of migraine headaches, ophthalmoplegic migraine is an uncommon and rare form, the incidence of which is approximately 0.7 per million. It presents predominantly with headache and ophthalmoplegia. One of more cranial nerves can be affected, however the third cranial nerve is most often affected. As a result, symptoms wise, mydriasis and ptosis are commonly seen. Patients generally recover completely within a few days or weeks, however residual deficits are known to occur in a minority of patients. One of the common generalised epilepsy syndromes is the juvenile myoclonic epilepsy (JME), its prevalence being roughly up to 10% of all patients with epilepsy. It usually begins in the second decade of life. Generalised tonic-clonic seizures myoclonic jerks absences constitute the main seizure types in JME. Studies indicate a definite association of epilepsy with migraine headaches and a significant number of migraneurs are found to be epileptic. Conversely, patients with epilepsy are two times more likely to have migraine, as compared to their first degree relatives without migraine. We report a known case of a female patient of JME having a history of classical migraine with aura presenting to us with headache and ophthalmoplegia. She was extensively evaluated to rule out other causes of isolated third cranial nerve palsy, with all the investigations being negative for any obvious cause. She was treated with non-steroidal anti-inflammatory drugs for the acute attack and was subsequently put on antimigraine medication, propranolol during her hospital stay, with which her ptosis recovered completely after 2 weeks. The patient was later started on tablet divalproex sodium, which the patient continues to take on a long-term basis, especially because of its efficacy as an antimigraine prophylaxis agent and a potent drug against JME.