Phenotypic analysis of juvenile myoclonic epilepsy in Indian families

OBJECTIVES: Phenotypic analysis of juvenile myoclonic epilepsy (JME) is presented to document the variations in disease expression. MATERIAL AND METHODS: Information on seizure type and frequency, seizure precipitating factors, electro-encephalographic (EEG) data, response to antiepileptic drugs (AEDs) and family history was collected on 500 Indian probands and 61 relatives with JME. RESULTS: The overall clinical features, EEG characteristics, and familial occurrence were similar to other reports. JME probands and relatives having absences (56 of 561, 10%), those with only myoclonic jerks (MJ) or MJ with one generalized tonic clonic seizure (GTCS) in remission without treatment (five of 561, 1%) and those who required valproic acid (VPA) and another AED for seizure control (19 of 561, 3%) are examples of differential disease expression within JME. Seizures among those having photoparoxysmal response (PPR) on EEG responded very well to VPA alone while those with all three seizure types (MJ, GTCS and absences) were poor responders. CONCLUSIONS: Recognition of clinical 'subtypes' among JME could have therapeutic implications and help improve JME phenotypic characterization for molecular studies.     

Epilepsy with impulsive petit mal (Juvenile Myoclonic Epilepsy)

Juvenile myoclonic epilepsy (JME) is a special syndrome within the primary generalized epilepsies which is characterized clinically by irregular jerks of shoulders and arms (so-called impulsive petit mal) after awakening and electroencephalographically by bilateral-synchronous 4-6/s spike-wave complexes, often in the form of multispike-waves. The age of onset for this syndrome which occurs in 4-6% of all epilepsies is predominantly between 12 and 18 years. It mostly starts with isolated jerks which as a rule are soon followed by generalized tonic-clonic seizures (TCS). Jerks and TCS are provoked by sleep deprivation and predominantly occur after awakening (awakening epilepsy). Sleep deprivation and photostimulation are also very efficient in provoking specific EEG patterns. Exogenous factors have no etiological significance. Genetic studies suggest a polygenetic mode of inheritance and a lower threshold of manifestation in women. JME can be controlled very well by valproate and/or primidone. A complete cure, nevertheless, does not seem to be possible. Within the group of primary generalized epilepsies beginning in adolescence JME is closely related nosologically to the syndrome of juvenile absences and the syndrome of pure grand mal on awakening.     

Adult-onset autosomal dominant myoclonic epilepsy: report of a family with an overlooked epileptic syndrome.

OBJECTIVE: Myoclonic epilepsy is a common epileptic syndrome with high genetic contribution. We described a pedigree in which 10 individuals presented with a non-progressive, adult-onset myoclonic epilepsy. MATERIALS AND METHODS: The pedigree was constructed and analyzed. Six affected members were studied with clinical grounds, mental status, neurophysiology, video-electroencephalographic (EEG), brain magnetic resonance imaging (MRI) and mutational analysis of GABRA1 (GABRA1A, which endoces the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A). Clinical and EEG data were collected from six unaffected members. RESULTS: Autosomal dominant hereditary was shown. The age of seizure onset was approximately 40. All the individuals had myoclonic seizures and a normal cognitive level. Bilateral symmetric jerks of the shoulders, arms or legs featured the myoclonic seizure. Ictally, the consciousness was not affected. The ictal EEG demonstrated bilateral spikes-and-waves. The occurrence of myoclonic seizures was not associated with sleepiness. Rare generalized tonic-clonic seizures occurred in two individuals. No absence or accompanying involuntary movements were observed. A lower dose of valproic acid (200-500 mg/D) (clonazepam 0.5 mg/D in a patient) was required to stop the myoclonic seizures. CONCLUSIONS: The clinical features of late adult-onset autosomal dominant myoclonic epilepsy are similar to juvenile myoclonic epilepsy (JME), which is a common generalized epileptic syndrome with a significant hereditary component. But the age of onset, rare association of other seizure patterns, and non-relation of seizure onset to sleepiness suggest that this may be a distinct familial epileptic syndrome different from recognized familial myoclonic epilepsies.     

Gene Mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy, Childhood Absence Epilepsy, Epilepsy with Grand Mai Seizures, and Early Childhood Myoclonic Epilepsy

Summary: Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.     

Delayed diagnosis of juvenile myoclonic epilepsy.

Fifteen cases of juvenile myoclonic epilepsy (JME) were identified from one hundred and eighty consecutive patients referred to a new epilepsy clinic at St Thomas' Hospital between April 1989 and December 1990, a prevalence of 8.3%. Of these, only one was referred with a putative diagnosis of JME. Diagnosis of the other patients on referral included "epilepsy", "grand mal", "temporal lobe epilepsy", "photoconvulsive epilepsy" and "alcohol-induced epilepsy". At least 11 of the 15 patients had been seen by a neurologist in the United Kingdom before referral. Definitive diagnosis was delayed by a mean of 14.5 years. In seven patients inappropriate anticonvulsants had been prescribed. Control of seizures was improved in most patients after diagnosis. Factors responsible for the delay in diagnosis include lack of familiarity with the syndrome, failure to elicit a history of myoclonic jerking and high prevalence of focal abnormalities on the EEG. Precipitation of fits by alcohol and sleep deprivation may not be recognised by the physician as part of the syndrome of JME. Diagnosis may also be delayed in patients whose absence and generalised tonic-clonic seizures pre-date myoclonic jerks.     

Idiopathic generalized epilepsies misdiagnosed as partial epilepsies

Idiopathic generalized epilepsy (IGE) is often not recognized with serious consequences on the sufferers. We examined factors contributing to the missed diagnosis of IGE in 41 adults attending our epilepsy clinic with diagnosis of partial epilepsy who had semiology or EEG findings suggesting a possible differential diagnosis. After careful re-evaluation, the diagnosis of IGE was established in 25 patients: 22 (88%) with JME, one with juvenile absence, one with perioral myoclonia with absences, one with eyelid myoclonia with typical absences. Myoclonic jerks, the hallmark of the JME and other IGE, were not usually reported by patients or misdiagnosed as focal motor seizures. Brief and infrequent absence seizures and focal EEG abnormalities were other factors contributing to not recognizing JME. All 25 patients did not achieve seizure control before re-evaluation of diagnosis. After appropriate diagnosis of IGE and change of AED to valproate or valproic acid, 19 (76%) became seizure free and six (24%) had a significant improvement on seizure control. Association with lamotrigine provided further improvement in three of these patients. An appropriate questioning to identify myoclonic and absence seizures and a proper interpretation in the context of whole clinical constellation are essential for a correct seizure classification and diagnosis of IGE in adults.     

Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy

BACKGROUND: In the face of availability of newer antiepileptic drugs (AEDs) such as lamotrigine and topiramate, there is need to reassess the role of older AEDs in the treatment of juvenile myoclonic epilepsy (JME). OBJECTIVES: To explore whether lamotrigine and topiramate monotherapy or polytherapy can be effective options in the treatment of JME, and to determine whether older AEDs, such as phenytoin and carbamazepine, have a role in the treatment of JME. DESIGN: A retrospective cohort study. SETTING: A large academic teaching hospital. PATIENTS: Seventy-two consecutive JME patients treated with valproic acid, lamotrigine, topiramate, phenytoin, or carbamazepine between April 1, 1991, and March 31, 2001. METHODS: We compared the efficacy of valproic acid, lamotrigine, and topiramate monotherapy or polytherapy in the control of different seizure types of JME, and compared their efficacy and tolerability with the efficacy and tolerability of phenytoin and carbamazepine. RESULTS: Seizure outcome did not differ when patients receiving valproic acid monotherapy (n = 36) were compared with those receiving lamotrigine monotherapy (n = 14), and when patients receiving valproic acid polytherapy (n = 22) were compared with those receiving lamotrigine polytherapy (n = 21) or topiramate polytherapy (n = 15) (P>.05 for all). The combined data of myoclonic seizure control by all 3 AEDs were poorer when compared with the combined data of generalized tonic-clonic seizure control by all 3 AEDs (P =.03), but not when compared with the combined data of absence seizure control by all 3 AEDs (P =.43). Valproic acid, lamotrigine, and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures (P<.01 for all), but not of generalized tonic-clonic seizures (P>.11 for all). CONCLUSIONS: Lamotrigine and topiramate are effective alternative options to valproic acid in the treatment of JME. Lamotrigine is an effective option as monotherapy and polytherapy. Topiramate is an effective option as polytherapy, but more data are needed to determine if it is an effective option as monotherapy. More effective therapy is needed to improve myoclonic seizure control. Older AEDs, such as phenytoin and carbamazepine, may not be indicated in JME patients.     

Idiopathic Generalized Epilepsies of Adolescence

Summary:  The prevalence of idiopathic generalized epilepsies (IGEs) has been assessed as being 15–20% of all epilepsies. The seizure types in IGEs are typical absences, myoclonic jerks, and generalized tonic–clonic seizures (TCS), alone or in varying combinations and with variable severity. The seizures tend to be more frequent on awakening and with sleep deprivation. This group of clinical conditions includes among others, age-related epilepsy syndromes of adolescence such as juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized TCS or epilepsy with grand mal on awakening (EGMA). The classification of IGEs follows two schools of thought; one maintains that IGEs are a group of different and separate syndromes while the other suggests that IGEs are one biological continuum. Patients with IGEs may have mild impairment of cognitive functions, especially verbal memory and other frontal lobe functions, despite a normal IQ, and some seem to have characteristic personality traits, although further studies are needed to support this theory. They appear to lack a degree of self-control, to neglect their physical needs, and are poorly compliant with therapy. Some patients become obstinate and are impressionable. The cognitive and behavioral aspects of these patients suggest an involvement of frontal lobes.     

Overlap cases of eyelid myoclonia with absences and juvenile myoclonic epilepsy.

Eyelid myoclonia with absences (EMA) and juvenile myoclonic epilepsy (JME) are two separate epileptic syndromes included in the new classification of epilepsies and epileptic syndromes by ILAE in 2001. Both are idiopathic generalized epilepsies with their clinical onset in the first two decades. EMA is characterized by eyelid myoclonia associated with absences and photosensitivity. Self-induced seizures are frequently seen in EMA. It can be associated with mildly mental retardation and resistance to treatment. JME includes three types of generalized seizures: typical absences, myoclonic jerks and generalized tonic-clonic seizures. The myoclonic jerks occur almost exclusively on awakening, involve preferently the upper extremities, may rarely affect the lower extremities or the entire body. More severe attacks may be accompanied by a fall. The myoclonic jerks occur rarely in EMA. They are usually mild and are freqently restricted to the upper extremities. Generalized tonic-clonic seizures, photosensitivity and generalized polyspike-wave discharges provoked by eye closure are features of both epileptic syndromes. In this study, we describe four female patients with eyelid myoclonia associated with absences, myoclonic jerks causing falling down and rare generalized tonic-clonic seizures. All patients had good school performance and total seizure control under sodium valproate treatment. Their EEGs show generalized polyspike-wave discharges with a frequency of 3.5-6Hz always appearing a few seconds after eye closure and photoparoxysmal response. These patients show the characterictics of both epileptic syndromes. It is clinically important to make a syndromic diagnosis for an optimum advise on treatment, lifestyle restrictions and prognosis. In this study, we have gathered evidence that EMA and JME are dynamic syndromes that tend to evolve into one another.     

Outcome of lamotrigine treatment in juvenile myoclonic epilepsy

Bodenstein‐Sachar H, Gandelman‐Marton R, Ben‐Zeev B, Chapman J, Blatt I. Outcome of lamotrigine treatment in juvenile myoclonic epilepsy.
Acta Neurol Scand: 2011: 124: 22–27.
© 2011 John Wiley & Sons A/S. Objectives – To determine the response rate of patients with juvenile myoclonic epilepsy (JME) to lamotrigine (LTG) and identify predictive factors for treatment response. Material and methods – Medical records of 62 patients with JME were reviewed for demographic, clinical, and EEG parameters. We determined clinical response to LTG and compared LTG responders with non‐responders. Results – There were 35 LTG responders (56%) and 27 non‐responders (44%). JME patients without generalized tonic clonic seizures (GTCS) responded better to LTG (P = 0.04). Valproic acid (VPA) failure because of adverse events rather than lack of efficacy (P = 0.069) and delay in diagnosis (P = 0.07) showed a tendency toward good response to LTG. Conclusions – LTG should be considered a drug of first choice for JME patients without GTCS. LTG as second‐line treatment after VPA failure seems more appropriate for those patients whose reason for VPA failure is poor tolerability rather than lack of efficacy.     

Long-Term Course of Childhood Epilepsy with Intractable Grand Mal Seizures

Abstract: Twenty-nine children with childhood epilepsy characterized by frequent grand mal (generalized tonic-clonic) seizures in spite of maximal doses of antiepileptic drugs and by an early onset of seizures (before 1 :year of age) were followed up for more than 5 :years. The children were divided into 3 :groups: severe myoclonic epilepsy in infancy (SME), no SME, and intractable childhood epilepsy with generalized tonic-clonic seizures (GTC). In all the 3 :groups, the grand mal seizures persisted, whereas the other types of seizures tended to disappear as the patients aged, and the prognosis for mental development was poor. In the majority of cases in all the 3 :groups, the waking grand mal seizures altered to sleep grand mal seizures with aging. Two pairs of monozygotic twins with SME suggested that genetic factors play a role in this epileptic syndrome. Intractable childhood epilepsy with GTC is distinguished by the absence of other types of generalized seizures. It cannot be regarded as an epileptic syndrome, but its pathogenesis and treatment require further studies.     

Epilepsies with astatic seizures of late onset.

In 17 patients with a long course of epilepsy astatic seizures became apparent after the age of 14 years. In the patients' childhood astatic seizures had not been observed. The patients suffered from epilepsies with absences and awakening grand mal or psychomotor fits and sleeping grand mal. The EEG revealed spike-wave variant and spike-and-wave complexes as in the Lennox-Gastaut syndrome. Age dependency of Lennox-Gastaut syndrome is discussed. The described type of epilepsy can be understood as a "Lennox-Gastaut syndrome of late onset".     

Game-related seizures presenting with two types of clinical features.

We evaluated 22 patients with epileptic seizures in which the seizures were triggered by various games or game-related materials. Based on whether spontaneous seizure coexisted or not, these 22 patients were divided into two groups. Ten patients who experienced seizures exclusively while playing or watching specific games were referred to as Group I, while 12 patients that had both game-induced and spontaneous seizures were classified as Group II. The patients in Group I had a middle-age onset (39.1 years) with a male predominance (90%). The electroencephalogram (EEG) or brain magnetic resonance imaging revealed non-specific abnormalities in 60%, and the partial onset seizure was recognized in 30% of patients. Antiepileptic drugs had uncertain benefits in this group. In Group II, patients had a male predominance (67%), with onset during adolescence (16.3 years). Most of them had generalized tonic-clonic seizures, myoclonic seizures, and absences, and 42% showed epileptiform discharge on EEG. These 12 patients were categorized into idiopathic generalized epilepsies. Although photosensitivity was an important factor, higher mental activity seemed to be significant precipitants of seizures in Group II. Antiepileptic drugs were necessary and valproic acid alone or combined with clonazepam was effective in this group. The results showed that game-related seizures are not a unique and homogeneous syndrome and may consist of different mechanisms. Teenage onset, coexistent spontaneous seizure, and associated idiopathic generalized epilepsies were crucial factors in the determination of antiepileptic drug therapy. Moreover, avoiding the related games altogether may be a more productive preventive measure.     

Levetiracetam in juvenile myoclonic epilepsy: long-term efficacy in newly diagnosed adolescents

The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in juvenile myoclonic epilepsy (JME). The study group consisted of 32 patients with epilepsy (20 males, 12 females) with a mean age of 13 years 3 months (SD 7y 11mo) at seizure onset. LEV was administered as the first drug; all patients were followed up at 6 and 12 months. The dose that achieved seizure control ranged from 1000 to 2500mg/daily. At 6-month evaluation: 15 patients were seizure free; 14 patients were responders (>50% reduction in seizures); and three patients had marginal effects (<50% reduction of seizures). At 12-month evaluation: 29 patients were seizure free; three patients were responders. No patients reported adverse events. These data provide preliminary evidence that LEV may be effective for treating patients with newly diagnosed JME.     

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.     

Consensus on diagnosis and management of JME: From founder's observations to current trends

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME (“Janz syndrome”), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME.The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes.Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6–25 years).For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy.Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs).Results of an inventory of the different clinical management strategies are given.This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?     

Epileptic Seizures in the 4p- Syndrome: Report of Two Cases

Abstract: We report ictal phenomena in two patients with the 4p – syndrome captured on simultaneous video-EEG monitor. One patient, diagnosed as having partial epilepsy, had complex partial seizures and hemiconvulsive status epilepticus. This was associated with more severe mental retardation. The second patient was diagnosed as having the West syndrome and exhibited tonic spasms with a cluster formation. We conclude that various types of epileptic seizures may occur in patients with the 4p - syndrome, including grand mal and myoclonic seizures.     

Mapping the Gene for Juvenile Myoclonic Epilepsy

Summary: The practice of epileptology at a molecular level, where gene products are identified by gene mapping, will soon be possible for a growing number of epilepsies. Juvenile myoclonic epilepsy (JME) is the first of such epilepsies to be mapped to a chromosome, namely chromosome 6p21.3. Family studies of 68 JME probands from California revealed 50% of all families reported seizures in first- or second-degree relatives. Twelve percent of all family members other than the proband had epileptic seizures. Eighty percent of symptomatic siblings and 6% of asymptomatic siblings had diffuse 4- to 6-Hz multi-spike-wave complexes. Twelve percent of asymptomatic parents had diffuse, nonspecific slow waves mixed with spikes or sharp waves. JME is tightly linked to the Bf-HLA loci in chromosome 6. No matter what mode of inheritance is assumed, linkage to the clinical manifestations of JME and its associated EEG traits is indicated by lod scores over 3.0, as long as "EEG affected" but clinically asymptomatic family members are counted as affected during LIPED analysis. Studies are now being done to further localize the JME site. At the same time, further linkage studies should decide if JME is heterogeneous within itself and whether the same JME site in 6p21.3 underlies absence and grand mal epilepsies.     

Clinical features, EEG findings and diagnostic pitfalls in juvenile myoclonic epilepsy: a series of 63 patients

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalized epileptic syndrome distinctively characterized by myoclonic jerks often associated to generalized tonic-clonic seizures (GTCS) and typical absence seizures. In spite of typical clinical and EEG profiles, JME is widely underdiagnosed. In the present study we retrospectively revised clinical and EEG data of JME patients referring to our Epilepsy Service. A diagnosis of JME could be made in 63 patients, that is 5.7% of all the epileptic patients referring to our Service and 25.9% of those suffering from an idiopathic generalized epilepsy. General features as well as modality of onset and course of the syndrome of our JME subjects were in accordance with literature. Regarding EEG findings, asymmetries were detected in 38.1% of cases. At referral to our Service only 31.7% of JME patients were correctly diagnosed. Main factors responsible for misdiagnosis were failure in eliciting a history of myoclonic jerks and misinterpretation of myoclonic jerks as simple partial seizures. EEG asymmetries were misleading in 13 patients. In conclusion, a correct JME diagnosis is strictly dependent on the knowledge of the syndrome leading the interviewer to look for and correctly interpret myoclonic jerks whereas EEG is just an ancillary diagnostic tool.     

Valproic acid in the treatment of epilepsy during the pediatric age

We studied 85 pediatric patients with different types of epilepsy treated with valproic acid. The clinical and EEG follow-up were performed up to 10 months. Our EEG-clinical observations in this study show that this group of epilepsies during the pediatric age are extremely sensitive to valproic acid with minimal and tolerable side effects. Within a brief period of time an effective response was obtained in the case of epilepsy with myoclonicastatic seizures juvenile myoclonic epilepsy (impulsive petit mal), classical absence and photosensitive epilepsy.