Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years). METHODS: Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline. RESULTS: Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively. CONCLUSIONS: In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Perampanel in 12 patients with Unverricht-Lundborg disease.

OBJECTIVE: Perampanel (PER) was used in 12 patients with Unverricht-Lundborg disease (ULD) to evaluate its efficacy against myoclonus and seizures. METHODS: We treated 11 patients with EPM1 mutations (6 F, 5 M, aged 13-62 years) and a 43-year-old man with de novo KCNC1 mutation. PER was introduced by 2 mg steps at 2-4 week intervals until 6 mg/day, with a possible dose reduction or dose increase. RESULTS: Ten patients had a clear clinical response of myoclonus, and five were able to reduce concomitant therapy. Improvement was noted sometimes as soon as with 2 mg/day. Epileptic seizures stopped on PER in the six patients who still had experienced generalized tonic-clonic or myoclonic seizures (100%). Some abatement of efficacy on myoclonus was seen in two patients who still retained some benefit. Weight gain was reported in six patients (50%). Psychological and behavioral side-effects were observed in six patients (50%) and led to withdrawal of PER in three cases and dose reduction in three, with abatement of the problems. SIGNIFICANCE: This study provides evidence that for ULD patients, PER may show marked efficacy even in severe cases, particularly against myoclonus, but also against seizures. PER should thus be tried in ULD patients whose seizures are not satisfactorily controlled. Its use is limited because of psychological and behavioral side effects, with higher doses of approximately 6 mg/day or greater likely risk factors.

Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1). METHODS: Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate-severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice-daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2-week up-titration period, 12-week stable-dose maintenance period, and down-titration or entry into long-term follow-up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min-max) percent reduction from baseline in action myoclonus score is the following-N01187: placebo 5.6 (-81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (-50.0 to 73.6), BRV 50 mg/day 26.3 (-35.8 to 69.2), BRV 150 mg/day 16.9 (-50.0 to 73.6); N01236: placebo 17.5 (-170 to 61.5), BRV 5 mg/day -4.6 (-430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (-58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72-75% placebo-treated and 56-83% BRV-treated patients. SIGNIFICANCE: Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long-term follow-up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.

Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy.

OBJECTIVE: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. METHODS: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. RESULTS: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. INTERPRETATION: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

Can emotional stress trigger the onset of epilepsy?

OBJECTIVE: The aim of this study was to investigate the potential role of an acute adverse stress as "trigger" for the onset of epilepsy. METHODS: Among 4618 consecutive patients, twenty-two reported a major life event within three months before the onset of epilepsy. RESULTS: All patients had focal epilepsy except one with idiopathic generalized epilepsy. The temporal lobe was involved in 90% of patients with focal epilepsy. More precisely, 13 patients (62% of patients with focal epilepsy) had medial temporal lobe epilepsy (MTLE), two had lateral temporal lobe epilepsy, four had temporoparietooccipital junction epilepsy, and two patients had central lobe epilepsy. The mean age and the median age at onset of epilepsy for patients with MTLE were both 38 years (range: 9.5-65 years). Ten patients had right and three had left MTLE. Among patients with focal epilepsy, MRI was abnormal in 7 (33%) with hippocampal sclerosis in four, periventricular nodular heterotopia in two, and complex cortical dysgenesis in one. The mean age at onset of epilepsy for patients with brain lesions was 26 years (range: 9.5-49). Twelve patients (54%) reported a death as a triggering factor for the onset of their epilepsy. Seven patients (32%) reported that a relationship of trust had been broken. Three patients (14%) had been subjects of violence. No patient reported sexual abuse as a triggering factor. CONCLUSION: This study provides evidence that some patients (5/1000 patients) began their seizures in the wake of significant life events. The average age at onset of epilepsy is quite late, around age 30, even in the presence of brain lesions. These patients are emotionally and affectively more prone to have consequences of a stressful life event. The recognition and management of such situations may bring significant relief with improvement of the control of epilepsy.

Transition for patients with epilepsy due to metabolic and mitochondrial disorders.

The transition of adolescents with refractory epilepsy to the care of adult neurologists can be challenging. For those patients with epilepsy due to mitochondrial disorders, Lafora disease, Unverricht-Lundborg disease, and GLUT1 deficiency syndrome, a successful transition can be even more problematic for both caregivers and neurologists. Many of these patients require dietary treatments (ketogenic and modified Atkins diets) for long-term management of their epilepsy. For these patients, coordinating transfer of their dietary management is necessary.

Bilateral and synchronous "dents de scie" spikes: A highly specific EEG pattern of young adult Dravet syndrome.

BACKGROUND: In Dravet syndrome (DS), EEGs evolve over time. OBJECTIVE: To describe a peculiar EEG pattern in two adults with a de novo SCN1A gene mutation, in exon 5 (case 1) and 9 (case 2). METHODS: Two female patients underwent a prolonged video EEG (24 h) as part of their epilepsy assessment. RESULTS: In both cases, the EEG showed a very peculiar and stereotypical pattern of bilateral synchronous spikes at about 5-6 Hz. This activity was present during wakefulness and highly activated at sleep onset and in NREM sleep, which could show nearly continuous spike activity. This activity dramatically decreased in REM sleep and after awakening. This pattern of "dents de scie" (sawtooth) spikes maintained the same morphology throughout the entire EEG recording. In both patients, the spikes were favored by passive eye closure. During wakefulness, the spikes could evolve into atypical absences while keeping the same "dents de scie" pattern. Neither patient had tonic or myoclonic seizures at the time of the EEG assessment. Both were moderately retarded, and neither one had a typical DS gait disorder. Previous EEG recordings of case 1 performed at 9.5 and 18.5 years showed spike-waves, but the morphology did not correspond to the EEG recording observed at 22 years. CONCLUSIONS: Both patients have a similar electro-clinical phenotype. This "dents de scie" pattern appears to be very specific and could be pathognomonic in a subgroup of young adults with DS. Results of sleep EEG recording could be added to the diagnostic criteria for this syndrome.

Epilepsy with eyelid myoclonia (Jeavons syndrome): Generalized, focal, or combined generalized and focal epilepsy syndrome?

Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE). We report two untreated children on which EEGs were performed several hours after a generalized tonic-clonic seizure (GTCS). These showed a unilateral, nearly continuous posterior slowing. This slow-wave activity was associated with contralateral epileptiform activity in one case, while in the second case, it was associated with an ipsilateral activity. However, in the latter child, a few months later an independent focus on the contralateral side was observed. A diagnosis of focal occipital lobe epilepsy was proposed in both cases, and one child underwent a left occipital lobectomy at 3.5 years of age. Despite surgery, absences with EM persisted in this child, and a marked photosensitivity to photic stimulation was observed two years later. The focal slow wave activity of one occipital lobe several hours after a GTCS in these two subjects was in favor of a focal onset preceding the generalization. The EEG evidence for independent left and right posterior focus in these two cases, the persistence of EM, and the development of a marked photosensitivity to photic stimulation in the child who underwent an occipital lobectomy, allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures.

The history of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) has been the subject of intensive research over the past 25years. It was discovered stepwise in Switzerland and France in the 19th century, adequately described in Germany and Uruguay in the 1950s, and rediscovered in North America in the early 1980s. Juvenile myoclonic epilepsy represents the most common idiopathic epilepsy syndrome. As a tribute to the primary author of the first extensive and detailed clinical description of JME, it is also called the Janz syndrome. Juvenile myoclonic epilepsy is an archetypical epileptic syndrome, with a fairly homogenous presentation and a still largely unknown etiology. Its clinical spectrum now includes cognitive and psychiatric symptoms as significant copathologies, and the elucidation of its probably multiple genetic mechanisms is an ongoing process. Juvenile myoclonic epilepsy may not qualify as a "benign" epilepsy, but seizures in most patients can be managed adequately and patients will not suffer severe limitations in their lifetime expectations.

Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.

A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug. We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naïve) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60 mg) showed the strongest effect with an effect lasting up to 28 h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted.

Clinical aspects of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a recognizable, frequent epileptic syndrome. The most typical ictal phenomenon is bilateral myoclonia without loss of consciousness (M), with most patients also presenting with generalized tonic-clonic seizures (GTCSs) and some with absence seizures (ASs). The most striking features of JME are its onset around the time of puberty and the fact that seizure episodes occur after awakening from a sleep period or in the evening relaxation period and are facilitated by sleep deprivation and sudden arousal. Photic sensitivity is common in the EEG laboratory but uncommon or unrecognized in daily life. The clinical features of JME make it easy to diagnose. In recent years, awareness of JME has increased, and patients are often accurately diagnosed clinically before confirmation by EEG. The typical circumstance at diagnosis is a first GTCS episode, and one learns during the interview that the patient has had M in the morning for some time before the GTCS episode. There are only few differential diagnoses: the adolescent-onset progressive myoclonus epilepsies, or other forms of idiopathic generalized epilepsies of adolescence. With JME being so common, we propose that a first GTCS episode in a teenager should be considered as revealing JME until proven otherwise.

Management of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common form of epilepsy and a fairly lifelong disorder that may significantly lower a patient's expectations and potential for a full life. Luckily, it is also a highly treatable disorder, and up to 85% of patients with JME will enjoy satisfactory seizure control. Among anticonvulsants, valproate still stands out as the most efficacious drug, but may be poorly tolerated by some, and is considered unsafe for the fetuses of pregnant women. Alternatives have emerged in recent years, especially levetiracetam, but also topiramate, zonisamide or lamotrigine. In some cases, combination therapy may be useful or even required. One should not forget the potential aggravation induced not only by some commonly used anticonvulsants, especially carbamazepine and oxcarbazepine, but also, in some patients, by lamotrigine. In special settings, older drugs like benzodiazepines and barbiturates may be useful. But the management of JME should also include intervention in lifestyle, with strict avoidance of sleep deprivation and the management of copathologies, including the cognitive and psychiatric problems that are often encountered. With adequate management, there will only remain a small proportion of patients with uncontrolled epilepsy and all of its related problems. Juvenile myoclonic epilepsy is a condition in which the clinician has a fair chance of significantly helping the patient with medication and counseling.

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 (6-25years). 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?

Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism.

PURPOSE: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. METHODS: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). KEY FINDINGS: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10(-7)). SIGNIFICANCE: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.

Dravet syndrome: the long-term outcome.

Few studies focused on the long-term outcome of Dravet syndrome in adulthood are available in the literature, but all are concordant. In this article, we consider the outcomes of 24 patients followed at the Centre Saint-Paul, Marseille, up to the age of 50, and compare them to the patients reported in the literature. Five patients (20.8%) died, at a mean age of 24.8 years, one by status epilepticus, three by sudden unexpected death in epilepsy (SUDEP), and one of unknown cause. Epileptic seizures tend to become less frequent and less severe after childhood. Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its impact on seizure frequency and severity is milder than in infancy. Generalized convulsive seizures, mostly reported as generalized tonic-clonic seizures (GTCS), were the only seizure type observed in almost all of the patients, often with a focal onset. They are less frequent than in childhood and mostly nocturnal. Some of these major convulsive seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in some cases by a tonic vibratory state or clonic movements (Oguni et al., Brain Dev 2001;23:736-748; Akiyama et al., Epilepsia 2010;51:1043-1052). Other seizures like myoclonic seizures, atypical absences, and complex partial seizures (CPS) are less common in adulthood: Among our 24 patients, only 6 had atypical absences, and one myoclonic and one complex focal seizures. Electroencephalography (EEG) also changes with age but is still multiple and heterogenous, interictally and ictally. Photosensitivity and pattern sensitivity also showed a tendency to disappear before the age of 20. Motor abnormalities are common. Cerebellar features, including ataxia, dysarthria, intention tremor, and eye movement disorder, become more prominent. Walking is markedly impaired, often due to orthopedic signs such as kyphosis, kyphoscoliosis, flat feet, or claw feet. This symptomatology was minor during childhood and worsened during and after adolescence, despite physiotherapy. Mental retardation ranged from moderate to severe, with predominance of language impairment, and some patients had a major personality disorder, labeled autistic or psychotic. Dependency in adulthood is nearly constant: Only 3 of our 24 adult patients lived independently.

Lateralized Periodic Discharges: Which patterns are interictal, ictal, or peri-ictal?

There is an ongoing debate if Lateralized Periodic Discharges (LPDs) represent an interictal pattern reflecting non-specific but irritative brain injury, or conversely, is an ictal pattern. The challenge is: how to correctly manage these patients? Between this apparent dichotomous distinction, there is a pattern lying along the interictal-ictal continuum (IIC) that we may call "peri-ictal". Peri-ictal means that LPDs are temporally associated with epileptic seizures (although not necessarily in the same recording). Their recognition should lead to careful EEG monitoring and longer periods of video-EEG to detect seizure activity (clinical and/or subclinical seizures). In order to distinguish which kind of LPDs should be considered as representing interictal/irritative brain injury versus ictal/peri-ictal LPDs, a set of criteria, with both clinical/neuroimaging and EEG, is proposed. Among them, the dichotomy LPDs-proper versus LPDs-plus should be retained. Spiky or sharp LPDs followed by associated slow after-waves or periods of flattening giving rise to a triphasic morphology should be included in the definition of LPDs-plus. We propose defining a particular subtype of LPDs-plus that we call "LPDs-max". The LPDs-max pattern corresponds to an ictal pattern, and therefore, a focal non-convulsive status epilepticus, sometimes associated with subtle motor signs and epileptic seizures. LPDs-max include periodic polyspike-wave activity and/or focal burst-suppression-like patterns. LPDs-max have a posterior predominance over the temporo-parieto-occipital regions and are refractory to antiseizure drugs. Interpretations of EEGs in critically ill patients require a global clinical approach, not limited to the EEG patterns. The clinical context and results of neuroimaging play key roles.

Epilepsy with eyelid myoclonias (Jeavons syndrome): An electro-clinical study of 40 patients from childhood to adulthood.

PURPOSE: To describe the typical and atypical clinical and electroencephalographic (EEG) features of 40 patients with Jeavons syndrome (JS). METHOD: Retrospective analysis from two French tertiary centers. RESULTS: Forty patients were enrolled (31 females and 9 males; sex ratio F/M = 3.44; mean age at epilepsy onset: 6.2 ± 3.4 years [range: 1-15 years]). A positive family history of generalized genetic epilepsy was reported by 13 patients (32.5 %). Eyelid myoclonias with or without absence were the seizure onset in 29 patients (72.5 %), and generalized tonic-clonic seizures in 11 (27.5 %). Over the course of the disease, all had absences. Intellectual disability and psychiatric disorders were reported in 14 (35 %) and 18 patients (45 %), respectively. Focal EEG abnormalities were observed in 65 % of patients, with a posterior (57.7 %) or anterior (30 %) distribution. Generalized EEG discharges were identified in 37 patients (92.5 %). Epileptiform abnormalities were activated during NREM sleep and increased upon awakening. Response to intermittent light stimulation (ILS) was observed in 34 patients (85 %), with an unusual pattern of epileptiform abnormalities at the same frequency of the flashes in 20 patients. Patients with all seizure types were more likely to have this response (p = 0.017). CONCLUSION: JS is a lifelong genetic epileptic syndrome with onset in childhood, female preponderance, and a positive family history of epilepsy in one-third of the cases. Focal EEG abnormalities are frequent. Response to ILS appears different from other photosensitive syndromes, with an unusual pattern of photo-induced abnormal synchronization. Intellectual disability and psychiatric disorders are not rare.