Epilepsy With Myoclonic-atonic Seizures Research Articles

Efficacy of felbamate in a cohort of patients with epilepsy with myoclonic atonic seizures (EMAtS)

Epilepsy with myoclonic atonic seizures (EMAtS) is a rare childhood onset developmental and epileptic encephalopathy which is frequently refractory to medical therapy. The optimal antiseizure medication remains unknown. This study reports the efficacy of felbamate in children with EMAtS. Six large pediatric epilepsy centers performed a retrospective chart review on patients diagnosed with EMAtS at their institutions and collected data on felbamate usage and efficacy. Responders were classified as patients who had a 50% or greater reduction in seizures with a given therapy. Out of 259 patients, 37 (14%) were treated with felbamate. The efficacy of felbamate was 62%, which was greater than that of either levetiracetam or valproic acid (15%, p < 0.001% and 32%, p = 0.001 respectively) and similar to that of the ketogenic diet (69%, p = 0.8). Felbamate appears to be an effective treatment for EMAtS and should be strongly considered in the treatment course of this disease.

Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures

PurposeThis multicenter study aimed to evaluate the efficacy and tolerability of add-on cannabidiol (CBD) in treatment-resistant patients with epilepsy with myoclonic-atonic seizures (EMAtS) (n = 22) and Sturge Weber syndrome (SWS) with myoclonic-atonic seizures (n = 4). MethodsPatients who met the diagnostic criteria of treatment-resistant EMAtS or SWS with myoclonic-atonic seizures were included. Cannabidiol was added in doses ranging from 8 to 40 mg/kg/day. Efficacy was assessed by comparing seizure frequency before and after initiating CBD therapy.Neurologic examinations, brain magnetic resonance imaging, repeated prolonged electroencephalography (EEG) and/or video-EEG recordings, and neurometabolic studies were performed in all patients, and genetic investigations in 15. ResultsAfter a mean follow-up of 19 months, 15/26 patients (57.7%) who received add-on CBD had a >50% seizure decrease; three (11.5%) became seizure-free. The remaining 11 patients (42.3%) had a 25–50% seizure reduction. Drop attacks, including myoclonic-atonic seizures and generalized tonic-clonic seizures, as well as atypical absences and nonconvulsive status epilepticus responded well to CBD. In SWS patients, focal motor seizures without consciousness impairment and focal non-motor seizures with consciousness impairment were recognized in two each; in three a 30% reduction of focal seizures was observed. Side effects were mild and did not lead to CBD discontinuation. ConclusionThis study evaluating the use of add-on CBD in children with EMAtS or SWS with myoclonic-atonic seizures found that 15/26 (57.7%) had a >50% seizure reduction with good tolerability; three (11.5%) became seizure-free.

Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria.

The aim of this review is to propose the updated diagnostic criteria of epilepsy with myoclonic-atonic seizures (EMAS), which is a recent subject of genetic studies. Although EMAS has been well known as Doose syndrome, it is often difficult to diagnose due to a lack of consensus regarding some of the inclusion criteria. Along with progress in molecular genetic study on the syndrome, it becomes important to recruit electroclinical homogeneous EMAS patients, hence the validity of the clinical criteria should be verified based on recent clinical researches. At present, the most updated ILAE diagnostic manual of EMAS includes: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between 6 months and 6 years of age (peak: 2-4 years); (3) myoclonic-atonic seizures (MAS) are mandatory (4) presence of generalized spike-wave discharges at 2-3Hz without persistent focal spike discharges; and (5) exclusion of other myoclonic epilepsy syndromes. In the criteria, we should emphasize that the age at onset of MAS is between 2-5 years in (2), presence of myoclonic-atonic, atonic or myoclonic-flexor seizures (MASs) causing drop attacks associated with generalized spike-wave discharges is mandatory in (3), and epileptic spasms causing drop attacks must be excluded in (5). In the modified criteria, I propose that EMAS is redesignated as genetic generalized epilepsy with MASs, consistent with the familial genetic study conducted by Doose and the recent identification of candidate genes. It should also be noted that EMASs evolves to transient or long-lasting epileptic encephalopathy.

GABRB3-related epilepsy: novel variants, clinical features and therapeutic implications.

This study aimed to comprehensively examine the genetic and phenotypic aspects of GABRB3-related epilepsy and to explore the potential prospects of personalized medicine. Genetic testing was conducted in all epilepsy patients without acquired factors for epilepsy. Through the collaboration of multicenter in China, we analyzed the genotype-phenotype correlation and antiepileptic therapy of 26 patients with GABRB3-related epilepsy. Thirteen GABRB3 variants were novel, and 25 were de novo. The seizure onset age ranged from 1 to 21months (median age 3.75months). Seizure types predominated including focal seizures (92.3%), generalized tonic-clonic seizures (23.1%), and epileptic spasms (15.4%). Clinical features included cluster seizures (80.8%), fever sensitivity (53.8%), and developmental delay (96.2%). Neuroimaging was abnormal in 10 patients, including dysplasia of the cerebral cortex, dysplasia of the frontal and temporal cortex, delayed myelination, and corpus callosum dysplasia. Eleven patients were diagnosed with developmental and epileptic encephalopathy (DEE), four with West syndrome, three with epilepsy of infancy with migrating focal seizures (EIMFS), one with epilepsy with myoclonic-atonic seizures (EMAS), one with Dravet syndrome, and one with febrile seizures plus (FS+). Seizures were controlled in 57.7% of patients by valproate, levetiracetam, or perampanel in the majority. The clinical features of GABRB3-related epilepsy included seizure onset in early infancy, cluster seizures and fever sensitivity. Most patients manifest severe epilepsy phenotypes. Valproate, levetiracetam and perampanel seem to have positive effects on seizure control for patients with GABRB3 variants.

Morphometric analysis of spike-wave complexes (SWCs) causing myoclonic seizures in children with idiopathic myoclonic epilepsies – A positive SWC component correlates with myoclonic intensity

AimTo elucidate the morphological characteristics of spike-wave complexes (SWCs) causing myoclonic seizures (MS) in childhood-onset idiopathic myoclonic epilepsies. Subjects and MethodsThe subjects were 8 patients, including 4 with epilepsy with myoclonic-atonic seizures (EMAS), 3 with myoclonic epilepsy in infancy (MEI) and 1 with idiopathic unclassifiable myoclonic epilepsy. Morphometric parameters of the SWCs were compared between those with MS [SWC-MS (+)] and those without MS [SWC-MS (-)], and a correlation coefficient analysis was performed between the SWC parameters and the duration of myoclonic electromyogram (EMG) potentials. ResultsA total of 155 SWC-MS (+) (range: 7 ∼ 34) and 80 SWC-MS (-) (10 each as a control) were analyzed. Comparison of the parameters of the SWCs between SWC-MS (+) and SWC-MS (-) demonstrated that the depth and the width of the positive-sharp-components (PSC) in the SWC-MS (+) were significantly deeper in amplitude and longer in duration than those in the SWC-MS (-), respectively, in all 8 patients (P < 0.05), whereas the number of the polyphasic-multiple-spike-components (PMSC) and the height of negative-spike-components (NSC) were not significantly different in most of the patients, respectively. The depth and the width of PSC were also significantly correlated with the duration of myoclonic EMG potentials in all patients except one [depth of PSC (n = 7): r = 0.623 ∼ 0.888; width of PSC (n = 8): r = 0.676 ∼ 0.948, P < 0.05]. ConclusionsThis study revealed that the depth and width of PSC of the SWC are positively correlated with the MS intensity in childhood-onset idiopathic myoclonic epilepsies and are an important neurophysiological marker to generate MS.

Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures/ Doose syndrome

ObjectiveTo establish a standard framework for early phenotypic diagnosis, investigations, expected findings from investigations, evolution, effective therapies and prognosis in the syndrome of Epilepsy with myoclonic atonic seizures (EMAS) / Doose syndrome. MethodsA core study group (CSG) interested in EMAS was convened. CSG then identified and nominated 15 experts in the field of EMAS. This expert panel (EP) from English speaking nations was invited to participate in anonymous questionnaires. A literature review was provided to them (supplement 1). Three rounds of questionnaires were sent to identify areas of consensus, strength of consensus and areas of contention. ResultsStrong consensus was obtained regarding the clinical phenotype of EMAS: myoclonic atonic seizure was identified among others as a mandatory seizure type with typical onset of afebrile seizures between one and six years. A new term “stormy phase” (SP) was designated to delineate a characteristic phenotypic evolution in EMAS patients associated with seizure worsening. Strong consensus regarding the existence and time of onset of the SP, mandatory investigations to be performed early and later in the clinical course of EMAS, first and second tier treatment and prognostic factors for poor outcome were identified. Areas of lack of consensus included some seizure types that are necessary to diagnose EMAS, interictal EEG findings that prognosticate the course of EMAS, overall duration of SP, time to complete remission, and best approach to treat drug resistant EMAS. SignificanceExpert consensus on core diagnostic criteria of EMAS necessary for natural history studies, phenotype-genotype correlations, and clinical trials including comparative studies was demonstrated. Areas of disagreements (especially prognostic features; treatment options) need further research.

Epilepsy with myoclonic-atonic seizures (Doose syndrome): Clarification of diagnosis and treatment options through a large retrospective multicenter cohort.

Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date. Authors performed a retrospective chart review of patients with EMAS who received care at the authors' institutions. A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P=.005, χ2 ). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P<.001), seizure recorded on subsequent EEGs (P=.027), and failure to respond to diet therapy (P=.005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P<.001) and failure to achieve seizure freedom (P<.001). This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.

4478 Not just GLUT1: genome sequencing reveals genetic heterogeneity in Doose syndrome

OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligibility for the cohort included a potential diagnosis of EMAS by child neurology faculty at Children’s Hospital Colorado. Exclusion criteria included lack of drop seizures upon chart review or structural abnormality on MRI. Some individuals had prior genetic testing and priority for genome sequencing was given to individuals without clear genetic diagnosis based on previous testing. We analyzed single nucleotide variants (SNVs), small insertions and deletions (INDELs), and larger structural variants (SVs) from trio genomes and determined those that were likely contributory based on standardized American College of Medical Genetics (ACMG) criteria. RESULTS/ANTICIPATED RESULTS: Our initial analysis focused on variants in coding regions of known epilepsy-associated genes. We identified pathogenic or likely pathogenic variants in 6 different individuals involving 6 unique genes. Of these, 5 are de novo SNVs or INDELs and 1 is a de novo SV. One of these involve a de novo heterozygous variant in an X-linked gene (ARHGEF9) in a female individual. We hypothesize the skewed X-inactivation may result in primarily expression of the pathogenic variant. We anticipate identifying additional candidate variants in coding regions of genes previously not associated with EMAS or pediatric epilepsies as well as in noncoding regions of the genome. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite the genetic heterogeneity of EMAS, our initial analysis identified de novo pathogenic or likely pathogenic variants in 15% (6/40) of our cohort. As the cost continues to decline, short read genome sequencing represents a promising diagnostic tool for EMAS and other pediatric onset epilepsy syndromes. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose. SD has consulted for Upsher-Smith, Biomarin and Neurogene on an unrelated subject matter. GLC holds a research collaborative grant with Stoke therapeutics on unrelated subject matter.

Dramatic Improvement in Seizures With Phenytoin Treatment in an Individual With Refractory Epilepsy and a SCN1B Variant

Abstract We describe an individual with refractory epilepsy with myoclonic-atonic seizures (EMAS) and a suspected pathogenic variant in SCN1B, who had substantial improvement with phenytoin treatment. It is unknown whether SCN1B-related epilepsy improves or worsens with sodium channel blockers (SCBs), and this case demonstrates their potential benefit.

Genetic testing in a cohort of patients with potential epilepsy with myoclonic-atonic seizures

Epilepsy with myoclonic-atonic seizures (EMAS) accounts for 1–2% of all childhood-onset epilepsies. EMAS has been shown to have an underlying genetic component, however the genetics of this disorder is not yet well understood. The purpose of this study was to review genetic testing results for a cohort of EMAS patients. A retrospective chart review was conducted for 77 patients evaluated at Children’s Hospital Colorado with a potential diagnosis of EMAS. Genetic testing and biochemical testing was reviewed. Family history data was also collected. Seventy-seven percent of the cohort had at least one genetic test performed, and a molecular diagnosis was reached for six patients. Thirty-seven patients had a microarray, six of which identified a copy number variant. Only one was felt to contribute to the phenotype (2p16.3 deletion including NRXN1). Fifty-one patients had an epilepsy panel, two of which were positive (likely pathogenic variant in SCN1A, pathogenic variant in GABRG2). Of the six patients who had whole exome sequencing, two were negative, three were positive or likely positive, and one had multiple variants not felt to explain the phenotype. While EMAS is widely accepted to have a strong genetic component, the diagnostic yield of genetic testing remains low. This may be because several genes now thought to be associated with EMAS are not included on the more commonly ordered epilepsy panels, or have only recently been added to them.

Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures

IntroductionThere is overlap in the electroclinical features of many childhood epilepsy syndromes, especially those presenting with multiple seizure types, such as epilepsy with myoclonic-atonic seizures (EMAS) and Lennox-Gastaut syndrome (LGS). This study aimed to determine the frequency of diagnosis switching and the factors influencing epilepsy syndrome diagnosis in a cohort of children with possible EMAS, as well as to explore the relationship between epilepsy syndrome diagnoses, key electroclinical features, and clinically relevant outcomes. MethodsThis is a cross-sectional retrospective chart review of children treated at the Children’s Hospital of Colorado with a potential diagnosis of EMAS. ResultsThere were 77 patients that met eligibility criteria, including 39% (n = 30) with an initial diagnosis of EMAS and 74% (n = 57) with a final diagnosis of EMAS. On average, for the 65% of patients who received more than one epilepsy diagnosis, the first, second, and third diagnoses were received within one year, three years, and ten years after epilepsy onset, respectively. Final diagnosis was significantly related to obtaining at least a six-month period of seizure freedom, p = 0.03. Classic LGS traits, including paroxysmal fast activity, slow spike-and-wave, and tonic seizures were present in 50% of the overall cohort, although a minority of these patients had a final diagnosis of LGS. However, the presence of more LGS traits was associated with a higher likelihood of ongoing seizures. Adjusted for age of epilepsy onset, seizure freedom was half as likely for every additional LGS trait observed (0.49[0.31, 0.77], p = 0.002). ConclusionCurrent epilepsy syndrome classification has reduced applicability due to overlapping features. This results in diagnosis switching and limited prognostic value for patients with an overlapping clinical phenotype. Future studies should attempt to stratify patients based not only on epilepsy syndrome diagnosis, but also on the presence of various electroclinical traits to more accurately predict outcome.