Epileptic encephalopathies with myoclonic seizures in infants and children (severe myoclonic epilepsy and myoclonic-astatic epilepsy).

Myoclonic attacks are not characteristic of a specific syndrome. In infancy and early childhood, they are often observed in the context of syndromes that are associated with other types of seizures and with cognitive impairment but no obvious brain lesion. Characterization of the associated seizures and age of expression allows inclusion of a number of cases in two main subgroups: severe myoclonic epilepsy (SME, or Dravet syndrome) and myoclonic-astatic epilepsy (MAE). Severe myoclonic epilepsy is an epileptic encephalopathy with invariably poor outcome in which myoclonic seizures, though frequently observed, may be absent altogether in some children. Prolonged and repeated febrile and afebrile convulsive seizures starting in infancy are the main feature and are probably causally related to cognitive decline. One third of children harbor mutation of the SCN1A gene, but the genetics of SME is probably more complex than expected with simple monogenic disorders. Treatment is usually disappointing. Myoclonic-astatic epilepsy is perhaps more a conceptual category of idiopathic myoclonic epilepsy than a discrete syndrome. Childhood-onset myoclonic-astatic attacks are the characteristic seizures associated in most with episodes of nonconvulsive status and generalized tonic-clonic seizures. Outcome is unpredictable. Either remission within a few years with normal cognition or long-lasting intractability with cognitive impairment is possible. Likewise, the effectiveness of antiepileptic drugs is variable. A number of cases of myoclonic epilepsies in infancy and early childhood, however, remain unclassified, and intermediate forms between the different syndromes exist. They must be distinguished from other syndromes with frequent brief attacks and repeated falls, especially the Lennox-Gastaut syndrome. This differentiation is often difficult and may require extensive neurophysiologic studies.     

Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients

To report the authors' experience with diagnosis and management of Dravet syndrome, or severe myoclonic epilepsy in infancy, in the era of commercially available genetic testing, the authors performed a retrospective study of 16 patients diagnosed with Dravet syndrome at a tertiary care pediatric epilepsy center. They analyzed their clinical presentation, electroencephalographic findings, genetic (SCN1A gene) results, and treatment responses and compared the findings to previous reports. The patients presented with all the previously described characteristics of Dravet syndrome. Six of the 7 patients (86%) who were tested for SCN1A mutations had positive results. The best treatment combinations included topiramate, valproate, or the ketogenic diet. Dravet syndrome is a well-defined epileptic syndrome that needs larger recognition, particularly because commercial testing for SCN1A gene mutations is now available in the United States. Despite its reputation for seizure intractability, several treatment options may be particularly helpful, whereas others need to be avoided.     

Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults

Establishing an etiologic diagnosis in adults with refractory epilepsy and intellectual disability is challenging. We analyzed the phenotype of 14 adults with severe myoclonic epilepsy of infancy. This phenotype comprised heterogeneous seizure types with nocturnal generalized tonic-clonic seizures predominating, mild to severe intellectual disability, and variable motor abnormalities. The diagnosis was suggested by a characteristic evolution of clinical findings in the first years of life. Ten had mutations in SCN1A and one in GABRG2.     

Severe myoclonic epilepsy of infancy (Dravet syndrome): Clinical and genetic features of nine Turkish patients

Purpose:

Mutations of the α-1 subunit sodium channel gene (SCN1A) cause severe myoclonic epilepsy of infancy (SMEI). To date, over 300 mutations related to SMEI have been described. In the present study, we report new SCN1A mutations and the clinical features of SMEI cases.

Materials and Methods:

We studied the clinical and genetic features of nine patients diagnosed with SMEI at the Pediatric Neurology Department of Istanbul Medical Faculty.

Results:

Five patients had nonsense mutations, two had missense mutations, one had a splice site mutation and one had a deletion mutation of the SCN1A gene. Mutations at c.3705+5G splice site, p.trip153X nonsense mutation and deletion at c.2416_2946 have not been previously described. The seizures started following whole cell pertussis vaccination in all patients. The seizures ceased in one patient and continued in the other eight patients. Developmental regression was severe in three patients, with frequent status epilepticus. The type of mutation was not predictive for the severity of the disease. Two of the three patients with severe regression had nonsense and missense mutations.

Conclusions:

Dravet syndrome can be result of several different types of mutation in SCN1A gene. Onset of the seizures after pertussis vaccination is an important clue for the diagnosis and neuro- developmental delay should be expected in all patients.     

婴儿重症肌阵挛癫(癎)的临床特征及药物疗效分析

目的 探讨婴儿重症肌阵挛癫痫（severe myoclonic epilepsy in infancy，SMEI）的临床特征及抗癫痫药物疗效。方法 通过对4046例癫痫患者随访分析，根据国际抗癫痫联盟的分类标准诊断SMEI，分析患者的临床资料。结果 共收集到16例SMEI患者，其中散发病例8例，有热性惊厥或癫痫家族史者8例，根据发作形式诊断为典型SMEI10例，边缘型SMEI6例，患者有多种癫痫发作形式，伴有精神运动发育迟缓，部分患者有影像学异常。多重作用机制药物或作用于钠通道以外的药物治疗可能有效，患者预后差。结论 SMEI是一种少见的、严重的、治疗困难、预后差的癫痫综合征。     

Molecular basis of severe myoclonic epilepsy in infancy

Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) – positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies.     

Genetic predisposition to severe myoclonic epilepsy in infancy

PURPOSE: To address genetic predisposition to febrile convulsions (FCs) and epilepsy as an etiologic background of severe myoclonic epilepsy in infancy (SMEI). METHODS: Familial antecedents of epilepsy and FCs were analyzed in four groups of patients with SMEI (65 cases), FCs (57 cases), childhood absences (67 cases), and a control group of patients with no neurologic problems (64 cases). RESULTS: Patients with SMEI and those with FCs had significantly increased incidence of FCs in their relatives compared with those with absence epilepsy and with the control group. The incidence of epilepsy in relatives of patients with SMEI and absence epilepsy was increased compared with that in the control group and reached statistical significance. Epilepsy in relatives with SMEI had the characteristics of idiopathic generalized epilepsy. CONCLUSIONS: A genetic predisposition could determine three types of epileptic syndromes: FCs, idiopathic generalized epilepsy, and SMEI.     

Early diagnosis of severe myoclonic epilepsy in infancy.

Of 329 epileptic patients referred in a six year period with the first seizure occurring in the first year of life, 20 met the following criteria: generalized seizures excluding infantile spasms, myoclonic, tonic or absence seizures, at least one afebrile seizure, normal development prior to the first seizure, normal CT scan, and no etiology. Seventeen of these 20 patients developed the full pattern of severe myoclonic epilepsy in infancy (SMEI). This syndrome was recognizable from the second or third seizure in the first year of life, although epileptiform EEG abnormalities were lacking until the age of 11 to over 30 months. Therefore, based on the clinical pattern, the diagnosis of SMEI can be made with quite good reliability by the end of the first year of life.     

Hemiconvulsion–hemiplegia syndrome in a patient with severe myoclonic epilepsy in infancy

We report a 2-year-old girl who had repeated febrile or afebrile seizures since infancy. Prolonged left/right hemiconvulsions and myoclonus of the eyelids/extremities with generalization to tonic–clonic seizures, were refractory to antiepileptic agents. At age 1 year and 4 months, she contracted rotavirus infection, and developed status epilepticus with persistent right hemiclonic seizures. Left unilateral brain edema with subsequent emergence of cortical laminar necrosis and white matter lesions, and progressive atrophy of the left cerebral hemisphere were noted during this period. She showed residual right hemiparesis and mild intellectual disability, and had generalized/eyelid myoclonia and hot water epilepsy after a 5-month seizure-free period. Analysis for SCN1A , the gene encoding the neuronal voltage-gated Na⁺ channel α1 subunit revealed a nonsense mutation, R1892X. These indicate the potential risk in patients with severe myoclonic epilepsy in infancy (SMEI) to develop hemiconvulsion–hemiplegia (HH) syndrome. SCN1A mutations may need to be further explored in patients with HH syndrome without features of SMEI.     

Paroxysmal movement disorders in severe myoclonic epilepsy in infancy

We report on the electroclinical findings and the results of a molecular genetic study of a patient with typical severe myoclonic epilepsy in infancy (TSME) and three with borderline SME (BSME) who showed paroxysmal movement disorders, such as choreoathetosis, dystonia and ballismus, during their clinical course. BSME was defined as a clinical entity that shares common characteristics with TSME but lacks myoclonic seizures associated with ictal EEG changes. When the paroxysmal movement disorders were first observed, all the patients in this study were being treated with polytherapy including phenytoin (PHT), and these abnormal movements disappeared when PHT was discontinued or reduced. However, on other occasions, two of our cases also showed the same abnormal movements even when not being treated with PHT. One patient with TSME and two of the three patients with BSME had SCN1A gene mutations that lead to truncation of the associated protein. We conclude that paroxysmal movement disorders seen in SME patients were closely related to their AED therapy, especially the use of PHT. It is thought that patients with both TSME and BSME have some predisposition toward paroxysmal movement disorders, and that this predisposition is partly related to sodium channel dysfunction, although some other factors might influence the occurrence of this phenomenon.     

Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome)--a nationwide questionnaire survey in Japan

The aim of this study was to establish strategies for prophylaxis against status epilepticus (SE) associated with high fever and for management of ongoing SE in children with severe myoclonic epilepsy in infancy (SMEI). Methods: The investigation was performed retrospectively using a questionnaire, asking about medications, which was distributed to epilepsy specialists throughout Japan. All respondents were members of the Japan Epilepsy Society (JES) and/or the Japanese Society of Child Neurology (JSCN). Data from 109 SMEI patients (51 males and 58 females), 1–37 (M ± SD, 10.7 ± 6.53) years old, were used for this study. Of these 109 patients, 10 were excluded because they had not experienced SE, such that data from 99 patients were analyzed. Results: Among the anti-epileptic drugs (AEDs) used daily, excellent efficacy against SE evolution was obtained with the following: potassium bromide (KBr) (41.7%), zonisamide (ZNS) (13.5%), clobazam (CLB) (10.0%), valproate (VPA) (8.0%), phenobarbital (PB) (6.7%), and phenytoin (PHT) (2.6%). Excellent efficacy was not obtained with either clonazepam (CZP) or carbamazepine (CBZ). The diazepam (DZP) suppository was the most frequently given drug for prophylaxis against SE triggered by fever, but only 2 (2.4%) cases showed excellent results. Excellent efficacy in terminating ongoing SE was obtained with the following medications; intravenous barbiturates (75–100%), intravenous midazolam (MDZ) (68.8%), intravenous DZP (54.3%), intravenous lidocaine (Lid) (21.4%), and intravenous PHT (15.4%). Conclusions: Daily KBr was most efficacious for controlling seizures in SMEI patients. Early use of intravenous barbiturates is the most effective strategy in stopping SE in a subset of patients. Reliable efficacy in SE was not obtained with prophylactic DZP, intravenous benzodiazepines (BZPs), PHT and Lid.     

Topiramate in the treatment of severe myoclonic epilepsy in infancy

The aim of this study was to assess the effectiveness of topiramate (TPM) as an add-on regimen in reducing seizure rate in a population sample of patients diagnosed with severe myoclonic epilepsy in infancy (SME). Eighteen patients were evaluated. The mean observation time was 10.5 months (range, 6-18 months). Seizure frequency and type were recorded. Topiramate was administered as an add-on regimen at a starting dose of 1 mg kg(-1)and titrated to a maximum of 6-8 mg per kg per day. Different escalation rates were used, mainly weekly or fortnightly increments of dose. Three patients (16.6%) became seizure free, and 10 (55.6%) had a >50% reduction in seizure frequency: six of them (22.2%) achieved a reduction greater than 75%. Side-effects were observed in nine patients, eight with a weekly titration schedule and one with a fortnightly schedule. TPM is effective as adjunctive therapy for SME. Side-effects were mild and transient, generally related to rapid dosage titration.     

"Severe myoclonic epilepsy in infancy". Relevance for the clinician of severe epilepsy starting in infancy

'Severe myoclonic epilepsy in infancy' or Dravet syndrome is a clear example of the impact of severe epilepsy on the developing child. Presenting with febrile seizures in infancy, children later on develop a severe epileptic syndrome with mental retardation. Nearly all children have life-threatening status epilepticus during the first two years of life. The clinical diagnosis can now be confirmed by DNA-analysis in a majority of patients. Most patients have a de novo mutation in the alfa subunit of the neuronal sodium channel SCN1A. In the past few years' treatment of severe myoclonic epilepsy in infancy has changed. Prevention of seizures, avoiding anti-epileptic drugs which only block sodium channels, a simple combination of two major anti-epileptic drugs (sodium valproate and topiramate) and a strict acute seizure treatment significantly improve the quality of life for these patients. Long-term follow up is necessary to evaluate if we can also improve the development possibilities for these children.