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.     

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.     

Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome).

The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.     

Severe myoclonic epilepsy in infancy: toward an optimal treatment

Severe myoclonic epilepsy in infancy, or Dravet syndrome, is one of the catastrophic epilepsy syndromes. In the past, treatment was mainly based on valproate and phenobarbital. Recently, some of the new antiepilepsy drugs, such as topiramate and stiripentol, have been shown to be promising in the treatment of this epilepsy syndrome. The treatment regimen of 12 children with Dravet syndrome and proven mutations in the alpha subunit of the sodium channel SCN1A is reported here. Five patients on the "traditional" treatment regimen are compared with seven children on an "optimal" treatment regimen based on a combination of valproate and topiramate. With respect to the literature and our own experience, we propose guidelines for "optimal" treatment of children with severe myoclonic epilepsy in infancy. This includes prevention of hyperthermia, rigorous treatment of fever, avoiding stressful situations, maintenance treatment based on a combination of only two antiepilepsy drugs (ie, valproate and topiramate), and a strict acute seizure treatment based on benzodiazepines. To prevent long-lasting periods of status epilepticus, this acute seizure treatment must be taught to parents and caregivers.     

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.     

"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.     

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.     

Photosensitive benign myoclonic epilepsy in infancy

PURPOSE: To describe the electroclinical features of subjects who presented with a photosensitive benign myoclonic epilepsy in infancy (PBMEI). METHODS: The patients were selected from a group of epileptic subjects with seizure onset in infancy or early childhood. Inclusion criteria were the presence of photic-induced myoclonic seizures and a favorable outcome. Cases with less than 24 month follow up were excluded from the analysis. RESULTS: Eight patients were identified (4 males, 4 females). Personal history was uneventful. All of them had familial antecedents of epilepsy. Psychomotor development was normal in 6 cases, both before and after seizure onset. One patient showed a mild mental retardation and a further patient showed some behavioral disturbances. Neuroradiological investigations, when performed (5 cases), gave normal results. The clinical manifestations were typical and could vary from upward movements of the eyes to myoclonic jerks of the head and shoulders, isolated or briefly repetitive, never causing a fall. Age of onset was between 11 months and 3 years and 2 months. Characteristically, the seizures were always triggered by photic stimulation. Non photo-induced spontaneous myoclonic attacks were reported in 2 cases during the follow-up. Other types of seizures were present at follow-up in 2 cases. The outcome was favorable, even if, usually, seizure control required high AED plasma levels. Since the clinical symptoms were not recognized early, some patients were treated only many years after the onset of symptoms. CONCLUSION: Among BMEI patients, our cases constitute a subgroup in which myoclonic jerks were always triggered by photostimulation, in particular at onset of their epilepsy.     

A patient with myoclonic epilepsy in infancy followed by myoclonic astatic epilepsy

Myoclonic epilepsy in infancy (MEI) is a primary generalized epilepsy. According to the literature, the outcome of MEI is usually benign. Here we report a patient who developed myoclonic astatic epilepsy at age four, having been seizure free without antiepileptic drug treatment for 2 years after his recovery from MEI. At age four, a video-EEG-recording showed frequent head nodding (atonic seizures) and myoclonic astatic seizures associated with diffuse spikes or polyspikes and waves. The interictal EEG revealed frequent bursts of generalized 100-200 μV, 2-4 Hz spike-and-slow-wave complexes. Despite a general favorable outcome, more severe epilepsy syndromes may develop after MEI, and mental retardation is sometimes observed. Our case and the previous literature suggest that epilepsies following on from MEI often involve myoclonic seizures.     

Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data

Severe myoclonic epilepsy in infancy (SMEI) is a rare, but severe disorder with seizures typically resistant to conventional antiepileptic drugs. The objective of the present study was to systematically review the literature on the available treatments for SMEI. Databases searched included Medline, Embase, and Cochrane. We used a fixed effect model to summarize the odds ratio of seizures rates and a logistic model to evaluate the influence of patient characteristics on treatment effect. We found 23 uncontrolled studies and 2 randomized controlled trials (RCTs) that compared stiripentol with placebo. Overall, 64 children aged between 3 and 20 years were included in the two RCTs. The odds ratio of responding to stiripentol relative to placebo was 32 (CI: 6.2, 161) and stiripentol reduced seizure rate by 70% (93%; 47%). The multivariate analysis does not suggest any differences within subgroups of participants and cotherapy. Results of uncontrolled studies in children with SMEI are potentially biased and do not provide valid information on the benefits and harms of treatments. The two RCTs identified, however, were performed with the same objectives and design and showed that seizure frequency is greatly reduced by stiripentol in children with SMEI after 2 months of treatment.     

Benign myoclonic epilepsy in infancy: neuropsychological and behavioural outcome

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome of idiopathic generalized epilepsies with onset below 3 years of age. It has been reported that BMEI is associated with a good prognosis, however, recently some studies suggest less favourable neuropsychological outcome. We report a long-term follow-up of seven patients with BMEI. Seizure outcome and neuropsychological, cognitive, and behavioural evolution were discussed for each of them. At the end of follow-up, 86% of children showed neuropsychological and intellectual disorders: two children had mental retardation, three patients achieved a borderline IQ and one normal but low IQ. All but one displayed neuropsychological disabilities including fine motor skill deficits, attention deficits, and language impairment and learning disorders. Our clinical data and the previous reports suggest that the early onset of the seizures may be one of the main factors of the illness giving rise to a less favourable outcome. Additional interacting factors such as delayed start of treatment, and efficacy of the drugs may play an important role, too. We believe that BMEI does not exert, different from some epileptic encephalopathies, a quick destroying effect but may interfere with the growth of developing functions, which results in long-term neuropsychological disabilities.     

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.     

Benign myoclonic epilepsy in infancy followed by childhood absence epilepsy

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome included among idiopathic generalized epilepsies (IGE) and syndromes with age-related onset. Recently, it has been shown that a few patients with BMEI later had other epilepsy types mainly IGE but never childhood absence epilepsy (CAE).We report a patient who at 11 months of age showed isolated myoclonic jerks occurring several times a day. The ictal video-EEG and polygraphic recording revealed generalized discharge of spike-wave (SW) lasting 1–2 s associated with isolated bilateral synchronous jerk involving mainly the upper limbs controlled by valproic acid (VPA).At 6 years and 8 months the child developed a new electroclinical feature recognized as CAE. The ictal EEG disclosed a burst of rhythmic 3 Hz generalized SW.Our case is the first patient with BMEI reported in the literature who later developed a CAE.This finding suggests a common neurobiological and genetic link between different age-related epileptic phenotypes.     

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.     

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.