Sleep Abnormalities in Children With Dravet Syndrome

BackgroundMutations in the voltage-gated sodium channel SCN1A gene are responsible for the majority of Dravet syndrome cases. There is evidence that the Nav1.1 channel coded by the SCN1A gene is involved in sleep regulation. We evaluated sleep abnormalities in children with Dravet syndrome using nocturnal polysomnography.MethodsWe identified six children at our institution with genetically confirmed Dravet syndrome who had also undergone formal sleep consultation with nocturnal polysomnography. Indications for polysomnography were parental concern of daytime fatigue or sleepiness, hyperactivity, inattention, disruptive behavior, nighttime awakenings, or nocturnal seizures. Sleep studies were scored according to guidelines of the American Academy of Sleep Medicine and non–rapid eye movement cyclic alternating pattern was visually identified and scored according to established methods.ResultsThe mean age of the subjects at the time of polysomnography was 6 years. Standard polysomnography did not show any consistent abnormalities in the obstructive or central apnea index, arousal index, sleep efficiency, or architecture. Cyclic alternating pattern analysis on five patients showed an increased mean rate of 50.3% (vs 31% to 34% in neurological normal children) with a mild increase in A1 subtype of 89.4% (vs 84.5%). A2/A3 subtype (5.3% vs 7.3%) and B phase duration (22.4 vs 24.7 seconds) were similar to previously reported findings in neurologically normal children.ConclusionDespite parental concerns for sleep disturbance in patients with Dravet syndrome, we could not identify abnormalities in sleep macroarchitecture. Non–rapid eye movement sleep microarchitecture was, however, abnormal, with increased A1 subtype, somewhat resembling a tracé alternant pattern of neonates and possibly suggestive of cortical synaptic immaturity in Dravet syndrome. Larger studies are needed to replicate these results.     

Severe Myoclonic Epilepsy of Infants (Dravet Syndrome): Natural History and Neuropsychological Findings

Summary:  Severe Myoclonic Epilepsy in infancy (SMEI, or Dravet syndrome) is a drug-resistant epilepsy that occurs in the first year of life of previously healthy children. The main clinical features are prolonged and repeated febrile and afebrile generalized or unilateral convulsive seizures. In the course of the epilepsy, cognitive deterioration becomes evident, and interictal myoclonus, clumsiness and ataxia appear. One third of the children with SMEI show de novo mutations of the SCN1A gene, and additional familial genes probably contribute to the phenotype. While the clinical picture of SMEI has been well studied, neuropsychological data remain scarce. Global mental retardation, attention deficit and psychotic behavior have been reported but the long-term outcome has not been evaluated. We conducted a longitudinal neuropsychological study of children with SMEI. Twenty children, aged 11 months to 16 years, were prospectively examined using standardized neuropsychological tests. Correlation analysis with other clinical features was performed in 12 cases. Marked slowing or stagnation of psychomotor development, accompanied by psychotic or autistic traits and hyperactivity, was observed between the ages of one and four years. In the later stages (at ages 5 to 16 years), cognitive function stabilized but remained below normal. In children with a more favorable course, language capacities were better preserved than visuospatial functions, and behavior improved. The cognitive and behavioral impairment tended to correlate with the frequency of convulsive seizures (>5 per month). The data suggest that SMEI can be considered as a prototype of an epileptic encephalopathy.     

Retrospective multiinstitutional study of the prevalence of early death in Dravet syndrome

Purpose: A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. Methods: A questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and their prevalence of early death. Key Findings: Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome died. Data from 59 of these patients were analyzed. The patients’ ages at death ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The analysis showed that the risk of mortality remained high up to approximately 12 years of age. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and acute hepatopathy in one patient (1%). The incidence of sudden death reached a first peak at 1–3 years of age and reached a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a sharp peak at 6 years of age. Seven of 10 patients who underwent an SCN1A mutation analysis exhibited positive mutations without a specific mutation site. Significance: In the present study, the prevalence of Dravet syndrome–related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was the highest in infancy (1–3 years) and at early school ages (with a peak at 6 years), respectively. After approximately 12 years of age, the risk of mortality declined sharply. Neither the treatment nor the number of seizures was associated with any cause of mortality. In addition, it is difficult to predict which factors lead to a fatal outcome.     

Two mild cases of Dravet syndrome with truncating mutation of SCN1A

Background

SCN1A is the gene that codes for the neuronal voltage-gated sodium-channel alpha-subunit 1. It is generally considered that an SCN1A truncating mutation causes the severe phenotype of Dravet syndrome.

Partial Seizures in West Syndrome

Summary: Purpose: To study the occurrence of partial seizures (PS) and elucidate the characteristics of patients with West syndrome (WS) with PS.
Methods: We investigated the electroclinical and radiologic features in 92 children with WS who were older than 3 years at follow-up.
Results: Thirty-six (39.1%) children had PS at some time during the course of the disease. They had a significantly high incidence of asymmetric spasms, hemiparesis, and asymmetric hypsarrhythmia. Their seizure prognosis was significantly less favorable. PS appeared only before spasms (group A, six children), concomitant with spasms (group B, 18 children), and only after spasms ceased (group C, 12 children). Five children in group B had PS after spasms stopped. PS in group A and during the period of active spasms in group B showed high seizure frequency and variability of both seizures and EEG manifestations. The PS and EEG epileptiform discharges were mainly in parietal-posterior temporal-occipital, and central regions. Late PSs in group B and PSs in group C were characterized by stereotyped manifestations and relatively low seizure frequency. These PSs originated mostly from frontal regions.
Conclusions: In some children with WS, cortical lesions can induce both PS and spasms in series, whereas in others, both types of seizures occur with abnormally increased excitability throughout the cortex rather than as the result of a single cortical lesion. These findings suggest caution in interpreting focal discharges, which may fluctuate and are not necessarily indicative of a surgically accessible lesion. When the discharges are stable and correlate with an equally stable clinical pattern, the likelihood of an underlying cortical lesion is greater.     

Dravet syndrome - considerable delay in making the diagnosis

Objectives – To assess delay in diagnosis and clinical characteristics of Dravet syndrome based on the Dravet register at The National Centre for Epilepsy in Norway. Material and methods – Medical records of patients diagnosed with Dravet syndrome since 2007 were analysed. Results – Twenty‐two patients were identified. In 15, genetic screening disclosed mutations/deletions in the SCN1A gene. Average time from seizure onset to diagnosis was 7.4 years. Mean age at seizure onset was 6.7 months, nine had hemiconvulsions and 13 had generalized tonic‐clonic seizures. The seizures were precipitated by fever in 17, by external heating in three. During second year of life, multiple seizure types and cognitive and motoric stagnation occurred. No patients became seizure‐free with antiepileptic drugs. The effect of vagal nerve stimulation was disappointing. Conclusions – By making an early diagnosis, an extensive presurgical evaluation may be avoided, and the patient and their parents may be offered genetic guidance.     

A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation

A boy with a clinical history of pharmacologically resistant Dravet syndrome died suddenly after falling asleep. The autopsy concluded that the cause of death was sudden unexpected death in epilepsy (SUDEP). Postmortem molecular analysis of the SCN1A gene by multiplex ligation‐dependent probe amplification (MLPA), high‐resolution melting curve analysis (HRMCA), and sequencing revealed a frameshift duplication of adenosine at position 504. The incidence of this mutation is discussed as a potential cause of SUDEP.     

Risk of Subsequent Asthma in Children With Febrile Seizures: A Nationwide Population-Based Retrospective Cohort Study

BackgroundNo study has reported a relationship between febrile seizures and asthma; thus, we examined the association between these two disorders.MethodsWe identified 991 cases of children with febrile seizures as the case cohort, and the control group was matched according to age, sex, urbanization level, and their parents' occupation at a 1:4 ratio. We applied the Cox proportional hazards regression model to estimate the hazard ratios and 95% confidence intervals for asthma among the children with febrile seizures.ResultsAfter 11 years of follow-up, the asthma incidence in the febrile seizure group was approximately 5% higher than that in the control group (log-rank test, P < 0.0001). The risk of asthma in the febrile seizure group was 1.41 times higher than that in the control group (95% confidence interval, 1.21-1.65; P < 0.001). Furthermore, the risk of asthma development increased (0.96 vs 3.62) in conjunction with the frequency of febrile seizure-related medical visits (one to two visits vs more than four visits; P < 0.0001).ConclusionFebrile seizures may be associated with an increase in the risk of future asthma occurrence in children. We observed a significantly higher cumulative incidence of asthma occurrence in children with more febrile seizure-related medical visits.     

Dravet syndrome: Treatment options and management of prolonged seizures

Over time, with careful delineation of Dravet syndrome, we have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents including cannabidiol and fenfluramine have been demonstrated to be of benefit in clinical trials. We propose an algorithm for management, but appreciate that the positioning of newer agents is yet to be established.     

Dravet syndrome: Early clinical manifestations and cognitive outcome in 37 Italian patients

Aims of our study were to describe the early clinical features of Dravet syndrome (SMEI) and the neurological, cognitive and behavioral outcome. The clinical history of 37 patients with clinical diagnosis of SMEI, associated with a point mutation of SCN1A gene in 84% of cases, were reviewed with particular attention to the symptoms of onset. All the patients received at least one formal cognitive and behavior evaluation. Epilepsy started at a mean age of 5.7 months; the onset was marked by isolated seizure in 25 infants, and by status epilepticus in 12; the first seizure had been triggered by fever, mostly of low degree in 22 infants; the first EEG was normal in all cases. During the second year of life difficult-to-treat seizures recurred, mostly triggered by fever, hot bath, and intermittent lights and delay in psychomotor development became evident. At the last evaluation, performed at a mean age of 16 ± 6.9 years, mental retardation was present in 33 patients, associated with behavior disorders in 21. Our data indicate that the most striking features of SMEI are: the early onset of seizures in a previously healthy child, the long duration of the first seizure, the presence of focal ictal symptoms, and sensitivity to low-grade fever. Diagnosis of SMEI may be proposed by the end of the first year of life, and a definite diagnosis can be established during the second year based on the peculiar seizure-favoring factors, EEG photosensitivity and psychomotor slowing. The temporal correlation between high seizure frequency and cognitive impairment support the role of epilepsy in the clinical outcome, even if a role of channelopathy cannot be ruled out.     

Dravet syndrome with parkinsonian symptoms and intact dopaminergic neurons: A case report

IntroductionDravet syndrome (DS) is severe myoclonic epilepsy in infancy and associated with a heterozygous mutation of the gene for the sodium channel alpha 1 subunit (SCN1A). Recently, adult patients with DS have been reported to show parkinsonism, but no corresponding neuroimaging data are available. Here, we present neuroimaging data in 2 adult patients with DS showing parkinsonian symptoms.Case reportCase 1: A man who had intractable seizures from the age of 1 year and 2 months was diagnosed with DS at 7 with a mutation in the SCN1A gene. At 18, he had parkinsonian symptoms such as masked face and bradykinesia. At 20, he was admitted to our department. Dopamine transporter single-photon emission computed tomography (DAT SPECT) showed no decrease in striatal binding of ¹²³I–N–ω–fluoropropyl–2β–carbomethoxy–3β–(4–iodophenyl) nortropane (¹²³I-FP-CIT), and myocardial scintigraphy showed no decrease in cardiac uptake of ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG). Levodopa showed no significant improvement in his symptoms. Case 2: A woman who had febrile seizures at 4 months of age and myoclonic seizures at 1 year and 5 months was diagnosed with DS at 31. She had myoclonus, resting tremor, hypertonia, antecollis, crouch gait, and bradykinesia. DAT SPECT imaging showed no decrease in striatal FP-CIT binding, and levodopa did not improve her symptoms.DiscussionThe normal DAT SPECT and ¹²³I-MIBG results suggest that dopaminergic neurons projecting onto striatal neurons were not impaired in our patients, explaining the lack of response to levodopa. Thus, dopamine imaging can help to guide treatment decisions in patients with DS and parkinsonism.     

A case of Dravet syndrome with cortical myoclonus indicated by jerk-locked back-averaging of electroencephalogram data

We report a female patient with Dravet syndrome (DS) with erratic segmental myoclonus, the origin of which was first identified in the cerebral cortex by the detection of myoclonus-associated cortical discharges. The discharges were disclosed through jerk-locked back-averaging of electroencephalogram (EEG) data using the muscle activity of myoclonus as triggers. The detected spikes on the contralateral parieto-central region preceded myoclonic muscle activity in the forearms by 28–46 ms. The patient was six months old at the time of examination, and was developing normally before seizure onset at two months of age. She suffered from recurrent afebrile or febrile generalized tonic–clonic seizures that often developed into status epilepticus. Interictal EEG and brain magnetic resonance imaging (MRI) showed no significant findings. The amplitudes of the somatosensory-evoked potentials were not extremely large. She has a chromosomal microdeletion involving SCN1A and adjacent genes.     

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na_V1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na_V1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.     

A screening test for the prediction of Dravet syndrome before one year of age

PURPOSE: Our aim was to develop a screening test to predict Dravet syndrome before the first birthday based on the clinical characteristics of infants and the SCN1A mutation analysis. METHODS: Ninety-six patients who experienced febrile seizures before the age of one were enrolled. The patients were divided into two groups-the Dravet syndrome group (n = 46) and the non-Dravet syndrome group (n = 50). We compared the clinical characteristics before one year of age of the two groups. We analyzed all coding exons of the SCN1A gene by the direct sequencing method. Scores from 0 to 3 were assigned to each risk factor based on the odds ratio and p-value. RESULTS: An age of onset of febrile seizure or= 5, and prolonged seizures lasting more than 10 min. were regarded as significant risk factors for Dravet syndrome. Other factors highly predictive of this syndrome were hemiconvulsions, partial seizures, myoclonic seizures, and hot water-induced seizures. A total clinical score of six or above was the cutoff value indicating a high risk of Dravet syndrome. SCN1A missense and truncated mutations were detected significantly more often in the Dravet syndrome group than in the non-Dravet syndrome group. DISCUSSION: This simple screening test was designed to be used by general pediatricians. It could help to predict Dravet syndrome before one year of age. If the sum of the clinical risk score is >or= 6, then the performance of an SCN1A mutation analysis is recommended.