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.     

Acute encephalopathy in children with Dravet syndrome

Purpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome. Methods: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms. Key Findings: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8–184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion‐weighted images during the acute phase: cerebral cortex–dominant lesions with or without deep gray matter involvement and subcortical‐dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae. Significance: We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.     

Adult motor phenotype differentiates Dravet syndrome from Lennox‐Gastaut syndrome and links SCN1A to early onset parkinsonian features

Distinguishing adult patients with Lennox‐Gastaut syndrome from those with Dravet syndrome is challenging. We have previously reported that patients with Dravet syndrome present a very peculiar motor phenotype. Here we sought to confirm that this association was not linked to the chronic use of antiepileptic drugs or the many lifetime seizures. To this aim, we studied 14 adult patients with Lennox‐Gastaut syndrome and 14 adults with Dravet syndrome because both conditions share similar seizure severity. We found that antecollis and parkinsonian gait were significantly more common in the Dravet group, thus suggesting that these features are part of the Dravet syndrome adult phenotype.     

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.     

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.     

On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation

This study examines whether microdeletions and duplications of the gene encoding α1 subunit of the sodium channel (SCN1A) are underlying causes in Dravet syndrome (DS) with SCN1A missense mutation. Multiple exonic deletions were identified in 8/84 patients without mutation and 0/41 patients with missense mutations. Our findings indicate that while microdeletions are not rare in SCN1A-negative patients, they are not likely to be present simultaneously with other SCN1A mutations.     

Dravet syndrome: Seizure control and gait in adults with different SCN1A mutations

Purpose: Dravet syndrome (DS) is an aggressive epileptic encephalopathy. Pharmacoresistant seizures of several types plague most patients with DS throughout their lives. Gait difficulties are a common, but inconsistent finding. The majority of cases are caused by mutations in the SCN1A gene, but little information is available about how particular mutations influence the adult phenotype. The purpose of this study is to correlate different types of SCN1A mutations and (1) seizure control, (2) occurrence of convulsive status epilepticus (cSE), and (3) the presence of crouch gait in adult patients. Methods: In a cohort of 10 adult patients with DS caused by SCN1A mutations, we investigated seizure frequency, history of cSE, and gait. All patients were identified in the epilepsy clinic between 2009 and 2011. SCN1A mutations were divided into four different groups based on location or effect of the mutation. Retrospective chart review and recent physical examination were completed in all cases. Key Findings: All patients had a pathogenic mutation in the SCN1A gene. Four SCN1A mutations have not been described previously. Greater than 90% seizure reduction was observed (compared to childhood frequency) in six of seven patients with missense mutations in the pore‐forming region (PFR) of the Na_v1.1 protein (group A) and nonsense mutations (group B). One patient with a splice‐site mutation (group C) and another with a mutation outside the PFR (group D) became free of all types of seizures. cSE after the age of 19 years was observed in only one patient. Crouch gait, without spasticity, is identified as an element of the adult DS phenotype. However, only one half of our adult DS cohort demonstrated crouch gait. This feature was observed in five of seven patients from groups A and B. Significance: This study shows that seizure control improves and cSE become less frequent in DS as patients age, independent of their SCN1A mutation type. Complete seizure freedom was seen in two patients (groups C and D). Finally, this study shows that in DS, crouch gait can be observed in up to 50% of adults with SCN1A mutation. Although no definite statistical correlations could be made due to the small number of patients, it is interesting to note that crouch gait was observed only in those patients with nonsense mutations or mutations in the PFR. Future studies with larger cohorts will be required to formally assess an association of gait abnormalities with particular SCN1A mutations.     

Cerebral hemiatrophy and hemiparesis following hemiclonic status epilepticus in Dravet syndrome

Dravet syndrome is currently considered as an developmental and epileptic encephalopathy and, recently, mandatory, alert, and exclusionary criteria have been proposed. Here, we describe three patients with Dravet syndrome with the typical early presentation including febrile and afebrile alternating hemiclonic seizures due to loss-of-function SCN1A variants. Subsequently, they developed episodes of febrile focal status epilepticus (SE) associated with hemiparesis and cerebral hemiatrophy with posterior focal seizures, as a consequence of Dravet syndrome. This sequence of events has been previously published in patients with Dravet syndrome and does not contradict the recent classification by the International League Against Epilepsy (ILAE). The ILAE guidance identifies “Focal neurological findings” as alert criteria and “MRI showing a causal focal lesion” as exclusionary criteria for making an initial diagnosis of Dravet syndrome at presentation. Our three patients would correspond to a severe phenotype, similar to the well-known presentation of generalized atrophy following prolonged status epilepticus. Common genetic findings in cases of diffuse and unilateral brain involvement may help explain these clinical presentations. Further genotype–phenotype studies may provide additional insights into this electroclinical behavior.     

Comorbidities and predictors of health-related quality of life in Dravet syndrome

Purpose: Health‐related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s physical, social, and mental well‐being. There is a paucity of data focusing on HRQOL in specific epilepsy syndromes and their associated needs. In this study our aim was to describe the comorbidities and disease‐related predictors for HRQOL in Dravet syndrome, an epileptic encephalopathy, with defined genetic etiology. We anticipate that this will help us to better recognize and understand the needs of children and families and aid treatment planning in this severe epilepsy syndrome. Methods: One hundred sixty‐three individuals with Dravet syndrome and their families participated in the study. Detailed clinical and demographic information was available for each case. HRQOL was evaluated with two epilepsy‐specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument; the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). Key Findings: HRQOL was significantly lower for children with Dravet syndrome compared to normative data (p < 0.001). A cross‐sectional evaluation of measures across different age groups revealed that PedsQL generic core and cognitive function scales decreased in older age categories, indicating worse HRQOL (p < 0.001). Assessment of epilepsy severity demonstrated that symptoms were rated very severe in 10 (6%) of 162 cases, somewhat severe in 78 (48%) of 162, moderate in 51 (32%) of 162, and mild in 23 (14%) of 162 cases. The epilepsy severity correlated significantly with the IPES total impact score (r = 0.466, p < 0.001, n = 162). The IPES total impact scores in the Dravet group (n = 162) were significantly higher than scores measured in the original validation sample of epileptic children with and without learning difficulties (± SD) (21.0 ± 8.7 vs. 11.6 ± 5.4, t = 8.95, p < 0.001, n = 46). On the SDQ, 35% of children scored in the abnormal range for “conduct problems,” 66% for “hyperactivity/ inattention,” and 76% for “peer relationships.” Regression analysis revealed that young age at seizure onset (p = 0.019), presence of myoclonic seizures (p = 0.029), motor disorder (p = 0.048), learning difficulties (p = 0.002), epilepsy severity (p < 0.001), and behavioral difficulties (p < 0.001) each independently predicted poorer HRQOL. Behavioral problems such as hyperactivity/inattention were the strongest predictors of poorer HRQOL. Significance: This is the first comprehensive study of HRQOL in an etiologically well‐defined epilepsy syndrome. HRQOL in Dravet syndrome depends on a series of independent factors including seizure control, behavior, cognitive, and motor problems. Identification of specific comorbidities in Dravet syndrome will facilitate a distinct and multidisciplinary approach to management, addressing seizure control, behavior problems, cognitive difficulties, and motor impairment.     

Comorbidities and predictors of health-related quality of life in Dravet syndrome: A 10-year,prospective follow-up study

Objective

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, leading to reduced health-related quality of life (HRQOL). Prospective outcome data on HRQOL are sparse, and this study investigated long-term predictors of HRQOL in DS.

Methods

One hundred thirteen families of SCN1A-positive patients with DS, who were recruited as part of our 2010 study were contacted at 10-year follow-up, of which 68 (60%) responded. The mortality was 5.8%. Detailed clinical and demographic information was available for each patient. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument, the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ).

Results

Twenty-eight patients were 10–15 years of age (0–5 years at baseline) and 40 were ≥16 years of age (≥6 years at baseline). Patients 0- to 5–years-old at baseline showed a significant decline in mean scores on the PedsQL total score (p = .004), physical score (p < .001), cognitive score (p = .011), social score (p = .003), and eating score (p = .030) at follow-up. On multivariate regression, lower baseline and follow-up HRQOL for the whole cohort were associated with worse epilepsy severity and a high SDQ total score (R² = 33% and 18%, respectively). In the younger patient group, younger age at first seizure and increased severity of epilepsy were associated with a lower baseline HRQOL (R² = 35%). In the older age group, worse epilepsy severity (F = 6.40, p = .016, R² = 14%) and the use of sodium-channel blockers were independently associated with a lower HRQOL at 10-year follow-up (F = 4.13, p = .05, R² = 8%).

Significance

This 10-year, prospective follow-up study highlights the significant HRQOL-associated cognitive, social, and physical decline particularly affecting younger patients with DS. Sodium channel blocker use appears to negatively impact long-term HRQOL, highlighting the importance of early diagnosis and disease-specific management in DS.     

Successful use of fenfluramine as an add-on treatment for Dravet syndrome

Purpose: Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine‐like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome. Methods: Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add‐on therapy. Key Findings: Their ages at their last evaluation ranged from 3–35 years. The mean dosage of fenfluramine was 0.34 (0.12–0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1–19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure‐free for at least 1 year. In total, patients had been seizure‐free for a mean of 6 (1–19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow‐up; seizures reappeared in three of the seizure‐free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance. Significance: Compared with a recent long‐term follow‐up series in which a maximum of 16% of patients with Dravet syndrome were seizure‐free, our result of 70% of patients with Dravet syndrome remaining seizure‐free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.     

SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis

Objective:   We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene ( SCN1A ) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).
Methods:   Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).
Results:   Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5–6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.
Discussion:   Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2–3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.     

The incidence of SCN1A‐related Dravet syndrome in Denmark is 1:22,000: A population‐based study from 2004 to 2009

Dravet syndrome is a severe infantile‐onset epileptic encephalopathy associated with mutations in the sodium channel alpha‐1 subunit gene SCN1A. We aimed to describe the incidence of Dravet syndrome in the Danish population. Based on a 6‐year birth cohort from 2004 to 2009, we propose an incidence of 1:22,000, which is higher than what has been established earlier. We identified 17 cases with SCN1A mutation–positive Dravet syndrome. Fifteen patients were found, by conventional Sanger sequencing. Two additional patients with clinical Dravet syndrome, but without a detectable SCN1A mutation by Sanger sequencing, were diagnosed with a SCN1A mutation after using a targeted next‐generation sequencing gene panel.     

A retrospective study of the relation between vaccination and occurrence of seizures in Dravet syndrome

Dravet syndrome is a severe epileptic encephalopathy starting in the first year of life. Mutations in SCN1A can be identified in the majority of patients, and epileptic seizures in the setting of fever are a clinical hallmark. Fever is also commonly seen after vaccinations and provocation of epileptic seizures by vaccinations in patients with Dravet syndrome has been reported, but not systematically assessed. In a retrospective evaluation of 70 patients with Dravet syndrome and SCN1A mutations, seizures following vaccinations were reported in 27%. In 58% of these patients vaccination-related seizures represented the first clinical manifestation. The majority of seizures occurred after DPT vaccinations and within 72 h after vaccination. Two-thirds of events occurred in the context of fever. Our findings highlight seizures after vaccinations as a common feature in Dravet syndrome and emphasize the need for preventive measures for seizures triggered by vaccination or fever in these children.     

Five‐year extended follow‐up status of 10 patients with Dravet syndrome treated with fenfluramine

Dravet syndrome (DS) is a rare and therapy‐resistant epilepsy syndrome. A retrospective analysis of add‐on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long‐term response. Herein we present the results of a subsequent 5‐year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure‐free for the entire 5 years, and an additional four patients experienced seizure‐free intervals of at least 2 years. Fenfluramine was generally well‐tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long‐term control of convulsive seizures by low‐dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.     

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.