Nicole Chemaly

Patients with dravet syndrome in the era of stiripentol: A French cohort cross-sectional study

OBJECTIVE The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS). METHODS We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years. RESULTS Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (<5min, with last status epilepticus (SE) episode being before 4 years of age). Seizures occurred weekly (>3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type. CONCLUSIONS Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients.

Motor neuropathy contributes to crouching in patients with Dravet syndrome

Objective: Since SCN1A is expressed in the motor neuron initial segment, we explored whether motor neuron dysfunction could contribute to gait disturbance and orthopedic misalignment in patients with Dravet syndrome due to SCN1A mutations. Methods: We assessed 12 consecutive patients who presented to our institution between January and March 2013. All of them were older than 2 years and were positive for the SCN1A mutation. We performed nerve conduction velocity studies and needle EMG recordings. Results: We included 4 females and 8 males aged 2 to 17 years (median 7.5 years). All 12 patients showed gait disturbance regardless of age. Tendon reflexes were decreased in 4 of 12 patients. None presented cerebellar signs such as tremor, dysmetria, or adiadochokinesia. Nerve conduction study was normal or nearly normal in all patients, but EMG showed features of chronic denervation. Motor neuropathy/neuronopathy was definite in 7 patients and probable in 3. Conclusions: SCN1A mutations may alter axonal function, causing motor neuropathy/neuronopathy. This may contribute to gait disturbance and orthopedic misalignment, which is characteristic of patients with Dravet syndrome.

Do mutations in SCN1B cause Dravet syndrome

A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied. Genomic DNA was Sanger sequenced for mutations in the 6 exons of SCN1B. In 54 patients with DS recruited from four centres, no SCN1B mutations were identified. SCN1B mutation is not a common cause of DS.

Electrocorticographic telemetric recording in unrestrained mouse pups

BACKGROUND Early onset epileptic encephalopathies are rare paediatric diseases, with seizures resistant to drugs and impacting development of cognitive and motor functions. Many of them show monogenic aetiology and engineered animal models are crucial to understand the underlying mechanisms and propose treatment trials. These models have mostly been explored in vitro or in vivo under anaesthesia. This may affect the occurrence of epileptic activities and their clinical expression. These study conditions perturb social skills and are limited in time. NEW METHOD We developed a technique using telemetric recordings by means of the Data Science International (DSI) mouse transmitter to study long lasting electro-cortical activity in freely moving mice younger than three weeks, trying to minimally affect social interactions and development RESULTS: We describe how to implant telemetry EEG devices in mice aged P13 to P18, weighing 7-10 g, including the surgical procedure and the recovery phase. Normal EEG data and epileptic activities can be recorded up to 2 months after implantation in normally behaving animals. COMPARISONS WITH EXISTING METHODS Electrocorticographic studies of mouse pups are rare, and few devices allow EEG recording at these ages. Here, the telemetry devices used for adult mice were implanted in mouse pups. The surgical procedure was well tolerated. An adapted recovery protocol allowed EEG recording during the period of interest. CONCLUSION This technique was developed with currently used devices to enable better understanding of the pathophysiology of epileptic encephalopathies, chronic recording of seizures and helping the development of new therapies using chronic trials in the young animal.

Off-label use and manipulations of antiepileptic drugs in children: Analysis of the outpatient prescriptions in a tertiary center

OBJECTIVES Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy. METHODS We reviewed off-label use and manipulations of AEDs delivered to the outpatients epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses. RESULTS Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural-metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n=582): 40% inadequate (n=237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p<10-4) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them. CONCLUSION Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population.

Arterial spin labeling shows pre-epileptic tuber hyperperfusion in tuberous sclerosis complex

An 8-week-old girl, born at term, was referred for systematic evaluation1 of tuberous sclerosis complex prenatally revealed by cardiac rhabdomyomas. No clinical seizures were reported. Video-EEG revealed normal background in sleep and wake, no epileptic discharges, but focal rhythmic slow spikes and waves in the left temporal area (figure 1) predominantly during sleep. Brain MRI performed 3 hours after the EEG recording showed subependymal nodules and brain tubers. Arterial spin labeling imaging showed left temporal hyperperfusion corresponding to a tuber (figure 2). This case illustrates an unusual correlation between “pre-epileptic” EEG findings and tuber-limited hyperperfusion during systematic screening of an infant with prenatal diagnosis of tuberous sclerosis complex.

AEDS EFFICACY IN THE DRAVET SYNDROME: A CROSS-SECTIONAL STUDY

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

Antiepileptic treatment in dravet syndrome: an additional complexity for the families

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

On the use of intra-rectal valium in patients with dravet syndrome : family’s experience

Intra-rectal Diazepam (DZ) is the first rescue medication for acute prolonged convulsive seizures in children in many countries. In this study, we aimed at assessing the experience of the families of patients presenting Dravet Syndrome (DS) with respect to the use of intra-rectal DZ.