Mathilde Chipaux

Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: A prospective pilot study

We aimed to test the efficacy of ketogenic diet (KD) in patients with Dravet syndrome (DS) not satisfactorily controlled by antiepileptic drugs (AEDs). We included prospectively 15 DS patients aged >3 years with partial response to AEDs including stiripentol. All patients had a seizure diary and clinical examination with Conners and Achenbach scales before KD, at 1 month following onset and every 3 months thereafter. At 1 month, 10 patients (66%) had a decrease of seizure frequency ≥75%. Efficacy was maintained in eight responders at 3 and 6 months and in six responders at 9 months. Five patients (33%) remained on KD over 12 months, and one was seizurefree. In addition to efficacy on seizure frequency, KD was beneficial on behavior disturbances including hyperactivity. This effect was reported in all responders and in a few nonresponders. KD might have a double effect, on seizure control and on hyperactivity and behavior disturbances in patients with DS.

Unusual consequences of status epilepticus in Dravet syndrome

Although status epilepticus (SE) affects the course of Dravet syndrome (DS), it rarely alters dramatically psychomotor outcome. We report an unusual pattern in 3 patients who following refractory SE lasting respectively 2, 7 and 12h experienced persistent and severe cognitive and motor deterioration. We compared these patients to published data and to personal experience in Necker hospital, to find links between severe outcome and clinical features such as treatment or duration of refractory SE. The key point was that anoxoischemic-like lesions appeared on MRI although cardiovascular function had remained stable. Therefore, neither hemodynamic failure, nor abnormalities of cardiac rhythm could explain the lesions and neurological worsening. For theoretical reasons the responsibility of therapy common for the 3 patients, e.g., barbiturates was suspected.

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy.

Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

Stereo-electroencephalography (SEEG) in children surgically cured of their epilepsy

PURPOSE SEEG in children has a low morbidity and leads to a good surgical outcome, in particular in younger patients. We analysed, in detail, the SEEG data of patients that were subsequently cured by surgery. METHODS We selected the 48 children explored between 2009 and 2013 in our centre and surgically cured after SEEG-based resections with at least one-year follow-up. We retrospectively studied demographic and surgical data and paid particular attention to the data acquired during the invasive recording. Moreover, we compared the children younger than 5 years of age (group 1: 17 children) to those older than 5 years of age at the time of exploration (group 2: 31 patients). RESULTS SEEG was well tolerated. Only one patient had slight intracerebral bleeding seen on the post-operative CT-scan without any clinical consequence and which did not prevent the recording. SEEG explored at least four lobes in 59% of patients, either because of a suspected very widespread epileptogenic zone or because of the lack of a precise hypothesis. Auras were recorded only in group 2 (32% of patients, P=0.0009). Despite these difficulties, SEEG led to tailored resections including multilobar resections in 14% and infralobar resections in 69% of patients. The electrical pattern of seizures had no particularities as compared with adults. Interictal spikes and slow waves outside the resection zone were significantly less frequent in group 1 (P=0.02). In symptomatic epilepsies, the lesion matched the irritative zone in only 11% of patients and the ictal onset zone in 32% respectively. CONCLUSION Our study confirms the low morbidity of SEEG in children. SEEG can disclose a limited epileptogenic zone. Our data suggest that the epileptic network is less complex in younger patients, which has to be confirmed by a quantitative analysis of SEEG signals.

Epilepsy diagnostic and treatment needs identified with a collaborative database involving tertiary centers in France

To obtain perspective on epilepsy in patients referred to tertiary centers in France, and describe etiology, epilepsy syndromes, and identify factors of drug resistance and comorbidities.

Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy

DEP domain–containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid–sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit — brain somatic and germline — mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.

Refractory spasms of focal onset—A potentially curable disease that should lead to rapid surgical evaluation

PURPOSE Infantile spasms (IS) can occur as the only seizure type in children with surgically amenable epilepsies. Although early surgery has shown positive effects, little is known regarding outcomes. METHODS We retrospectively reviewed all children with IS referred to our tertiary center between 2002 and 2014 and try to define factors of outcome. RESULTS Sixty-eight children with focal onset seizures were referred: twenty children with a hemispheric implication and 48 with one or more lobes involved. The age of onset was significantly earlier in the hemispheric population (8.0 versus 16.7 months in the focal population). There was no difference in the age of onset between anterior and posterior onset zones, as we could expect regarding the maturation gradient. The epilepsy began earlier in life in tuberous sclerosis than in DNET. Only three children of the 48 non-hemispheric patients had a normal MRI at the time of the surgery. Temporal lobe was involved only in a third of the population. More than 86% of the patients were operated on. Patients with hemispheric lesions were operated on younger (2.6 years+/- 2.1 years) compared to 4.6+/- 3.5 years in the whole population. The most frequent etiologies were in descending order: dysplasia, ganglioglioma or dysembryoplastic tumours and tuberous sclerosis. The global seizure outcome was favorable (Engel 1a) in 74.6% of the patients, and 87.9% if the delay between the first seizure and the surgery was less than 36 months. It fell to 64.7% if the delay exceeded 50 months. CONCLUSION Spasms of focal onset have a similar postsurgical outcome as other seizure types so surgery may be an excellent option for treating selected patients with focal infantile spasms. Volume and type but not topography of the lesion influence the age of onset. MRI is very helpful to locate the pathology in the pediatric population, since only a small portion had a normal MRI.

CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy.

BACKGROUND Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome (DS) is a distinctive epilepsy syndrome often associated with de novo mutations in the SCN1A gene. However, 25-30% patients with SMEI/DS are negative for SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Given the overlapping and heterogeneous clinical features of CDKL5- and ARX-related epilepsies and SMEI/DS, we postulated that CDKL5 mutations in females and ARX mutations gene in males may be associated with early onset seizures forms of SMEI/DS. METHODS Twenty-eight patients with early onset SMEI/DS before 6 months negative for SCN1A mutational screening were selected and screened for mutations in the ARX gene in males (n=14) or the CDKL5 gene in females (n=14). RESULTS No mutations in either gene were found except one intronic variation of uncertain pathogenicity in the CDKL5 gene. All patients started seizures at mean age of 3.48 months. Thirteen patients had familial history of epilepsy or febrile seizures. Patients evolved toward refractory epilepsy with generalized tonic clonic seizures (18/28) and myoclonia (23/28) and severe neurological impairment with autistic features (13/28), ataxia (14/28) and spasticity (5/28). No patient ever exhibited infantile spasms, dystonia, or Rett-like features. INTERPRETATIONS Our results illustrate that mutation screening of ARX and CDKL5 is not effective in patients selected on the basis of clinical signs associated to early onset SMEI/DS. In addition, they might reflect that other phenotypic features associated with CDKL5 mutations (Rett-like features, infantile spasm) or ARX mutations (dystonia, spasticity) are more distinctive.

Electrophysiological technical procedures

The reliability of the interpretation of SEEG data depends entirely on the technical quality of the acquisition recording. Digitalization of data and the development of computer technology, over the last 20 years have transformed electrophysiological procedures. Recording equipment must be able to record concomitantly clinical events and brain electrical activity. Recording is carried out during wakefulness and sleep and with use of various activation methods (hyperventilation, intermittent photic stimulation). Intracerebral electrical stimulations (with low and high frequency) and the acquisition of evoked potentials complete the SEEG exploration. This chapter will discuss the characteristics of video-EEG recording equipment, procedures for acquisition and creation of SEEG montages, technical recording and activations, procedures of intracerebral electrical stimulations and the acquisition of evoked potentials.

Refractory epilepsy in preschool children with tuberous sclerosis complex: Early surgical treatment and outcome

PURPOSE Epilepsy surgery has been shown to be effective in treating focal epilepsy related to tuberous sclerosis complex (TSC). We analyzed the advantage of early surgical management in terms of seizure frequency and development. METHOD We retrospectively studied the 15 patients younger than 6 years who underwent resective surgery between 2006 and 2016. Fourteen of them had invasive monitoring while the 15th was operated on under corticography. RESULTS Epilepsy began before 5 months of age in all patients. Overall 13 patients (86%) had a dramatic improvement of epilepsy after surgery (Engel 1 and 2) including 9 patients (60%) seizure free (Engel 1 A). In the group of 9 patients younger than 20 months at the time of surgery who presented with catastrophic epilepsies, 77% are Engel 1 A and the other 23% Engel 2. In this subpopulation, no one developed autism and four (44%) regained normal development. CONCLUSIONS In early onset epilepsies associated with TSC, surgical treatment is highly effective, in particular when performed early. Invasive monitoring contributes to the successful outcome. Those data have to be confirmed by multicentric studies including quantitative analyses of the recordings.