Philippe Major

The natural history of epilepsy in tuberous sclerosis complex

Background:  Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.

Are cortical tubers epileptogenic? Evidence from electrocorticography

The purpose of this study was to characterize the epileptogenicity of tubers and surrounding cortex in patients with tuberous sclerosis complex (TSC). Three pediatric patients with TSC and intractable epilepsy underwent surgical resection of tubers associated with epileptogenic foci. In all patients, presurgical imaging revealed a prominent tuber that correlated on electroencephalography (EEG) with frequent interictal epileptiform discharges and electrographic seizures. Intracranial electrocorticography (ECoG) was performed using subdural grids placed over the tuber and surrounding cortex and depth electrodes positioned directly within the tuber. In all three patients, the depth electrode within the tuber was electrographically silent, whereas the surrounding cortical tissue showed significant epileptiform activity. The tuber and the electrically active adjacent cortex were resected. The patients experienced a drastic reduction in seizure frequency postsurgery. Epileptogenicity of cortical tubers may derive not from the lesion itself, but rather from the perturbation or abnormal development of the surrounding cortex.

The genetic landscape of infantile spasms

Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.

Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex.

Background: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of hamartomatous lesions in multiple organs, including tubers in the brain. The majority of patients with TSC have epilepsy. Some cortical tubers are epileptic foci, while others appear to be physiologically quiescent. It is unknown whether variations in tuber morphology may account for this difference. The objectives of this study were to determine the frequency of cyst-like tubers in patients with TSC, whether cyst-like tubers correlate with TSC genotype, and whether cyst-like cortical tubers are associated with a history of infantile spasms, epilepsy, or refractory epilepsy. Methods: A retrospective chart review was performed of 173 patients with TSC. MRI images were evaluated for the presence of at least one cyst-like cortical tuber. Patient charts were then reviewed for genetic mutation, a history of infantile spasms, epilepsy, and epilepsy refractory to more than three medications. Results: A total of 46% of patients had at least one cyst-like cortical tuber present on neuroimaging. Patients with a TSC2 mutation were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least one cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005), epilepsy (p = 0.0038), and refractory epilepsy (p = 0.0007) than patients without a cyst-like cortical tuber. Conclusion: Cyst-like cortical tubers are strongly associated with TSC2 gene mutation and a more aggressive seizure phenotype in patients with tuberous sclerosis complex.

Vigabatrin in the treatment of childhood epilepsy: A retrospective chart review of efficacy and safety profile

Purpose: To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies.

Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex.

OBJECTIVES The aim of the study described here was to characterize the efficacy and safety of vagus nerve stimulation in a population of patients with tuberous sclerosis complex (TSC) and intractable epilepsy. METHODS This retrospective study comprised 16 patients with TSC who underwent implantation of a vagus nerve stimulator for treatment of intractable epilepsy. RESULTS The average age at vagus nerve stimulator implantation was 15 years (range: 2-44, SD: 12.5) and the average duration of follow-up on VNS was 4 years (range: 0.5-8.6, SD: 2.3). Outcome was rated class I (>80% seizure frequency reduction) in 3 (19%), class II (50-79% reduction) in 5 (31%), class III (<50% reduction) in 2 (13%), class IV (magnet benefit only) in 1 (6%), and class V (no improvement) in 5 (31%) patients. Intermittent magnet use was effective in aborting seizures in 8 (50%). Five (31%) patients reported an improved level of functioning. CONCLUSION The findings suggest that the vagus nerve stimulation can be an effective and safe therapy for patients with TSC with intractable epilepsy.

Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is associated with the potential development of benign hamartomas, including subependymal giant cell astrocytomas (SEGAs). Intracranial hypertension can be caused by SEGAs due to their propensity to block the foramen of Monro. The traditional management approach is to monitor SEGAs with periodic neuroimaging and to resect those that exhibit serial growth and/or cause clinical signs of intracranial hypertension. Recent observations suggest that rapamycin therapy may induce partial regression of SEGAs, therefore providing a potential alternative to resection. The authors present the case of an 8-year-old girl with bilateral SEGAs that led to progressive hydrocephaly and incipient signs of papilledema. Three months after initiating rapamycin therapy, the SEGAs exhibited significant reduction in size (82.6% on the left and 46.7% on the right), and the lesions remained stable 5 months later. Compared with previous case reports, similar or even greater antitumor efficacy was achieved with much lower trough levels of rapamycin (10–15 compared with 3.3–4.5 ng/ml, respectively). The authors discuss various aspects of rapamycin therapy and address unresolved issues that highlight the need for further prospective clinical trials.

The combination of subdural and depth electrodes for intracranial EEG investigation of suspected insular (perisylvian) epilepsy

Purpose:  We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique.

Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: Preliminary results

Behavioral side effects related to the use of levetiracetam (LEV) in epilepsy are increasingly being recognized. Patients followed in our center have reported improvement of these side effects after starting pyridoxine (vitamin B(6)) supplements. Using mailed questionnaires, retrospective chart reviews, and phone call follow-ups, we analyzed 42 pediatric patients who had been treated with LEV and pyridoxine. Twenty-two patients started pyridoxine after being on LEV, and significant behavioral improvement was observed in nine (41%), no effect in eight (36%), deterioration in four (18%), and an uncertain effect in one. The effects of pyridoxine supplementation were observed during the first week. The remaining patients (20) were already on pyridoxine before LEV was started, started pyridoxine and LEV at the same time, or took pyridoxine intermittently. Pyridoxine is an easily available, inexpensive, and safe therapeutic option. Given these preliminary results, we plan to conduct a placebo-controlled cross-over study to better characterize these observations.

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.