Angus A. Wilfong

Everolimus treatment of refractory epilepsy in tuberous sclerosis complex

Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients.

MR-guided stereotactic laser ablation of epileptogenic foci in children☆

OBJECTIVE For about 30% of epilepsy patients, pharmaceutical therapy fails to control their seizures. MR-guided laser interstitial thermal therapy (MRgLITT) allows for real-time thermal monitoring of the ablation process and feedback control over the laser energy delivery. We report on minimally invasive surgical techniques of MRgLITT and short-term follow-up results from the first five pediatric cases in which this system was used to ablate focal epileptic lesions. METHODS We studied the patients with MRI of the brain, localized the seizure with video-EEG and used the Visualase Thermal Therapy 25 System for laser ablation of their seizure foci. RESULTS All 5 patients are seizure free and there were no complications as of 2-13-month follow-up. CONCLUSION MR-guided laser interstitial thermal therapy has a significant potential to be a minimally invasive alternative to more conventional techniques to surgically treat medically refractory epilepsy in children.

Hypothalamic hamartomas: optimal approach to clinical evaluation and diagnosis.

Hypothalamic hamartomas (HHs) present a difficult medical problem, manifested by gelastic seizures, which are often medically intractable. Although existing techniques offer modest surgical outcomes with the potential for significant morbidity, the relatively novel technique of magnetic resonance imaging (MRI)–guided stereotactic laser ablation (SLA) offers a potentially safer, minimally invasive method with high efficacy for the HH treatment. We report here on 14 patients with medically refractory gelastic epilepsy who underwent stereotactic frame–based placement of an MR‐compatible laser catheter (1.6 mm diameter) through a 3.2‐mm twist drill hole. A U.S. Food and Drug Administration (FDA)–cleared laser surgery system (Visualase, Inc.) was utilized to ablate the HH, using real‐time MRI thermometry. Seizure freedom was obtained in 12 (86%) of 14 cases, with mean follow‐up of 9 months. There were no permanent surgical complications, neurologic deficits, or neuroendocrine disturbances. One patient had a minor subarachnoid hemorrhage that was asymptomatic. Most patients were discharged home within 1 day. SLA was demonstrated to be a safe and effective minimally invasive tool in the ablation of epileptogenic HH. Because use of SLA for HH is being adopted by other medical centers, further data will be acquired to help treat this difficult disorder.

Zonisamide treatment for symptomatic infantile spasms

The authors evaluated zonisamide for symptomatic infantile spasms in 23 patients. Spasm cessation, EEG evolution, and tolerability were assessed for a mean duration of 6.5 months. Six patients (26%) had complete control with cessation of spasms and clearing of hypsarrhythmia. Mean latency time from onset of zonisamide treatment to complete spasm control was 19 days. There were no discontinuations due to adverse effects.

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING GW Pharmaceuticals.

Mutations in PURA Cause Profound Neonatal Hypotonia, Seizures, and Encephalopathy in 5q31.3 Microdeletion Syndrome

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.

Zonisamide for absence seizures

This chart review investigated the efficacy and safety of zonisamide in 45 patients aged < or = 18 years with absence seizures. Of these patients, 23 (51.1%) achieved freedom from absence seizures. Two patients discontinued zonisamide, 1 for increased seizures and 1 for sleepiness and inefficacy. These data support the efficacy of zonisamide in treating absence seizures.

Dysfunction of executive and related processes in childhood absence epilepsy

The nature and extent of the neuropsychological difficulties associated with childhood absence epilepsy (CAE) remain unclear. Because aberrant thalamocortical rhythms have been implicated in the pathogenesis of CAE, it was hypothesized that children with CAE would show greater difficulties in neuropsychological domains that are thought to be subserved by basal ganglia-thalamocortical circuits. Multivariate analysis of variance was used to compare the neuropsychological functioning of 16 children with CAE with that of 14 children with type 1 diabetes mellitus and 15 healthy children. The CAE group did not perform differently from the other groups on measures of intellectual functioning, memory, academic achievement, fine motor speed, or processing speed. In contrast, significant differences were found in problem solving, letter fluency, complex motor control, attention/behavioral inhibition, and psychosocial functioning. These results suggest that children with CAE show difficulties in neuropsychological functions thought to be subserved by the same regions implicated in the pathogenesis of the disorder.

Dual pathology in Rasmussen's encephalitis: a study of seven cases and review of the literature.

Dual pathology has previously been reported in less than 10% of cases of Rasmussens encephalitis (RE). Given the rarity of RE, it appears unlikely that dual pathology in RE is merely a coincidence. We therefore reviewed all cases of RE experienced in our institution to assess for an additional/associated pathology. A total of seven patients with RE were identified in our archives. Seven children (4 boys and 3 girls, age range: 3–16 years, mean: 9.5 years) with medically refractory epilepsy underwent surgical resection for intractable seizures. The surgical specimens were examined with routine neurohistological techniques, and immunohistochemistry was performed with an extensive panel of antibodies for viruses, lymphocytes, microglia/macrophages, human leukocyte antigen (HLA)‐DR, astrocytes, and neurons. Relevant literature was reviewed. Microscopically, all seven cases demonstrated the inflammatory pathology of RE in the cortex and white matter with leptomeningeal and perivascular lymphocytic infiltration, microglial nodules with/without neuronophagia, neuronal loss and gliosis. The HLA‐DR antibody was extremely helpful in highlighting the extent of microglial cell proliferation/activation that was not appreciable with standard histology. An unexpected finding in all seven cases was the presence of cortical dysplasia. In our series of seven cases, there was co‐occurrence of the inflammatory/destructive pathology of RE with malformative/dysplastic features in cortical architecture in 100% of cases, raising questions about the possible relationships between the two entities. Awareness of the possibility of dual pathology in RE is important for clinical and pathological diagnosis, and may affect the management and outcome of these patients. Immunohistochemistry is very helpful to make a definitive diagnosis of both pathologies.

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC). Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life. Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months. Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. Classification of evidence: This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control.