Charuta Joshi

Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

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.

Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

BACKGROUND Malignant migrating partial seizures in infancy is a devastating pharmacoresistent epileptic encephalopathy of unknown etiology characterized by onset in the first 6 months of life, continuous migrating focal seizures with corresponding multifocal electroencephalographic discharges, developmental deterioration, and early mortality. Recent widespread interest in the nonpsychoactive component of the cannabis plant, cannabidiol, as a potential treatment for refractory devastating epilepsies has led to individual trials initiated by families or physicians in states that have legalized medical marijuana with anecdotal success. PATIENT DESCRIPTION We describe a now 10-month-old boy with malignant migrating partial seizures in infancy who made developmental gains and demonstrated sustained seizure reduction with the addition of cannabidiol to his antiepileptic regimen. CONCLUSION This report supports a role for cannabidiol in the treatment of malignant migrating partial seizures in infancy.

Eyelid myoclonia with absences: Routine EEG is sufficient to make a diagnosis

PURPOSE To identify the prevalence, clinical characteristics and routine EEG features of the syndrome of eyelid myoclonia with absences (EMA) using a retrospective case control study design. METHODS EEGs from 1996 to 2005 were searched using the following keywords: eyelid flutter, eyelid blinking, tics, idiopathic generalized epilepsy, clinical absence, atypical absence and photoparoxysmal response. During the same period, patients with a diagnosis of idiopathic generalized epilepsy were identified. Patients with mainly eyelid fluttering/eyelid blinking as their seizure semiology were divided into EMA and non-EMA groups using previously published criteria and compared using parametric (Students t-test) and non-parametric tests (Chi square) where appropriate. A p-value of <0.05 was considered significant. RESULTS The keywords identified 997 patients, 288 patients were diagnosed with idiopathic generalized epilepsy; 126 had eyelid fluttering/blinking as their major seizure semiology. After excluding 51 patients due to incomplete data, of 75 remaining patients, 26 (9.03%) had EMA. Patients with EMA were (1) older at time of first EEG (OR=2.86; 95% CI=7.00-10.23; p=0.005) (2) more likely to have an event on routine EEG (OR=3.62; 95% CI=1.28-10.19; p=0.01) (3) had >3 events per day (OR=9.73; 95% CI=2.06-45.96; p=0.0012) (4) had higher prevalence of developmental delay (OR=4.46; 95% CI=1.36-14.67; p=0.01) and (5) had normal EEG background compared to the non-EMA group. CONCLUSION EMA is not uncommon; diagnosis can be made with good clinical history and routine EEG. As developmental delay is a common association with EMA in this study, early identification and treatment are important.

Ketogenic diet – A novel treatment for early epileptic encephalopathy due to PIGA deficiency

We describe the presentation and workup of two brothers with early-onset epileptic encephalopathy who became seizure-free on a ketogenic diet. Extensive testing culminated in whole exome sequencing, which led to the diagnosis of phosphatidyl inositol glycan biosynthesis class A protein (PIGA) deficiency. This familial case highlights the importance of genetic testing for early-onset epileptic encephalopathies and underscores the potential value of a ketogenic diet in the treatment of this condition.

Pediatric Optic Neuritis: Does a Prolonged Course of Steroids Reduce Relapses? A Preliminary Study

BACKGROUND Optic neuritis is an important pediatric disorder causing visual impairment. Because of the absence of pediatric-specific studies, data extrapolated from the adult-based optic neuritis treatment trial are used to guide management of pediatric patients. Recent literature promotes a prolonged course of oral steroids to prevent relapses. However, there are no published data to support this view. Patients who were recently treated in our hospital received a longer course of steroids, relative to those treated several years ago. We hypothesized that a longer course of steroids results in fewer relapses and better final visual acuity. METHODS A retrospective analysis of 26 consecutive patients (age 4.5-19 years) treated for optic neuritis within the past 10 years was conducted. Patients received either a short course (2 weeks) or a prolonged course (more than 2 weeks) of steroids. Some patients were not treated. Mean follow-up was 70 weeks (3 weeks-10 years). Comparisons were made among the groups receiving 2 weeks of steroid treatment (16 of 26 patients) and greater than 2 weeks of steroid treatment (seven of 26 patients) to evaluate relapse rate, eventual visual acuity, and reported side effects. RESULTS There were no significant differences in the relapse rates, reported side effects, and final visual acuity in the two treatment groups. CONCLUSIONS In this cohort, a prolonged course of steroids was not associated with reduced relapse rate, increased side effects, or improved visual outcome. This cohort was small, but the results do not identify any reason to deviate from the common approach of optic neuritis treatment, which is 2 weeks of steroids.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results

Since 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.

Gelastic seizures in tuberous sclerosis complex: case report and literature review.

Gelastic seizures are typically associated with hypothalamic hamartoma. Given the rarity of gelastic seizures, pathways for the motor and emotional aspects of laughter have been hypothesized but remain unclear. The authors perform a literature review to discuss what is known about these pathways. They also report a child who presented with tuberous sclerosis complex initially without cutaneous stigmata, who later developed gelastic seizures. Only 2 case reports of patients with tuberous sclerosis complex who subsequently developed gelastic epilepsy have previously been reported. In discussing his case, the authors postulate additional etiologies for gelastic seizures.

Telemedicine in pediatric neurology.

The stress that the coronavirus pandemic has produced on the health services and the disruption it has caused in the care of other pathologies and their follow-up in outpatient visits have led us to promote and incorporate telemedicine in our routine medical practice. Telemedicine refers to remote or non-face-to-face medical attention, a new method of administering medical care by accredited professionals, which optimises resources and increases their scope. One drawback for child teleneurology is that our diagnoses require direct observation of the child and carrying out an examination as though playing a game. Mainly in the youngest stages, a new patient evaluated by telemedicine can be more difficult to diagnose and manage, and therefore some neuropaediatricians have chosen to carry out only follow-up visits, medication management and outcome reviews. Telemedicine, however, also has many benefits, such as the possibility of giving rapid advice, coordination among professionals and reaching the patient where and when it is difficult for classical medicine to do so. The aim of this article is to review the possible indications of telemedicine in child neurology, starting out from the fact that we should never delay the diagnosis of something that can be treated, both at the present time and in an eventual situation of resurgence of the pandemic. The advance of telemedicine will depend on the implementation of technology, on solving legal and security/privacy issues, on its clinical outcomes and on the extent to which patients demand and accept these virtual visits.

Fatal Outcome in Hemiconvulsion-Hemiplegia Syndrome

Hemiplegia-hemiconvulsion-epilepsy syndrome is characterized by prolonged unilateral clonic seizures in a child followed by the development of hemiplegia. Focal status epilepticus results in unilateral cerebral edema of the epileptic hemisphere in the acute phase followed by cerebral hemiatrophy. Literature in the last 5 years does not describe malignant cerebral edema or resultant death. We report a case of a 3-year-old girl with hemiplegia-hemiconvulsion-epilepsy syndrome who died due to malignant cerebral edema and temporal lobe herniation. The first indication of worsening of clinical status after being seizure free was voltage suppression on continuous electroencephalography (EEG). We describe neuroimaging, EEG findings, and neuropathologic findings at autopsy and review pertinent literature. We also evaluate the evolving role of continuous EEG monitoring in the pediatric intensive care unit.