News Topics: Pediatric Epilepsy

Risk Factors for Seizures Among Young Children Monitored With Continuous Electroencephalography in Intensive Care Unit: A Retrospective Study

Objective: cEEG is an emerging technology for which there are no clear guidelines for patient selection or length of monitoring. The purpose of this study was to identify subgroups of pediatric patients with high incidence of seizures.

Study Design: Researchers conducted a retrospective study on 517 children monitored by cEEG in the intensive care unit (ICU) of a children’s hospital. The children were stratified using an age threshold selection method. Using regression modeling, we analyzed significant risk factors for increased seizure risk in younger and older children. Using two alternative correction procedures, we also considered a relevant comparison group to mitigate selection bias and to provide a perspective for our findings.

Results: Researchers discovered an approximate risk threshold of 14 months: below this threshold, the seizure risk increases dramatically. The older children had an overall seizure rate of 18%, and previous seizures were the only significant risk factor. In contrast, the younger children had an overall seizure rate of 45%, and the seizures were significantly associated with hypoxic-ischemic encephalopathy (HIE; p = 0.007), intracranial hemorrhage (ICH; p = 0.005), and central nervous system (CNS) infection (p = 0.02). Children with HIE, ICH, or CNS infection accounted for 61% of all seizure patients diagnosed through cEEG under 14 months.

Conclusions: An extremely high incidence of seizures prevails among critically ill children under 14 months, particularly those with HIE, ICH, or CNS infection.

A Novel GABAergic Dysfunction in Human Dravet Syndrome Suggests GABAA Receptors Could Be the Target of Therapy

OBJECTIVE: Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation SCN1A, leading to a defective sodium channel that contributes to pathogenic brain excitability. A ?-aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by GABAergic therapies. However, up to now the physiological mechanisms underlying the GABAergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here researchers studied, for the first time, human GABAA -evoked currents using cortical brain tissue from Dravet syndrome patients.

METHODS: Researchers transplanted in Xenopus oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age-matched controls. Additionally, experiments were performed on oocytes expressing human ?1?2?2 and ?1?2 GABAA receptors. GABAA currents were recorded using the two-microelectrodes voltage-clamp technique. Quantitative real-time polymerase chain reaction, immunohistochemistry, and double-labeling techniques were carried out on the same tissue samples.

RESULTS: We found (1) a decrease in GABA sensitivity in Dravet syndrome compared to controls, which was related to an increase in ?4- relative to ?1-containing GABAA receptors; (2) a shift of the GABA reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters NKCC1/KCC2 expression ratio; (3) an increase of GABAA currents induced by low doses of cannabidiol both in Dravet syndrome and tuberous sclerosis complex comparable to that induced by a classical benzodiazepine, flunitrazepam, that still persists in ?-less GABAA receptors.

SIGNIFICANCE: This study indicates that a dysfunction of the GABAergic system, considered as a feature of brain immaturity, together with defective sodium channels, can contribute to a general reduction of inhibitory efficacy in Dravet brain, suggesting that GABAA receptors could be a target for new therapies.

Progress Report on New Antiepileptic Drugs: A Summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in More Advanced Clinical Development

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13?16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy.

This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium?chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec?butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older.

The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo?controlled randomized controlled trials, with promising efficacy and safety results.

Pilot Study: Rapamycin has Positive Effects on Seizures in Tuberous Sclerosis Complex in Years 1-2 but Effects Decline After Year 2

PURPOSE: The purpose of this study was to evaluate the long-term results of eight cases diagnosed with tuberous sclerosis complex (TSC) and receiving rapamycin therapy because of epileptic seizures and/or accompanying TSC findings.

METHOD: Rapamycin therapy was initiated at a dose of 1.5?mg/m2. Seizure frequency, electroencephalographic (EEG) findings, renal and cranial imaging findings, and cutaneous lesions over 3- to 6-month periods during follow-up and treatment were evaluated.

RESULTS: Four girls and four boys aged 4-16?years at the start of rapamycin therapy and now aged 9-24?years were evaluated. Duration of rapamycin therapy was 1-5?years, and the monitoring period after commencement of rapamycin therapy lasted 5-8?years. Positive effects were observed at 9-12?months in three out of six cases of renal angiomyolipoma (AML) and in the second year of treatment in one. An increase in AML dimensions was observed in three cases after treatment was stopped. Seizure control was established in the first year of rapamycin therapy in all cases. An increased frequency of seizures was observed in three cases after the second year of treatment. No seizure recurrence was determined in the second year of treatment with rapamycin in five out of eight cases. Recurrence of seizure was observed in 6-12?months after the discontinuation of rapamycin in three cases.

CONCLUSION: Rapamycin therapy exhibits positive effects on epileptic seizures in cases of TSC in 1-2 ?years but these positive effects on seizure control of rapamycin therapy decline after the second year. Larger case series are still needed to determine the duration and effectiveness of treatment in childhood.

High Vigabatrin Dosage is Associated with Lower Risk of Infantile Spasms Relapse Among Children with Tuberous Sclerosis Complex

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses.

We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P?=? 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 – 0.90, P?=? 0.026).

This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

Neurelis Files New Drug Application with the FDA for VALTOCO™ (Diazepam Nasal Spray), An Investigational Treatment for Pediatric, Adolescent, and Adult Epilepsy Patients

Neurelis, Inc. announced that the company has submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for VALTOCOTM (diazepam nasal spray) as a treatment for epilepsy patients six years and older who experience increased bouts of seizure activity, also known as cluster or acute repetitive seizures. Earlier this year, the FDA provided conditional acceptance for use of the name “VALTOCO” for the product previously referred to in clinical development as “NRL-1”.

VALTOCO, Neurelis’ lead product candidate, is a proprietary formulation of diazepam incorporating the unique combination of a vitamin E-based solution and Intravail® absorption enhancement. The FDA previously granted Neurelis both Orphan Drug designation for VALTOCO in November of 2015 and Fast Track designation in December of 2016. There are over 3.4 million people with epilepsy in the United States with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, about 170,000 are at risk for cluster or acute repetitive seizures.

Study Reveals New Therapeutic Target for Pediatric Tumor-Associated Intractable Epilepsy

Featuring the work of CURE Grantee Dr. Jeong Ho Lee

Pediatric brain tumors are characterized by frequent complications due to intractable epilepsy compared to adult brain tumors. However, the genetic cause of refractory epilepsy in pediatric brain tumors has not been elucidated yet, and it is difficult to treat patients because the tumors do not respond to existing antiepileptic drugs and debilitate children’s development.

A research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors. Their research results were published online in Nature Medicine on September 17.

Seizure Outcomes Best With Complete Resective Surgery In Pediatric Patients With Polymicrogyria

Abstract

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG.

METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed.

RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%).

SIGNIFICANCE: We present one of the largest surgical series of pediatric polymicrogyria patients. Seizure outcomes were best with complete resection/disconnection of polymicrogyria. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive polymicrogyria.

Diagnostic Efficacy And Study Quality Of Home Video Telemetry And Inpatient Video Telemetry For Epilepsy Are Similar In Pediatric Patients

Abstract

PURPOSE: Home Video Telemetry (HVT) combines ambulatory EEG with simultaneous video recording. No previous reports have compared HVT and inpatient video telemetry (IVT) in a purely paediatric population. This study compares HVT and IVT in this group in terms of diagnostic efficacy, recording quality and acceptability to parents/carers.

METHODS: 33 HVT and 29 IVT patients aged 1-17 years were included. Information regarding patient demographics, ictal capture, diagnostic utility, recording quality (e.g. video clarity, EEG artefacts) and parent/carer preferences was documented. Difficulties using HVT equipment were recorded.

RESULTS: 62% of IVT patients and 64% of HVT patients had typical attacks during the recording. 59% of IVT and 70% of HVT recordings were considered to have answered the referral question. Study quality was similar in both groups. In HVT studies the rate of equipment difficulties was 52%; problems included camera positioning and failure to turn on the infrared button at night. Diagnostic information was lost in 15% of patients. 76% of parents/carers of HVT patients would choose this investigation again.

CONCLUSIONS: The diagnostic efficacy and study quality of home video telemetry and inpatient video telemetry are similar in paediatric patients. Home video telemetry is acceptable to most parents/carers. User error may compromise the investigation in a minority of cases but did not impact on diagnostic utility. Adoption of home video telemetry investigation could provide an accessible and economic alternative to inpatient video telemetry.