KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients.

OBJECTIVE: To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. METHODS: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients. RESULTS: The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed. CONCLUSIONS: KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in "hot spots" known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy.

Transition from Pediatric to Adult Specialty Care for Adolescents and Young Adults with Refractory Epilepsy: A Quality Improvement Approach.

Adolescents and young adults with refractory epilepsy are particularly vulnerable to serious medical and psychosocial challenges during transition from pediatric to adult care. Quality improvement methods were used to address the transition process on an academic medical campus. Outcomes achieved were decreased time from referral to first appointment in the adult clinic, H=8.2, p=0.004, r=0.43; and increased social work referrals using decision support, z=10.0, p=0.0006, OR=6.13. As measured by the 13-item Patient Activation Measure, pre-post change in patient activation as an outcome of self-management education was not statistically significant.

Project Access: Strategies to improve care for children and youth with epilepsy: illustrations of recommendations in the IOM report on the epilepsies.

Project Access (PA), funded by the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), provided grants to state and local agencies to improve awareness, provide education, design, test, pilot and evaluate system changes, and improve quality of services and access to early diagnosis and comprehensive, coordinated health care and related services for children and youth with epilepsy residing in rural and medically underserved areas. In 2011, the Institute of Medicine of the National Academies (IOM) published a series of 13 recommendations addressing unmet psychosocial, medical, and public health needs of individuals with epilepsy, including children and youth. This paper examines the synergy between these two projects showing how the strategies utilized in the PA demonstration projects can address the IOM recommendations and how these recommendations can inform future initiatives for improving care for children and youth with epilepsy.

A consensus-based approach to patient safety in epilepsy monitoring units: recommendations for preferred practices.

Patients in an epilepsy monitoring unit (EMU) with video-EEG telemetry have a risk for seizure emergencies, injuries and adverse events, which emphasizes the need for strategies to prevent avoidable harm. An expert consensus process was used to establish recommendations for patient safety in EMUs. Workgroups analyzed literature and expert opinion regarding seizure observation, seizure provocation, acute seizures, and activity/environment. A Delphi methodology was used to establish consensus for items submitted by these workgroups. Fifty-three items reached consensus and were organized into 30 recommendations. High levels of agreement were noted for items pertaining to orientation, training, communication, seizure precautions, individualized plans, and patient/family education. It was agreed that seizure observation should include direct observation or use of closed-circuit camera. The use of continuous observation was strongest in patients with invasive electrodes, at high risk for injury, or undergoing AED withdrawal. This process provides a first step in establishing EMU safety practices.

Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial.

PURPOSE: Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial-onset seizures (POS). METHODS: Randomized, double-blind, placebo-controlled, noninferiority safety study. Children (4-16 years; IQ > or =65) with > or =1 POS during 4 weeks before screening despite taking 1-2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20-60 mg/kg/day) or placebo for 12 weeks. RESULTS: Ninety-nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent-to-treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale-Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two-sided 90% confidence interval (CI)] 0.19 (-4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (-9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning-2 indexes and Leiter-R Examiner's Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; > or =50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam-treated and 85.3% placebo-treated patients; those reported by > or =10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression. DISCUSSION: Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated.

The autism-epilepsy connection.

The high prevalence of epilepsy in children with autism supports a neurobiologic etiology for autism. It remains unclear whether seizures and epileptiform activity on the EEG are causative or comorbid. It is also uncertain if focal epileptiform EEG abnormalities may be associated with stable cognitive impairment. Even less clear is whether these EEG abnormalities can result in the combination of language and social dysfunction seen in autistic spectrum disorders.

Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison.

Few randomized, controlled trials evaluating antiepileptic drug (AED) efficacy and tolerability have focused solely on patients with juvenile myoclonic epilepsy (JME). We conducted a pilot, randomized controlled trial comparing topiramate (N=19) and valproate (N=9) in adolescents/adults with JME to evaluate clinical response when these broad-spectrum agents are titrated to optimal effect. Rating scales were used to systematically assess tolerability. Among patients completing 26 weeks of treatment, 8 of 12 (67%) in the topiramate group and 4 of 7 (57%) in the valproate group were seizure-free during the 12-week maintenance period. Median daily dose was 250mg topiramate or 750mg valproate. Two (11%) topiramate-treated patients and one (11%) valproate-treated patient discontinued due to adverse events. Systemic toxicity scores, but not neurotoxicity scores, differed substantially between the two groups; greater systemic toxicity was associated with valproate. Our preliminary findings that topiramate may be an effective, well-tolerated alternative to valproate warrant validation in a double-blind trial.

Early postnatal development of sensory gating.

Sensory gating represents the nervous system's ability to inhibit responding to irrelevant environmental stimuli. In order to characterize the early development of acoustic sensory gating, suppression of auditory evoked potential component P1 (i.e. P50) in response to paired clicks was measured during REM sleep in healthy infants (1-4 months) that were without genetic risk for disrupted sensory gating function (i.e. having a relative with schizophrenia). As a group, the subjects exhibited significant response suppression. A correlation between increasing age and stronger response suppression was uncovered, even within this restricted age range. Parallel changes in sleep physiology could not be ruled out as the explanation for this change. Nevertheless, these results demonstrate that the neural circuits underlying sensory gating are functional very early in postnatal development.