The Efficacy and Safety of Rapid Cycling Vagus Nerve Stimulation in Children With Intractable Epilepsy.

PURPOSE: Vagus nerve stimulation (VNS) is an effective adjunctive therapy for drug-resistant epilepsy. Nevertheless, information is lacking regarding optimization of stimulation parameters to improve efficacy. Our study examines the safety and efficacy of rapid duty cycle VNS (OFF time ≤1.1 minute keeping duty cycle less than 50%) in pediatric cohort with intractable epilepsy. METHODS: Retrospective chart review of 50 patients (one to 17 years) with drug-resistant epilepsy treated with VNS between 2010 and 2015 at a single pediatric epilepsy center. Safety and tolerability data were aggregated across all patient visits to determine frequency of adverse events between differing duty cycles. We also compared seizure reduction rates for each patient at (1) last regular duty cycle visit, (2) first rapid duty cycle visit, and (3) last recorded rapid duty cycle visit. RESULTS: Rapid duty cycle was well tolerated, with no adverse events reported in 96.6% patient encounters. At the last visit before switching to rapid duty cycle 45.5% patients were showing response to VNS (seizure reduction rates ≥50%). This rate increased to 77.3% after switching to rapid duty cycle and remained at 77.4% at the last rapid duty cycle visit. Fifteen patients (34.1%) became responders to VNS after switching to rapid cycling; another 19 (43.2%) maintained their response with mostly improved seizure reduction rates. In only a few instances, responders became nonresponders after switching to rapid duty cycle. CONCLUSIONS: Rapid duty cycle VNS is probably safe and well tolerated; it may also be more efficacious than regular cycling VNS in some patients. This study highlights the necessity of prospective, long-term, double-blinded studies for understanding the advantages of this VNS modality.

Initiating the ketogenic diet in infants with treatment refractory epilepsy while maintaining a breast milk diet.

PURPOSE: The ketogenic diet has been found to be safe and effective in the treatment of drug resistant epilepsy in childhood. The age range of children undergoing this treatment has steadily been going down. There is strong evidence that it is a safe alternative in infants with drug resistant seizures. The American Academy of Pediatrics strongly supports continuing a breast milk diet until infants are at least six months of age. The purpose of this study is to evaluate the safety and efficacy of the ketogenic diet in infants while maintaining a breast milk diet. METHOD: This is a cohort study of 9 infants between the ages of 1 and 13 months with drug resistant epilepsy treated with the ketogenic diet while maintained on breast milk. The data from the first two patients was gathered retrospectively while the other seven were studied prospectively. RESULTS: We show that all nine infants achieved and maintained ketosis effectively. While one infant had no change in seizure frequency, three were seizure free at the first follow-up visit and four had a burden of seizure reduction greater than 50%. The diet was overall well tolerated, although one child required a hospital stay for dehydration and metabolic acidosis. CONCLUSION: The ketogenic diet can be safely and effectively initiated in infants while continuing human breast milk feedings.

Ketogenic diet efficacy in the treatment of intractable epileptic spasms.

OBJECTIVE: To determine the efficacy of the ketogenic diet in controlling epileptic spasms after failing traditional antiepileptic medication therapy. METHODS: This is a prospective, case-based study of all infants with epileptic spasms who were referred for treatment with the ketogenic diet at our hospital between 2009 and 2012. All subjects continued to have epileptic spasms with evidence of hypsarrhythmia or severe epileptic encephalopathy on electroencephalography despite appropriate medication treatments. The diet efficacy was assessed through clinic visits, phone communications, and electroencephalography. Quality of life improvement was charted based on the caregiver's perspective. RESULTS: Twenty infants (15 males) were included in the study. The mean age at seizure onset was 4.5 months. Age at ketogenic diet initiation was 0.3 to 2.9 years (mean 1.20, standard deviation 0.78). Fifteen patients had epileptic spasms of unknown etiology; three had perinatal hypoxic ischemic encephalopathy, one had lissencephaly, and one had STXBP1 mutation. Fifteen infants failed to respond to adrenocorticotropin hormone and/or vigabatrin before going on the ketogenic diet. Three months after starting the diet, >50% seizure reduction was achieved in 70% of patients (95% CI 48-86). These results were maintained at 6- and 12-month intervals. All eight of the patients followed for 24 months had >50% seizure reduction (95% CI 63-100). At least 90% seizure reduction was reported in 20% of patients at 3 months (95% CI 7-42), 22% (95% CI 8-46) at 6 months, and 35% (95% CI 17-59) at 12 months. The majority of patients (63%) achieved improvement of their spasms within 1 month after starting the diet. Sixty percent of patients had electroencephalographic improvement. All caregivers reported improvement of the quality of life at the 3-month visit (95% confidence interval 81-100). This ratio was 94% at 6 months (95% CI 72-99) and 82% at 12 months (95% CI 58-95). CONCLUSION: The ketogenic diet is a safe and potentially effective method of treatment for patients with epileptic spasms, especially those who do not respond to customary medication therapies.

Receptors and other signaling proteins required for serotonin control of locomotion in Caenorhabditis elegans.

A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans uses serotonin as a neurotransmitter to regulate locomotion, providing a genetic system to analyze serotonin signaling. From large-scale genetic screens we identified 36 mutants of C. elegans in which serotonin fails to have its normal effect of slowing locomotion, and we molecularly identified eight genes affected by 19 of the mutations. Two of the genes encode the serotonin-gated ion channel MOD-1 and the G-protein-coupled serotonin receptor SER-4. mod-1 is expressed in the neurons and muscles that directly control locomotion, while ser-4 is expressed in an almost entirely non-overlapping set of sensory and interneurons. The cells expressing the two receptors are largely not direct postsynaptic targets of serotonergic neurons. We analyzed animals lacking or overexpressing the receptors in various combinations using several assays for serotonin response. We found that the two receptors act in parallel to affect locomotion. Our results show that serotonin functions as an extrasynaptic signal that independently activates multiple receptors at a distance from its release sites and identify at least six additional proteins that appear to act with serotonin receptors to mediate serotonin response.