Eric H. Kossoff

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

The Ketogenic Diet: One Decade Later

The ketogenic diet, a high fat, adequate protein, low carbohydrate diet, has, during the past decade, had a resurgence of interest for the treatment of difficult-to-control seizures in children. This review traces its history, reviews its uses and side effects, and discusses possible alternatives and the diet’s possible mechanisms of action. Finally, this review looks toward possible future uses of the ketogenic diet for conditions other than epilepsy.

Effect of an External Responsive Neurostimulator on Seizures and Electrographic Discharges during Subdural Electrode Monitoring

Summary:  Purpose: Approved neural‐stimulation therapies for epilepsy use prolonged intermittent stimulation paradigms with no ability to respond automatically to seizures.

The ketogenic diet.

Background:The ketogenic diet is a low-carbohydrate, adequate-protein, and high-fat diet with a long history of use for the treatment of intractable seizures in children. This dietary therapy has been enjoying increasing popularity in recent years, despite the availability of increasing numbers of new antiepileptic drugs and surgical treatments. Review Summary:The authors review the history of the ketogenic diet, the traditional protocol in initiating it, possible mechanisms of its action, evidence for efficacy, and side effects. In addition, they highlight some of the areas of active research in this field as well as future directions and unanswered questions. Conclusion:The ketogenic diet is an efficacious and relatively safe treatment of intractable seizures. Despite its long history, however, much remains unknown about the diet, including its mechanisms of action, the optimal protocol, and the full range of its applicability. Investigations of the diet are providing new insight into the mechanisms behind seizures and epilepsy itself, as well as possible new therapies.

A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy.

Summary:  Purpose: The Atkins diet may induce ketosis as does the ketogenic diet, without restrictions on calories, fluids, protein, or need for an inpatient fast and admission. Our objective was to evaluate the efficacy and tolerability of a modified Atkins diet for intractable childhood epilepsy.

Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome.

Background: Surgical removal of one hemisphere has been performed for several decades to treat intractable unihemispheric epilepsy. A prior case series focused on the outcomes after 58 surgeries at Johns Hopkins Hospital in 1997. This series, and an additional 53 cases, were reviewed to bring the outcomes up to date. Methods: Charts of the 111 patients undergoing hemidecortications at the Pediatric Epilepsy Center from 1975 to 2001 were reviewed and families were contacted. Three children died in the immediate perioperative period and three were lost to follow-up immediately after surgery. Follow-up ranged from 3 months to 22 years. Results: Two children died several years later due to intractable seizures. Overall, 65% are seizure-free, 21% have occasional, non-handicapping seizures, and 14% have troublesome seizures. Eighty percent are on one anticonvulsant or none and 89% are able to walk without assistance. Etiology strongly predicted seizure outcome. Patients with migrational disorders are less likely to be seizure-free than all other etiologies (predominantly Rasmussen and congenital vascular injuries) combined (51% vs 71%, p = 0.05). Conclusions: Hemidecortication continues to be a beneficial procedure in reducing seizure frequency in cases of unilateral cortical epilepsy. Fewer children with migrational disorders are seizure-free.

A Prospective Study of the Modified Atkins Diet for Intractable Epilepsy in Adults

Purpose: The ketogenic diet is not typically offered to adults with epilepsy due to the significant lifestyle alterations needed for its use. The modified Atkins diet has been recently demonstrated to be therapeutic for children without the need for an admission, fasting period, weighing of foods, or fluid, calorie, and protein restriction.

Efficacy of the Atkins diet as therapy for intractable epilepsy

The ketogenic diet is effective for treating seizures in children with epilepsy. The Atkins diet can also induce a ketotic state, but has fewer protein and caloric restrictions, and has been used safely by millions of people worldwide for weight reduction. Six patients, aged 7 to 52 years, were started on the Atkins diet for the treatment of intractable focal and multifocal epilepsy. Five patients maintained moderate to large ketosis for periods of 6 weeks to 24 months; three patients had seizure reduction and were able to reduce antiepileptic medications. This provides preliminary evidence that the Atkins diet may have a role as therapy for patients with medically resistant epilepsy.

Levetiracetam Psychosis in Children with Epilepsy

Summary:  Purpose: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children.

Long-term use of the ketogenic diet in the treatment of epilepsy.

Long-term outcomes of the ketogenic diet in the treatment of epilepsy have not previously been reported. A retrospective chart review of children treated with the ketogenic diet for more than 6 years at the Johns Hopkins Hospital was performed. The response was documented at clinic visits and by telephone contacts; laboratory studies were obtained approximately every 6 to 12 months. Satisfaction and tolerability were assessed by means of a brief parental telephone questionnaire. In all, 28 patients (15 males, 13 females), currently aged 7 to 23 years, were identified. The median baseline seizure frequency per week at diet onset was 630 (range 1-1400). Diet duration ranged from 6 to 12 years; 19 remain on the diet currently. After 6 years or more, 24 children experienced a more than 90% decrease in seizures, and 22 parents reported satisfaction with the diets efficacy. Ten children were at less than the 10th centile for height at diet initiation; this number increased to 23 at the most recent follow-up (p=0.001). Kidney stones occurred in seven children and skeletal fractures in six. After 6 years or more the mean cholesterol level was 201mg/dl, high-density lipoprotein was 54mg/dl, low-density lipoprotein was 129mg/dl, and triglycerides were 97mg/dl. Efficacy and overall tolerability for children are maintained after prolonged use of the ketogenic diet. However, side effects, such as slowed growth, kidney stones, and fractures, should be monitored closely.