Eileen P. G. Vining

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.

Efficacy of the Ketogenic Diet for Intractable Seizure Disorders: Review of 58 Cases

Summary: The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty‐four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.

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.

The Cognitive Outcome of Hemispherectomy in 71 Children

Summary:  Purpose: Long‐term neuropsychological outcome was studied in 71 patients who underwent hemispherectomy for severe and intractable seizures at The Johns Hopkins Hospital between 1968 and 1997 and who agreed to participate. Seizures were due to cortical dysplasias (n = 27), Rasmussen syndrome (n = 37), or vascular malformations or strokes (n = 7). Both presurgical and follow‐up results are available and reported for 53 patients.

Motor and sensory cortex in humans: Topography studied with chronic subdural stimulation

Classic neurosurgical teaching holds that once the Rolandic fissure (Rf) has been located, there are distinct differentiated primary motor and sensory functional units confined within a narrow cortical strip: Brodmanns Areas 4 and 6 for primary motor units in front of the Rf and 3, 1, and 2 for sensory units behind the Rf. To test this assumption, we examined in detail the records of cortical mapping done by electrical stimulation of the cerebral cortex via implanted subdural electrode grids in 35 patients with seizure disorders. Of 1381 stimulations of the electrode sites, 346 (25.1%) produced primary motor or motor-arrest and sensory responses in contralateral body parts: 56.8% were primary motor responses; 16.2% were motor-arrest; 22.5% were sensory; and the remaining 4.5% were mixed motor and sensory responses. Two-thirds (65.9%) of the primary motor responses were located within 10 mm of the Rf, and the remaining one-third (34.1%) were more than 10 mm anterior to the Rf or were posterior to the Rf. Furthermore, in the patient group with brain lesions, fewer than one-third (28.1%) of the responses were within the 10-mm narrow anterior strip. Our study reconfirmed that a significant number--at least one-third--of motor responses are distributed outside the classic narrow cortical strip. In patients with brain lesions, the motor representation is further displaced outside the narrow strip. This finding indicates that primary motor cortex may extend beyond the gyrus immediately anterior to the Rf.

Clinical Aspects of the Ketogenic Diet

Summary:  The ketogenic diet remains a valuable therapeutic option for patients with intractable epilepsy. Clinical aspects of the diets success may provide insights into epileptogenesis and anticonvulsant action. The diets efficacy has been established primarily through large case series. The diet has been used successfully in patients with many different epilepsy syndromes in countries around the world. Potential adverse effects can be avoided with careful attention during the diets initiation and maintenance phases. In the last decade, variations to the classical ketogenic diet have been utilized. Ketogenic diets now are being used for diseases other than epilepsy. This critical analysis of the diet should provide the impetus for further clinical and basic research into the diets application and mechanisms of action.

Language recovery after left hemispherectomy in children with late-onset seizures

We investigated the language capabilities of the isolated right hemisphere in 6 children (age, 7–14 years) after left hemidecorticectomy for treatment of Rasmussens syndrome. Patients were right‐handed before surgery and had at least 5 years of normal language development before the onset of seizures. Language testing included speech sound (phoneme) discrimination, single word and phrasal comprehension, repetition, and naming. Within 4 to 16 days after surgery, patients showed improved phoneme discrimination compared with their performance shortly before surgery. Other language functions remained severely impaired until at least 6 months after surgery. By 1 year after surgery, receptive functions were comparable with, or surpassed, patient presurgery performance. Although word repetition was intact by 1 year after surgery, naming remained impaired, and patient speech was limited largely to production of single words. These results suggest that the right hemisphere is innately capable of supporting multiple aspects of phoneme processing. Recovery of higher level receptive and, to a lesser extent, expressive language functions is attributed to plasticity of the right hemisphere, which appears to persist beyond the proposed critical period for language acquisition and lateralization.

The pathology of Rasmussen syndrome: Stages of cortical involvement and neuropathological studies in 45 hemispherectomies

Summary:  Purpose: Rasmussen syndrome (RS) is a rare form of epilepsy characterized by progressive destruction of a single hemisphere. To characterize the profile of cortical involvement in RS, we studied the pathological changes in the cerebral cortex of 45 hemispherectomies performed at Johns Hopkins Hospital between 1985 and 2002.