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.

Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project.

PURPOSE: Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. METHODS: One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. KEY FINDINGS: LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGS(u) completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. SIGNIFICANCE: LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome.

The epilepsy phenome/genome project.

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Disparities in Access to Neurologic Telemedicine During the COVID-19 Pandemic: A Bronx Tale.

OBJECTIVE: To determine whether there is a disparity in access to telemedical care that may be a function of socioeconomic status, language, or other demographic factors during the peak of the coronavirus disease 2019 (COVID-19) pandemic at a highly affected urban center (Montefiore Medical Center) in Bronx, NY. METHODS: We retrospectively investigated potential patient characteristics that might be associated with an increased likelihood of receiving a telephone visit as opposed to a televideo visit for patients followed in the pediatric neurology, adult epilepsy, and general neurology practices at Montefiore Medical Center during the 30-day period starting April 2, 2020, at the peak of the COVID-19 pandemic in New York. RESULTS: We found that patients who had telephone encounters, as opposed to televideo encounters, were overall older, less likely to have commercial insurance, and more likely to have Medicaid. Among pediatric patients, a preferred language other than English was also associated with a higher proportion of telephone encounters. New patients in both the adult and pediatric groups were more likely to have televideo visits. CONCLUSIONS: Our findings identify demographic factors, including age, insurance type, and language preference, which may play a role in access to televideo encounters among neurology patients in an urban center during the COVID-19 pandemic. We suggest several potential practice, institution, and community-based interventions, which might further expand access to televideo care for neurology patients.

Value of routine screening for bone demineralization in an urban population of patients with epilepsy.

BACKGROUND: Reduced bone mineral density (BMD) is increasingly recognized in patients receiving antiepileptic drug therapy. The precise prevalence is not known due to variability across populations studied. We set out to characterize the prevalence of abnormal BMD in an urban population of patients with epilepsy with the intent to determine the value of routine BMD screening. METHODS: We performed a cross-sectional study of 130 consecutive patients seen thorough our Comprehensive Epilepsy Center. BMD was measured using dual X-ray absorptiometry and was reported as T-score and Z-score. Additional information collected for each patient included age, race, gender, current and prior AEDs, ambulatory state, menopausal state, concomitant medications potentially associated with reduced bone mineralization, and comorbid illness potentially associated with reduced bone mineralization. Associations between reduced bone mineralization and variables were tested for significance using Fisher's exact test, Student's t-test, and Wilcoxon rank sum test. RESULTS: The average age of the entire study population was 43.5 (+/-12.5) years. Fifty-five percent of patients had T-score less than or equal to -1, the WHO criterion for osteopenia in postmenopausal women. The prevalence of Z-scores less than -2.0 was 15%, which is more than sixfold greater than expected. The markers for decreased BMD included older age or menopause in women, longer duration of therapy, and a history of use of phenytoin or phenobarbital. Assisted ambulation was also associated with low BMD. CONCLUSION: Our results indicate that reduced bone mineralization is prevalent and a significant health concern in an urban population of patients with epilepsy. Because of the high prevalence of reduced bone mineralization reported in numerous studies including this study, routinely screening for reduced bone mineralization is warranted in patients receiving anticonvulsant therapy.

A novel nonpharmacologic treatment for photosensitive epilepsy: a report of three patients tested with blue cross-polarized glasses.

PURPOSE: Pharmacotherapy for photosensitive epilepsy is not always effective and is associated with well-recognized toxicities. Nonpharmacologic approaches to the management of photosensitive epilepsy have included the use of sunglasses of various types. Blue lenses have been shown to suppress the photoparoxysmal response more effectively than lenses of other colors with similar overall transmittances. Recently, cross-polarized glasses have shown promise. The axes of polarization of the two lenses of such glasses are perpendicular to one another. We tested the effect of combining the use of blue and cross-polarized lenses in three patients with photosensitive epilepsy. METHODS: We recorded the EEG response to photic stimulation, television screens, and computer monitors in three patients with photosensitive epilepsy. If photoparoxysmal responses were provoked in any of these scenarios, testing was repeated with the patient wearing nonpolarized, parallel-polarized, and blue cross-polarized sunglasses. RESULTS: One of our patients had clinical seizures that were inadequately suppressed with moderate doses of valproate (VPA) but completely suppressed with blue cross-polarized lenses. The second patient's photoparoxysmal response was suppressed by both parallel-polarized and blue cross-polarized glasses, whereas the third patient's photoparoxysmal response was not suppressed by either. CONCLUSIONS: These preliminary data suggest that blue cross-polarized lenses may be useful in the treatment of photosensitive epilepsies and that their efficacy can be predicted in the EEG laboratory.