Joseph I. Sirven

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.

Seizure Prophylaxis in Patients With Brain Tumors: A Meta-analysis

OBJECTIVE To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.

The Ketogenic Diet for Intractable Epilepsy in Adults: Preliminary Results

Summary: Purpose: Little is known concerning the efficacy and adverse effects of the ketogenic diet in adults with refractory epilepsy. This review reports preliminary results in 11 adults prospectively treated with the diet who had previously failed to gain seizure control with two or more medications and/or surgery.

Frequency of seizures in patients with newly diagnosed brain tumors: A retrospective review

Brain tumors may lead to symptomatic epilepsy. A retrospective analysis was undertaken to evaluate the frequency of seizure as the presenting symptom leading to brain tumor diagnosis in adults. One hundred and forty-seven consecutive patients with newly diagnosed brain tumors were analyzed regarding the frequency of seizures as the initial presenting symptoms and those subsequently developing seizures. One hundred twelve patients had primary central nervous system tumors (CNS) and 35 had metastatic lesions. Statistical evaluation was carried out using the Chi-square test with p values of <0.05 considered to be statistically significant. Astrocytomas and meningiomas were the most common primary CNS tumors in this study. Of these, oligodendrogliomas and grade 2 astrocytomas were significantly more likely to present with seizures (p<0.001). Seizures were a frequent presenting symptom, occurring in over 38% of those with primary brain neoplasms and 20% of those with cerebral metastases. Primary location of tumor also correlated amongst primary CNS tumors and was associated with a trend in seizure risk: parietal (80%); temporal (74%); frontal (62%); and occipital (0%) (p<0.5). The findings highlight the importance of obtaining appropriate evaluation for underlying malignancy in adults with new-onset seizures as well as provide more information to the patient for prognosis and counseling.

Vagus nerve stimulation therapy for epilepsy in older adults

Article abstract The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

Seizure-Related Motor Vehicle Crashes in Arizona Before and After Reducing the Driving Restriction From 12 to 3 Months

OBJECTIVE To evaluate whether changing the seizure-free interval in Arizona from 12 months to 3 months affected the number of seizure-related motor vehicle crashes. METHODS We performed a time trend study with analysis of motor vehicle crash reports in the state of Arizona 3 years before (1991-1993) and 3 years after (1994-1996) the seizure-free interval was decreased from 12 to 3 months. The number of motor vehicle crashes related to seizures, other medical conditions, and other nonmedical crashes was compared before and after the law changed. Other population trends, including population growth, registered vehicles, and registered drivers, are also reported. RESULTS Seizure-related crashes increased from 125 to 136 for the 3 years before and 3 years after the law changed, respectively. The total rate of seizure-related crashes did not increase on the basis of an incidence rate difference of -0.03/10(9) miles (95% confidence interval [CI], -0.30 to 0.24) and a relative risk of 0.98 (95% CI, 0.77 to 1.24). Over the same time interval, crashes related to other medical conditions increased from 288 to 310, respectively, for an incidence rate difference of -0.09/10(9) miles (95% CI, -0.51 to 033) and a relative risk of 0.97 (95% CI, 0.82 to 1.13). Fatalities due to seizure-related crashes decreased during the same period, whereas the number of multiple vehicle crashes increased. CONCLUSION The rate of seizure-related crashes did not significantly increase in the state of Arizona after the seizure-free interval was reduced from 12 to 3 months.

Temporal lobectomy outcome in older versus younger adults

Article abstract A total of 340 patients age 50 years and older were compared with 30 patients younger than 50 years, all of whom had anterior temporal lobectomy for refractory epilepsy. Seizure outcome, neuropsychological test scores, and change in driving status were analyzed. Age and duration of epilepsy were related independently to outcome, but laterality of interictal sharp waves (an early epilepsy risk factor) and presence of tumor were not. Sixteen patients (52%) in the older group and 257 patients (75.6%) in the younger group (p < 0.008) were seizure free. Postoperative neuropsychological outcome and driving status were similar in older and younger patients.

Complementary/alternative medicine for epilepsy in Arizona

The NIH defines complementary or alternative medicine (CAM) as those healthcare and medical practices not currently an integral part of conventional medicine. It is estimated that 42% of the US population regularly use some form of CAM therapies for various medical conditions, with nearly 600 million visits made to CAM practitioners at an estimated cost of

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

30 billion a year.1 Despite the commonplace nature of CAM treatments, there are few data regarding the scope of CAM use for seizures and how individuals with epilepsy (IWE), their families, and their health care professionals utilize CAM treatments. The purpose of this study is to begin to define the extent to which CAM treatments are used for epilepsy by surveying Epilepsy Foundation of Arizona (EFAZ) members, a representative sample of IWE, and health professionals that manage them to assess educational needs regarding CAM for IWE and their physicians. A 40-question survey was mailed to the EFAZ membership (n = 3,100) in September 2002, with a second mailing to those individuals who had not responded. IWE, their families, and their health professionals were questioned regarding the level of seizure control and their perceptions on the various CAM treatments for seizures. The instrument collected …

Topiramate in older patients with partial-onset seizures: A pilot double-blind, dose-comparison study

BACKGROUND Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.