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Objective To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal‐ (partial‐) onset seizures. Methods This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400‐1200 mg once daily), two phase 3 trials of ESL monotherapy (1200‐1600 mg once daily), and their open‐label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+]), incidences of hyponatremia‐related treatment‐emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. Results The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open‐label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+] measurement ≤125 mEq/L, 10 mEq/L decrease in [Na+] from baseline

Objectives To describe the characteristics of epilepsy in patients with Neurofibromatosis type 1 (NF1). Methods Analysis of a cohort of consecutive NF1 patients seen in our NF1 clinic during a three-year period. Results Of the 184 NF1 patients seen during that period, 26 had epilepsy and three had febrile seizures. Of the 26, 17 (65%) had localization-related epilepsy, seven of whom (41%) were drug resistant. Six (23%) had apparently primary generalized epilepsy (0/6 drug resistant), two (8%) Lennox-Gastaut syndrome, and one (4%) West syndrome (all three were drug-resistant). As compared to the patients with no epilepsy, those with epilepsy were more likely to have MRI findings of mesial temporal sclerosis (MTS) (23% vs. 5%, p = 0.0064), and cerebral hemisphere tumors (31% vs. 10%, p = 0.0079), but not of the other MRI findings including neurofibromatosis bright objects, or optic gliomas. Three of the six patients with MTS underwent temporal lobectomy with subsequent control of their seizures with confirmation of MTS on pathology in 3/3 and presence of coexisting focal cortical dysplasia (FCD) in 2/3. We also have observed three additional patients outside the above study with the association of NF1, MTS, and intractable epilepsy. Significance Epilepsy is relatively common in NF1, often occurs in patients with brain tumors or with MTS which can coexist with FCD, can be associated with multiple types of epilepsy syndromes, and when localization-related is often drug-resistant. Patients with NF1 and MTS can respond to medial temporal lobectomy and may have coexisting medial temporal lobe cortical dysplasia.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

To evaluate the sensitivity and specificity of a panel of quantitative EEG (qEEG) trends for seizure detection in adult intensive care unit (ICU) patients when reviewed by neurophysiologists and non-neurophysiologists.One hour qEEG panels (n = 180) were collected retrospectively from 45 ICU patients and were distributed to 5 neurophysiologists, 7 EEG technologists, and 5 Neuroscience ICU nurses for evaluation of seizures. Each panel consisted of the following qEEG tools, displayed separately for left and right hemisphere electrodes: rhythmicity spectrogram (rhythmic run detection and display; Persyst Inc), color density spectral array, EEG asymmetry index, and amplitude integrated EEG. The reviewers did not have access to the raw EEG data.For the reviewer's ability to detect the presence of seizures on qEEG panels when compared with the gold standard of independent raw EEG review, the sensitivities and specificities are as follows: neurophysiologists 0.87 and 0.61, EEG technologists 0.80 and 0.80, and Neuroscience ICU nurses 0.87 and 0.61, respectively. There was no statistical difference among the three groups regarding sensitivity.Quantitative EEG display panels are a promising tool to aid detection of seizures by non-neurophysiologists as well as by neurophysiologists. However, even when used as a panel, qEEG trends do not appear to be adequate as the sole method for reviewing continuous EEG data.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio

Summary 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.

Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 genotype, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and −2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.

Thirty-seven infants with myelomeningocele received brainstem auditory evoked potentials (BAEPs) at a median age of eight days. No infant had brainstem dysfunction at the time of testing. Median follow-up was at 30 months. Of 12 infants who subsequently developed brainstem dysfunction at a median age of three months, 11 had had abnormal neonatal BAEPs. In contrast, only 10 of 25 infants who did not develop brainstem dysfunction had abnormal BAEPs. The mean average I-V interpeak latencies was greater among those who developed symptoms than among those who did not. Neonatal BAEPs can identify a group of asymptomatic infants with myelomeningocele who need close follow-up for the subsequent development of brainstem dysfunction.

Summary Background The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. Methods We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. Findings We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2 , and ALDH5A1 were most notable. Interpretation The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

To establish the number of monitoring days needed to distinguish psychogenic nonepileptic seizures (PNES) from epileptic seizures (ES) in adult patients admitted for video/EEG monitoring (VEM), we performed a retrospective chart review on 199 consecutive admissions for behavioral event diagnosis with VEM. Of the 199 adult patients admitted for VEM, 83.9% (n = 167) had a clinical event during admission, and a definitive diagnosis was made in 75.9% (n = 151). Of patients who had clinical events, 87.7% (n = 143) had their first event on admission day 1 or 2. Factors associated with ES (vs PNES) included an abnormal baseline EEG (P < 0.001), an abnormal brain MRI (P = 0.01), and history of events lasting less than 1minute (P = 0.01). There was no association between time to first event and discharge diagnosis. VEM differentiated between ES and PNES in the majority of adult patients evaluated. Most behavioral events were characterized within 2 days of admission.

Sleep is one of the best-documented factors influencing the expression of seizures and interictal discharges. Janz studied the relation between seizures and the sleep/wake cycle and divided the epilepsies into three categories: nocturnal, awakening, and diffuse. Since then, the effect of sleep on the ictal and interictal manifestations of epilepsy has been studied extensively. Many seizures are activated by sleep or arousal from sleep. Interictal discharges are also seen more commonly during sleep, with the greatest activation seen during nonrapid eye movement sleep. Sleep not only increases the frequency of epileptiform abnormalities, but also may alter their morphology and distribution. Sleep deprivation also facilitates both epileptiform abnormalities and seizures. Seizures, on the other hand, also impact sleep. Epileptic patients demonstrate multiple sleep abnormalities, including an increased sleep latency, fragmented sleep, increased awakenings and stage shifts, and an increase in stages 1 and 2 of nonrapid eye movement sleep. These disturbances may in turn be modulated by antiepileptic treatment. This review summarizes the interactions between sleep and epilepsy, including the timing of seizures during the sleep/wake cycle, the influence of sleep on various seizure disorders, the effects of sleep deprivation, and the changes in sleep patterns caused by seizures and their treatment.

The authors describe a method for demonstrating the tonic and phasic couplings between suitably time-aligned surface eletromyographs (sEMGs) and the simultaneously recorded EEGs. The method, based on independent component analysis, was applied to data recorded from two normal subjects performing sustained submaximal contractions or continual repetitive movements of the arm. Augmented datasets, consisting of the EEG and either the sEMG from a single muscle (subject 1) or a combination of sEMGs from several muscles (subject 2), were analyzed with independent component analysis to determine the EEG/sEMG coupling. Each derived coupling consisted of a spatial distribution on the scalp and a waveform representing an EEG channel combination coactivating with the sEMG. The combinations of sEMGs, derived by applying independent component analysis to the simultaneous sEMG recordings from several muscles to create sEMG independent components (ICs), were either tonic or phasic with differing periods of activation. The topographic distributions on the scalp of the couplings between the EEG and sEMG ICs were different for each sEMG IC. The spatial distributions of the couplings between tonic sEMG ICs or single-muscle sEMGs and the EEG followed topographic patterns in sensorimotor regions. Phasic couplings were bifrontal, lateral, and bioccipital. Calculation of coherence between the sEMG ICs and calculated EEG combinations agreed well with the frequency spectra of the independent component analysis-derived coupling waveforms. These preliminary results demonstrate that detection of both the tonic and phasic coupling between the sEMG and the EEG is possible when monitoring unpaced proximal arm movement. This may thus be a practical means of exploring the dynamic cortical/muscle relationships in subjects unable to perform fine finger movements, such as patients recovering from stroke.

Background. The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. Objective. To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations.¶Materials and methods. A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67–71 years; mean = 28.6) with filamin-1 gene mutations. ¶Results. In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations.¶Conclusion. Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.

Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients . Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy.

Movement disorders such as tremor and ataxia occur commonly during therapy with antiepileptic drugs (AEDs). Dystonias, however, are rare. Blepharospasm, although reported with neuroleptic agents, has never been reported with AEDs. Our patient developed blepharospasm during therapy with lamotrigine.

Summary: Changes in EEGs during cardiac arrest have been described in detail by many authors; however, mortality because of an EEG has never been reported. The authors report the case of a patient who developed cardiac arrest causally related to administration of succinylcholine for reduction of excessive amounts of myogenic artifact during an EEG. This case indicates the need for caution when doing an EEG study in an intensive care unit setting.

We report a case of relapsing polychondritis with focal sensorimotor seizures, aseptic meningitis, and migratory leptomeningeal enhancement on contrast MRI. These abnormalities on imaging studies correlated accurately with laterality of the patient's seizures, facilitating early aggressive management of his neurologic symptoms.

Summary: Purpose: This retrospective study reports the long-term surgical outcome of patients with medically refractory epilepsy and vascular malformations who were treated with lesionectomy. A detailed analysis of surgical failures had been performed in an attempt to define predictors of surgical success and failure. Methods: Fifteen patients with medically intractable epilepsy and angiographically occult vascular malformations (AOVMs) were treated surgically with lesionectomy at Duke University Medical Center. Lesionectomy consisted of removal of the AOVM and surrounding hemosiderin-stained brain only, without the use of electrocorticography (ECoG) to guide resection. Results: Eleven (73%) patients are seizure free after lesionectomy. Three showed no significant improvement, and one patient died, presumably after a seizure. Age of onset, duration of seizures, age at resection, and gender did not affect outcome. All patients with neocortical AOVMs in whom EEG findings correlated with the site of the lesion were seizure free after lesional resection. Treatment failures were associated with the presence of multiple intracranial lesions, poorly localized or diffuse EEG findings, discordant positron emission tomography (PET) imaging, or with a lesion in close proximity to the limbic system. Conclusions: Lesionectomy, with removal of surrounding hemosiderin-stained brain, can be considered the procedure of choice in carefully selected patients with epilepsy with occult vascular malformations.

Much has been written about sexual dysfunction in men with epilepsy. We wanted to determine the frequency and nature of sexual disorders in our highly selected population of male veterans. Charts of the 184 men with epilepsy followed in the Neurodiagnostic Clinic, Veterans Affairs Medical Center, Durham, NC were reviewed to determine reports of sexual dysfunction. Demographics, type of epilepsy, localization, and antiepileptic drugs (AEDs) at the time of complaints were noted. These patients were compared to 20 men with epilepsy without reported sexual dysfunction (control group). Forty-one (22%) patients complained of sexual dysfunction (impotence 56%, decreased libido 37%, difficulty maintaining erection 22%, and other disorders 15%). Mean age at evaluation was 48.3 years for patients and 44.8 years for controls. Mean age of onset of seizures was 34.0 and 29.3 years for patients and controls, respectively. 93% of patients and 95% of controls had partial seizures. The AEDs (phenytoin, carbamazepine, valproate, phenobarbital, and primadone) were used with approximately equal frequency in both groups. Fifty-nine percent of patients and 65% of controls were on monotherapy, 34% and 25% on dual therapy, 5% each on triple therapy, and 2% and 5% on no medication. Sexual dysfunction is a common problem in our population of veteran men with epilepsy. Age of onset and type of seizures and the medications used were comparable in patients and controls.

Two patients in whom consciousness and memory were retained during bilateral clonic or tonic-clonic seizures are reported on, and three patients reported on previously are reviewed. Ictal semiology differed from myoclonic and supplementary motor seizures, which are other seizure types characterised by bilateral motor movements and retained awareness. In the two new patients ictal pain was a prominent feature. It is proposed that propagation of seizure activity may be confined to the sensorimotor areas bilaterally while sparing the neural structures involved in maintaining consciousness and in processing language and memory. This unusual type of seizure may be misdiagnosed as a pseudoseizure. Detailed description of the ictal events and further laboratory evaluation including video-EEG monitoring may be necessary to make the distinction.

We report clinical and EEG features of 65 probands with juvenile myoclonic epilepsy (JME) and the occurrence and character of epilepsy among 664 blood relatives of 26 of the 65 probands with a positive family history of seizures. Forty-six families from India and 19 families from the United States were investigated. Among the probands, sex distribution was equal; the mean age at onset of generalized tonic-clonic seizures (GTCS) and myoclonic jerks was 14.2 and 14.3 years, respectively; myoclonic jerks alone occurred in 2 (3%); 5 (8%) had absence seizures; and bilaterally symmetrical polyspike and wave complexes were evident during interictal EEG in 50 (77%). Twenty-six probands (40%) had blood relatives with seizures. Clinical and EEG features were similar in Indian and American probands and in probands with and without a family history of seizures. Sixty-two blood relatives had seizures: 38 (61%) had idiopathic generalized epilepsy (IGE), including 11 (18%) with JME; 9 (15%) had single, spontaneous generalized seizures before age 30 years; and the remainder had febrile convulsions (4, 6%) or symptomatic, partial or unclassified epilepsy (11, 18%). Both the proportion of family members observed to have epilepsy and the epilepsy syndrome expressed in family members varied as a function of the degree of relation. First-degree relatives had greater occurrence of epilepsy, IGE, and JME than did more distant blood relatives. These data suggest that JME is a complex genetic disorder and support a multigenic pattern of inheritance.

Malformations of neuronal migration such as lissencephaly (agyria-pachygyria spectrum) are wellknown causes of mental retardation and epilepsy that are often genetic. For example, isolated lissencephaly sequence and Miller-Dieker syndrome are caused by deletions involving a lissencephaly gene in chromosome 17p13.3, while many other malformation syndromes have autosomal recessive inheritance. In this paper, we review evidence supporting the existence of two distinct X-linked malformations of neuronal migration. X-linked lissencephaly and subcortical band heterotopia (XLIS) presents with sporadic or familial mental retardation and epilepsy. The brain malformation varies from classical lissencephaly, which is observed in males, to subcortical band heterotopia, which is observed primarily in females. The XLIS gene is located in chromosome Xq22.3 based on the breakpoint of an X-autosomal translocation. Bilateral periventricular nodular heterotopia (BPNH) usually presents with sporadic or familial epilepsy with normal intelligence, primarily in females, although we have evaluated two boys with BPNH and severe mental retardation. The gene for BPNH has been mapped to chromosome Xq28 based on linkage studies in multiplex families and observation of a subtle structural abnormality in one of the boys with BPNH and severe mental retardation.NEUROLOGY 1996;47: 331-339

We performed temporal lobectomy in 23 young patients with intractable complex partial seizures (CPS) at an average age of 14.5 years. At a mean follow-up interval of 4.8 years, we reevaluated the patients to assess the surgical outcome; 74% were seizure-free. Cognitive testing showed slight improvement in Full-scale I.Q. scores and in some subtest scores. Wechsler Memory Scales had not changed significantly from the preoperative scores. Both pre- and postoperative Minnesota Multiphasic Personality Inventories 168 (MMPIs) were obtained in nine patients; and only postoperative MMPIs were obtained in 18. Pre- and postoperative social function, reported by the patients in a structured interview with a clinical psychologist (H.S.S.), was scored by a rating scale. All patients reported postoperative improvement in social function, although of variable degree. Patients were divided into a well-adjusted and a poorly adjusted group based on their postoperative social function. As compared with the well-adjusted group, the poorly adjusted group reported more preoperative social problems, had lower preoperative and postoperative I.Q. scores, had poorer postoperative seizure control, and had higher postoperative MMPI scores.

Grey matter heterotopias, demonstrated by MRI, may present with a broad spectrum of clinical severity. We have studied 33 patients with periventricular nodular heterotopias (PNH); 19 (58%) had unilateral and 14 (42%) bilateral lesions. Thirteen of the 19 patients (68%) with unilateral subependymal nodules of grey matter had, in addition, unilateral focal subcortical heterotopias (SNH), comprising 39% of the entire group. Most had normal intellectual and motor function but some presented with mild mental retardation and neurological deficits. Recurrent seizures were described in 82%, mainly partial attacks with temporo-parieto-occipital auras. Nodular heterotopias led to unilateral or bilateral independent temporal epileptic discharges in 47% of epileptic patients with PNH alone and in 61% of those who had SNH in addition. Extratemporal or multilobar, unilateral or bilateral interictal spiking was present in 10 other patients (36%). Two first degree relatives of patients with seizures were affected but had no seizures, three were investigated for other apparently unrelated neurological symptoms: memory impairment, vertigo or transient ischaemic attacks in one person each. Contiguous ovoid nodules of grey matter, symmetrically lining both lateral ventricles, were described in nine patients. Seven of them were female, including four with familial incidence of PNH. Such lesions may explain the familial occurrence of epilepsy in some families. Seven patients underwent anterior temporal resection: two patients with unilateral subependymal and focal subcortical heterotopias were seizure free or significantly improved. Four patients, three with PNH alone and one with additional subcortical nodules, did not improve significantly after surgery. The remaining patient was followed for less than 6 months.

Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Aims: An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin. Materials & methods: We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296). HLA-A*3101 was imputed from genome-wide association study data. We applied genome-wide association to study lamotrigine- and phenytoin-induced cADR, and total cADR cases combined. Results: Neither HLA-A*3101 nor any other genetic marker significantly predicted lamotrigine- or phenytoin-induced cADRs. Conclusion: HLA-A*3101 does not appear to be a predictor for lamotrigine- and phenytoin-induced cADRs in Europeans. Our genome-wide association study results do not support the existence of a clinically relevant common variant for the development of lamotrigine- or phenytoin-induced cADRs. As a predictive marker, HLA-A*3101 appears to be specific for carbamazepine-induced cADRs. Original submitted 5 September 2011; Revision submitted 10 November 2011

Sixty consecutive patients admitted for possible surgical treatment of intractable epilepsy underwent 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) as part of a standardized presurgical protocol. Patients were classified as having temporal lobe or extratemporal epilepsy based on all available information excluding PET. Of 35 patients categorized as having temporal lobe epilepsy, 27 (77%) had unilateral temporal lobe hypometabolism that always correlated with electrophysiologic localization of the seizure focus. In 19 patients categorized as having extratemporal epilepsy, only six (32%) had an abnormal PET study and in only one patient did PET assist in subsequent localization of the seizure focus. Four patients with extratemporal epilepsy had falsely localizing information obtained on PET. The results of this study demonstrate that PET is of less clinical utility in the presurgical evaluation of patients with extratemporal epilepsy as compared to patients with temporal lobe epilepsy.

Background:\ud \ud Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations.\ud Methods:\ud \ud We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.\ud Results:\ud \ud The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10−8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10−6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS–TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).\ud Conclusions:\ud \ud The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.)

We report a patient with lateralized right-sided ictal scalp EEG activity contralateral to left mesial temporal seizure onset as documented by depth electrodes. Subsequent left temporal lobectomy revealed mesial temporal sclerosis and resulted in a marked reduction (97%) in seizure frequency. This case illustrates the frequently discussed, but rarely documented, occurrence of false lateralization of scalp EEG seizure onset in a patient with temporal lobe epilepsy.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The present study was performed to determine whether the intraoperative monitoring of brainstem auditory evoked potentials (BAEPs) during microvascular decompression operations is effective in preventing profound hearing loss or deafness in the ipsilateral ear. The authors retrospectively compared the auditory morbidity of posterior fossa microvascular decompression surgery for the treatment of tic douloureux and hemifacial spasm before and after the introduction of routine intraoperative BAEP monitoring in 1984. Each patient underwent a similar procedure performed by the same surgeon. The two patient groups were comparable with regard to age, sex, and indications for surgery, Auditory morbidity did not decline with the increasing experience of the surgeon prior to 1984; 10 (6.6%) of 152 primary operations (151 patients) in which monitoring was not performed were followed by a profound ipsilateral hearing loss or deafness. In the monitored group, none of 109 operations (104 patients) caused profound hearing loss or deafness. This significant decline in auditory morbidity is attributed by the authors to the use of intraoperative BAEP monitoring, which allows the surgeon to alter the operation in response to degradations in the wave patterns. Based on our experience and that of others, we believe that intraoperative BAEP monitoring is of value in reducing the auditory morbidity of posterior fossa microvascular decompression surgery.

We compared scalp ictal EEG in complex partial seizures originating in extratemporal regions with seizures originating in the temporal lobe. All patients were seizure-free for 2 or more years after appropriate cortical resection confirming focus of seizure onset. The electroencephalographer reviewing seizures was blind to patient identity. Extratemporal seizures were shorter, more difficult to lateralize, and had postictal slowing less often. Confident lateralization of seizure onset could not be made in 19% of the seizures, usually because onset was diffuse or artifact obscured the seizure. When lateralization judgments were thought possible, lateralization errors occurred in only 3% of the seizures. Five percent of the seizures had no detectable scalp ictal changes.

Subject objective To determine the optimal number of therapist-guided Cognitive-Behavioral Insomnia Therapy (CBT) sessions required for treating primary sleep-maintenance insomnia. Design and setting Randomized, parallel-group, clinical trial at a single academic medical center. Outpatient treatment lasted 8 weeks with final follow-up conducted at 6 months. Participants 86 adults (43 women; mean age 55.4 +/- 9.7 years) with primary sleep-maintenance insomnia (nightly mean wake time after sleep onset [WASO] = 93.4 +/- 44.5 minutes). Interventions One (week 1), 2 (weeks 1 and 5), 4 (biweekly), or 8 (weekly) individual CBT sessions scheduled over an 8-week treatment phase, compared with an 8-week no-treatment waiting period (WL). Measurement Sleep diary and actigraphy measures of total sleep time, onset latency, WASO, total wake time, and sleep efficiency, as well as questionnaire measures of global insomnia symptoms, sleep related self-efficacy, and mood. Results Statistical tests of subjective/objective sleep measures favored the 1- and 4-session CBT doses over the other CBT doses and WL control. However, comparisons of pretreatment data with data acquired at the 6-month follow-up showed only the 4-session group showed significant long-term improvements in objective wake time and sleep efficiency measures. Additionally, 58.3% of the patients receiving 4 CBT sessions met criteria for clinically significant improvement by the end of treatment compared to 43.8% of those receiving 1 CBT session, 22.2% of those provided 2 sessions, 35.3% of those receiving 8 sessions, and 9.1% of those in the control condition. Conclusion Findings suggest that 4 individual, biweekly sessions represents the optimal dosing for the CBT intervention tested. Additional dose-response studies are warranted to test CBT models that contain additional treatment components or are delivered via group therapy.

EEG remains the primary technique in the diagnosis, characterization, and localization of partial seizures. This review examines the significance and character of interictal epileptiform abnormalities, periodic lateralized epileptiform discharges, and ictal patterns in patients with partial epilepsy. Interictal epileptiform discharges are common and assist in the diagnosis and localization of partial seizures. Fortunately, true "false positive" EEGs with focal epileptiform abnormalities are distinctly rare. Periodic lateralized discharges have characteristics of both interictal and ictal activity and are an area of controversy as to their clinical significance. Ictal patterns in partial seizures are variable, with the most distinctive features seen in seizures from a mesial temporal lobe origin. The unifying EEG feature of a partial seizure is in its evolution. A partial seizure begins with a clear delineation of the onset of activity that is distinct from the preceding background, followed by an evolution of this activity in both frequency and amplitude and terminating with an identifiable cessation of the rhythmic pattern that merges again into the background activity.

The purpose of this paper was to determine the incidence of depression in our sleep disorders clinics (and it's relation to patient characteristics) and to determine whether the incidence of depression varies in patients with and without sleep apnea.The Beck Depression Inventory (BDI) was administered to evaluate patients for depression. We reviewed records of all new patients between November, 1995 and May, 1996 and determined their BDI scores and polysomnogram (PSC) results. Patients were divided based on their respiratory disturbance index (RDI); a cut off value of 15 was chosen. Patients were re-divided based on the BDI score (13 or greater suggestive of depression). The age, sex, body mass index (BMI), BDI or RDI (as appropriate) and arousal indices were compared.Sixty-three patients were enrolled; 29% were depressed. BDI scores and PSG data were available in 42 patients. Those with a high RDI had significantly lower BDI scores and higher arousal indices. Those with a high and low BDI scores were not significantly different in any of the parameters evaluated.Symptoms of depression are commonly seen in a sleep clinic. In patients with symptoms suggestive of SA but with low RDI scores, a diagnosis of depression should be entertained. The presence of depression, however, should not negatively influence a decision to perform PSG.

It is generally believed that obstructive sleep apnea (OSA) causes depression in some patients, yet it is unknown whether this depression is an actual clinical phenomenon or purely a result of overlapping somatic/physical symptoms shared by both disorders. The present study investigated changes in both somatic and affective/cognitive symptoms of depression associated with the introduction of continuous positive airway pressure (CPAP) treatment for OSA. Participants were 39 outpatients (35 males, 4 females) with no current or past mental health problems, diagnosed with OSA in a hospital sleep disorders clinic. The Beck Depression Inventory (BDI) was administered prior to treatment and again 3 months after CPAP. Total BDI scores improved after CPAP, independent of objectively monitored CPAP compliance rates. Both somatic and affective/ cognitive symptoms of depression improved in a similar manner after treatment. Our findings suggest that depressive symptoms experienced by OSA patients are not solely the result of physical OSA symptoms but include a mood component as well. We introduce a hypothetical model to conceptualize the relationship between OSA and depression.

Determination of side of seizure onset is critical for a successful outcome following epilepsy surgery. Little is known about the significance of lateralized seizure termination. Sustained seizure activity contralateral to side of seizure onset, following termination of ictal activity ipsilateral to side of onset, may suggest the presence of an independent focus. Such activity, if present, should predict a poor outcome. We studied side of seizure termination in 13 patients undergoing monitoring with bitemporal depth electrodes and correlated this to outcome following anterior temporal lobectomy (ATL). Side of seizure onset was determined for all seizures during that evaluation. Based on side of final cessation of ictal activity, patients were classified as having ipsilateral final termination or simultaneous termination (Group 1; N=6) or contra-lateral or mixed final termination (Group 2; N=7). The Duke outcome classification system was used. At the end of 2 years follow-up, 6/6 patients in Group 1 and 3/7 patients in Group 2 were seizure free. We conclude that lateralized seizure termination during evaluation with depth electrodes may be useful in predicting outcome following ATL. Continued seizure activity contralateral to side of seizure onset (following termination of ictal activity ipsilateral to side of onset) predicts a poor outcome. This may indicate the presence of an independent seizure focus opposite to the side of surgery.

Study objectives This study was conducted to exam the degree to which cognitive-behavioral insomnia therapy (CBT) reduces dysfunctional beliefs about sleep and to determine if such cognitive changes correlate with sleep improvements. Design The study used a double-blind, placebo-controlled design in which participants were randomized to CBT, progressive muscle relaxation training or a sham behavioral intervention. Each treatment was provided in 6 weekly, 30-60-minute individual therapy sessions. Setting The sleep disorders center of a large university medical center. Participants Seventy-five individuals (ages 40 to 80 years of age) who met strict criteria for persistent primary sleep-maintenance insomnia were enrolled in this trial. Interventions N/A. Measurements and results Participants completed the Dysfunctional Beliefs and Attitudes About Sleep (DBAS) Scale, as well as other assessment procedures before treatment, shortly after treatment, and at a six-month follow-up. Items composing a factor-analytically derived DBAS short form (DBAS-SF) were then used to compare treatment groups across time points. Results showed CBT produced larger changes on the DBAS-SF than did the other treatments, and these changes endured through the follow-up period. Moreover, these cognitive changes were correlated with improvements noted on both objective and subjective measures of insomnia symptoms, particularly within the CBT group. Conclusions CBT is effective for reducing dysfunctional beliefs about sleep and such changes are associated with other positive outcomes in insomnia treatment.