Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

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, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

Challenges in identifying Lennox-Gastaut syndrome in adults: A case series illustrating its changing nature.

The variable presentation and progression of Lennox-Gastaut syndrome (LGS) can make it difficult to recognize, particularly in adults. To improve diagnosis, a retrospective chart review was conducted on patients who were diagnosed as adults and/or were followed for several years after diagnosis. We present 5 cases that illustrate changes in LGS features over time. Cases 1 and 2 were diagnosed by age 8 with intractable seizures, developmental delay, and abnormal EEGs with 1.5-2 Hz SSW discharges. However, seizure type and frequency changed over time for both patients, and the incidence of SSW discharges decreased. Cases 3, 4, and 5 were diagnosed with LGS as adults based on current and past features and symptoms, including treatment-resistant seizures, cognitive and motor impairment, and abnormal EEG findings. While incomplete, their records indicate that an earlier LGS diagnosis may have been missed or lost to history. These cases demonstrate the need to thoroughly and continuously evaluate all aspects of a patient's encephalopathy, bearing in mind the potential for LGS features to change over time.

Differential gene expression in dentate granule cells in mesial temporal lobe epilepsy with and without hippocampal sclerosis.

OBJECTIVE: Hippocampal sclerosis is the most common neuropathologic finding in cases of medically intractable mesial temporal lobe epilepsy. In this study, we analyzed the gene expression profiles of dentate granule cells of patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis to show that next-generation sequencing methods can produce interpretable genomic data from RNA collected from small homogenous cell populations, and to shed light on the transcriptional changes associated with hippocampal sclerosis. METHODS: RNA was extracted, and complementary DNA (cDNA) was prepared and amplified from dentate granule cells that had been harvested by laser capture microdissection from surgically resected hippocampi from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis. Sequencing libraries were sequenced, and the resulting sequencing reads were aligned to the reference genome. Differential expression analysis was used to ascertain expression differences between patients with and without hippocampal sclerosis. RESULTS: Greater than 90% of the RNA-Seq reads aligned to the reference. There was high concordance between transcriptional profiles obtained for duplicate samples. Principal component analysis revealed that the presence or absence of hippocampal sclerosis was the main determinant of the variance within the data. Among the genes up-regulated in the hippocampal sclerosis samples, there was significant enrichment for genes involved in oxidative phosphorylation. SIGNIFICANCE: By analyzing the gene expression profiles of dentate granule cells from surgically resected hippocampal specimens from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis, we have demonstrated the utility of next-generation sequencing methods for producing biologically relevant results from small populations of homogeneous cells, and have provided insight on the transcriptional changes associated with this pathology.

Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.

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.

Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

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.

Genetic and environmental correlates of topiramate-induced cognitive impairment.

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.

Testing the reliability and validity of DSM-IV-TR and ICSD-2 insomnia diagnoses. Results of a multitrait-multimethod analysis.

CONTEXT: Distinctive diagnostic classification schemes for insomnia diagnoses are available, but the optimal insomnia nosology has yet to be determined. OBJECTIVES: To test the reliability and validity of insomnia diagnoses listed in the American Psychiatric Association's DSM-IV-TR and the International Classification of Sleep Disorders, second edition (ICSD-2). DESIGN: Multitrait-multimethod correlation design. SETTING: Two collaborating university medical centers, with recruitment from January 2004 to February 2009. PARTICIPANTS: A total of 352 adult volunteers (235 of whom were women) who met research diagnostic criteria for insomnia disorder. MAIN OUTCOME MEASURES: Goodness-of-fit ratings of 10 DSM-IV-TR and 37 ICSD-2 insomnia diagnoses for each patient. Ratings were provided by 3 clinician pairs who used distinctive assessment methods to derive diagnostic impressions. Correlations computed within and across clinician pairs were used to test reliability and validity of diagnoses. RESULTS: Findings suggested that the best-supported DSM-IV-TR insomnia categories were insomnia related to another mental disorder, insomnia due to a general medical condition, breathing-related sleep disorder, and circadian rhythm sleep disorder. The category of primary insomnia appeared to have marginal reliability and validity. The best-supported ICSD-2 categories were the insomnias due to a mental disorder and due to a medical condition, obstructive sleep apnea, restless legs syndrome, idiopathic insomnia, and circadian rhythm sleep disorder-delayed sleep phase type. Psychophysiological insomnia and inadequate sleep hygiene received much more variable support across sites, whereas the diagnosis of paradoxical insomnia was poorly supported. CONCLUSIONS: Both the DSM-IV-TR and ICSD-2 provide viable insomnia diagnoses, but findings support selected subtypes from each of the 2 nosologies. Nonetheless, findings regarding the frequently used DSM-IV-TR diagnosis of primary insomnia and its related ICSD-2 subtypes suggest that their poor reliability and validity are perhaps due to significant overlap with comorbid insomnia subtypes. Therefore, alternate diagnostic paradigms should be considered for insomnia classification.

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.).

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

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<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

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.

CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.

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.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

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.

Dose-response effects of cognitive-behavioral insomnia therapy: a randomized clinical trial.

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.

Video/EEG monitoring in the evaluation of paroxysmal behavioral events: duration, effectiveness, and limitations.

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.

Changes in depressive symptoms after continuous positive airway pressure treatment for obstructive sleep apnea.

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.

Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy.

STUDY OBJECTIVES: Sleep studies at Duke University Medical Center were retrospectively reviewed to investigate causes of excessive daytime sleepiness (EDS) in our myotonic dystrophy1 (DM1) patient population, identified by an abnormal CTG expansion on chromosome 19. Excessive daytime sleepiness, an accentuated desire for sleep or the occurrence of sleep episodes that interfere with normal wakefulness, is common in patients with DM1. Sleep abnormalities, such as central and obstructive sleep apnea, have been extensively reported; however, many DM1 patients suffer from EDS in the absence of any identified respiratory dysrhythmia. DESIGN: Nineteen DM1 patients, with the clinical diagnosis and genetic confirmation in the proband or a related family member, had a sleep evaluation. Polysomnogram (PSG) and mean sleep latency test (MSLT) results were retrospectively reviewed. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Most DM1 patients demonstrated grade 3 (distal weakness) or grade 4 (mild to moderate proximal weakness) on the myotonic dystrophy impairment rating scale. All patents had a PSG, with 13 patients having an MSLT the following day. Clinically significant respiratory abnormalities on PSG, defined in this study as a respiratory disturbance index > 15 and/or upper airway resistance syndrome, could not explain the EDS observed in 14 of 19 patients. Decreased mean sleep latency was observed in 12 of 13 patients evaluated by MSLT, while sleep onset REM sleep was seen in 8 of 13 patients. Pathologic REM onset (2 or more SOREMs on MSLT) was seen in 5 of 13 patients, with 3 of those 5 patients having a PSG with RDI < or = 5. CONCLUSIONS: Most DM1 patients did not have significant respiratory abnormalities on PSG to explain the manifested EDS. Objective sleepiness is common in DM1, and pathologic REM pressure can be commonly observed. These observations imply an intrinsic hypersomnolence sometimes accompanied by abnormal REM pressure may be an integral part of EDS in DM1 patients.