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Aim: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. Method: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20–30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20–30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. Results: Seven participants (one female, six males; age range 5–23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. Interpretation: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. What this paper adds: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B 6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.

Background Epilepsy and multiple sclerosis (MS) are two neurological diseases known to greatly influence a patient’s life. The primary aim of this study was to describe the prevalence of sexual dysfunction in patients with epilepsy and MS and investigate whether there is an association between disease, sexual function, and physical and mental health. A secondary aim was to investigate whether there is a difference in sexual function between patients with MS and epilepsy. Methods A total of 414 patients were included in this descriptive cross-sectional study. Three patient report questionnaires were used for measurements: the Changes in Sexual Function Questionnaire (CSFQ) cut-off score; the Short Form 36 Health Survey (SF-36) divided into the Physical Component Summary (PCS) and Mental Component Summary (MCS), and the Life Satisfaction—11 (LiSat-11). Results Patients with MS constituted 62% (n = 258) of the participants and patients with epilepsy 38% (n = 156). The prevalence of sexual dysfunction was 68% in women and 77% in men. No differences were found between patients with MS and epilepsy (p = 0.184), except for the CSFQ desire domain, as patients with epilepsy more often had a desire problem (p = 0.029). On the SF-36, patients with MS scored significantly worse on the PCS (p = 0.000). Patients with epilepsy scored significantly worse on the MCS (p = 0.002). No significant differences were found on the LiSat-11. Regression analysis with CSFQ as the dependent variable showed an association with the PCS in men and an association with both PCS and MCS in women. Conclusions In this study, the cohort of patients with MS and epilepsy had negatively affected sexual function. The only significant difference between patients with MS and epilepsy in sexual function measured by the CSFQ-14, was found in the frequency of desire, in which a larger number of patients with epilepsy reported sexual dysfunction. In the studied cohort, sexual function in women is associated with both physical and mental health, and in men with physical health. These results should be considered when caring for patients with epilepsy and MS.

Objective: Depression and anxiety symptoms are common among patients with epilepsy, but are relatively under-researched in patients with both epilepsy and intellectual disability (ID). The aim was to investigate whether epilepsy and ID characteristics are associated with mood, anxiety, and quality of life. Materials and Methods: Adult patients with epilepsy and ID who rely on tertiary epilepsy care were included (N = 189). Mood, anxiety, and quality of life were assessed by standardized questionnaires. Epilepsy and ID characteristics were retrieved from patient charts or determined by psychometric instruments. Results: Elevated levels of depressive and anxiety symptoms were present in 21.7% and 12.7%, respectively. Anxiety was significantly associated with a focal epilepsy type and ID domain discrepancy (substantial difference between two domains of adaptive behavior), but was negatively related to seizure frequency and drug load of mood-stabilizing antiepileptic drugs. Depressive symptoms were not significantly related to epilepsy characteristics, but a severe ID and ID domain discrepancy was associated with more depressive symptoms. Quality of life was significantly worse in those with multiple seizure types and ID domain discrepancy. Conclusion: Whereas anxiety and quality of life are associated with individual epilepsy characteristics, this could not be confirmed for depressive symptoms in patients with epilepsy and ID, despite its high prevalence.

Supplemental Digital Content is available in the text., Background: The role of diabetes mellitus, liver disease, and epilepsy as risk factors for Dupuytren disease remains unclear. In this systematic review and meta-analysis, the strength and consistency of these associations were examined. Methods: The MEDLINE, EMBASE, and Web of Science databases were searched for articles reporting an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy published before September 26, 2016. The frequencies of Dupuytren disease and diabetes mellitus, liver disease, and epilepsy were extracted, as was information on potential confounders. Generalized linear mixed models were applied to estimate pooled odds ratios, adjusted for confounders. Heterogeneity between studies was quantified using an intraclass correlation coefficient and was accounted for by a random effect for study. Results: One thousand two hundred sixty unique studies were identified, of which 32 were used in the meta-analyses. An association between Dupuytren disease and diabetes mellitus was observed (OR, 3.06; 95 percent CI, 2.69 to 3.48, adjusted for age), which was stronger for type 1 diabetes mellitus than for type 2 diabetes mellitus but was not statistically significant (p = 0.24). An association between Dupuytren disease and liver disease was observed (OR, 2.92; 95 percent CI, 2.08 to 4.12, adjusted for sex). Dupuytren disease and epilepsy were associated, yielding an OR of 2.80 (95 percent CI, 2.49 to 3.15). Heterogeneity between studies was moderate to low. Conclusions: These findings demonstrate an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy. Prospective, longitudinal studies are needed to elucidate the pathways causing these associations.

Background Vagus nerve stimulation (VNS) can induce a sleep apnea syndrome (SAS), which in turn can worsen seizure control and represents a cardiovascular risk factor. Epidemiology of VNS-induced SAS has received little attention to date. The purpose of this study was to estimate the VNS-induced SAS prevalence and to explore clinical variables potentially correlating with its development. Methods We analyzed the computerized medical records of 18 consecutive adults treated for refractory epilepsy with VNS, implanted between May 2008 and October 2015. Patients underwent sleep polygraphy or polysomnography before and after VNS implantation. Between patients with and without SAS, we compared variables related to epilepsy type and device parameters. Results Two patients had SAS and were treated before implantation; one improved after VNS, the other worsened. Four other patients developed SAS after VNS: induced/aggravated SAS occurred in 5/18 patients (prevalence: 27.8%). Only 2 of them had symptoms: one complained of important snoring, the other reported seizure worsening. All 5 patients were successfully treated by combinations of continuous positive airway pressure (cPAP), positional therapy, or VNS parameters modification. There was no statistically significant difference between potential predictors. Conclusion Despite the relatively modest clinical impact on epilepsy, in view of the associated cardiovascular risk factor development, easy treatment, and the relatively high SAS prevalence, routine screening for SAS before and after VNS implantation may represent a reasonable practice.

Purpose The brains of patients with epilepsy may exhibit various morphological abnormalities, which are often not directly visible on structural MR images, as they may be focally subtle or related to a more large-scale inconspicuous disorganization of brain structures. To explore the relation between structural brain organization and epilepsy characteristics, including severity and cognitive co-morbidity, we determined structural covariance networks (SCNs). SCNs represent interregional correlations of morphologic measures, for instance in terms of cortical thickness, between various large-scale distributed brain regions. Methods Thirty-eight patients with focal seizures of all subtypes and 21 healthy controls underwent structural MRI, neurological, and IQ assessment. Cortical thickness was derived from the structural MRIs using FreeSurfer. Subsequently, SCNs were constructed on a group-level based on correlations of the cortical thicknesses between various brain regions. Individual SCNs for the epilepsy patients were extracted by adding the respective patient to the control group prior to the SCN construction (i.e. add-one-patient approach). Calculated network measures, i.e. path length, clustering coefficient and betweenness centrality were correlated with characteristics related to the severity of epilepsy, including seizure history and age at onset of epilepsy, and cognitive performance. Results Stronger clustering in the individual SCN was associated with a higher number of focal to bilateral tonic-clonic seizures during life time, a younger age at onset, and lower cognitive performance. The path length of the individual SCN was not related to the severity of epilepsy or cognitive performance. Higher betweenness centrality of the left cuneus and lower betweenness centrality of the right rostral middle frontal gyrus were associated with increased drug load and younger age at onset, respectively. Conclusions These results indicate that the correlations between interregional variations of cortical thickness reflect disease characteristics or responses to the disease and deficits in patients with epilepsy with focal seizures., Highlights • Interregional cortical thicknesses relations reflect the severity of epilepsy • Stronger clustering is associated with more seizures in patients with epilepsy • Stronger clustering is associated with younger onset age in patients with epilepsy • Stronger clustering is associated with lower IQ in patients with epilepsy • Betweenness centrality is associated with drug load and age at onset

Objective: Shed light on cognitive deterioration in Accelerated Cognitive Ageing (ACA) in epilepsy from a neuropsychological point of view in order to improve clinical diagnostics. Methods: We compared the IQ-profile including GAI, OPIE IV-premorbid IQ and deterioration-scores of 21 epilepsy patients with ACA with 21 matched epilepsy patients without ACA (Epilepsy Controls) and 16 age- and education-matched Healthy Controls. Memory was also evaluated. Results: Premorbid IQs were equal in all groups. Deterioration was apparent in the ACA-group in the WAIS-IV FSIQ and PRI, whereas no deterioration was found in the two control groups. PSI was impaired in both epilepsy groups, though with more impairment seen in the ACA-group. The VCI remained unimpaired. The FSIQ-GAI discrepancy was equal in both patient groups and significantly larger than in the Healthy Controls. WMS-IV memory indices were of average level in all groups. Memory impairment in ACA was not statistically different from the Epilepsy Controls. 85.7% of ACA-patients could be correctly classified through factors DET_FSIQ and PSI. Conclusions: Cognitive deterioration in ACA is characterized by an average drop of 19 IQ-points in FSIQ and PRI. Verbal abilities remain unimpaired. Impairments in fluid functions compromise cognitive abilities in epilepsy, but only partially contribute to cognitive deterioration in ACA. PSI proved to have some diagnostic value in differentiating epilepsy patients from healthy controls, but fails to differentiate between ACA and Epilepsy Controls. A comparison made between OPIE-IV equations and obtained IQs leads to a significant better detection of cognitive deterioration in epilepsy than the use of GAI-FSIQ discrepancies alone.

Objective: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10 −9). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Pour les patients souffrant d'épilepsie, la survenue d'un accident de la circulation à cause d'une crise d'épilepsie est une problématique majeure. Afin de réduire le risque d'accident, la Commission de la circulation routière de la Ligue suisse contre l'épilepsie a publié des directives concernant la capacité de conduite d'un véhicule en cas d'épilepsie. Ces directives ont été modifiées, la dernière fois, en 2015. Selon elles, la durée de carence est différente selon la catégorie du véhicule concernée et l'origine de l'événement comitial (première crise provoquée ou non provoquée). Une évaluation approfondie après la survenue du premier épisode est obligatoire afin d‘éviter des restrictions inutilement prolongées. Les directives dont disponibles sur : www.epi.ch/wp-content/uploads/flyer-Epilepsie_fuehrerschein-licence-conduire-2016.pdf

Epileptogenesis is a multistage process and seizure susceptibility can be influenced by stress early in life. Wistar Audiogenic Rat (WAR) strain is an interesting model to study the association between stress and epilepsy, since it is naturally susceptible to seizures and present changes in the hypothalamus-pituitary-adrenal (HPA) axis activity. All these features are related to the pathogenic mechanisms usually associated with psychiatric comorbidities present in epilepsy. Therefore, the current study aimed to evaluate the neonate HPA axis function and maternal care under control and stress conditions in the WAR strain. Maternal behavior and neonate HPA axis were evaluated in Wistar and WAR strains under rest and after the presence of stressors. We observed that WAR pups present higher plasmatic corticosterone concentration as compared to Wistar pups. Although WAR dams do not show significant altered maternal behavior at rest, there is a higher latency to recover the litter in the pup retrieval test, while some did not recover all the litter. Wistar Audiogenic Rat dams presented similar behaviors to Wistar dams to a female intruder and maternal care with the pups in the maternal defense test. Taken together, these findings indicate that the WAR strain could show HPA axis disruption early in life and dams present altered maternal behavior under stressful events. Those alterations make the WAR strain an interesting model to evaluate vulnerability to epilepsy and its associated neuropsychiatric comorbidities.

ObjectiveTo develop and prospectively evaluate a method of epileptic seizure detection combining heart rate and movement.MethodsIn this multicenter, in-home, prospective, video-controlled cohort study, nocturnal seizures were detected by heart rate (photoplethysmography) or movement (3-D accelerometry) in persons with epilepsy and intellectual disability. Participants with >1 monthly major seizure wore a bracelet (Nightwatch) on the upper arm at night for 2 to 3 months. Major seizures were tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others, including clusters (>30 minutes) of short myoclonic/tonic seizures. The video of all events (alarms, nurse diaries) and 10% completely screened nights were reviewed to classify major (needing an alarm), minor (needing no alarm), or no seizure. Reliability was tested by interobserver agreement. We determined device performance, compared it to a bed sensor (Emfit), and evaluated the caregivers’ user experience.ResultsTwenty-eight of 34 admitted participants (1,826 nights, 809 major seizures) completed the study. Interobserver agreement (major/no major seizures) was 0.77 (95% confidence interval [CI] 0.65–0.89). Median sensitivity per participant amounted to 86% (95% CI 77%–93%); the false-negative alarm rate was 0.03 per night (95% CI 0.01–0.05); and the positive predictive value was 49% (95% CI 33%–64%). The multimodal sensor showed a better sensitivity than the bed sensor (n = 14, median difference 58%, 95% CI 39%–80%, p < 0.001). The caregivers' questionnaire (n = 33) indicated good sensor acceptance and usability according to 28 and 27 participants, respectively.ConclusionCombining heart rate and movement resulted in reliable detection of a broad range of nocturnal seizures.

Depression is relatively common among patients with epilepsy, but often with predominant atypical symptoms. Some antiepileptic drugs show positive psychotropic effects, but these are not always sufficient to stabilize mood in epilepsy patients. Antidepressants are recommended to treat atypical depression but are not always effective and present a certain risk of seizure provocation. Thus, new treatment options are welcome. Here, we describe three cases of refractory epilepsy with atypical depression in which olanzapine, contrary to its earlier reported proconvulsant effect, showed excellent antidepressant action and resulted in seizure control. Possible mechanisms of this action are discussed.

Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.\ud \ud Conclusion:\ud \ud Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Complex auditory hallucinations are often characterized by hearing voices and are then called auditory verbal hallucinations (AVHs). While AVHs have been extensively investigated in psychiatric patients suffering from schizophrenia, reports from neurological patients are rare and, in most cases, incomplete. Here, we characterize AVHs in 9 patients suffering from pharmacoresistant epilepsy by analyzing the phenomenology of AVHs and patients' neuropsychological and lesion profiles. From a cohort of 352 consecutively examined patients with epilepsy, 9 patients suffering AVHs were identified and studied by means of a semistructured interview, neuropsychological tests, and multimodal imaging, relying on a combination of functional and structural neuroimaging data and surface and intracranial EEG. We found that AVHs in patients with epilepsy were associated with prevalent language deficits and damage to posterior language areas and basal language areas in the left temporal cortex. Auditory verbal hallucinations, most of the times, consisted in hearing a single voice of the same gender and language as the patient and had specific spatial features, being, most of the times, perceived in the external space, contralateral to the lesion. We argue that the consistent location of AVHs in the contralesional external space, the prominence of associated language deficits, and the prevalence of lesions to the posterior temporal language areas characterize AVHs of neurological origin, distinguishing them from those of psychiatric origin.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter.AIMS: We investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic subtypes.METHODS: This study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1×1M Agilent). Clinical data were based on a parent interview and medical record review.RESULTS: All patients with AS based on a deletion had epilepsy. Epilepsy was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases. Laughter-induced postural muscle tone loss occurred only among deletion cases. We found no differences in severity of epilepsy between children with a larger Class I or a smaller Class II deletions, or between the total group with a deletion compared to children with pUPD or a UBE3A mutation. The drugs most frequently prescribed were benzodiazepines in monotherapy, or a combination of benzodiazepines and valproic acid.CONCLUSION: Epilepsy is very common in patients with AS, especially in patients with a deletion. Postural muscle tone loss and collapsing during outbursts of laughter were seen in patients with a deletion only.

To the Editor , We read with interest the recent paper by Bardai et al ,1 which reports that epilepsy and antiepileptic drugs (AEDs) were independently associated with sudden cardiac death (SCD). We are unconvinced that such a clear distinction between disease and drug effects can be made in this study as all people with epilepsy were by definition taking AEDs. We believe this is why SCD risk in those with epilepsy (table 2) and in AED users with epilepsy (table …

Pediatr Nephrol

Two cases of priapism recently experienced were repor t e d. Case 1, a 41-year-old male, had epilepsy and Case 2, a 35-year-old male, was suffering from chronic alcoholism, hence they were both diagnosed as neurogenic secondary priapism. Review of literatures made us interested in the excellent effectiveness of some proteolytic enzymes, among conservative therapeutic measures, for the treatment of the disease. Thus, a-kimotrypsin buccal tablets were given to Case 1 and combined oral tablets of streptokinase and streptodornase was given to Case 2, with which complete disappearance of priapism and recovery of normal potency were attained successfully in both cases. The proteolytic enzymes thus demonstrated their usefulness in the conserva t ive treatment of priapism, and it is desirable to use them as early as possible.

Bourneville-Pringle phacomatosis was seen in a 4-year-old boy with enlarged kidney on both sides. Laparotomy revealed polycystic kidneys. Two and a half years after operation, the patient showed the renal function unchanged, but he is unable to go to school because of increasing frequency of epileptic seizures and poor development of intelligence. From the social point of view, prognosis in this case is quite hopeless. Discussions were made on the renal abnormalities frequently associated with this disease based on about thirty cases reported in Japan.

Two cases of priapism recently experienced were repor t e d. Case 1, a 41-year-old male, had epilepsy and Case 2, a 35-year-old male, was suffering from chronic alcoholism, hence they were both diagnosed as neurogenic secondary priapism. Review of literatures made us interested in the excellent effectiveness of some proteolytic enzymes, among conservative therapeutic measures, for the treatment of the disease. Thus, a-kimotrypsin buccal tablets were given to Case 1 and combined oral tablets of streptokinase and streptodornase was given to Case 2, with which complete disappearance of priapism and recovery of normal potency were attained successfully in both cases. The proteolytic enzymes thus demonstrated their usefulness in the conserva t ive treatment of priapism, and it is desirable to use them as early as possible.