Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies

Summary Background De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. Findings We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. Interpretation Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. Funding DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation ‘no epilep’ (Germany)

Diagnosis of comorbid migraine without aura in patients with idiopathic/genetic epilepsy based on the gray zone approach to the International Classification of Headache Disorders 3 criteria

BackgroundMigraine without aura (MwoA) is a very frequent and remarkable comorbidity in patients with idiopathic/genetic epilepsy (I/GE). Frequently in clinical practice, diagnosis of MwoA may be challenging despite the guidance of current diagnostic criteria of the International Classification of Headache Disorders 3 (ICHD-3). In this study, we aimed to disclose the diagnostic gaps in the diagnosis of comorbid MwoA, using a zone concept, in patients with I/GEs with headaches who were diagnosed by an experienced headache expert.MethodsIn this multicenter study including 809 consecutive patients with a diagnosis of I/GE with or without headache, 163 patients who were diagnosed by an experienced headache expert as having a comorbid MwoA were reevaluated. Eligible patients were divided into three subgroups, namely, full diagnosis, zone I, and zone II according to their status of fulfilling the ICHD-3 criteria. A Classification and Regression Tree (CART) analysis was performed to bring out the meaningful predictors when evaluating patients with I/GEs for MwoA comorbidity, using the variables that were significant in the univariate analysis.ResultsLonger headache duration (<4 h) followed by throbbing pain, higher visual analog scale (VAS) scores, increase of pain by physical activity, nausea/vomiting, and photophobia and/or phonophobia are the main distinguishing clinical characteristics of comorbid MwoA in patients with I/GE, for being classified in the full diagnosis group. Despite being not a part of the main ICHD-3 criteria, the presence of associated symptoms mainly osmophobia and also vertigo/dizziness had the distinguishing capability of being classified into zone subgroups. The most common epilepsy syndromes fulfilling full diagnosis criteria (n = 62) in the CART analysis were 48.39% Juvenile myoclonic epilepsy followed by 25.81% epilepsy with generalized tonic-clonic seizures alone.ConclusionLonger headache duration, throbbing pain, increase of pain by physical activity, photophobia and/or phonophobia, presence of vertigo/dizziness, osmophobia, and higher VAS scores are the main supportive associated factors when applying the ICHD-3 criteria for the comorbid MwoA diagnosis in patients with I/GEs. Evaluating these characteristics could be helpful to close the diagnostic gaps in everyday clinical practice and fasten the diagnostic process of comorbid MwoA in patients with I/GEs

Current Views on the Use of Valproic Acid in Women

WOS: 000474456600002Vaiproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs for idiopathic generalized epilepsy, chronic or migraine headache, and bipolar disorder; however concerns about teratogenic effects have resulted in limited usage of the drug in women of childbearing potential. The aim of this review was to assess the current status of recommendations for the use of VPA according to international drug commissions and other recent reports

Evaluation of the effects of shift work on parasomnia prevalence

Shift work is increasingly common in industrialized countries but is associated with numerous health problems, especially sleep disorders. This study compared the frequency of NREM (confusional arousal, sleep terrors, sleepwalking, sleep-related eating disorder), REM parasomnias (REM sleep behavior disorder, nightmare disorder), and isolated symptoms/normal variants (sleeptalking) between shift workers and daytime workers. A total of 1473 participants in 3 different professional groups and working different shift schedules (daytime, night, or rotating shifts) were included. Participants completed a questionnaire consisting of 132 questions about parasomnia, occupational stress, history of occupational and traffic accidents, depression, and other sleep disorders. The lifetime parasomnia prevalence was 43.7% and the 1-year parasomnia prevalence was 24.4% overall. The 1-year parasomnia prevalence was 27.5% among shift workers and 13% among daytime workers. This rate was highest among rotating shift workers (27.9%), followed by night shift workers (21.2%), and lowest in daytime workers (13%) (P < .001). The most common parasomnias reported were sleep terrors, confusional arousals, and sleeptalking. Parasomnia prevalence rates among workers with and without a history of occupational accidents were 43.7% and 24.2%, while those of workers with and without a history of car accidents were 47.4% and 23.8%, respectively (P < .001). Shift work was associated with higher parasomnia prevalence. Working rotating shifts in particular was an independent risk factor for parasomnia. The parasomnias most frequently associated with shift work were confusional arousal, sleeptalking, and sleep terrors. It should be kept in mind that higher parasomnia rates may increase the risk of occupational and traffic accidents in this population

The Effect of Lacosamide Polytherapy on Seizure Prognosis in Focal Epilepsies

Objectives:What is expected from anti-epileptic treatment is low side effects and drug-drug interactions as well as high efficacy. In this study, the efficacy of lacosamide in polytherapy and its effect on prognosis were evaluated.Methods:Seventy-seven patients with focal epilepsy who were followed up for at least 1 year and using lacosamide were included in the study. The antiepileptic drugs they use, the side effects of the drugs, neuroimaging and electrophysiological examinations were evaluated.Results:A total of 77 patients, including 35 women (44.9%) and 42 men (55.1%), were included in the study. The mean age was 33.9±10.6 (min: 19 max: 67). Average age of seizure onset was 12.6±10.7, and none of the patients were using Lacosamide (LKS) as monotherapy. Although only 3 patients were receiving dual therapy, the remaining 74 patients were receiving 3 or more antiepileptic treatments. While 33 of the patients (42.9%) had a decrease in the frequency of seizures after LKS treatment.Conclusion:Although the percentage of efficacy was obtained as low according to literature information, lacosamide is effective in resistant focal epilepsies with an efficiency of 42.9%. Especially in patients who use drugs other than antiepileptic drugs due to comorbid diseases, the absence of drug-drug interaction and the absence of serious side effects that require termination of treatment may be an indication that it can be used safely

Frequency and economic burden of psychogenic non-epileptic seizures in patients applying for disability benefits due to epilepsy

Background Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures and are often misdiagnosed as epilepsy. Objective To investigate the frequency of PNES and to calculate the economic burden of the patients who admitted to video-electroencephalographicmonitoring (VEM) to obtain a diagnosis of epilepsy in order to apply for disability retirement. Methods The present retrospective study included 134 patients who required disability reports between 2013 and 2019 and had their definite diagnoses after VEM. Following VEM, the patients were divided into three groups: epilepsy, PNES, and epilepsy + PNES. Results In total, 22.4% (n = 30) of the patients were diagnosed with PNES, 21.6% (n = 29) with PNES and epilepsy, and 56% (n = 75), with epilepsy. The frequency of PNES among all patients was of 44% (n = 59). In patients with PNES alone, the annual cost of using anti-seizure medication was of 160.67 ± 94.04 dollars; for psychostimulant drugs, it was of 148.3 ± 72.48 dollars a year; and the mean direct cost for diagnostic procedures was of 582.9 ± 330.0 (range: 103.52–1601.3) dollars. Conclusions Although it is challenging to determine the qualitative and quantitative total cost in these patient groups, early diagnosis and sociopsychological support will reduce the additional financial burden on the health system and increase the quality of life of the patients

Sleep Disturbance in Systemic Sclerosis and the Associations Between Sleep and Pulmonary Hypertension: A Pilot Study

Objective: Major differences in sleep architecture are observed in patients with systemic sclerosis (SSc). The aim of this study was to investigate the sleep pattern and frequency of obstructive sleep apnea (OSA) in patients with SSc, and compare sleep patterns in patients with and without pulmonary hypertension (PH). Materials and Methods: Patients with SSc and symptoms of hypersomnia or insomnia who underwent polysomnography examinations were evaluated. The clinical data of patients were obtained from the patient files. The subjects were separated into two groups (PH-positive and PH-negative). OSA was defined as an apnea-hypopnea index (AHI) ≥5. Sleep parameters were evaluated between the groups. Results: Thirty-six patients with SSc (88.9% females; mean age: 53.1±11.2 years), 27 with diffuse SSc, and 9 with limited-type SSc were enrolled in the study. Approximately 30.6% of the patients with SSc had AHI ≥5 and 13.9% of patients had AHI ≥15. Eight patients with SSc (22.2%) had a periodic leg movement index (PMLI) above 5/h. The percentages of patients with AHI ≥5 and AHI ≥15 were 25.9% and 7.4% in the PH-negative group and 44.4% and 33.3% in the PH-positive group, respectively. The duration of the rapid eye movement sleep stage was significantly shorter in patients with SSc and PH than in those without PH (p=0.02). The percentages of patients with PMLI >5/h were 14.8% in the PH-negative group and 44.4% in the PH-positive group (p=0.086). Conclusion: Sleep disorders are more commonly observed in patients with SSc. Furthermore, OSA and PH are associated with SSc

The REM-sleep-related characteristics of narcolepsy: a nation-wide multicenter study in Turkey, the REMCON study

Introduction: Narcolepsy type 1 (NT1) is caused by hypocretin deficiency, the pathophysiology of narcolepsy type 2 (NT2) has not been delineated. Except for the hypocretin deficiency and cataplexy, all clinical and laboratory features used in the diagnosis of NT2 are identical to those used for NT1. The aim of this study was to assess the rapid eye movement (REM) sleep-related characteristics in the patients with narcolepsy; the characteristics of REM sleep in polysomnography (PSG) and multiple sleep latency test (MSLT) recordings, the quantification of REM sleep without atonia (RSWA) and atonia index, and the analysis of rapid eye movements (REMs) during REM sleep

Exploring shared triggers and potential etiopathogenesis between migraine and idiopathic/genetic epilepsy: Insights from a multicenter tertiary-based study

Introduction: Migraine and epilepsy are two episodic disorders that share common pathophysiological mechanisms. The aim of our research was to assess the possible shared etiopathogenesis by analyzing the relations of headache, and seizure triggers, based on information obtained from a national cohort surveying the headache characteristics of 809 patients who had been diagnosed with idiopathic/genetic epilepsy. Material and methods: Our study utilized data from a multi-center, nationwide investigation of headaches in 809 patients with idiopathic/genetic epilepsy. Out of these, 508 patients reported complaints related to any type of headache (333 Migraines, 175 Headaches of other types). In the initial phase of the study encompassing the entire sample of 809 epilepsy patients, differences in seizure triggers were assessed between the migraine group (n = 333) and the non-migraine group (n = 476). Additionally, the subsequent part of the study pertains to a subgroup of the entire patient group, namely those affected by all types of headaches (n = 508), and differences in headache triggers were assessed among migraine patients (n = 333) and those with other types of headaches (n = 175). Similar differences were observed between epilepsy patients with and without a family history of epilepsy. Results: The most frequently reported seizure triggers in all I/GE group (n = 809) were stress (23%), sleep deprivation (22%) and fatigue (18%), respectively. The most frequently reported headache triggers in migraine patients were stress (31%), sleep deprivation (28%), and noise (26%). The occurrence of menstruation-triggered seizures in individuals with migraine and I/GE was found to be considerably higher than those without migraine. The most common triggers for seizure and headache among the individuals with a positive family history of epilepsy were determined to be light stimuli and sleep deprivation. Conclusion: In conclusion, our study provides valuable insights into the overlapping triggers including sleep patterns, stress levels, and menstrual cycles, etc. and potential shared etiology of migraine and I/GE. Recognizing these connections may facilitate the development of more precise therapeutic strategies and underscore the significance of adopting a holistic, multidisciplinary approach to the management of these intricate neurological conditions. Further research is essential to explore in greater depth the shared mechanisms underpinning these associations and their implications for clinical practice

Headache in idiopathic/genetic epilepsy: Cluster analysis in a large cohort

Objective The link between headache and epilepsy is more prominent in patients with idiopathic/genetic epilepsy (I/GE). We aimed to investigate the prevalence of headache and to cluster patients with regard to their headache and epilepsy features. Methods Patients aged 6-40 years, with a definite diagnosis of I/GE, were consecutively enrolled. The patients were interviewed using standardized epilepsy and headache questionnaires, and their headache characteristics were investigated by experts in headache. Demographic and clinical variables were analyzed, and patients were clustered according to their epilepsy and headache characteristics using an unsupervised K-means algorithm. Results Among 809 patients, 508 (62.8%) reported having any type of headache; 87.4% had interictal headache, and 41.2% had migraine. Cluster analysis revealed two distinct groups for both adults and children/adolescents. In adults, subjects having a family history of headache, >= 5 headache attacks, duration of headache >= 24 months, headaches lasting >= 1 h, and visual analog scale scores > 5 were grouped in one cluster, and subjects with juvenile myoclonic epilepsy (JME), myoclonic seizures, and generalized tonic-clonic seizures (GTCS) were clustered in this group (Cluster 1). Self-limited epilepsy with centrotemporal spikes and epilepsy with GTCS alone were clustered in Cluster 2 with the opposite characteristics. For children/adolescents, the same features as in adult Cluster 1 were clustered in a separate group, except for the presence of JME syndrome and GTCS alone as a seizure type. Focal seizures were clustered in another group with the opposite characteristics. In the entire group, the model revealed an additional cluster, including patients with the syndrome of GTCS alone (50.51%), with >= 5 attacks, headache lasting >4 h, and throbbing headache; 65.66% of patients had a family history of headache in this third cluster (n = 99). Significance Patients with I/GE can be clustered into distinct groups according to headache features along with seizures. Our findings may help in management and planning for future studies