Different relationships between epilepsy syndromes and autoimmune diseases.

OBJECTIVE: Our objective was to study the relationship between epilepsy and autoimmune diseases in two different types of epilepsy: idiopathic generalized epilepsies (IGEs) and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). The contribution of the human leukocyte antigen (HLA) system to this relationship was analyzed. METHODS: Adult patients with IGEs and MTLE-HS at a tertiary epilepsy center were consecutively enrolled between January 2016 and December 2020. RESULTS: A total of 664 patients, 422 with IGEs and 242 with MTLE-HS, were included. Patients with IGEs were 15 years younger, on average, than patients with MTLE-HS (p < .001). The frequency of autoimmune diseases was 5.5% (n = 23) and 4.5% (n = 11) in patients with IGEs and MTLE-HS, respectively (p = .716). The mean age of autoimmune disease onset was 20 ± 15.6 years in patients with IGEs and 36.7 ± 16.5 years in patients with MTLE-HS (p < .05). Clinical manifestations of autoimmune diseases preceded epilepsy onset in 30.4% of patients with IGEs (i.e., in early childhood); in the other patients, epilepsy appeared before autoimmune disease onset. In all but one patient with MTLE-HS and autoimmune diseases, the autoimmune diseases appeared after epilepsy onset from adolescence onward. SIGNIFICANCE: Our study indicates two relationship patterns: a bidirectional association between IGEs and autoimmune diseases and a unidirectional relationship between MTLE-HS and autoimmune diseases. The involvement of genetic susceptibility factors (such as the HLA system), autoinflammatory mechanisms, female sex, and antiseizure medications in these relationships are discussed.

Effects of antiepileptic drugs on sleep architecture parameters in adults.

Objectives: Physiological and restorative sleep is fundamental for physical and mental well-being. Polysomnography parameters are objective methods to access sleep structure. Antiepileptic drugs (AEDs) are a group of drugs whose interference in the sleep structure is still not well known, especially in what concern the new ones. We did a systematic review of the literature to compare the effect of classic and newer AEDs on sleep architecture. Material and Methods: A search was performed in PubMed and Scopus, using keywords "sleep" and "antiepileptics", and each AED combined with "sleep". Only studies concerning objective measures were selected. Results: 63 articles were included, only 21 were randomized, controlled and double-blinded. Studies not only in epilepsy, but also in restless leg syndrome, bruxism, insomnia, fibromyalgia and obstructive sleep apnea were found. Among classic AEDs, carbamazepine has a negative effect on sleep while phenobarbitone has a slightly dose-dependent interference and is also the only one to reduce N3 stage. Valproic acid has little to no effect while clobazam and clonazepam have a positive effect. No conclusion can be drawn about phenytoin. All of them reduce REM stage. In the newer AEDs group gabapentine, lamotrigine, perampanel, pregabaline and tiagabine increase N3 sleep in best evidence. Lacosamide and zonisamide appear to be innocent while levetiracetam reduces REM sleep. Conclusion: Studies found used different methodologies not always addressing the analysis on the same parameters. In spite of these, newer AEDs have less effects on sleep structure when compared with classic AEDs but furthermore robust evidence is needed.

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis.

Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and Methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

Female preponderance in genetic generalized epilepsies.

INTRODUCTION: Epilepsy is more prevalent in men but Genetic Generalized Epilepsies (GGE) seem to be more common in women. A predominant maternal inheritance has been previously described in GGE. Our objective was to determine sex and inheritance patterns in a GGE population compared to mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS). METHODS: We performed a prospective observational study including adult GGE and MTLEHS patients followed up at a tertiary epilepsy center from January 2016 to December 2019. Patients' familial history was obtained by a detailed questionnaire. Clinical and demographic data was retrieved from clinical notes. RESULTS: A cohort of 641 patients, 403 with GGE and 238 with MTLEHS, was analyzed. GGE was more common in women than MTLEHS (58.8% vs 44.5%, OR=1.63, p = 0.004). Compared to MTLEHS patients, more GGE patients had familial history of epilepsy (45.4% vs 25.2%; p<0.001). The GGE group had a higher percentage of female relatives with epilepsy (55% vs 37%; p = 0.006). The prevalence of maternal inheritance was not different between GGE and MTLEHS groups (62.9% vs 57.7%; p = 0.596). Photosensitivity was more common in females than in males (44.7% vs 34.3%, p = 0.036). CONCLUSION: There is a female preponderance in GGE when compared to MTLEHS, as both GGE patients and their affected relatives are more frequently women. The prevalence of maternal inheritance was not higher in GGE than in MTLEHS.

New 2013 incidence peak in childhood narcolepsy: more than vaccination?

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

Immunogenetic protective factors in Genetic Generalized Epilepsy.

BACKGROUND: Genetic Generalized Epilepsies (GGEs) are a heterogeneous group of syndromes characterized by generalized seizure activity that affects both hemispheres, with mainly genetic causes. Neuroinflammation has been established as an important mechanism in epileptogenesis. The ability to develop an appropriated immune response is strongly determined by immunogenetic factors. In this setting, our aim was to evaluate potential associations between GGEs and immunogenetic factors. METHODS: The rs16944 (IL-1ß -511 T > C) polymorphism and the HLA-DRB1 locus were genotyped in a Portuguese GGE population. Association with two clinicopathological features, photosensitivity and refractoriness, was investigated. This case-control study included 323 GGE patients (187 F, 136 M, 34.0 ± 13.9 years of age), 145 of which with JME diagnosis (88 F, 57 M, 34.1 ± 14.0 years), and 282 healthy controls (174 F, 108 M, 37.7 ± 11.6 years). RESULTS: Decreased frequencies of the HLA-DRB1*09 and DRB1*13 alleles were observed in the GGE population. HLA-DRB1*07 frequency was increased in JME. Rs16944 allelic frequencies were similar between patients and controls. CONCLUSIONS: These results, not entirely consistent with previous reports, suggest that HLA molecules may have a complex role in epileptogenesis.

Apolipoprotein E isoforms and susceptibility to genetic generalized epilepsies.

Background: Apolipoprotein E (ApoE) is the main lipoprotein secreted in brain. It has a critical immunomodulatory function, influences neurotransmission and it is involved in repairing damaged neurons. ApoE e4 is an isoform of ApoE with altered function, and was previously associated with early onset epilepsy and refractoriness, both in animal models and in patients with focal epilepsies. There is a limited knowledge on ApoE's role in Genetic Generalized Epilepsies (GGE).Aim: To determine if ApoE isoforms are risk factors for GGE development.Methods: A group of 337 GGE patients (193 F, 144 M, 33.6 ± 14.2 years) was compared with a group of 342 healthy individuals in a case-control genetic association study. ApoE genotyping was performed using PCR-RFLP.Results: The genotypic frequency of ApoE e3/e2 was lower in GGE patients relative to controls (6.5% in GGE vs. 11.7% in controls, p = 0.019, OR (95% CI) = 0.53 (0.305-0.905). No associations with other clinical data such as photosensitivity or age at disease onset were observed.Conclusion: Our results show that ApoE e3/e2 genotype may be a protective factor for GGE development. There is evidence that this genotype could be neuroprotective, preventing oxidative damage and promoting neuronal survival. Although replication studies are warranted, our data suggest that ApoE isoforms have a role in epileptogenic mechanisms regardless of the specific epileptic manifestations.

Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro-inflammatory cytokines such as IL-1ß and TNF-α, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Expression of these cytokines can be modulated by polymorphisms such as rs16944 and rs1800629, respectively, both of which have been associated with febrile seizures (FS) and MTLE-HS development. The human leukocyte antigen (HLA) system has also been implicated in diverse epileptic entities, suggesting a variable role of this system in epilepsy. Our aim was to analyse the association between immunogenetic factors and MTLE-HS development. For that rs16944 (-511 T>C, IL-1ß), rs1800629 (-308 G>A, TNF-α) polymorphisms and HLA-DRB1 locus were genotyped in a Portuguese Population. METHODS: We studied 196 MTLE-HS patients (108 females, 88 males, 44.7 ± 12.0 years, age of onset = 13.6 ± 10.3 years, 104 with FS antecedents) and 282 healthy controls in a case-control study. RESULTS: The frequency of rs16944 TT genotype was higher in MTLE-HS patients compared to controls (14.9% in MTLE-HS vs. 7.7% in controls, p = 0.021, OR [95% CI] = 2.20 [1.13-4.30]). This association was independent of FS antecedents. No association was observed between rs1800629 genotypes or HLA-DRB1 alleles and MTLE-HS susceptibility. Also, no correlation was observed between the studied polymorphisms and disease age of onset. CONCLUSION: The rs16944 TT genotype is associated with MTLE-HS development what may be explained by the higher IL-1ß levels produced by this genotype. High IL-1ß levels may have neurotoxic effects or imbalance neurotransmission leading to seizures.

Brain expression of inflammatory mediators in Mesial Temporal Lobe Epilepsy patients.

Neuroinflammation may be central in epileptogenesis. In this study we analysed inflammatory reaction markers in brain tissue of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) patients. TLR4, IL-1ß and IL-10 gene expression as well as the presence of activated HLA-DR+ microglia was evaluated in 23 patients and 10 cadaveric controls. Inflammation characterized by the presence of HLA-DR+ microglia and TLR4, IL-1ß overexpression was evident in hippocampus and anterior temporal cortex of MTLE-HS patients. Anti-inflammatory IL-10 was also overexpressed in MTLE-HS patients. Our results show that hippocampal neuroinflammation extends beyond lesional limits, as far as the anterior temporal cortex.

Psychosocial factors as predictors of quality of life in chronic Portuguese patients.

BACKGROUND: Chronic illnesses are diseases of long duration and generally of slow progression. They cause significant quality of life impairment. The aim of this study was to analyse psychosocial predictors of quality of life and of subjective well-being in chronic Portuguese patients. METHODS: Chronic disease patients (n = 774) were recruited from central Portuguese Hospitals. Participants completed self-reported questionnaires assessing socio-demographic, clinical, psychosocial and outcome variables: quality of life (HRQL) and subjective well-being (SWB). MANCOVA analyses were used to test psychosocial factors as determinants of HRQL and SWB. RESULTS: After controlling for socio-demographic and clinical variables, results showed that dispositional optimism, positive affect, spirituality, social support and treatment adherence are significant predictors of HRQL and SWB. Similar predictors of quality of life, such as positive affect, treatment adherence and spirituality, were found for subgroups of disease classified by medical condition. CONCLUSIONS: The work identifies psychosocial factors associated with quality of life. The predictors for the entire group of different chronic diseases are similar to the ones found in different chronic disease subgroups: positive affect, social support, treatment adherence and spirituality. Patients with more positive affect, additional social support, an adequate treatment adherence and a feel-good spirituality, felt better with the disease conditions and consequently had a better quality of life. This study contributes to understanding and improving the processes associated with quality of life, which is relevant for health care providers and chronic diseases support.

Compliance to continuous positive airway pressure therapy in a group of Portuguese patients with obstructive sleep apnea syndrome.

INTRODUCTION: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an emerging public health concern. Although different treatments for OSAHS had been proposed, continuous positive airway pressure (CPAP) is the first-line treatment in moderate to serious OSAHS in which success can be achieved by increasing compliance to CPAP. MATERIALS AND METHODS: This study analyzes long-term CPAP compliance in patients with OSAHS on CPAP therapy for at least 1 month, who began CPAP therapy between January 2004 and December 2006, followed up at a Portuguese Sleep Outpatient Clinic in Santo António Hospital. Only effective data of CPAP use had been considered. During the first year of CPAP therapy, 96 patients were enrolled and followed up, but 15 patients had discontinued CPAP treatment. CPAP was used on average 5.1 h per day and in 80.1% of the total follow-up days. When compliance is defined as the use of CPAP for a minimum of 4 h per day in at least 70% of the follow-up days, only 54% of patients were classified as compliants during the first year. RESULTS AND CONCLUSION: No statistically significant differences were found throughout the first year (p > 0.05) in terms of the percentage of compliants, controlling for demographic and clinic variables. None of the demographic and clinical baseline variables studied were found to be significant predictor of CPAP compliance (p > 0.05). This study diagnosed a low compliance to CPAP therapy in the studied sample, warning to the need of developing further studies in this area and to the need of implementing strategies to increase CPAP compliance.

Task-specific contribution of the human striatum to perceptual-motor skill learning.

Acquisition of new perceptual-motor skills depends on multiple brain areas, including the striatum. However, the specific contribution of each structure to this type of learning is still poorly understood. Focusing on the striatum, we proposed (a) to replicate the finding of impaired rotary pursuit (RP) and preserved mirror tracing (MT) in Huntington's disease (HD); and (b) to further explore this putative learning dissociation with other human models of striatal dysfunction (i.e., Parkinson's disease and focal vascular damage) and two new paradigms (i.e., Geometric Figures, GF, and Control Stick, CS) of skill learning. Regardless of the etiology, participants with damage to the striatum showed impaired learning of visuomotor tracking skills (i.e., RP and GF), whereas the ability to learn skills that require motor adaptation (i.e., MT and CS) was not affected. These results suggest a task-specific involvement of the striatum in the early stages of skill learning.

Neuropsychological predictors of quality of life in focal epilepsy.

Spontaneous complaints of outpatients with focal epilepsy often stress the relationship between cognitive deficits and Quality of Life (QOL). Consequently, the aim of the present study was to find the best neuropsychological predictors of QOL in individuals with focal epilepsy, in order to guide their ambulatory health care. A sample of 71 Portuguese patients was studied: 40 female, 47 married, with a mean age of 37.48 years (S.D.=11.79, 16-62), mean education of 7.93 (S.D.=4.05, 3-17), and focal epilepsy of moderate severity. A Socio-demographic and Clinical Questionnaire, the SF-36 v1, the Cognitive Functioning Scale from the ESI-55, a Seizure Control scale (items from the Liverpool Seizure Severity Scale), and several neuropsychological tests were used. Semantic Fluency was the only predictor of Physical Functioning, Role Functioning - Physical, and Mental Health; I.A. Test predicted Bodily Pain; and Attentive Matrices predicted General Health, Vitality, and Role Functioning - Emotional. The Mental Component of the SF-36 v1 was predicted by Attentive Matrices, and the Physical Component was predicted by Semantic Fluency. Cognitive Functioning was predicted by the Token Test. Social Functioning and Seizure Control presented no statistically significant correlation with the neuropsychological indicators used. These results underscore the importance of cognitive performance to the QOL of individuals with focal epilepsy, supporting the systematic screening of cognitive performance in this population. Additionally, they suggest cognitive rehabilitation has the potential to improve these individuals' QOL.

The contribution of spirituality to quality of life in focal epilepsy.

People with epilepsy of comparable severity may differ widely in quality of life (QOL), suggesting a role for unexplored individual aspects. This study considered the possible role of spirituality. Thirty-two patients with focal epilepsy completed scales for QOL (World Heath Organization QOL, WHOQOL 100), spirituality (WHO Spirituality, Religiousness, and Personal Beliefs), depression, anxiety, and cognitive efficiency, as well as neuropsychological testing. The QOL and spirituality scales exhibited satisfactory internal consistency. Factor analyses of the scale and test scores yielded separate spiritual (Personal Meaning, Inner Energy, Awe and Transcendence, and Openness), affective (Mood), and cognitive (Cognition, Memory, and Perceived Cognitive Efficiency) factors. The total WHOQOL 100 score was significantly predicted by the Awe and Transcendence and Mood factors. The spiritual, Mood, and Cognition factors significantly predicted single QOL domains. These preliminary results highlight the contribution of spirituality to QOL in epilepsy, encouraging future studies. This could influence the conceptualization and assessment of QOL in these patients.

What does an epileptiform spike look like in MEG? Comparison between coincident EEG and MEG spikes.

Recent investigations suggest that there are differences between the characteristics of EEG and MEG epileptiform spikes. The authors performed an objective characterization of the morphology of epileptiform spikes recorded simultaneously in both EEG and MEG to determine whether they present the same morphologic characteristics. Based on a stepwise approach, the authors performed a computer analysis of EEG and MEG of a set of coincident epileptiform transients selected by a senior clinical neurophysiologist in recordings of three patients with drug-resistant epilepsy. A computer-based algorithm was applied to extract parameters that could be used to describe quantitatively the morphology of the transients, followed by a statistical comparison over the extracted metrics of the EEG and MEG waveforms. EEG and MEG coincident events were statistically different with respect to several morphologic characteristics, such as duration, sharpness, and shape. The differences found appear to be a consequence of MEG signals not being influenced by volume propagation through the tissues with different conductivities that surround the brain, compared with EEG, and of the different orientation of the underlying dipolar sources. The results indicate that visual inspection of MEG spikes and automatic spike-detector algorithms should use criteria adapted to the specific characteristics of the MEG, and not simply those used on conventional EEG.