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Aim. This paper is a report of part of a study to investigate the burden experienced by families giving care to a relative with dementia, the consequences of care for the mental health of the primary caregiver and the strategies families use to cope with the care giving stressors. Background. The cost of caring for people with dementia is enormous, both monetary and psychological. Partners, relatives and friends who take care of patients experience emotional, physical and financial stress, and care giving demands are central to decisions on patient institutionalization. Method. A volunteer sample of 172 caregiver/care recipient dyads participated in the study in Cyprus in 2004-2005. All patients were suffering from probable Alzheimer's type dementia and were recruited from neurology clinics. Data were collected using the Memory and Behaviour Problem Checklist, Burden Interview, Center for Epidemiological Studies-Depression scale and Ways of Coping Questionnaire. Findings. The results showed that 68.02% of caregivers were highly burdened and 65% exhibited depressive symptoms. Burden was related to patient psychopathology and caregiver sex, income and level of education. There was no statistically significant difference in level of burden or depression when patients lived in the community or in institutions. High scores in the burden scale were associated with use of emotional- focused coping strategies, while less burdened relatives used more problemsolving approaches to care-giving demands. Conclusion. Caregivers, especially women, need individualized, specific training in how to understand and manage the behaviour of relatives with dementia and how to cope with their own feelings. [ABSTRACT FROM AUTHOR]

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Purpose: Amyloid-β (Aβ) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aβ antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood-brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device., Methods: The initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD. Pulsed FUS was applied using a single-element FUS transducer of 1 MHz (80 mm radius of curvature and 50 mm diameter). The success and extent of BBBD were assessed by Evans Blue extravasation and brain damage by hematoxylin and eosin staining. 5XFAD mice were divided into different subgroups; control (n = 1), FUS + MBs alone (n = 5), antibody alone (n = 5), and FUS + antibody combined (n = 10). The changes in antibody deposition among groups were determined by immunohistochemistry., Results: It was confirmed that the antibody could not normally enter the brain parenchyma. A single treatment with MBs-enhanced pulsed FUS using the optimized protocol (1 MHz, 0.5 MPa in-situ pressure, 10 ms bursts, 1% duty factor, 100 s duration) transiently disrupted the BBB allowing for non-invasive antibody delivery to amyloid plaques within the sonicated brain regions. This was consistently reproduced in ten mice., Conclusion: These preliminary findings should be confirmed by longer-term studies examining the antibody effects on plaque clearance and cognitive benefit to hold promise for developing disease-modifying anti-Aβ therapeutics for clinical use., (© 2023. The Author(s).)

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in Cx32 mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.

Background and Objectives: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants., Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes., Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms., Discussion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K V 3.2 in the regulation of brain excitability., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nicolaou, Tanteles, Votsi, Zamba-Papanicolaou, Papacostas, Christodoulou and Christou.)

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3 , DLK1 , KISS1 , and KISS1R genes were investigated in patients with CPP., Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative ( n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed., Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP., Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neocleous, Fanis, Toumba, Gorka, Kousiappa, Tanteles, Iasonides, Nicolaides, Christou, Michailidou, Nicolaou, Papacostas, Christoforidis, Kyriakou, Vlachakis, Skordis and Phylactou.)

Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyte-oligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aβ deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyte-astrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aβ toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation., (Copyright © 2020 Angeli, Kousiappa, Stavrou, Sargiannidou, Georgiou, Papacostas and Kleopa.)

Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia., Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied., Results: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14) , in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia., Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives., (Copyright © 2020 Stefani, Kousiappa, Nicolaou, Papathanasiou, Oulas, Fanis, Neocleous, Phylactou, Spyrou and Papacostas.)

Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least three decades. To this end, the most common approach has been to consider short-length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long-duration scalp EEG data (21-94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network-based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder affecting a substantial proportion of the elderly Cypriot population. The objective of this study was to evaluate PD risk variants that have been identified previously in Genome Wide Association Studies (GWAS) and to find environmental factors that are predictors for PD onset in the Cypriot population. Methods: A case-control study was conducted with a total of 235 PD patients and 464 healthy controls of Greek-Cypriot ethnicity. Demographic and lifestyle characteristics, exposure to PD risk factors and clinical data were collected. Moreover, 13 previously GWAS-identified PD risk variants were genotyped. Univariate and multivariate regression analyses examined the association between a number of environmental and genetic factors and PD. Results: Multivariable regression analysis revealed that exposure to both pesticides and other toxic substances ( P = 0.03), severe head injury accompanied with fainting ( P = 0.001), nuts consumption ( P = 0.004), red meat consumption ( P = 0.02), and soft drinks consumption ( P = 0.008) were increasing the risk for PD, whereas cumulative smoking ( P = 0.02), and fish consumption ( P = 0.02) were decreasing the risk for PD. Five out of the 13 tested SNPs (rs12185268, rs6599389, rs356220, rs13312, and rs17649553) were confirmed to be nominally significantly associated ( P < 0.05) with PD risk in the Cypriot population. Conclusions: Collectively, this case-control study has shed some light on the nature of PD epidemiology in Cyprus, by demonstrating a number of genetic and environmental determinants of PD in the Cypriot population., (Copyright © 2019 Georgiou, Demetriou, Christou, Heraclides, Leonidou, Loukaides, Yiasoumi, Pantziaris, Kleopa, Papacostas, Loizidou, Hadjisavvas and Zamba-Papanicolaou.)

Background and Purpose: Progressive multifocal leukoencephalopathy (PML) is a debilitating disease of the central nervous system caused by the ubiquitous polyomavirus JC (JCV) in immunocompromised hosts. In recent years, a new subpopulation of patients at risk for PML has emerged, due to the growing use of immunomodulatory or immunosuppressive therapies in autoimmune diseases such as multiple sclerosis (MS). The anti-JCV antibody index is used as a stratification tool in assessing the risk of developing PML. The objective of this study was to retrospectively describe the prevalence of anti-JCV antibodies in the MS population in Cyprus., Methods: We retrospectively collected the demographics of 214 MS patients in Cyprus who were screened for anti-JCV antibodies using the STRATIFY JCV™ assay between September 2011 and June 2018. Logistic regression analysis was used to examine the effect of demographic variables on seropositivity, and bivariate tests were used to assess the association between demographic characteristics and JCV AI index., Results: A total of 214 MS patients in Cyprus were tested. Overall anti-JCV antibody prevalence was 45.8% (95% confidence interval 37.2%-55.8%). We could not establish a significant association between seropositivity and increasing age or sex. In the subgroup analysis of natalizumab-treated patients, the annual seroconversion rate was 4.5%., Conclusions: Overall seroprevalence of anti-JCV antibodies in MS patients in Cyprus using the STRATIFY JCV assay was lower than the worldwide reported mean. Although previously reported, in our study, the anti-JCV antibody seropositivity was not associated with increasing age or sex., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper.

This research investigates the chronic effect of moderate to severe traumatic brain injury on brain white matter integrity, as reflected by diffusion tensor imaging metrics, and the assessment of their correlation to neuropsychological response. Thirteen male participants with traumatic brain injury (8.4 years average post-injury time) were compared to a matched group of neurologically healthy controls. None of the traumatic brain injury subjects had received post-acute neurocognitive and/or neuropsychological rehabilitation. Between-group comparison of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity was performed for the whole brain and corpus callosum. An extensive battery of visual and verbal memory tasks was employed for the comparative assessment of neurocognitive performance. Between-group and within-group performance differences were correlated with fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity of corpus callosum. Significant changes in global fractional anisotropy, mean diffusivity, and radial diffusivity were associated with traumatic brain injury. Visual memory capacity was reduced in traumatic brain injury, and this deficit was correlated to white matter integrity loss at the corpus callosum. Participants with traumatic brain injury underperformed controls in verbal memory as well, but no correlation with corpus callosum diffusion tensor imaging properties was established. Between-group performance difference was correlated with corpus callosum diffusion metrics in several tasks. Significant correlations were found between corpus callosum diffusion tensor imaging metrics and neuropsychological response within the traumatic brain injury group. Changes in whole brain and corpus callosum diffusion tensor metrics inflicted by moderate to severe traumatic brain injury are still evident several years post-injury and relate to neurocognitive impairment, while loss of white matter integrity seems to correlate with episodic and working memory impairment., Competing Interests: The authors declare no competing interests., (©2019 Yiannakkaras et al. Published by IMR press. All rights reserved.)

It is well-established that both volume conduction and the choice of recording reference (montage) affect the correlation measures obtained from scalp EEG, both in the time and frequency domains. As a result, a number of correlation measures have been proposed aiming to reduce these effects. In our previous work, we have showed that scalp-EEG based functional brain networks in patients with epilepsy exhibit clear periodic patterns at different time scales and that these patterns are strongly correlated to seizure onset, particularly at shorter time scales (around 3 and 5 h), which has important clinical implications. In the present work, we use the same long-duration clinical scalp EEG data (multiple days) to investigate the extent to which the aforementioned results are affected by the choice of reference choice and correlation measure, by considering several widely used montages as well as correlation metrics that are differentially sensitive to the effects of volume conduction. Specifically, we compare two standard and commonly used linear correlation measures, cross-correlation in the time domain, and coherence in the frequency domain, with measures that account for zero-lag correlations: corrected cross-correlation, imaginary coherence, phase lag index, and weighted phase lag index. We show that the graphs constructed with corrected cross-correlation and WPLI are more stable across different choices of reference. Also, we demonstrate that all the examined correlation measures revealed similar periodic patterns in the obtained graph measures when the bipolar and common reference (Cz) montage were used. This includes circadian-related periodicities (e.g., a clear increase in connectivity during sleep periods as compared to awake periods), as well as periodicities at shorter time scales (around 3 and 5 h). On the other hand, these results were affected to a large degree when the average reference montage was used in combination with standard cross-correlation, coherence, imaginary coherence, and PLI, which is likely due to the low number of electrodes and inadequate electrode coverage of the scalp. Finally, we demonstrate that the correlation between seizure onset and the brain network periodicities is preserved when corrected cross-correlation and WPLI were used for all the examined montages. This suggests that, even in the standard clinical setting of EEG recording in epilepsy where only a limited number of scalp EEG measurements are available, graph-theoretic quantification of periodic patterns using appropriate montage, and correlation measures corrected for volume conduction provides useful insights into seizure onset.

Objective: The aim of this study was to examine the effects of experiential avoidance (EA) on the indirect relationship of chronic pain patients' illness representations to pain interference, through pain catastrophising Design and main outcome measure: The sample consisted of 162 patients diagnosed with an arthritis-related or a musculoskeletal disorder. The effects of EA on the pathway between illness representations, pain catastrophising and pain interference were examined with PROCESS, a computational tool for SPSS Results: After controlling for patient and illness-related variables and pain severity, the 'illness representations-pain catastrophising-pain interference' pathway was interrupted at the higher levels of EA. The reason was that, at the high levels of EA, either the relation of illness representations to pain catastrophising or the relation of pain catastrophising to pain interference was not statistically significant., Conclusion: The findings indicate that EA is not a generalised negative response to highly aversive conditions, at least as far as the factors examined in this study are concerned. EA may rather reflect a coping reaction, the impact of which depends on its specific interactions with the other aspects of the self-regulation mechanism. At least in chronic pain, EA should become the focus of potential intervention only when its interaction with the illness-related self-regulation mechanism results in negative outcomes.

Objective: This paper proposes supervised and unsupervised algorithms for automatic muscle artifact detection and removal from long-term EEG recordings, which combine canonical correlation analysis (CCA) and wavelets with random forests (RF)., Methods: The proposed algorithms first perform CCA and continuous wavelet transform of the canonical components to generate a number of features which include component autocorrelation values and wavelet coefficient magnitude values. A subset of the most important features is subsequently selected using RF and labelled observations (supervised case) or synthetic data constructed from the original observations (unsupervised case). The proposed algorithms are evaluated using realistic simulation data as well as 30min epochs of non-invasive EEG recordings obtained from ten patients with epilepsy., Results: We assessed the performance of the proposed algorithms using classification performance and goodness-of-fit values for noisy and noise-free signal windows. In the simulation study, where the ground truth was known, the proposed algorithms yielded almost perfect performance. In the case of experimental data, where expert marking was performed, the results suggest that both the supervised and unsupervised algorithm versions were able to remove artifacts without affecting noise-free channels considerably, outperforming standard CCA, independent component analysis (ICA) and Lagged Auto-Mutual Information Clustering (LAMIC)., Conclusion: The proposed algorithms achieved excellent performance for both simulation and experimental data. Importantly, for the first time to our knowledge, we were able to perform entirely unsupervised artifact removal, i.e. without using already marked noisy data segments, achieving performance that is comparable to the supervised case., Significance: Overall, the results suggest that the proposed algorithms yield significant future potential for improving EEG signal quality in research or clinical settings without the need for marking by expert neurophysiologists, EMG signal recording and user visual inspection., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We investigated the correlation of epileptic seizure onset times with long term EEG functional brain network properties. To do so, we constructed binary functional brain networks from long-term, multichannel electroencephalographic data recorded from nine patients with epilepsy. The corresponding network properties were quantified using the average network degree. It was found that the network degree (as well as other network properties such as the network efficiency and clustering coefficient) exhibited large fluctuations over time; however, it also exhibited specific periodic temporal structure over different time scales (1.5hr-24hr periods) that was consistent across subjects. We investigated the correlation of the phases of these network periodicities with the seizure onset by using circular statistics. The results showed that the instantaneous phases of the 3.5hr, 5.5hr, 12hr and 24hr network degree periodic components are not uniformly distributed, suggesting that functional network properties are related to seizure generation and occurrence.

Objectives: Characterize the scale and pattern of long-term atrophy in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in chronic moderate-severe traumatic brain injury (TBI) and its relationship to neurocognitive outcomes., Participants: The TBI group consisted of 17 males with primary diagnosis of moderate-severe closed head injury. Participants had not received any systematic, post-acute rehabilitation and were recruited on average 8.36 years post-injury. The control group consisted of 15 males matched on age and education., Main Measures: Neurocognitive battery included widely used tests of verbal memory, visual memory, executive functioning, and attention/organization. GM, WM, and CSF volumes were calculated from segmented T1-weighted anatomical MR images. Voxel-based morphometry was employed to identify brain regions with differences in GM and WM between TBI and control groups., Results: Chronic TBI results in significant neurocognitive impairments, and significant loss of GM and WM volume, and significant increase in CSF volume. Brain atrophy is not widespread, but it is rather distributed in a fronto-thalamic network. The extent of volume loss is predictive of performance on the neurocognitive tests., Conclusion: Significant brain atrophy and associated neurocognitive impairments during the chronic stages of TBI support the notion that TBI results in a chronic condition with lifelong implications.

Background: Sudden unexpected death in epilepsy (SUDEP) affects 0.09-9.3 per 1,000 person-years depending on the population studied and constitutes the most common cause of death in people with epilepsy. The purpose of this study was to analyze epidemiological data of patients with SUDEP, identify possible risk factors in the population of a tertiary referral center and provide a review of the literature aiming to raise awareness of this phenomenon., Methods: Data for this study originate from the records of the Cyprus Institute of Neurology and Genetics in Nicosia Cyprus. We performed a systematic review of patients with epilepsy who had died between 1997 and 2012 and identified those whose death circumstances met the definition of SUDEP. Information was collected regarding sex, age, type of seizures, anti-epileptic therapies, and circumstances of death. Ethical approval was obtained from the institutional medical ethics committee., Results: Four hundred and forty four new patients were diagnosed with epilepsy among referrals to the epilepsy clinic and were followed to the end of the study period. Seven patients, six males, were identified who met criteria for SUDEP. The average age was 30 years. All patients had had either primary or secondary tonic-clonic seizures. Most were on polypharmacy, and two had Vagus Nerve Stimulation implanted. Most deaths were unwitnessed and nocturnal. The overall incidence rate for SUDEP in this population was 2.13 deaths/1000 person-years. Overall Cumulative Incidence (or lifetime risk) was calculated at 15.76 SUDEP deaths/1,000 patients., Conclusions: In our series, SUDEP was primarily a nocturnal and unwitnessed event that affected primarily young males. Among both males and females patients, 36.8% of all deaths were due to SUDEP. The major risk factor identified was the occurrence of generalized tonic-clonic seizures signifying that every effort should be made to control this type of seizures. Hippokratia 2015; 19 (4): 338-343.

Two cases with partial onset epilepsy who developed status epilepticus (SE) on lacosamide (LCM) monotherapy are reported. LCM is an effective adjunctive antiepileptic drug (AED) for partial-onset epilepsy and as infusion in SE. It has also shown efficacy in monotherapy. The reported cases achieved control of seizures with adjunctive LCM treatment and were afterwards converted to monotherapy. Both patients subsequently developed SE while on LCM monotherapy. They were on monotherapy for at least 2 months after withdrawal of concomitant AEDs precluding the possibility of withdrawal-induced SE. Pharmacovigilance is indicated when LCM is administered in monotherapy in order to assess its proper therapeutic potential and its putative limitations especially in cases where it may prove ineffective. Moreover, vigilance is necessary whenever any concomitant antiepileptic is tapered regardless of the substances used. Higher doses may be needed when an AED is used in monotherapy., (2015 BMJ Publishing Group Ltd.)

We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes.

Automatic detection and removal of muscle artifacts plays an important role in long-term scalp electroencephalography (EEG) monitoring, and muscle artifact detection algorithms have been intensively investigated. This paper proposes an algorithm for automatic muscle artifacts detection and removal using canonical correlation analysis (CCA) and wavelet transform (WT) in epochs from long-term EEG recordings. The proposed method first performs CCA analysis and then conducts wavelet decomposition on the canonical components within a specific frequency range and selects a subset of the wavelet coefficients for subsequent processing. A set of features, including the mean of wavelet coefficients and the canonical component autocorrelation values, are extracted from the above analysis and subsequently used as input in a random forest (RF) classifier. The RF classifier produces a similarity measure between observations and selects a subset of the most important features by comparing the original data with a set of synthetic data that is constructed based on the latter. The RF predictor output is finally used in combination with unsupervised clustering algorithms to discriminate between contaminated and non-contaminated EEG epochs. The proposed method is evaluated in epochs of 30 min from scalp EEG recordings obtained from three patients with epilepsy and yields a sensitivity of 71% and 80%, as well as a specificity of 81% and 85% for k-means and spectral clustering, respectively.

Introduction: Reports about cervical vestibular evoked myogenic potentials (cVEMPs) in central nervous system lesions are scarce. Our experience with cerebellar lesions is still evolving, with only a few cases published. The purpose of this article is to present our cVEMP findings of 3 cases with cerebellar lesions., Materials and Methods: cVEMPs were performed using unilateral 120-dB peak SPL intensity 1 kHz tone air-conducted sound stimulation with contralateral masking noise, with recording from the tonically active sternocleidomastoid muscle., Results: Brain MRI scans showed a small focal lesion in the right middle cerebellar peduncle in our first case, 2 foci in the right middle cerebellar peduncle and cerebellar hemisphere in our second case, and lesions in the right superior and inferior cerebellar peduncles near the fourth ventricle in our final case. All cVEMPs were normal., Discussion: cVEMPs seem to be unaffected by at least certain cerebellar peduncle and hemispheric lesions. Although an abnormal cVEMP result may suggest noncerebellar dysfunction, further work is needed, as the lesions reported may not be interrupting the known cerebellovestibular pathways. Normal cVEMP responses may also or otherwise be due to affected vestibular nuclei influenced by the above cerebellar lesions not being part of the cVEMP pathway.

The clinical differentiation between simple partial epileptic seizures of temporal lobe origin and panic attacks is often difficult on clinical grounds alone, because both conditions are characterized by common symptomatology which includes the feeling of fear, autonomic system dysfunction, disorientation and alternation of the level of consciousness when these conditions evolve clinically. The symptoms stem from common pathophysiologic and anatomic substrates of these two conditions, localized in the limbic system, especially the amygdala. We present the case of a young woman who had a febrile seizure in childhood and subsequent episodes of fear accompanied by tremor and possible alteration of consciousness followed by headache. These spells were diagnosed as panic attacks during her teenage years and she was given Clobazam in order to suppress them. The patient responded well for several years without attacks but her symptoms reappeared following discontinuation of her medication in order to conceive. At that time a detailed history was taken from her spouse and further clinical evaluation raised the suspicion of seizures especially due to the fact that her spells were characterized by alteration of consciousness; she was therefore referred for additional investigations which included admission to a monitoring unit for epilepsy. Long-term video-EEG recording revealed the presence of simple partial seizures with secondary generalization confirming the clinical impression. She was subsequently treated with antiepileptic medications; however the patient's condition worsened to the point where she became pharmacoresistant having failed several antiepileptic drug trials in monotherapy or combination. An MRI scan of the brain revealed the presence of right-sided mesial temporal sclerosis, a known consequence of febrile seizures. Her seizures were nocturnal tonic-clonic and gradually worsened to the point of occurring during most nights. She was therefore referred for a presurgical evaluation which confirmed that the epileptic focus was associated with the area of mesial temporal sclerosis. The epileptic focus was successfully removed from the right anterior temporal lobe and since then she remained free of seizures whereas, in addition, the presumed symptoms of panic attacks also resolved. This case indicates the occasional difficulty in diagnosing simple partial seizures and how it may be confused with psychiatric conditions. Therefore, the treating physician, especially the psychiatrist, should remain vigilant when treating cases of panic attacks, especially when they present with either atypical symptomatology, such as the case described, or when they do not respond to appropriately chosen treatment; such cases may warrant referral for further investigation.

Seizure detection and prediction studies using scalp- or intracranial-EEG measurements often focus on short-length recordings around the occurrence of the seizure, normally ranging between several seconds and up to a few minutes before and after the event. The underlying assumption in these studies is the presence of a relatively constant EEG activity in the interictal period, that is presumably interrupted by the occurrence of a seizure, at the time the seizure starts or slightly earlier. In this study, we put this assumption under test, by examining long-duration scalp EEG recordings, ranging between 22 and 72 hours, of five patients with epilepsy. For each patient, we construct functional brain networks, by calculating correlations between the scalp electrodes, and examine how these networks vary in time. The results suggest not only that the network varies over time, but it does so in a periodic fashion, with periods ranging between 11 and 25 hours.

Objective: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with epileptic seizures sometimes observed in the same patients. In this study, we used evoked responses to study the pathogenesis of epilepsy in MS., Methods: Patients with a diagnosis of definite MS and who had EPs performed (visual (VEP), brainstem auditory (BAEP) and short latency somatosensory (upper (USSEP) and lower (LSSEP))) were retrospectively included in this study. They were divided into three groups; Group I: Patients with no epilepsy and who were not taking anti-epileptic drugs (AED); Group II: Patients with epilepsy and taking AEDs; and Group III: Patients with no epilepsy who were taking AEDs for symptoms related to neuropathic pain., Results: Three hundred and fifty-five patients were included in this study; Group I: 229 patients (64.5%), Group II: 20 patients (5.6%) and Group III: 106 patients (29.9%). The proportion of patients with abnormal BAEP and USSEP was higher in Group II., Conclusions: A positive association exists between the presence of epilepsy in MS patients and BAEP and USSEP abnormalities. Analysis of Group III ruled out AED use as a factor., Significance: Brainstem lesions may be the cause of epileptogenicity in MS., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To demonstrate the clinical feasibility of using surface electrodes for recording flash electroretinography (ERG), using the stimulation standards of the International Society for the Clinical Electrophysiology of Vision (ISCEV), without pupillary dilation., Methods: Eighteen physiologically normal volunteers were tested. Surface recording electrodes were placed over the middle third of the lower eyelid of each eye, and the reference electrode placed on the temple. The recording filters and method of stimulation for the standard flash cone, 30 Hz flicker, rod, standard combined and oscillatory responses were those recommended by the ISCEV. Four patients with a history of visual dysfunction were also examined., Results: The amplitudes of the responses were noted to have a high signal to noise ratio, allowing us to average only a few responses. The waveform configurations were almost identical to those published using other recording methods. Patients with retinitis pigmentosa and early onset retinal dystrophy had abnormal responses, whereas patients with Stargardt's Syndrome and spasm of accommodation had responses within normal limits., Conclusions: This study has established the clinical feasibility of performing flash ERG using surface skin electrodes, with no pupillary dilation and using the stimulation standards of the ISCEV.

Case: We present the case of a boy with tuberous sclerosis who was referred for evaluation and treatment of his intractable epileptic seizures, having failed multiple anti-epileptic drug trials. He was subsequently treated with Levetiracetam that was gradually titrated to an effective dose, achieving full suppression of his seizures. Thereafter, his concomitant anti-epileptic drugs were gradually reduced and eventually discontinued. He remained on monotherapy with Levetiracetam, which continued to fully control his seizures. His EEG tracings before and after treatment are presented and compared, showing normalization of the latter., Conclusion: Levetiracetam appears to be effective in treatment-resistant seizures which are symptomatic to tuberous sclerosis when used adjunctively as well as in monotherapy. This is the first report in the English literature regarding its use and efficacy in this condition.

Vagus nerve stimulation (VNS) is an acceptable and effective adjunctive therapy for pharmacoresistant epilepsy. It is generally well tolerated and the most frequent side effects reported include respiratory dysfunction. We report the case of a female patient with intractable epilepsy who was implanted with the device and achieved a significant reduction in the number of her seizures. However, she developed central-type sleep apnea documented polysomnographically. Upon reduction of her VNS parameters, the apnea resolved and her sleep study reverted to normal. To our knowledge, this is the first case reported with polysomnographic evidence of VNS induction of central-type sleep apnea.

Objective: To present and discuss a case of a woman who for many years was presumed to have nonepileptic seizures (NES), but proved to actually have both electrical and non-electrical seizures, the latter occurring in a close temporal association with the former. To also discuss the seimiology her true as well as NES and compare to other cases identified from a literature review on this subject., Materials and Methods: Closed-circuit video-EEG monitoring was performed in order to capture and subsequently analyse the patient's events., Results: During video-EEG monitoring, she proved to have short electrical seizures followed by psychogenic elaborations. Her NES had obscured her true seizures for a number of years., Conclusions: Psychogenic elaboration of an epileptic seizure (ES) may occur in the same patient and the latter may obscure the former. The use of video-EEG monitoring may delineate the correct diagnosis and help clarify the relationship of the two types of events.

The exact location of the vestibular cortex in humans has not yet been established. Isolated lesions in the insula are exceptional. We describe a patient with recurrent episodes of vertigo and imbalance following a small lesion in the anterior insula. Myogenic and neurogenic vestibular evoked potentials were both performed using auditory stimuli. The former was recorded from the sternocleidomastoid muscle and the latter from the parietal areas on the scalp. Brainstem auditory evoked potentials, threshold latency series, pure tone audiometry and video nystagmography were also performed, as was brain MRI. All evoked potential studies and pure tone audiometry were within normal limits, ruling out peripheral and brainstem causes for the patient's symptoms. Video nystagmography revealed high slow phase velocities bilaterally with caloric stimulation, and saccadic tracking on the smooth pursuit examination. The MRI revealed a small lesion in the right anterior insula. To our knowledge this is the first reported case of vestibular symptoms and signs from a lesion in the anterior insula on MRI. In addition, its effects on the nystagmogram suggest that this area may be part of the pathway that controls smooth pursuit.

Purpose: Vestibular evoked myogenic potentials (VEMPs) uses high intensity clicks with recording from the tonically active sternocleidomastoid muscle, taking advantage of the close proximity of the saccule to the oval window. Our group has used the same stimulus to record Vestibular Evoked Neurogenic Potentials (VENPs) directly from the brain. VEMPs are now regarded the electrophysiological gold standard in peripheral vestibular system examination. We present a case of peripheral vestibular dysfunction to show that both VEMPs and VENPs provide similar results during recovery., Methods: A case of Meniere's Disease in recovery is examined. VEMPs were recorded using a 105 dB nHL click stimulus from the ipsilateral sternocleidomastoid muscle. VENPs were recorded using an ipsilateral parietal to Fpz montage and a 1 kHz tone-pip stimulus. Standard BAEPs and threshold latency series (TLS) were performed., Results: VEMP and VENP were unobtainable from the left side at initial presentation in a patient with Meniere's Disease, with normal BAEP and TLS bilaterally. After one month of therapy both the VEMP and VENP normalized., Conclusions: As VEMPs are known to originate from the vestibular system, the parallel VENP result suggests the same for the latter VENP may prove to be useful and complement VEMP in determining vestibular dysfunction.

Objectives: Symptoms of disequilibrium in multiple sclerosis (MS) are common. Neurogenic vestibular evoked potentials (NVsEPs) are saccular responses to tone-pip acoustic stimuli and are recordable from the parietal areas ipsilaterally to the stimulated ear. We wished to determine possible correlations of abnormal findings in NVsEP with clinical neurological findings related to the vestibular system, and demyelination seen on MRI., Patients and Methods: NVsEPs were performed by delivering a 1 kHz tone-pip stimulus monoaurally with contralateral masking noise via headphones. Brainstem auditory evoked potentials were performed in the standard manner., Results: Thirty-three patients had either been diagnosed with MS or had possible MS. There is statistical evidence that the presence of symptoms is likely to give an abnormal NVsEP, but no correlation exists between the presence or absence of vestibular symptoms and signs and an abnormal BAEP. No correlation was found between the presence of brainstem lesions on MRI and an abnormal NVsEP. Correlation exists between abnormal NVsEP and the level of disability using Expanded Disability Status Scale scores., Conclusion: We have found that with increasing involvement of abnormal NVsEPs, there is a significant correlation with symptoms and signs that can be referred to the vestibular system.

Published correlations between electrophysiological and surgical findings are relatively rare in cases of ulnar nerve compression at the wrist, compared to the more common compression of the ulnar nerve at the elbow. We describe a patient who presented with clinical and electrodiagnostic findings of a pure motor ulnar neuropathy involving the territory of the deep branch. Surgical exploration revealed that a ganglion cyst caused compression of the deep ulnar motor branch at Guyon's canal. This case illustrates the usefulness of electrodiagnostic studies in the localization of nerve entrapment prior to surgery.

Objectives: To demonstrate that neurogenic vestibular evoked potentials (NVsEP) may be specific to the vestibular system using three cases of vestibular system dysfunction and normal auditory function,, Methods: Neurogenic vestibular evoked potentials were performed by recording from the parietal areas of the scalp using a tone-pip auditory stimulus via headphones. Brainstem auditory evoked potentials (BAEPs) and NVsEP were performed in all three cases., Results: Brainstem auditory evoked potentials were within normal limits in all three cases. All three patients showed abnormalities in their NVsEP In the third case, the responses normalized after treatment., Conclusions: The findings support further the hypothesis that NVsEP are specific to the vestibular system and are a separate response from the BAEP SIGNIFICANCE: Neurogenic vestibular evoked potentials is an easy examination to carry out and can be performed in any clinical neurophysiological laboratory that is familiar with BAEPs. Examinations used to diagnose vestibular system disorders at present include the glycerol dehydration test, electrocochleography, myogenic vestibular evoked potentials and electronystagmography. Neurogenic vestibular evoked potentials may also prove to be useful.

The case of an adolescent with Kleine-Levin syndrome is presented who exhibited a consistent and predictable photoparoxysmal self-limited response to intermittent photic stimulation during all relapses of his hypersomnic phase. A possible cause of this association that has not been previously reported is speculated based on observations concerning the two disorders.

Objectives: In the present study we set out to obtain normative values for radial nerve F-waves, with surface recording from the extensor indicis muscle., Methods: Forty-nine patients with unrelated complaints were tested. Surface recording electrodes were placed on the extensor indicis muscle. This was found by asking the patient to extend the second digit against resistance. The active surface recording electrode was placed over the most distal portion of the muscle, near the radial border of the ulnar bone near the wrist. Stimulation was performed near the lateral epicondyle between the radial and ulnar bones., Results: The mean F-wave minimum latency was found to be 20.55 ms, with an upper limit of 24.35 ms. The absolute interside minimum latency difference was found to have a mean of 0.55 ms, with a maximum of 1.7 ms. The mean amplitude of the F-waves was 145.61 microV and the mean mF/M ratio was 0.022. F-waves were unobtainable in 2/62 (3.2%) of limbs. Normative values for the radial nerve motor response were also obtained. Three cases are described to illustrate the usefulness of the above technique., Conclusions: It is technically feasible to record radial nerve F-waves from the extensor indicis muscle.

Kleine-Levin syndrome is a rare self-limited disorder which usually affects adolescent males and is characterized by episodic hypersomnia, increased appetite, and behavioral/psychiatric disturbances. Individuals are normal between the attacks. The case of an adolescent boy is presented who suffered from recurrent sleepiness, hyperphagia, and behavioral disturbances such as rocking, punching and pacing, and was originally misdiagnosed as suffering from encephalitis. Before the diagnosis of Kleine-Levin was given, the patient underwent unnecessary investigations and treatment which, in turn, complicated his clinical condition both physically as well as psychologically. In the course of five years he had four such episodes which appeared to have progressively milder manifestations. Between episodes he was normal. It is important that the diagnosis is suspected early, especially in adolescent males who present with recurrent episodes of somnolence, increased appetite, and abnormal behavior, since it most often represents a benign and self-limited entity and does not warrant extensive investigations or treatment. It is also important to distinguish this syndrome from more serious organic and psychiatric diseases with more serious prognoses. The differential diagnosis of this syndrome is discussed and a review of the literature is presented including evidence and hypotheses regarding its pathophysiology.

The coexistence of mental retardation and retinitis pigmentosa has been well described in a number of congenital syndromes such as the Lawrence-Moon and Bardet-Biedl disorders. In contrast to this, little information is available regarding the association of acquired dementia with retinitis pigmentosa. This report summarizes the clinical features of a developmentally normal adult having the unusual symptom complex of retinitis pigmentosa, early-onset dementia, sensorineural hearing loss, and sensorimotor neuropathy. Though the coexistence of retinitis pigmentosa and dementia in this particular patient may be completely coincidental, it could be representative of a previously unrecognized subset of dementing illness. The literature pertaining to related symptom complexes is reviewed and discussed.