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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

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1., Methods: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed., Results: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006)., Significance: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Transcranial magnetic stimulation (TMS)-evoked EEG potentials (TEPs) have been used to study the excitability of different cortical areas (CAs) in humans. Characterising the interhemispheric symmetry of TMS-EEG may provide further understanding of structure-function association in physiological and pathological conditions. We hypothesise that, in keeping with the underlying cytoarchitectonics, TEPs in contralateral homologous CAs share similar, symmetric spectral features, whilst ipsilateral TEPs from different CAs diverge in their waveshape and frequency content. We performed single-pulse (<1 Hz) navigated monophasic TMS, combined with high-density EEG with active electrodes, in 10 healthy participants. We targeted two bilateral CAs: premotor and motor. We compared frequency power bands, computed Pearson correlation coefficient (R) and Correlated Component Analysis (CorrCA) to detect divergences, as well as common components across TEPs. The main frequency of TEPs was faster in premotor than in motor CAs (p < .05) across all participants. Frequencies were not different between contralateral homologous CAs, whilst, despite closer proximity, there was a significant difference between ipsilateral premotor and motor CAs (p > .5), with frequency decreasing from anterior to posterior CAs. Correlation was high between contralateral homologous CAs and low between ipsilateral CAs. When applying CorrCA, specific components were shared by contralateral homologous TEPs. We show physiological symmetry of TEP spectral features between contralateral homologous CAs, whilst ipsilateral premotor and motor TEPs differ despite lower geometrical distance. Our findings support the role of TEPs as biomarker of local cortical properties and provide a first reference dataset for TMS-EEG studies in asymmetric brain disorders., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Alternating Hemiplegia of Childhood (AHC) is characterised by paroxysmal hemiplegic episodes and seizures. Remission of hemiplegia upon sleep is a clinical diagnostic feature of AHC. We investigated whether: 1) Hemiplegic events are associated with spectral EEG changes 2) Sleep in AHC is associated with clinical or EEG spectral features that may explain its restorative effect., Methods: We retrospectively performed EEG spectral analysis in five adults with AHC and twelve age-/gender-matched epilepsy controls. Five-minute epochs of hemiplegic episodes and ten-minute epochs of four sleep stages were selected from video-EEGs. Arousals were counted per hour of sleep., Results: We found 1) hemispheric differences in pre-ictal and ictal spectral power (p = 0.034), during AHC hemiplegic episodes 2) 22% reduced beta power (p = 0.017) and 26% increased delta power (p = 0.025) during wakefulness in AHC versus controls. There were 98% more arousals in the AHC group versus controls (p = 0.0003)., Conclusions: There are hemispheric differences in spectral power preceding hemiplegic episodes in adults with AHC, and sleep is disrupted., Significance: Spectral EEG changes may be a potential predictive tool for AHC hemiplegic episodes. Significantly disrupted sleep is a feature of AHC., Competing Interests: The authors have declared that no competing interests exist.

Objective: To elucidate the effects of single and paired-pulse TMS on seizure activity at electrographic and clinical levels in people with and without epilepsy., Methods: A cohort of 35 people with epilepsy, two people with alternating hemiplegia of childhood (AHC) with no epilepsy, and 16 healthy individuals underwent single or paired-pulse TMS combined with EEG. Clinical records and subject interviews were used to examine seizure frequency four weeks before and after TMS., Results: There were no significant differences in seizure frequency in any subject after TMS exposure. There was no occurrence of seizures in healthy individuals, and no worsening of hemiplegic attacks in people with AHC., Conclusions: No significant changes in seizure activity were found before or after TMS., Significance: This study adds evidence on the safety of TMS in people with and without epilepsy with follow-up of four weeks after TMS., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP., Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5 c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures., Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5 c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia., Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Although described as non-progressive, alternating hemiplegia of childhood (AHC) can display a sudden deterioration, anecdotally reported mainly in childhood. Outcome in adulthood is uncertain., Objectives: Aim of this study is to describe the long-term follow-up of neurological function in adults with AHC., Methods: Seven adults with AHC were included in this retrospective single-center study. Clinical history and previous investigation data were gathered from the review of medical records. Video-documented neurological examination was performed at the last follow-up visit in four out of the seven reported indivisuals., Results: Over a median follow-up of 16 years, neurological outcome and trajectories were heterogeneous. All individuals showed new neurological signs or symptoms. Three experienced a serious irreversible neurological deterioration after prolonged quadriplegic episodes and/or status epilepticus in their second or third decade. One patient died at age 29., Conclusions: This video-series suggests that AHC in adulthood is not stationary; larger cohorts are needed to identify genotype-phenotype correlations and clinically useful outcome predictors., Competing Interests: The authors report no sources of funding and no conflicts of interest., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Background and Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS., Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected., Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline., Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS., (© 2020 European Academy of Neurology.)

Objective: To explore the phenotypic spectrum of RHOBTB2 -related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals., Methods: Individuals with RHOBTB2 -related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review., Results: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2 , confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3 , these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients., Conclusion: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations., (© 2021 American Academy of Neurology.)

In this cohort study, we aim to compare outcomes from coronavirus disease 2019 (COVID-19) in people with severe epilepsy and other co-morbidities living in long-term care facilities which all implemented early preventative measures, but different levels of surveillance. During 25-week observation period (16 March-6 September 2020), we included 404 residents (118 children), and 1643 caregivers. We compare strategies for infection prevention, control, and containment, and related outcomes, across four UK long-term care facilities. Strategies included early on-site enhancement of preventative and infection control measures, early identification and isolation of symptomatic cases, contact tracing, mass surveillance of asymptomatic cases and contacts. We measured infection rate among vulnerable people living in the facilities and their caregivers, with asymptomatic and symptomatic cases, including fatality rate. We report 38 individuals (17 residents) who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive, with outbreaks amongst residents in two facilities. At Chalfont Centre for Epilepsy (CCE), 10/98 residents tested positive: two symptomatic (one died), eight asymptomatic on weekly enhanced surveillance; 2/275 caregivers tested positive: one symptomatic, one asymptomatic. At St Elizabeth's (STE), 7/146 residents tested positive: four symptomatic (one died), one positive during hospital admission for symptoms unrelated to COVID-19, two asymptomatic on one-off testing of all 146 residents; 106/601 symptomatic caregivers were tested, 13 positive. In addition, during two cycles of systematically testing all asymptomatic carers, four tested positive. At The Meath (TM), 8/80 residents were symptomatic but none tested; 26/250 caregivers were tested, two positive. At Young Epilepsy (YE), 8/80 children were tested, all negative; 22/517 caregivers were tested, one positive. Infection outbreaks in long-term care facilities for vulnerable people with epilepsy can be quickly contained, but only if asymptomatic individuals are identified through enhanced surveillance at resident and caregiver level. We observed a low rate of morbidity and mortality, which confirmed that preventative measures with isolation of suspected and confirmed COVID-19 residents can reduce resident-to-resident and resident-to-caregiver transmission. Children and young adults appear to have lower infection rates. Even in people with epilepsy and multiple co-morbidities, we observed a high percentage of asymptomatic people suggesting that epilepsy-related factors (anti-seizure medications and seizures) do not necessarily lead to poor outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder. Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed. Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF. Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS.

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation., Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations., Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge., Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Interferon-β (IFN-β) is often discontinued in RRMS patients due to its most common side effect, the flu-like syndrome (FLS). The mechanisms underlying IFN β-induced FLS symptoms are still unclear. The endocannabinoid system (ECS) is a key regulator of pain and inflammation. Thus we tested the hypothesis that the ECS could be involved in FLS severity by exploring the effect of genetic polymorphisms with functional impact on the ECS, on patient-reported FLS symptoms. GG-carriers of the transient-receptor-potential-vanilloid-1 (TRPV1) single nucleotide polymorphism rs222747 reported greater pain and weakness during FLS. This study suggests that the TRPV1 channel is involved in FLS severity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)-associated progressive multifocal leukoencephalopathy (PML)., Methods: The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses., Results: A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome., Conclusions: PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future., Classification of Evidence: This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX., (© 2017 American Academy of Neurology.)

Background: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease., Objective: To assess the role of RANTES in the regulation of cortical excitability., Methods: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro., Results: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP., Conclusion: RANTES correlates with inflammation and synaptic excitability in MS brains., (© The Author(s), 2016.)

Background: Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS)., Methods: One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored., Results: CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein., Conclusions: Measurement of CSF lactate may be helpful, in conjunction with other biomarkers of tissue damage, as an early predictor of disease severity in RRMS patients. A better understanding of the alterations of mitochondrial metabolic pathways associated to RRMS severity may pave the way to new therapeutic targets to contrast axonal damage and disease severity.

Some multiple sclerosis (MS) patients reported an improvement after percutaneous transluminal angioplasty (PTA) for chronic cerebrospinal venous insufficiency (CCSVI), despite the lack of correspondence with objective outcome scores. The objective was to assess neurologic and quality of life scores before and after PTA for CCSVI in an observational study after a self-decided approach. 44 consecutive MS patients (21/23 M/F; median age 43 years, SD 9.8) who underwent PTA were evaluated before endovascular treatment for CCSVI and after 12 months. Neurologic outcome was assessed with EDSS, the annualized relapse rate (ARR) and frequency of new lesions at MRI after PTA. Quality of life was evaluated through the MSQoL-54 questionnaire. No modification in the ARR (p = 0.829), worsening of disability status (p = 0.002) and new lesions at MRI in 29.6 % of patients were found, in contrast to an improvement both in physical and mental domains of MSQoL-54 (p = 0.003). Multiple logistic regression showed EDSS score before PTA to be predictor of an increase of >10 points in MSQoL-54 mental domain (OR 0.52, 95 % CI, 0.31-0.89, p = 0.018). Spontaneously performed approach to CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement.