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Alpha-synuclein (alpha-syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). alpha-Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma alpha-syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma alpha-syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, alpha-syn was elevated early in the development of PD and specific PD treatment did not change plasma alpha-syn levels. (c) 2010 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response., Methods: Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity., Results: After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients., Conclusion: Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA., Competing Interests: FR-J received research grants and travel support for speaking engagements from Janssen, Biogen, Novartis, Roche, Sanofi-Genzyme, Bristol-Myers-Squibb and Merck. JG-G received research support, compensation for participating on advisory boards, lecture fees, and/or travel support from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Novartis, Roche, and Teva. EF received research support, compensation for participating on advisory boards, speaking fees, and/or funding for travel from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Merck, Novartis, and Roche. VM-L received consulting and speaking fees from Almirall, Biogen, Genzyme, Janssen, Merck, Novartis, Roche, Terumo, Sanofi, Teva, and Bristol Myers Squibb. CD-P received funding for training and scientific meetings from Sanofi, Merck, Novartis and Roche. SS received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. AQ is funded by a grant from the Fundación Francisco Soria y Melguizo and has received funding from Merck, Novartis, and Horizon Therapeutics to attend conferences. LR-T received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers-Squibb, TEVA, and Horizon. SM-Y received honoraria for participating on advisory boards and for collaborations as consultant and scientific communications and also received research support as well as funding for travel and congress expenses from Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, Almirall, and Bristol Myers Squibb. EM received research grants, travel support, or honoraria for speaking engagements from Almirall, Merck, Roche, Sanofi, Bristol Myers Squibbb, Biogen, Janssen, and Novartis. AL-R received speaker and consultation fees from Biogen, Janssen, Novartis, Roche and Sanofi, and congress travel support from Roche. LBo received research grants and travel support from Merck, Roche, Novartis, Sanofi, Horizon and Bristol Myer Squibb. JC-G received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Bayer, Janssen, BMS, and Bial. FB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Bristol Myer Squibb, Genzyme, Johnson & Johnson, Merck, Novartis, Roche, Sanofi, Teva. MM-G received compensation for consulting services and speaking fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, BMS, Janssen, Roche, Horizon, and Viatris. JG-D received honoraria as speaker, advisor and researcher from Almirall, Bristol Myers Squibb, Biogen, Janssen, Merck, Novartis, Roche, Teva, and Sanofi. MM-M received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck Serono, Novartis, Bayer Schering Pharma, Bristol Myers Squibb and Roche. JM-L received honoraria as a consultant, lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Almirall, Biogen, Bristol-Meyers-Squibb, Horizon, Johnson & Johnson, Merck, Neuraxpharm, Novartis, Roche, Sandoz, Sanofi and UCB. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. LV received research grants and personal fees from Merck, Roche, Sanofi, Bristol Myers Squibb, Biogen, and Novartis. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodríguez-Jorge, Fernández-Velasco, Villarrubia, Gracia-Gil, Fernández, Meca-Lallana, Díaz-Pérez, Sainz de la Maza, Pacheco, Quiroga, Ramió-Torrentà, Martínez-Yélamos, Bau, Monreal, López-Real, Rodero-Romero, Borrega, Díaz, Eguía, Espiño, Chico-García, Barrero, Martínez-Ginés, García-Domínguez, De la Fuente, Moreno, Sainz-Amo, Mañé-Martínez, Caminero, Castellanos, Gómez López, Labiano-Fontcuberta, Ayuso, Abreu, Hernández, Meca-Lallana, Martín-Aguilar, Muriel García, Masjuan, Costa-Frossard and Villar.)

Background: Patients with multiple sclerosis (MS) have to deal with a variable disease trajectory often associated with disability and productivity loss., Objective: This study aimed to assess illness-related uncertainty and associated correlates in patients with relapsing-remitting multiple sclerosis (RRMS) beyond the near diagnosis phase., Methods: We conducted a multicenter, non-interventional study including patients diagnosed with RRMS (2017 revised McDonald criteria) and a disease duration of 3 to 8 years. Perceived uncertainty was measured using the Mishel Uncertainty of Illness Scale (MUIS). Associations between the MUIS and different patient-based outcome measures were analyzed using Spearman's rank correlation., Results: A total of 201 patients were studied (mean age (standard deviation): 38.7 (8.4) years, 71.4 % female). The median disease duration (interquartile range) was 6.0 (4.0-7.0) years and the median EDSS score was 1.0 (0.0-2.0). The mean MUIS score was 38.2 (10.8). Perceived uncertainty was positively correlated with fatigue (p < 0.001), symptom severity (p < 0.001), anxiety (p < 0.001), depressive symptoms (p < 0.001), and a threatening illness perception (p < 0.001), and negatively correlated with self-management (p < 0.001), self-efficacy (p < 0.001), processing speed (p < 0.001), knowledge of MS (p = 0.006), and quality of life (p < 0.001)., Conclusion: Illness-related uncertainty was common in a population of mid-stage RRMS. Identifying uncertainty and its associated factors may be useful for implementing preventive strategies to help patients cope with the disease throughout life., Competing Interests: Declaration of competing interest J.S. received honoraria for lecturing, consulting or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche and Sanofi. J.M-M. served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche and Teva. F.B. received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi and Teva. A.A. received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall and Novartis. J.S-M. received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and participated in clinical trials of Biogen, Merck and Roche. L.B. received compensation for consulting services, speaking honoraria and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall and Teva. M. G-G. received honoraria as speaker from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi and Bial. S.E. received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche and Almirall. C.C. received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. E.F-D. received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche and Sanofi. O.C. received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen and Merck. A.O. received research grants, travel support, advisory activities or honoraria for speaking engagements from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. A.L-R. received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche and Sanofi. A. M. received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. E.A. received speaking honoraria from Roche, Novartis, Merck, Sanofi and Biogen. E.S. and J.M. are employees of Roche Farma Spain. The rest of the authors declared no potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The presence of cortical atrophy (focal or diffuse) prior to the development of symptoms of cognitive impairment could predict the earliest cases of neurodegenerative disease in patients with REM sleep behavior disorder (RSBD). We reviewed the usefulness of cranial CT and MRI as early markers of cortical atrophy in patients with RSBD at our center., Patients and Methods: Retrospective observational descriptive analysis of patients diagnosed with RSBD from October 2012 to October 2022. All with cranial CT or MRI, evaluated by a neuroradiologist., Results: 54 patients were included, 21 women (38.88%), 33 men (61.12%), mean age at diagnosis of RSBD: 69.04±12.625 years. Of the 54 patients, 44 (81.48%) had imaging tests consistent with their age, and 10 had atrophy greater than expected for their age. Of the 54 patients, 21 (38.88%) with a diagnosis of neurodegenerative disease, 33 (61.12%) persist as idiopathic, almost all with more than 5years of evolution (range of 1 to 10years of evolution without diagnosis). Of the 10 (18.52%) patients with greater atrophy, all were diagnosed with neurodegenerative disease (8 in 1year, 2 in 8years)., Conclusions: Almost half of our series have developed a neurodegenerative disease in the first 10years of evolution. The majority of them presented global cortical atrophy measured by the GCA scale in the first year of diagnosis, without other neurological symptoms. Patients who did not show cortical atrophy at diagnosis have not yet developed the neurodegenerative disease in 10years of evolution. In our experience, the absence of cortical atrophy on cranial MRI or CT (measured by scales such as GCA) at the diagnosis of RSBD seems to predict slower progression cases. These data should be corroborated with larger series., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p -value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ES and JM are employees of Roche Farma Spain. JS received honoraria for lecturing, consulting, or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche, and Sanofi. JMM served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche, and Teva. FJB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. AA received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen, and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall, and Novartis. JLSM received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in clinical trials from Biogen, Merck, and Roche. LB received compensation for consulting services, speaking honoraria, and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall, and Teva. MGG received speaking honoraria from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi, and Bial. SE received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche, and Almirall. CC received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. EFD received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche, and Sanofi. OC received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen, and Merck. AO received research grants, travel support, advisory activities, and honoraria for speaking from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. ALR received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi. AM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. EA received speaking honoraria from Roche, Novartis, Merck, Sanofi, and Biogen. The rest of the authors declared no potential conflicts of interest. The abstract of this article was presented at the European Congress of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) as a poster presentation with interim findings (PCR178; Copenhagen, Denmark; November 14, 2023)., (© The Author(s), 2024.)

We analysed the co-existence of psychopathology in patients with narcolepsy at our centre. We performed an observational retrospective descriptive analysis of patients with a diagnosis of narcolepsy, with and without psychopathology, who attended our sleep disorders unit from October 2012 to October 2021. A total of 51patients with narcolepsy (mean [SD] age 41.10 [14.71] years; 23 [45.1%] males and 28 [54.90%] females) were included. In all, 27 patients (52.94%) and 24 patients (47.06%) had narcolepsy with and without cataplexy, respectively. Of the total, 18 (33.33%) had a mood disorder: 18 with anxiety disorder (33.33%). Of these patients 14 (27.45%) had major depression, two (4%) had attempted suicide, one (2%) had manic outbreak, and one (2%) had substance abuse. Of the 18 patients with anxiety and depression, 10 (55.55%) and eight (44.44%) had narcolepsy with and without cataplexy, respectively. In the comparative analysis, a statistically significant relationship was found between younger age and the presence of anxiety. The prevalence of anxiety and depression in patients with narcolepsy was triple that of the general population, especially in younger patients. Psychopathology precedes the diagnosis of narcolepsy in most patients, not being reactive to diagnosis. This high prevalence suggests a possible biological relationship between both disorders, which should be assessed with larger studies., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019., Patients and Methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019., Results: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7., Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.

Using recent optimized electrodiagnostic criteria sets, we aimed at verifying the accuracy of initial nerve conduction studies (NCS) in classic very early Guillain-Barré syndrome (VEGBS), ≤ 4 days after onset, compared with the results of serial NCS. This is a retrospective study based on unreported and consecutive VEGBS patients admitted to two university hospitals between 2015 and 2019. Each patient had serial NCS in at least four nerves. Initial NCS studies were done within 4 days after onset, and serial ones from days 20 to 94. Electrophysiological recordings were blinded evaluated by four of the authors, GBS subtype being established accordingly. Seven adult classic VEGBS patients were identified with a median age of 58 years. At first NCS, GBS subtyping was only possible in 1 case that exhibited an axonal pattern, the remaining patterns being equivocal in 3, and mixed (combining axonal and demyelinating criteria) in the remaining 3. Upon serial NSC there was a rather intricate evolution of electrophysiological GBS patterns, 3 of them being classified as axonal or demyelinating, and the remaining 4 as equivocal or mixed. NCS in VEGBS systematically allows detection of changes suggestive of peripheral neuropathy, though even after serial studies accurate GBS subtyping was only possible in 43% of cases. We provide new pathophysiological insights for better understanding of the observed electrophysiological changes., (© 2021. Belgian Neurological Society.)

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019., Patients and Methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019., Results: We gathered data from a total of 1.809 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 920 patients were men (50.8%) and 889 were women (49.2%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7., Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials., (Copyright © 2021 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission., Patients and Methods: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020., Results: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay ( P  = .002; 95% CI: 4.032-6.022; OR: 3,594)., Conclusions: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay., (© 2020 Sociedad Española de Neurología. Published by Elsevier España, S.L.U.)

Concerning the letter by Moriguchi et al., we describe our experience with a case of encephalopathy with and atypical damage on magnetic resonance imaging (MRI) in a patient with severe infection due to the SARS-CoV2 virus. A 56-year-old woman, without previous pathologies, developed cough, fever, and respiratory failure for five days, after returning from a 6-day trip to Venice. Chest radiography shows a large bilateral interstitial infiltrate. In the first 24 hours, she was admitted to the Intensive Care Unit (ICU) for severe respiratory failure and positive protein chain reaction-PCR in nasal exudate. She needed intubation for ten days. In the first 48 hours outside the ICU, she developed an acute confusional syndrome (hyperactive delirium). Neurological examination showed temporal-spatial disorientation and incoherent fluent speech. An electroencephalogram (EEG) showed generalized hypovoltaic activity. Cranial magnetic resonance imaging showed a bilateral and symmetrical increase in the supratentorial white matter's signal intensity, with a discrete thickening of both temporal lobes, with a slight increase in signal intensity and a sequence of normal diffusion. The lumbar puncture showed no changes (glucose 71 mg/dL, protein 30 mg/dL, 1 leukocyte). Within 72 hours of starting symptoms, she was neurologically asymptomatic. Our final diagnosis was an inflammatory encephalopathy related to a SARS-CoV2 infection., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases., Objectives: To perform the largest PD genome-wide association study restricted to a single country., Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses., Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls., Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Aphasic status epilepticus is an uncommon entity that should be included in the differential diagnosis of persistent and sudden language disorders. In our study, we describe seven patients admitted with clinical and electroencephalographic diagnosis of aphasic status, who were studied with both neuroimaging and electroencephalogram. The mean age was 65.9 years (range of 39-89). Three of the patients had previously been diagnosed of epilepsy. The aphasia was global in six patients. In one case, we found foci of the left hemorrhagic contusions. The initial electroencephalogram (EEG) was not conclusive of status in two patients. In one patient, neuroimaging showed left hemispheric hypoperfusion, compatible with postictal changes. Six out of seven patients required at least two antiepileptic drugs. Three patients died of systemic complications (infectious causes), whereas the other four cases had a complete recovery. Our study highlights that a second EEG study might be necessary to confirm epileptiform activity, when clinical features and other tests suggest an epileptic origin. An early and specific treatment, avoiding or diminishing comorbidities, might significantly improve the prognosis of these patients.

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.

Introduction: Status epilepticus (SE) is a neurological emergency associated with significant mortality and morbidity. We analyse characteristics of this entity in our population., Methods: Data from electronic medical records of adults diagnosed with SE were collected retrospectively from 5 hospitals over 4 years., Results: Data reflected 84 episodes of SE in 77 patients with a mean age of 60.3 years. Of this sample, 52.4% had a previous history of epilepsy. Status classification: 47.6% tonic-clonic, 21.4% complex partial, 17.9% partial motor, 6% partial simple, 3.6% myoclonic, and 3.6% subtle SE. Based on the duration of the episode, SE was defined in this study as early stage (up to 30min) in 13.1%, established (30-120min) in 20.2%, refractory (more than 120min) in 41.7%, and super-refractory (episodes continuing or recurring after more than 24h of anaesthesia) in 13.1%. Ten patients (11.9%) died when treatment failed to control SE. The cumulative percentage of success achieved was 8.3% with the first treatment, 27.3% for the second, 48.7% for the third, 58.2% for the fourth, 70.1% for the fifth, 80.8% for the sixth, 83.2% for the seventh, and 84.4% for the eighth., Conclusions: In our study, we found that SE did not respond to treatment within 2h in approximately half the cases and 11.9% of the patients died without achieving seizure control, regardless of the type of status. Half the patients responded by the third treatment but some patients needed as many as 8 treatments to resolve seizures. Using large registers permitting analysis of the different types and stages of SE is warranted., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio = 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group. In the EOPD and FPD groups, we identified 11 known pathogenic mutations among 15 patients (40.5%). GBA (E326K, N370S, D409H, L444P) mutations were identified in 7 patients (18.9%); LRRK2 (p.R1441G and p.G2019S) in 3 patients (8.1%); biallelic PARK2 mutations (p.N52fs, p.V56E, p.C212Y) in 4 cases (10.8%) and PINK1 homozygous p.G309D in 1 patient (2.7%). An EOPD patient carried a single PARK2 heterozygous mutation (p.R402C), and another had a novel heterozygous mutation in VPS35 (p.R32S), both of unknown significance. Moreover, pathogenic mutations in GBA (E326K, T369M, N370S, D409H, L444P) and LRRK2 (p.R1441G and p.G2019S) were identified in 13 patients (13.4%) and 4 patients (4.1%), respectively, in the LOPD group. A large number of known pathogenic mutations related to PD have been identified. In particular, GBA and LRRK2 mutations appear to be considerably frequent in our population, suggesting a strong Jewish influence. Further research is needed to study the contribution of the novel found mutation p.R32S in VPS35 to the pathogenesis of PD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating., Methods: We report clinical and neurophysiological results of 13 patients with CTX diagnosed in Spain., Results: In 8 patients (62%), peripheral neuropathy was demonstrated (4 demyelinating, 3 axonal, and 1 mixed; 3 predominantly motor and 5 sensorimotor). All patients had clinical signs/symptoms of peripheral neuropathy. Upper limb somatosensory evoked potentials (SSEPs) were affected in 38% of patients, and lower limb SSEPs in 67%. Fifty percent of patients had delayed brainstem auditory evoked potentials, and 43% had affected visual evoked potentials., Discussion: In this series, polyneuropathy was predominantly sensorimotor and demyelinating. Neurophysiological studies correlated only partially with clinical follow-up. Therefore, we recommend neurophysiological follow-up studies only if clinical symptoms are present., (Copyright © 2011 Wiley Periodicals, Inc.)

Background/objective: Mitochondrial dysfunction, oxidative stress and protein metabolism impairment are the main molecular events underlying the pathogenesis of Parkinson's disease (PD). However, only few studies have addressed the changes produced by these phenomena in the blood of PD patients. Our purpose was to compare oxidative stress between newly diagnosed PD patients (ntPD) and PD patients under treatment (tPD). We also analyzed changes in plasma activity of several aminopeptidases (AP) involved in the metabolism of various active peptides., Methods: Plasma lipid peroxide (LPO) and lactate (LAC) concentrations were measured by colorimetric methods, and plasma AP activities were determined by fluorometric assay., Results: LPO and LAC concentrations were significantly elevated in ntPD and tPD patients versus controls, but there were no differences between the PD groups. Alanine-, cystine- and aspartate-AP activities were significantly lower in tPD versus ntPD patients. Nondenaturing electrophoresis and Western blot results confirmed these findings., Conclusions: The plasma LPO and LAC levels were high in both PD groups, indicating that they are elevated at an early stage of PD and are not affected by anti-PD treatment. The higher AP activities in ntPD versus tPD patients suggest that anti-PD treatment may improve protein metabolism while not altering oxidative stress. A therapy directed to reduce oxidative stress and normalize AP activity may be useful in the treatment of PD., (Copyright © 2010 S. Karger AG, Basel.)

Huntington's disease (HD) is a genetic neurodegenerative disorder. Oxidative stress, mitochondrial dysfunction, and protein metabolism impairment have been implicated in its pathogenesis. However, the contribution of these phenomena to HD onset or progression is not well known, and they have been less studied in peripheral blood. We analyzed plasma lipid peroxide (LPO) and lactate (LAC) concentrations as indicators of oxidative stress and mitochondrial dysfunction in symptomatic HD patients (sHD) and asymptomatic HD gene carriers (aHD). We also measured the plasma activity of aminopeptidases (APs), an important group of proteolytic enzymes. LPO and LAC concentrations were significantly elevated in sHD patients but not in aHD carriers. Aspartate and glutamate AP activities were significantly reduced in sHD patients and aHD carriers. These findings demonstrate that sHD patients are under oxidative stress, which may favor progression of the disease. Plasma AP activity was decreased before the appearance of HD symptoms and oxidative stress and may be related to protein metabolism impairment. These results indicate that therapy directed to improve oxidative stress and normalize AP activity may be useful in the treatment of HD. They also suggest that decreased plasma AP activity in aHD carriers may predict the future onset of HD symptoms.

Introduction: Central pontine myelinolysis (CPM) is a disease characterized by the destruction of the myelin in the brainstem, generally associated with alcoholism, rapid correction of hyponatremia and other electrolytic alterations. The clinical symptoms, etiopathogenic factors, neuroimaging and evolution of the series of patients diagnosed of central pontine/extrapontine myelinolysis (CPEM) are described., Methods: Review of all the clinical histories with diagnoses of CPM made in our hospital since 1989. All the cases were reviewed, ruling out those having a magnetic resonance or clinical picture not clearly consistent with the diagnosis. Age, symptoms, comorbidity, associated metabolite alterations and clinical evolution were analyzed., Results: 13 cases whose ages ranged from 28 to 81 years were identified. Hyponatremia was identified during the clinical course in six patients, with neurological worsening associated to its correction in 3 of them. No sodium disorders were identified in 7 patients. Seven of the patients had associated alcoholism. Hyperintense lesions were found in all the cases in T2 sequences and FLAIR in the brainstem consistent with the typical pattern of the osmotic demyelinization syndrome. The severity of the clinical picture identified varied from a symptomatic patient to coma in 9 cases. In regards to the clinical course, four patients completely recovered, eight had residual symptoms with different severity and one patient died., Conclusions: The series is representative of the clinical and etiopathogenic spectrum of the osmotic demyelinization syndrome. Most of the clinically symptomatic patients improve if the secondary complications are controlled.

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.

Introduction: Acute cerebrovascular disease (ACVA) makes up a high proportion of the neurological patients admitted to hospital, but we do not know the exact figures in our setting. We consider that it would be useful if the use of health-care resources for attending these patients was to be evaluated and studied by the neurologists who direct them., Objective: To analyze a predetermined series of variables related to strokes in our setting. Patients and methods. We made a descriptive analysis by means of a questionnaire, recording variables related to the admission to the neurology department of patients with probable ACVA, at 100 days and with further evaluation 6 months later., Results: We recorded 107 cases with ACVA confirmed in 101 of 104 patients with averages of: 70.54 years, average admission 13.53 days and intrahospital mortality 5.8%. The most common neurological findings were paralysis and speech disorder. The proportion of ischaemic stroke as compared with haemorrhagic stroke was 87.5% to 12.5%. The prevalence of usual risk factors was: arterial hypertension, diabetes and cardiopathy. The percentage of patients given rehabilitation treatment during their admission was 41.34%. A proportion, 37.2%, of the patients were referred to Hospital San Rafael for convalescence and treatment. The average time before evaluation by a neurologist was 30.23 hours. Eleven of 86 patients who answered a weekly questionnaire died (12.8%) and 54/86 had no rehabilitation treatment during the week (62.8%)., Conclusions: We found no differences in the epidemiological characteristics as compared with other studies. The excessive lapse of time before attending the emergency department was striking, as was the delay in receiving neurological attention since there was no emergency neurologist available and fewer haemorrhagic strokes since there was no neurosurgical service available. There was little use of salicylates as a platelet anti-aggregrant agent on discharge from hospital, little rehabilitation treatment six months after the stroke, and twice as much mortality as when the patients were in hospital. We consider that a more detailed and extensive analysis would be fully justified in our setting, preferably with more people interested in the early and late treatment of ACVA taking part and prolonged follow-up of these patients.