Background and objective Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. Methods We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. Results We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. Conclusions While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

ABSTRACTAimsSarcoendoplasmic reticulum Ca2+‐ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca2+ homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to myopathy. We describe four patients suffering from a novel myopathy caused by a homozygous missense variant in ATP2A2.MethodsWe studied a family with four individuals suffering from an adult‐onset skeletal myopathy. We evaluated the clinicopathological phenotype, muscle imaging, and genetic workup including whole genome sequencing and segregation analysis. SERCA2 expression in skeletal muscle was assessed. Functional studies to evaluate Ca2+ handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed.ResultsFour sisters developed slowly progressive proximal weakness in adulthood. Biopsy findings showed small vacuoles restricted to type I myofibres. Ultrastructural analysis showed sarcotubular dilation and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G > A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested that there was SERCA2 mislocalisation in patient myofibres. Western blotting did not show changes in the amount of protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca2+ reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation.ConclusionsWe report a novel adult‐onset vacuolar myopathy caused by a homozygous variant in ATP2A2. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca2+ dysregulation in slow‐twitch skeletal myofibres highly support the pathogenicity of the variant.

Idiopathic REM sleep behavior disorder (iRBD) is a prodromal marker of the alpha-synucleinopathies, in which autonomic nervous system (ANS) involvement may occur. We aimed to characterize the presence and severity of subjective and objective ANS dysfunction in iRBD and assess its capacity to predict short-term clinical progression to a synucleinopathy. Prospective study of patients with polysomnography-confirmed iRBD in whom symptomatic ANS involvement was assessed using the Composite Autonomic Symptom Score (COMPASS-31) and objective dysfunction with the Composite Autonomic Severity Score (CASS). Baseline ANS data were compared between those who later developed a synucleinopathy and those who did not. We evaluated 25 subjects with iRBD without risk factors for autonomic neuropathy and at least 6 months of follow-up (mean: 19 months). At the end of the study, seven (28

ABSTRACTOBJECTIVETo perform a nationwide epidemiological study of Guillain-Barré syndrome (GBS) in Spain, analysing background incidences and seasonal variation and trying to identify incidence changes during the COVID-19 years.METHODSObservational study collecting all GBS diagnoses from National Epidemiological Surveillance Network (RENAVE) collected by the Ministry of Health. Patients discharged with GBS as main diagnosis and admitted during 2018-2021 were included. Data on the incidence of SARS-CoV-2 infections and vaccinations were obtained from the National Epidemiology Centre.RESULTSIn total, 3147 cases were included, 832 in 2018, 861 in 2019, 670 in 2020 and 784 in 2021. Nationwide hospital incidence was 1.78 in 2018, 1.71 in 2019, 1.41 in 2020 and 1.66 in 2021, with an increased frequency in males, elderly population, and in the winter season. Eleven percent of GBS patients needed ventilatory support. GBS and SARS-CoV-2 incidences did not correlate with one another (r=-0.29, p=0.36). GBS incidence decreased during 2020 and during COVID-19 lockdown period in comparison to the same months of 2018-2019. No relationship was found between vaccines and GBS cases during vaccination roll-out in 2021.INTERPRETATIONIncidence of GBS in Spain is similar to that of other countries. Despite prior reports describing a significant increase in COVID-19-associated GBS in Spain, we detected a significant drop of GBS incidence during the SARS-CoV-2 pandemic, probably due to prevention measures. No relationship was found between SARS-CoV-2 or vaccinations and GBS incidences at the population level but data on relationship of vaccinations and GBS at the individual level were not available.

Introduction: Malignant middle cerebral artery infarction (MCI) needs rapid intervention. This study aimed to enhance the prediction of MCI using computed tomography perfusion (CTP) with varied quantitative benchmarks. Materials and Methods: We retrospectively analyzed 253 patients from a single-center registry presenting with acute, severe, proximal large vessel occlusion studied with whole-brain CTP imaging at hospital arrival within the first 24 h of symptoms-onset. MCI was defined by clinical and imaging criteria, including decreased level of consciousness, anisocoria, death due to cerebral edema, or need for decompressive craniectomy, together with midline shift ⩾6 mm, or infarction of more than 50% of the MCA territory. The predictive accuracy of baseline ASPECTS and CTP quantifications for MCI was assessed by receiver operating characteristic (ROC) area under the curve (AUC) while F-score was calculated as an indicator of precision and sensitivity. Results: Sixty-three out of 253 patients (25%) fulfilled MCI criteria and had worse clinical and imaging results than the non-MCI group. The capacity to predict MCI was lower for baseline ASPECTS (AUC 0.83, F-score 0.52, Youden’s index 6), than with perfusion-based measures: relative cerebral blood volume threshold <40% (AUC 0.87, F-score 0.71, Youden’s index 34 mL) or relative cerebral blood flow threshold <35% (AUC 0.87, F-score 0.62, Youden’s index 67 mL). CTP based on rCBV measurements identified twice as many MCI as baseline CT ASPECTS. Discussion and conclusion: CTP-based quantifications may offer enhanced predictive capabilities for MCI compared to non-contrast baseline CT ASPECTS, potentially improving the monitoring of severe ischemic stroke patients at risk of life-threatening edema and its treatment.

AbstractThe clinical status and treatment response of patients with peripheral neuropathies (PN) rely on subjective and inaccurate clinical scales. Wearable sensors have shown success in evaluating gait and balance in individuals with other neurological disorders. We aimed to explore the ability of biomechanical analysis via wearable technology to monitor disease activity in PN by conducting a single-center, longitudinal study to analyze gait parameters in PN patients and healthy controls using wearable sensors. First, we analyzed the sensor’s ability to detect changes in ataxia and steppage gait severity and found significant differences in spatiotemporal and angular variables. Second, we found correlations between biomechanical features and clinical scales linked to specific gait phenotypes. Finally, we demonstrated that this technology captures clinical changes in gait features over time. Our study provides proof-of-concept that wearable technology effectively detects and grades gait impairment, captures clinically relevant changes, and could enhance gait assessment in routine care and research for PN patients.

BACKGROUND AND OBJECTIVES:Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).METHODS:A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples.RESULTS:Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies.DISCUSSION:Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Background and Objectives Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-na & iuml;ve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype. Methods Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed. Results Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-na & iuml;ve anti-HMGCR+ patients was observed, compared with controls. Discussion WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.

Castleman disease (CD) is a rare lymphoproliferative disorder. Two main variants have been described: unicentric or multicentric (UCD/MCD). MCD can be idiopathic or related to human herpesvirus 8 (HHV8) infection in the setting of immune deficiency. MCD is more severe than UCD and is usually accompanied by other systemic symptoms. Peripheral neuropathy can be associated with MCD in isolation or as part of a wider spectrum of symptoms, the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). Compared with POEMS-neuropathy, CD-neuropathy is often milder, sensory, and not painful. There are few reports of CD-neuropathy with cranial nerve involvement, only affecting the optic and trigeminal nerves. We present a 50-year-old patient who developed bilateral facial weakness, numbness of hands and feet, sensory ataxia, and progressive walking difficulties over 3 weeks. Nerve conduction studies showed sensory-motor axonal symmetric neuropathy with signs of demyelination in cranial segments. He had history of human immunodeficiency virus infection, well controlled under antiretroviral treatment. Upon admission, he developed fever and pancytopenia, and diffuse lymphadenopathies were detected. An axillary lymph node biopsy was performed showing HHV8-positive small follicles, lymphodepletion, and penetrating vessels with interfollicular polyclonal plasmocytosis, supporting the diagnosis of CD, and adjacent focus of HHV8+ Kaposi sarcoma. He was treated with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) chemoimmunotherapy regimen. The neuropathy progressively resolved, both clinically and electrophysiologically, over a period of 6 months in parallel with the remission of CD. CD-associated neuropathy may present as bifacial weakness and limb paraesthesia, mimicking the variant of Guillain-Barré syndrome. The neurological symptoms may have a subacute progression leading to important disability. The outcome is good with chemoimmunotherapy, with parallel recovery of the neuropathy and the CD.

© Author(s) (or their employer(s)) 2022. No commercial reuse. See rights and permissions. Published by BMJ. CASE REPORT A 33yearold Japanese woman, 13 weeks pregnant, developed progressive nausea and vomiting. The vomiting episodes were accompanied by headache, occasional lowgrade fever and excessive sleepiness with subsequent diplopia. She had developed hyperemesis gravidarum in a previous pregnancy but had been otherwise well. The neurological examination showed confusion, sleepiness and involuntary nonrhythmic eye movements, suggesting opsoclonus. There was no ophthalmoparesis, ataxia, myoclonus or meningism. Blood tests showed hypokalaemia, evidence of renal failure, leucocytosis and abnormal liver function tests. CT scan of head was normal and cerebrospinal fluid examination was normal with negative microbiology, including common viruses and flaviviruses. HIV and hepatotropic viruses were negative. We gave her intravenous fluids and antiemetics along with intravenous thiamine and corticosteroids to treat hyperemesis gravidarum. MR scan of brain (figure 1) showed fluidattenuated inversion recovery (FLAIR) and diffusionweighted imaging (DWI) hyperintensities in area postrema, periaqueductal grey matter, mammillary bodies, mesencephalic tegmentum and both dorsomedial thalami. Serum antiaquaporin4 and antimyelin oligodendrocyte protein(MOG) antibodies were negative. Over the following days, her altered mental status and opsoclonus progressively improved, though slight horizontal nystagmus persisted to the right. Finally, she was diagnosed with hyperemesis gravidarum causing electrolyte disturbances and thiamine deficiency leading to Wernicke’s encephalopathy. Her liver renal function abnormalities were corrected and she was discharged 3 weeks later on a tapering dose of corticosteroids. Two months later, her neurological examination showed no nystagmus, mild gait instability without ataxia and mild anterograde memory loss.

OBJECTIVE:To investigate the incidence of coronavirus disease 2019 (COVID-19) in a single-center cohort of patients with MS and to explore the contribution of their comorbidities and therapies to the outcome.METHODS:A cross-sectional mixed-method study was conducted involving an email-based, self-administered questionnaire sent on May 21, 2020, to 586 patients with MS followed at the MS Unit of Hospital Clinic, University of Barcelona, along with telephone interview, and review of electronic medical records until June 18, 2020. The cumulative incidence of confirmed COVID-19 (positive PCR or antibody test) and all COVID-19 cases (confirmed and suspected) from the start of the pandemic was compared with the population estimates for Barcelona.RESULTS:A total of 407 patients (69.5%) completed the survey. Most of the responders (67%) were female. The responders had a median age of 48 years (range 19-86), relapsing-remitting disease (84%), at least 1 comorbidity (45%), and were on disease-modifying therapy (DMT; 74.7%). COVID-19 was confirmed in 5 patients (1.2%) and suspected in 46 (11.3%). The cumulative incidence of confirmed COVID-19 cases was similar to that of the general population but was almost 2-fold higher when all cases were considered (p < 0.001). Six patients (11.7%) were hospitalized, of which 5 had good recovery and 1 died. Hospitalized patients were more frequently male, had diabetes and had progressive forms of MS (p < 0.05). DMT was not associated with the risk of infection or the outcome.CONCLUSIONS:In the studied MS cohort, the incidence of COVID-19 was higher than that of the general population; however, most patients did not require hospitalization and had a good outcome despite the frequent presence of comorbidities and treatment with DMT.

Objective To investigate the incidence of coronavirus disease 2019 (COVID-19) in a single-center cohort of patients with MS and to explore the contribution of their comorbidities and therapies to the outcome. Methods A cross-sectional mixed-method study was conducted involving an email-based, self-administered questionnaire sent on May 21, 2020, to 586 patients with MS followed at the MS Unit of Hospital Clinic, University of Barcelona, along with telephone interview, and review of electronic medical records until June 18, 2020. The cumulative incidence of confirmed COVID-19 (positive PCR or antibody test) and all COVID-19 cases (confirmed and suspected) from the start of the pandemic was compared with the population estimates for Barcelona. Results A total of 407 patients (69.5%) completed the survey. Most of the responders (67%) were female. The responders had a median age of 48 years (range 19–86), relapsing-remitting disease (84%), at least 1 comorbidity (45%), and were on disease-modifying therapy (DMT; 74.7%). COVID-19 was confirmed in 5 patients (1.2%) and suspected in 46 (11.3%). The cumulative incidence of confirmed COVID-19 cases was similar to that of the general population but was almost 2-fold higher when all cases were considered (p < 0.001). Six patients (11.7%) were hospitalized, of which 5 had good recovery and 1 died. Hospitalized patients were more frequently male, had diabetes and had progressive forms of MS (p < 0.05). DMT was not associated with the risk of infection or the outcome. Conclusions In the studied MS cohort, the incidence of COVID-19 was higher than that of the general population; however, most patients did not require hospitalization and had a good outcome despite the frequent presence of comorbidities and treatment with DMT.

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome that can include headache, altered consciousness, visual disturbances, and seizures, usually related to autoregulatory cerebral failure and hypertension. The neuroimaging is essential to diagnosis, showing white matter vasogenic edema in posterior areas. We present a case of a 66-year-old woman with severe pneumonia by SARS-CoV-2 who developed a posterior reversible encephalopathy syndrome with a typical clinical and radiological presentation, after being treated with anti-interleukin treatment (anakinra and tocilizumab) following local guidelines. We report a case of posterior reversible encephalopathy syndrome in a patient with COVID-19 disease, possibly related to anti-IL-1 or anti-IL-6, suggesting that anti-interleukin treatments may cause this syndrome, at least in patients with predisposing conditions such as infections and hydroelectrolytic disorders.

A national outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China, rapidly evolving to the coronavirus disease 2019 (COVID-19) pandemic. Neurologic complications of COVID-19 include headache, confusion, hyposmia, and dysgeusia,[1][1] with