Showing papers in "European Journal of Neurology in 2021"

Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

Abstract: BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response.

Abstract: Background and purpose Information regarding multiple sclerosis (MS) patients with the 2019 novel coronavirus disease (COVID-19) is scarce. The study objective was to describe the incidence and characteristics of MS patients with COVID-19, to identify susceptibility and severity risk factors and to assess the proportion of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologies according to disease-modifying treatments. Methods This was a retrospective study of an MS cohort analysing data collected between February and May 2020. Cases were identified through an email survey and clinical visits. The relationship of demographic and MS characteristics with COVID-19 and of the disease-modifying treatments with SARS-CoV-2 serostatus were examined. Results Data from 48 suspected cases out of 758 valid respondents and from 45 COVID-19 cases identified through clinical visits were collected. Incidence was 6.3%. Nineteen (20.3%) patients were hospitalized and two (2.2%) died. Multivariable models determined that age (odds ratio [OR] per 10 years 0.53, 95% confidence interval [CI] 0.34-0.85), contact with a confirmed case (OR 197.02, 95% CI 56.36-688.79), residence in Barcelona (OR 2.23, 95% CI 1.03-4.80), MS duration (OR per 5 years 1.41, 95% CI 1.09-1.83) and time on anti-CD20 treatment (OR per 2 years 3.48, 95% CI 1.44-8.45) were independent factors for presenting COVID-19 and age (OR per 10 years 2.71, 95% CI 1.13-6.53) for a severe COVID-19. Out of the 79 (84.9%) with serological test, 45.6% generated antibodies, but only 17.6% of those on anti-CD20 therapies. Lymphopaenia or immunoglobulin levels did not relate to COVID-19. Conclusions Multiple sclerosis patients present similar incidence, risk factors and outcomes for COVID-19 as the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be at a higher risk of COVID-19 and less than 20% generate an antibody response. Only age was related to severity.

Neurological outcome and quality of life 3 months after COVID-19: A prospective observational cohort study.

Abstract: BACKGROUND AND PURPOSE: To assess neurological manifestations and health-related quality of life (QoL) 3 months after COVID-19. METHODS: In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16-item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36-item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist-5) 3 months after disease onset. RESULTS: Of 135 consecutive COVID-19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3-month follow-up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID-19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain-Barre syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3-month follow-up. Self-reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow-up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively. CONCLUSIONS: Despite recovery from the acute infection, neurological symptoms were prevalent at the 3-month follow-up. Above all, smelling disorders were persistent in a large proportion of patients.

European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.

Abstract: Objective To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Results Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).

Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis.

Abstract: Background and purpose Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection predisposes patients to arterial and venous thrombosis. This study aimed to systematically review the available evidence in the literature for cerebral venous thrombosis (CVT) in association with coronavirus disease-2019 (COVID-19). Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases to identify cases of COVID-19-associated CVT. The search period spanned 1 January 2020 to 1 December 2020, and the review protocol (PROSPERO-CRD42020214327) followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Identified studies were evaluated for bias using the Newcastle-Ottawa scale. A proportion meta-analysis was performed to estimate the frequency of CVT among hospitalized COVID-19 patients. Results We identified 57 cases from 28 reports. Study quality was mostly classified as low. CVT symptoms developed after respiratory disease in 90%, and the mean interval was 13 days. CVT involved multiple sites in 67% of individuals, the deep venous system was affected in 37%, and parenchymal hemorrhage was found in 42%. Predisposing factors for CVT beyond SARS-CoV-2 infection were present in 31%. In-hospital mortality was 40%. Using data from 34,331 patients, the estimated frequency of CVT among patients hospitalized for SARS-CoV-2 infection was 0.08% (95% confidence interval [CI]: 0.01-0.5). In an inpatient setting, CVT accounted for 4.2% of cerebrovascular disorders in individuals with COVID-19 (cohort of 406 patients, 95% CI: 1.47-11.39). Conclusions Cerebral venous thrombosis in the context of SARS-CoV-2 infection is a rare, although there seems to be an increased relative risk. High suspicion is necessary, because the diagnosis of this potentially life-threatening condition in COVID-19 patients can be challenging. Evidence is still scarce on the pathophysiology and potential prevention of COVID-19-associated CVT.

Long‐term efficacy and safety of erenumab in migraine prevention: results from a 5‐year, open‐label treatment phase of a randomized clinical trial

Abstract: Background and purpose Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long-term therapy. Methods This study was an open-label, 5-year treatment phase following a 12-week, double-blind, placebo-controlled trial in adults with episodic migraine. Patients initially received open-label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine-specific medication (AMSM) days, and health-related quality of life. Results Of 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open-label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was -5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was -4.4 (0.3) days at the end of 5 years. Patient-reported outcomes indicated stable improvements in disability, headache impact, and migraine-specific quality of life. Exposure-adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient-years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient-years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure. Conclusions Treatment with erenumab was associated with reductions in migraine frequency and improvements in health-related quality of life that were maintained for at least 5 years. No new safety signals were observed.

Cognitive decline among individuals with history of mild symptomatic SARS-CoV-2 infection: A longitudinal prospective study nested to a population cohort.

Abstract: Background and purpose Neurological complications of SARS-CoV-2 infection are noticed among critically ill patients soon after disease onset. Information on delayed neurological sequelae of SARS-CoV-2 infection is nil. Following a longitudinal study design, the occurrence of cognitive decline among individuals with a history of mild symptomatic SARS-CoV-2 infection was assessed. Methods Stroke- and seizure-free Atahualpa residents aged ≥40 years, who had pre-pandemic cognitive assessments as well as normal brain magnetic resonance imaging and electroencephalogram recordings, underwent repeated evaluations 6 months after a SARS-CoV-2 outbreak infection in Atahualpa. Patients requiring oxygen therapy, hospitalization, and those who had initial neurological manifestations were excluded. Cognitive decline was defined as a reduction in the Montreal Cognitive Assessment (MoCA) score between the post-pandemic and pre-pandemic assessments that was ≥4 points greater than the reduction observed between two pre-pandemic MoCAs. The relationship between SARS-CoV-2 infection and cognitive decline was assessed by fitting logistic mixed models for longitudinal data as well as exposure-effect models. Results Of 93 included individuals (mean age 62.6 ± 11 years), 52 (56%) had a history of mild symptomatic SARS-CoV-2 infection. Post-pandemic MoCA decay was worse in seropositive individuals. Cognitive decline was recognized in 11/52 (21%) seropositive and 1/41 (2%) seronegative individuals. In multivariate analyses, the odds for developing cognitive decline were 18.1 times higher among SARS-CoV-2 seropositive individuals (95% confidence interval 1.75-188; p = 0.015). Exposure-effect models confirmed this association (β = 0.24; 95% confidence interval 0.07-0.41; p = 0.006). Conclusions This study provides evidence of cognitive decline among individuals with mild symptomatic SARS-CoV-2 infection. The pathogenesis of this complication remains unknown.

Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity.

Abstract: Background and purpose Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. Methods Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. Results Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. Conclusions Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.

Encephalitis as a neurological complication of COVID-19: A systematic review and meta-analysis of incidence, outcomes, and predictors.

Abstract: Background and purpose Although COVID-19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to COVID-19 infection. Encephalitis is an inflammatory condition of the brain that has been described as a severe neurological complication of COVID-19. Despite a growing number of reported cases, encephalitis related to COVID-19 infection has not been adequately characterised. To address this gap, this systematic review and meta-analysis aims to describe the incidence, clinical course, and outcomes of patients who suffer from encephalitis as a complication of COVID-19. Methods All studies published between 1 November 2019 and 24 October 2020 that reported on patients who developed encephalitis as a complication of COVID-19 were included. Only cases with radiological and/or biochemical evidence of encephalitis were included. Results In this study, 610 studies were screened and 23 studies reporting findings from 129,008 patients, including 138 with encephalitis, were included. The average time from diagnosis of COVID-19 to onset of encephalitis was 14.5 days (range = 10.8-18.2 days). The average incidence of encephalitis as a complication of COVID-19 was 0.215% (95% confidence interval [CI] = 0.056%-0.441%). The average mortality rate of encephalitis in COVID-19 patients was 13.4% (95% CI = 3.8%-25.9%). These patients also had deranged clinical parameters, including raised serum inflammatory markers and cerebrospinal fluid pleocytosis. Conclusions Although encephalitis is an uncommon complication of COVID-19, when present, it results in significant morbidity and mortality. Severely ill COVID-19 patients are at higher risk of suffering from encephalitis as a complication of the infection.

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

Abstract: BACKGROUND Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. We report clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency (EMA). METHODS Data on Adverse Drug Reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. We compared post-vaccination CVST to 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium. RESULTS We identified 213 CVST cases: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19), vaccination and 26 after a mRNA vaccine (25 Pfizer/BioNTech, BNT162b2 and 1 Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95%CI 50-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95%CI 0-13%), and in 7/100 (7%, 95%CI 3-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, there were 39 (21%) reported COVID-19 PCR tests performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95%CI 29-47%) had died, compared to 2/10 (20%, 95%CI 6-51%) in the mRNA vaccine group and 3/100 (3%, 95%CI 1-8%) in the pre-COVID-19 group. Mortality among patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95%CI 39-60%). CONCLUSIONS CVST occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 was associated with thrombocytopenia.

Neurological autoimmune diseases following vaccinations against SARS-CoV-2: a case series.

Abstract: BACKGROUND AND PURPOSE: Population-based studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may trigger immune-mediated thrombotic thrombocytopenia (VITT) raising concerns for other autoimmune responses. The aim was to characterize neurological autoimmunity after SARS-CoV-2 vaccinations. METHODS: In this single-centre prospective case study patients with neurological autoimmunity in temporal association (≤6 weeks) with SARS-CoV-2 vaccinations and without other triggers are reported. Clinical, laboratory and imaging data were collected with a median follow-up of 49 days. RESULTS: In the study period 232,603 inhabitants from the main catchment area of our hospital (Rhein-Neckar-Kreis, county) received SARS-CoV-2 vaccinations. Twenty-one cases (new onset n = 17, flares n = 4) diagnosed a median of 11 days (range 3-23) following SARS-CoV-2 vaccinations (BNT162b2 n = 12, ChAdOx1 n = 8, mRNA-1273 n = 1) were identified. Cases included VITT with cerebral venous sinus thrombosis (n = 3), central nervous system demyelinating diseases (n = 8), inflammatory peripheral neuropathies (n = 4), myositis (n = 3), myasthenia (n = 1), limbic encephalitis (n = 1) and giant cell arteritis (n = 1). Patients were predominantly female (ratio 3.2:1) and the median age at diagnosis was 50 years (range 22-86). Therapy included administration of steroids (n = 15), intravenous immunoglobulins in patients with Guillain-Barre syndrome or VITT (n = 4), plasma exchange in cases unresponsive to steroids (n = 3) and anticoagulation in VITT. Outcomes were favourable with partial and complete remissions achieved in 71% and 24%, respectively. Two patients received their second vaccination without further aggravation of autoimmune symptoms under low-dose immunosuppressants. CONCLUSIONS: In this study various neurological autoimmune disorders encountered following SARS-CoV-2 vaccinations are characterized. Given the assumed low incidence and mostly favourable outcome of autoimmune responses, the benefits of vaccinations outweigh the comparatively small risks.

Prevalence, clinical characteristics and outcomes of Guillain-Barré syndrome spectrum associated with COVID-19: a systematic review and meta-analysis.

Abstract: BACKGROUND AND PURPOSE: Mounting evidence supports an association between Guillain-Barre syndrome spectrum (GBSs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, GBSs in the setting of coronavirus disease 2019 (COVID-19) remains poorly characterized, whilst GBSs prevalence amongst COVID-19 patients has not been previously systematically evaluated using a meta-analytical approach. METHODS: A systematic review and meta-analysis of observational cohort and case series studies reporting on the occurrence, clinical characteristics and outcomes of patients with COVID-19-associated GBSs was performed. A random-effects model was used to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs), compared to non-COVID-19, contemporary or historical GBSs patients. RESULTS: Eighteen eligible studies (11 cohorts, seven case series) were identified including a total of 136,746 COVID-19 patients. Amongst COVID-19 patients, including hospitalized and non-hospitalized cases, the pooled GBSs prevalence was 0.15‰ (95% CI 0%-0.49‰; I2 = 96%). Compared with non-infected contemporary or historical controls, patients with SARS-CoV-2 infection had increased odds for demyelinating GBSs subtypes (OR 3.27, 95% CI 1.32%-8.09%; I2 = 0%). In SARS-CoV-2-infected patients, olfactory or concomitant cranial nerve involvement was noted in 41.4% (95% CI 3.5%-60.4%; I2 = 46%) and 42.8% (95% CI 32.8%-53%; I2 = 0%) of the patients, respectively. Clinical outcomes including in-hospital mortality were comparable between COVID-19 GBSs patients and non-infected contemporary or historical GBSs controls. CONCLUSION: GBSs prevalence was estimated at 15 cases per 100,000 SARS-CoV-2 infections. COVID-19 appears to be associated with an increased likelihood of GBSs and with demyelinating GBSs variants in particular.

European guideline and expert statements on the management of narcolepsy in adults and children.

Abstract: Background and aim Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. Methods The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. Results A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. Conclusion The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

Abstract: BACKGROUND AND PURPOSE Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I$^{2}$ statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I$^{2}$ = 0%, P = 0.82). CONCLUSIONS Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.

Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature.

Abstract: Background Headache is identified as a common post-COVID sequela experienced by COVID-19 survivors. The aim of this pooled analysis was to synthesize the prevalence of post-COVID headache in hospitalized and non-hospitalized patients recovering from SARS-CoV-2 infection. Methods MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers, were searched up to 31 May 2021. Studies or preprints providing data on post-COVID headache were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Random effects models were used for meta-analytical pooled prevalence of post-COVID headache. Data synthesis was categorized at hospital admission/symptoms' onset, and at 30, 60, 90, and ≥180 days afterwards. Results From 9573 studies identified, 28 peer-reviewed studies and 7 preprints were included. The sample was 28,438 COVID-19 survivors (12,307 females; mean age: 46.6, SD: 17.45 years). The methodological quality was high in 45% of the studies. The overall prevalence of post-COVID headache was 47.1% (95% CI 35.8-58.6) at onset or hospital admission, 10.2% (95% CI 5.4-18.5) at 30 days, 16.5% (95% CI 5.6-39.7) at 60 days, 10.6% (95% CI 4.7-22.3) at 90 days, and 8.4% (95% CI 4.6-14.8) at ≥180 days after onset/hospital discharge. Headache as a symptom at the acute phase was more prevalent in non-hospitalized (57.97%) than in hospitalized (31.11%) patients. Time trend analysis showed a decreased prevalence from the acute symptoms' onset to all post-COVID follow-up periods which was maintained afterwards. Conclusion This meta-analysis found that the prevalence of post-COVID headache ranged from 8% to 15% during the first 6 months after SARS-CoV-2 infection.

Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: A critical systematic review.

Abstract: BACKGROUND AND PURPOSE: Neuropathological studies can elucidate the mechanisms of nervous system damage associated with SARS-CoV-2 infection. Despite literature on this topic is rapidly expanding, correlations between neurological symptoms and brain pathology findings in COVID-19 patients remain largely unknown. METHODS: We performed a systematic literature review on neuropathological studies in COVID-19, including 438 patients from 45 articles published by April 22, 2021. We retrieved quantitative data regarding demographic, clinical, and neuropathological findings. We carried out a Wilcoxon rank sum test or χ2 test to compare patients' subgroups based on different clinical and brain pathology features. RESULTS: Neuropathological findings in COVID-19 patients were microgliosis (52.5%), astrogliosis (45.6%), inflammatory infiltrates (44.0%), hypoxic-ischemic lesions (40.8%), edema (25.3%), and hemorrhagic lesions (20.5%). SARS-CoV-2 RNA and proteins were identified in brain specimens of 41.9% and 28.3% of subjects, respectively. Detailed clinical information was available from 245 patients (55.9%), and among them, 96 subjects (39.2%) had presented with neurological symptoms in association with typical COVID-19 manifestations. We found that: (i) the detection rate of SARS-CoV-2 RNA and proteins in brain specimens did not differ between patients with versus those without neurological symptoms; (ii) brain edema, hypoxic-ischemic lesions, and inflammatory infiltrates were more frequent in subjects with neurological impairment; (iii) neurological symptoms were more common among older individuals. CONCLUSIONS: Our systematic revision of clinical correlates in COVID-19 highlights the pathogenic relevance of brain inflammatory reaction and hypoxic-ischemic damage rather than neuronal viral load. This analysis indicates that a more focused study design is needed, especially in the perspective of potential therapeutic trials.

Predictive factors for a severe course of COVID-19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival.

Abstract: Background and purpose Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID-19) mainly due to respiratory muscle weakness, older age and long-term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID-19 in MG patients and risk of MG exacerbation during COVID-19. Methods We evaluated clinical features and outcomes after COVID-19 in 93 MG patients. Results Thirty-five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID-19. Higher forced vital capacity (FVC) values tested before COVID-19 were shown to be protective against severe infection (95% CI 0.934-0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047-1.232). Long-term chronic corticosteroid treatment worsened the course of COVID-19 in MG patients (95% CI 1.784-111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448-2.935), mycophenolate mofetil (95% CI 0.91-12.515) and ciclosporin (95% CI 0.029-2.212) did not influence the course of COVID-19. MG patients treated with rituximab had a high risk of death caused by COVID-19 (95% CI 3.216-383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885-10.87). Conclusions As the most important predictors of severe COVID-19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long-term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.

COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.

Abstract: Background in multiple sclerosis (MS), disease-related factors and dysfunctional coping might favour the development of mental distress induced by COVID-19 containment measures. Methods we explored the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown. Structural equation modeling (SEM) was applied to information collected via web-survey to identify modifiable factors that could account for mental distress. Results 845 subjects (497 MS and 348 controls) were included in the study. MS patients showed higher scores than controls for depression (p=0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The SEM explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (β=0.509 and β=0.836, p Conclusion as practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool to face COVID-19 related mental distress.

European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment:

Abstract: The optimal management of post-stroke cognitive impairment remains controversial. These joint European Stroke Organisation (ESO) and European Academy of Neurology (EAN) guidelines provide evidence-...

Safety of the BNT162b2 COVID-19 vaccine in multiple sclerosis (MS): Early experience from a tertiary MS center in Israel.

Abstract: Background and purpose Although the COVID-19 vaccines are currently recommended for people with multiple sclerosis (MS), the fact that they were not specifically tested in people with MS raises uncertainty regarding their safety in this population. The purpose of this study was to report real-life safety data of the BNT162b2 COVID-19 vaccine in a cohort of MS patients. Methods An anonymous survey was distributed to 425 MS patients. Participants were asked general demographic and disease-related questions and specific questions regarding the safety profile of the COVID-19 vaccine. Results Of the 425 MS patients, 262 completed the questionnaire. The median (range) participant age was 42 (22-79) years, 199 participants were women (75.9%), and 66 participants (25.2%) had associated comorbidities. A total of 198 participants (75.6%) were treated with disease-modifying therapies. In all, 239 participants (91.2% of the responders) had received the BNT162b2 COVID-19 vaccine. Of these, 182 (76.1%) were aged 55 years. Adverse events were reported by 136 participants (56.9%; 52.5% of those aged 55 years; p = 0.1517) and 36 participants (15.1%) reported new or worsening neurological symptoms following the vaccination, the most frequent being sensory disturbances (21 participants, 58.3%). Most symptoms occurred within the first 24 h after vaccination and resolved within 3 days. A total of 28 participants (77.8%) did not require any medication to treat their symptoms. Conclusions This survey indicates an overall favorable safety profile of the BNT162b2 vaccine in people with MS. These data should be confirmed in further prospective, large-scale studies.

Functional motor disorders associated with other neurological diseases: Beyond the boundaries of "organic" neurology.

Abstract: Background and purpose The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid FMDs"), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases ("pure FMDs"). Methods For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables). Results Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non-neurological comorbidities. Conclusions Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non-neurological diseases.

Muscle involvement in SARS-CoV-2 infection.

Abstract: BACKGROUND AND PURPOSE: Since the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several reports indicated neurological involvement in COVID-19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia. METHODS: Creatine kinase, markers of inflammation, pre-existing diseases and statin use were extracted from records of Austrian hospitalised COVID-19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID-19 patients were additionally compared to an historical group of hospitalised influenza patients. RESULTS: Three hundred fifty-one patients with SARS-CoV-2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID-19 and in 28% of influenza patients. CK was higher in severe COVID-19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID-19 patients were older, more frequently male, had more comorbidities, and more frequently had a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID-19, and 35.7% of intensive care unit (ICU)-admitted patients had CK levels >1000 U/l compared to only 4.7% of ICU-admitted COVID-19 patients. CONCLUSIONS: HyperCKemia occurs in a similar frequency in COVID-19 and influenza infection. CK levels were lower in COVID-19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date, it remains unclear whether hyperCKemia is due to a virus-triggered inflammatory response or direct muscle toxicity.

Olfactory bulb and mucosa abnormalities in persistent COVID-19 induced anosmia: a Magnetic Resonance Imaging study.

Abstract: The olfactory effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that causes the novel coronavirus disease 2019 (COVID-19), have been well documented among other neurologic manifestations. Although olfaction recovers within a few days in most cases, some patients develop a more protracted course of olfactory impairment, lasting for several weeks. To date, there are no reports on Magnetic Resonance Imaging (MRI) findings in patients with persistent anosmia or hyposmia due to COVID-19. Hence, we performed a pilot case control study on MRI findings in recovered COVID-19 patients with protracted olfactory dysfunction.

The European Academy of Neurology COVID-19 registry (ENERGY): an international instrument for surveillance of neurological complications in patients with COVID-19.

Abstract: The COVID-19 pandemic is a global public health issue. Neurological complications have been reported in up to one-third of affected cases, but their distribution varies significantly in terms of prevalence, incidence and phenotypical characteristics. Variability can be mostly explained by the differing sources of cases (hospital vs. community-based), the accuracy of the diagnostic approach, and the interpretation of the patients' complaints. Moreover, after recovering, patients can still experience neurological symptoms. To obtain a more precise picture of the neurological manifestations and outcome of the COVID-19 infection, an international registry (ENERGY) has been created by the European Academy of Neurology (EAN) in collaboration with European national neurological societies and the Neurocritical Care Society and Research Network (NCRN). ENERGY can be implemented as a stand-alone instrument for patients with suspected or confirmed COVID-19 patients AND neurological findings or as an addendum to an existing registry not targeting neurologic symptoms. Data are also collected to study the impact of neurological symptoms and neurological complications on outcomes. The variables included in the registry have been selected in the interest of most countries, to favour pooling with data from other sources, and to facilitate data collection even in resource-poor countries. Included are adults with suspected or confirmed COVID-19 infection, ascertained through neurological consultation, and providing informed consent. Key demographic and clinical findings are collected at registration. Patients are followed up to 12 months in search of incident neurological manifestations. As of August 19, 254 centres from 69 countries and four continents have made requests to join the study.

Rapid onset of functional tic-like behaviours in young adults during the COVID-19 pandemic.

Abstract: BACKGROUND AND PURPOSE: Clinicians have reported an increase in functional tic-like behaviours in children and youth during the COVID-19 pandemic. We describe adults developing rapid onset of functional tic-like behaviours between May 2020 and June 2021. METHODS: Data were analysed from the Adult Tic Disorders Registry, a single-site,12-month prospective cohort study that began enrolment in January 2021. We compared clinical features of participants with Tourette syndrome or persistent motor/vocal tic disorder to participants with rapid onset tic-like behaviours. RESULTS: Thirty-three participants registered between January and June of 2021; nine had rapid onset tic-like behaviours, and 24 had Tourette syndrome or persistent motor tic disorder. Participants with rapid onset tic-like behaviours were younger (19.9 vs. 38.6 years, p = 0.003), had older age at onset (15.3 vs. 10.1, p = 0.0009), and were more likely female (p < 0.0001). They had higher motor and vocal tic severity and impairment scores (all p < 0.01) and were more likely to have complex arm/hand motor tics (p < 0.0001), complex vocal tics (p < 0.0001), and coprolalia (p = 0.004). They had significantly higher scores on all mental health symptom self-report measures (all p < 0.05) and were significantly more likely to be diagnosed with depression (p = 0.03). CONCLUSIONS: The clinical features that help differentiate rapid onset tic-like behaviours from Tourette syndrome or persistent motor tic disorder include their phenomenology, onset age, and clinical course. Rapid onset tic-like behaviours are a distinct subtype of functional neurological disorder that has emerged during the COVID-19 pandemic in young people and appears to be strongly socially influenced.

Subthalamic beta band suppression reflects effective neuromodulation in chronic recordings.

Abstract: BACKGROUND AND PURPOSE Biomarkers for future adaptive deep brain stimulation still need evaluation in clinical routine. Here, we aimed to assess stimulation-induced modulation of beta-band activity and clinical symptoms in a Parkinson's disease patient during chronic neuronal sensing using a novel implantable pulse generator. METHODS Subthalamic activity was recorded OFF and ON medication during a stepwise increase of stimulation amplitude. Off-line fast fourier transfom -based analysis of beta-band activity was correlated with motor performance rated from blinded videos. RESULTS The stepwise increase of stimulation amplitude resulted in decreased beta oscillatory activity and improvement of bradykinesia. Mean low beta-band (13-20 Hz) activity correlated significantly with bradykinesia (ρ = 0.662, p < 0.01). CONCLUSIONS Motor improvement is reflected in reduced subthalamic beta-band activity in Parkinson's disease, supporting beta activity as a reliable biomarker. The novel PERCEPT neurostimulator enables chronic neuronal sensing in clinical routine. Our findings pave the way for a personalized precision-medicine approach to neurostimulation.

Headache during SARS-CoV-2 infection as an early symptom associated with a more benign course of disease: a case-control study.

Abstract: BACKGROUND AND PURPOSE: Headache is an important manifestation during SARS-CoV-2 infection. In this study, the aim was to identify factors associated with headache in COVID-19 and headache characteristics. METHODS: This case-control study includes COVID-19 hospitalized patients with pneumonia during March 2020. Controls comprise COVID-19 patients without headache and the cases are COVID-19 patients with headache. Demographic, clinical and laboratory data were obtained from the medical records. Headache characteristics were evaluated by semi-structured telephonic interview after discharge. RESULTS: Of a total of 379 COVID-19 patients, 48 (13%) developed headache. Amongst these, 30 (62%) were men and the median age was 57.9 (47-73) years. Headache was associated with younger age, fewer comorbidities and reduced mortality, as well as with low levels of C-reactive protein, mild acute respiratory distress syndrome and oropharyngeal symptoms. A logistic multiple regression model revealed that headache was directly associated with D-dimer and creatinine levels, the use of high flow nasal cannula and arthromyalgia, whilst urea levels, beta-lactamic treatment and hypertension were negatively associated with headache. COVID-19-associated headache characteristics were available for 23/48 (48%) patients. Headache was the onset symptom in 8/20 (40%) patients, of mild or moderate intensity in 17/20 (85%) patients, with oppressive characteristics in 17/18 (94%) and of holocranial 8/19 (42%) or temporal 7/19 (37%) localization. CONCLUSIONS: Our results show that headache is associated with a more benign SARS-CoV-2 infection. COVID-19-associated headache appears as an early symptom and as a novel headache with characteristics of headache attributed to systemic viral infection. Further research addressing the underlying mechanisms to confirm these findings is warranted.

Multiple sclerosis and COVID-19: how many are at risk?

Abstract: Background and purpose The coronavirus disease 2019 (COVID-19) pandemic challenges neurologists in counseling multiple sclerosis (MS) patients with respect to their risk for and by severe acute respiratory syndrome coronavirus 2 and in guiding disease-modifying treatment (DMT). The objective was to determine the frequency and distribution of currently known risk factors for COVID-19 mortality in an MS population. Methods Multiple sclerosis patients with at least one complete case report between January 1, 2015 and December 31, 2019 from the Innsbruck MS database were cross-sectionally included. Frequencies of currently estimated COVID-19 mortality risk factors were analyzed, and the cumulative risk was calculated by a recently developed score. For every risk group, the proportions of patients under DMT and immunosuppressive treatment were determined. Results Of 1931 MS patients, 63.4% had low risk of COVID-19 mortality, 26% had mild risk, 8.8% had a moderate risk, whereas a combined 0.9% had high or very high risk of COVID-19 mortality. Of the patients at high or very high risk, only one patient received DMT and none had an immunosuppressive therapy. Conclusions In a population-based MS cohort, the proportion of patients at high risk of COVID-19 mortality is below 1%. Importantly, the vast majority of these MS patients did not receive any DMT.

Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination.

Abstract: BACKGROUND AND PURPOSE: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time. METHODS: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published. RESULTS: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died. CONCLUSION: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.

SARS-CoV-2-associated Guillain-Barre syndrome in 62 patients.

Abstract: With interest we read the review article by De Sanctis et al. about 18 patients with Guillain‐Barre syndrome (GBS) associated with the SARS‐CoV‐2 infection (COVID‐19) [1]. Acute, inflammatory, demyelinating polyneuropathy (AIDP) was the most frequent subtype of GBS. We have the following comments and concerns.