SARS-CoV-2 antibodies in inflammatory neurological conditions: a multicentre retrospective comparative study.

It is well established that neurological and non-neurological autoimmune disorders can be triggered by viral infections. It remains unclear whether SARS-CoV-2 infection induces similar conditions and whether they show a distinctive phenotype. We retrospectively identified patients with acute inflammatory CNS conditions referred to our laboratory for antibody testing during the pandemic (March 1 to August 31, 2020). We screened SARS-COV-2 IgA/IgG in all sera by ELISA and confirmed the positivity with additional assays. Clinical and paraclinical data of SARS-COV-2-IgG seropositive patients were compared to those of seronegative cases matched for clinical phenotype, geographical zone, and timeframe. SARS-CoV-2-IgG positivity was detected in 16/339 (4%) sera, with paired CSF positivity in 3/16. 5 of these patients had atypical demyelinating disorders and 11 autoimmune encephalitis syndromes. 9/16 patients had a previous history of SARS-CoV-2 infection and 6 of them were symptomatic. In comparison with 32 consecutive seronegative controls, SARS-CoV-2-IgG-positive patients were older, frequently presented with encephalopathy, had lower rates of CSF pleocytosis and other neurological autoantibodies, and were less likely to receive immunotherapy. When SARS-CoV-2 seropositive versus seronegative cases with demyelinating disorders were compared no differences were seen. Whereas seropositive encephalitis patients less commonly showed increased CSF cells and protein, our data suggest that an antecedent symptomatic or asymptomatic SARS-CoV-2 infection can be detected in patients with autoimmune neurological conditions. These cases are rare, usually do not have specific neuroglial antibodies.

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses.

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the central nervous system (CNS), can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations, and persistence of SARS-CoV-2 reservoirs. In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common Coronaviruses - 229E, HKU1, NL63, OC43) in the serum and cerebrospinal fluid (CSF) from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC, compared to serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2; IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 vs 66.5 years, respectively, p = 0.55; females 33% vs 44%, p = 0.52), but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common Coronaviruses, including 229E, HKU1, NL63, and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an original antigenic sin (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Is there a correlation between MOG-associated disorder and SARS-CoV-2 infection?

BACKGROUND AND PURPOSE: Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) distinguish a group of inflammatory disorders which can be preceded by specific or non-specific infections. A few single cases have been reported in association with SARS-CoV-2 infection, but a specific study on the correlation between COVID-19 and myelin oligodendrocyte glycoprotein (MOG)-associated disorder (MOGAD) has not yet been performed. The aim of this study was to determine the impact of the pandemic on this condition. METHODS: We analysed SARS-CoV-2 serology in patients newly diagnosed with MOGAD (1 August 2020 to 31 May 2021). MOG-Ab-seronegative age- and time-matched subjects were used as controls. SARS-CoV-2 immunoglobulin G (IgG) levels were analysed using an anti-SARS-CoV-2 US Food and Drug Administration-approved ELISA assay and confirmed with a trimeric anti-SARS-CoV-2 S1/S2 IgG immunochemiluminescent test, concomitantly assaying the anti-receptor binding domain (RBD) of spike protein IgG and anti-RBD total Ig. We actually compared the number of cases referred in each of the last 3 years. RESULTS: Presence of SARS-CoV-2 IgG antibodies was more common (12/30, 40%) in MOGAD patients than in controls (6/30, 20%), although the difference was not significant (p = 0.16; odds ratio 2.67, 95% confidence interval 0.85-9.17). The most common clinical presentations of MOGAD SARS-CoV-2-seropositive patients included optic neuritis (n = 6) and myelitis (n = 3). The number of diagnosed cases increased over the last 3 years, in particular, when including cases referred to us before the COVID-19 pandemic, in the initial phase of the first wave and in the late phase of the second wave (n = 9, rate 10.6% in 2019; n = 13, rate 12.3% in 2020; n = 15, rate 14.7% in 2021). CONCLUSION: Our findings provide preliminary data on SARS-CoV-2 as a potential trigger of MOGAD.

Safety profile of SARS-CoV-2 vaccination in patients with antibody-mediated CNS disorders.

OBJECTIVES: In this retrospective multicenter study, we evaluated the safety of SARS-CoV-2 vaccination in patients harboring autoantibodies targeting neuronal surface and/or synaptic antigens. METHODS: From eight Italian Neurology Units, we included patients with: a) serum and/or CSF positivity for specific neuronal autoantibodies; b) a compatible neurological syndrome; and c) available follow-up ≥6 weeks after vaccination with any of the approved SARS-CoV-2 vaccines. Demographics, clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Disease relapses were considered "post-infectious" or "post-vaccination" when occurring within 6 weeks from infection/vaccination. RESULTS: We included 66 patients; 7/66 (11%) had a previous history of SARS-CoV-2 infection and 1/7 (14%) had post-infection relapses. BNT162b2-Pfizer-BioNTec was administered in 55 cases (83.3%) and mRNA-1273-Moderna in 11 (16.7%). The median number of doses administered per patient was 2 (1-3) and >50% of patients did not experience side effects. Five patients (8%) had post-vaccination relapses (seizure 3/5); 4/5 improved after immunotherapy, while one did not receive immunotherapy and worsened. Patients with post-vaccination relapses had higher disability scores at vaccination (p = 0.025), a trend favoring Leucine-rich glioma-inactivated protein 1 LGI1 glutamic acid decarboxylase 65 (GAD65) antibodies (p =  0.054) and shorter time from last relapse (p = 0.057). DISCUSSION: Our data support the safety of SARS-CoV-2 vaccines in patients with neurological disorders associated with antibodies to neuronal and synaptic antigens.

Risk of disease relapse following COVID-19 vaccination in patients with AQP4-IgG-positive NMOSD and MOGAD.

Post-vaccination disease relapses have been reported in patients with MOGAD and AQP4-IgG+NMOSD. In this retrospective multicenter Italian study we assessed the frequency of relapses after SARS-CoV-2 vaccination. We included 56 cases: MOGAD, 30; AQP4-IgG+NMOSD, 26. Vaccines received were BNT162b2-Pfizer-BioNTech in 42 patients and mRNA-1273-Moderna in 14 patients. Six patients had a history of SARS-CoV-2 infection; two of them experienced a post-infection disease relapse (MOGAD). The frequency of relapses within one month of SARS-CoV-2 vaccination was 4% (1/26) in the AQP4-IgG+NMOSD group and 0% in the MOGAD group. In these patients the potential benefits of vaccination overcome the risk of relapses.

SARS-CoV-2 pandemic and epilepsy: The impact on emergency department attendances for seizures.

INTRODUCTION: The risk of acquiring SARS-CoV-2 in a hospital setting and the need of reorganizing the Emergency Departments (EDs) to cope with infected patients have led to a reduction of ED attendances for non-infectious acute conditions and to a different management of chronic disorders. METHODS: We performed a retrospective study evaluating the frequency and features of ED attendances for seizures during the lockdown period (March 10th-April 30th 2020) in the University Hospital of Trieste, Italy. We studied the possible pandemic impact on the way patients with seizures sought for medical assistance by comparing the lockdown period to a matched period in 2019 and to a period of identical length preceding the lockdown (January 18th-March 9th 2020). RESULTS: A striking decrease in total ED attendances was observed during lockdown (4664) compared to the matched control (10424) and to the pre-lockdown (9522) periods. A similar reduction, although to a lesser extent, was detected for seizure attendances to the ED: there were 37 during lockdown and 63 and 44 respectively during the two other periods. Intriguingly, during the lockdown a higher number of patients attended the ED with first seizures (p = 0.013), and more EEGs (p = 0.008) and CT brain scans (p = 0.018) were performed; there was a trend towards more frequent transport to the ED by ambulance (p = 0.061) in the lockdown period. CONCLUSIONS: Our data suggest that the pandemic has affected the way patients with seizures access the Health Care System.