Clinical and Structural Biological Studies of Central Nervous System Inflammatory Demyelinating Diseases Related to COVID-19 Vaccines (preprint)

Various vaccines have been developed in response to the SARS-CoV-2 pandemic, and the safety of vaccines has become an important issue. COVID-19 vaccines-related central nervous system inflammatory demyelinating diseases (CNS IDDs) have been reported recently. We present one case of AstraZeneca vaccine-related myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease and literature review another 78 patients published from January 2020 to October 2022. Patients were divided into three vaccine groups (viral vector, mRNA and inactivated vaccines) for further analyses. Among 79 patients with COVID-19 vaccines-related CNS IDDs, 49 (62%) cases received viral vector vaccines, 20 (25.3%) received mRNA vaccines and 10 (12.7%) received inactivated vaccines. Twenty-seven cases (34.2%) were confirmed with autoantibodies, including 15 patients (19%) with anti-MOG, 11 (13.9%) with anti-aquaporin 4 (AQP4), and one (1.3%) with both antibodies. Significantly, more males developed CNS IDDs post viral vector vaccines compared to mRNA and inactivated vaccines. Patients receiving mRNA vaccines were older than other groups. Furthermore, mRNA and inactivated vaccines correlated more with anti-AQP4 antibodies, while viral vector vaccines showed higher MOG positivity. The research suggests potential associations between COVID-19 vaccines-related CNS IDDs and gender, age, and autoantibodies, contingent on vaccine types. Protein sequence analysis implies similarities between the S protein and AQP4/MOG. Further studies may elucidate the mechanisms of CNS IDDs, aiding vaccine selection for specific groups.

Demyelination in Patients with Post-COVID Depression (preprint)

Depression is one of the most severe sequelae of COVID-19, with major depressive disorder often characterized by disruption in white matter (WM) connectivity , stemming from changes in brain myelination. This study aimed to quantitatively assess brain myelination in clinically diagnosed post-COVID depression using recently proposed MRI method, macromolecular proton fraction (MPF) mapping. The study involved 63 recovered COVID-19 patients (52 mild, 11 moderate, 2 severe) at 13.5±10.0 months post-recovery, with matched controls without prior COVID-19 history (n=19). A post-COVID depression group (PCD, n=25) was identified based on psychiatric diagnosis, while a comparison group (noPCD, n=38) included participants with neurological COVID-19 complications, excluding clinical depression. Fast MPF mapping revealed extensive demyelination in PCD patients, particularly in juxtacortical WM (predominantly occipital lobe and medial surface), WM tracts (inferior fronto-occipital fasciculus (IFOF), posterior thalamic radiation, external capsule, sagittal stratum, tapetum), and grey matter (GM) structures (hippocampus, putamen, globus pallidus, and amygdala). The noPCD group also displayed notable demyelination but with less magnitude and propagation. Multiple regression analysis highlighted IFOF demyelination as the primary predictor of PCD presence and severity according to Hamilton scores. The number of post-COVID symptoms was a significant predictor of PCD presence while the number acute of symptoms was a significant predictor of PCD severity. This study, for the first time, reveals extensive demyelination in numerous WM and GM structures in PCD, outlining IFOF demyelination as a key biomarker.

Critical role of TLR activation in viral replication, persistence, and pathogenicity of Theiler's virus.

Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1ß, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4+ T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.

The impact of the COVID-19 pandemic on neuropsychiatric and sleep disorders, and quality of life in individuals with neurodegenerative and demyelinating diseases: a systematic review and meta-analysis of observational studies.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected the mental health, sleep and quality of life, especially in individuals with chronic disease. Therefore, the purpose of this systematic review and meta-analysis was to investigate the impact of the COVID-19 pandemic on neuropsychiatric disorders (depression, anxiety, stress), sleep disorders (sleep quality, insomnia) and quality of life in individuals with Parkinson's disease (PD), Multiple Sclerosis (MS) and Alzheimer's disease (AD) compared to healthy controls. METHODS: Seven databases (Medline, Embase, ScienceDirect, Web of Science, The Cochrane Library, Scielo and Lilacs) were searched between March 2020 and December 2022. Observational studies (i.e., cross-sectional, case-control, cohort) were included. GRADE approach was used to assess the quality of evidence and strength of the recommendation. Effect size was calculated using standardized mean differences (SMD; random effects model). A customized Downs and Black checklist was used to assess the risk of bias. RESULTS: Eighteen studies (PD = 7, MS = 11) were included. A total of 627 individuals with PD (healthy controls = 857) and 3923 individuals with MS (healthy controls = 2432) were analyzed. Twelve studies (PD = 4, MS = 8) were included in the meta-analysis. Individuals with PD had significantly elevated levels of depression (very low evidence, SMD = 0.40, p = 0.04) and stress (very low evidence, SMD = 0.60, p < 0.0001). There was no difference in anxiety (p = 0.08). Individuals with MS had significantly higher levels of depression (very low evidence, SMD = 0.73, p = 0.007) and stress (low evidence, SMD = 0.69, p = 0.03) and low quality of life (very low evidence, SMD = 0.77, p = 0.006). There was no difference in anxiety (p = 0.05) and sleep quality (p = 0.13). It was not possible to synthesize evidence in individuals with AD and sleep disorder (insomnia). CONCLUSION: In general, the COVID-19 pandemic negatively impacted individuals with PD and MS. Individuals with PD showed significantly higher levels of depression and stress; and individuals with MS presented significantly higher depression and stress levels, as well as significantly lower quality of life when compared to healthy controls. Further studies are needed to investigate the impact of the COVID-19 pandemic in individuals with AD.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Inducible nitric oxide synthase deficiency promotes murine-ß-coronavirus induced demyelination.

BACKGROUND: Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by activated neuroglial cells, CNS infiltrating leukocytes, and their reciprocal interactions through inflammatory signals. An inflammatory stimulus triggers inducible nitric oxide synthase (NOS2), a pro-inflammatory marker of microglia/macrophages (MG/Mφ) to catalyze sustained nitric oxide production. NOS2 during neuroinflammation, has been associated with MS disease pathology; however, studies dissecting its role in demyelination are limited. We studied the role of NOS2 in a recombinant ß-coronavirus-MHV-RSA59 induced neuroinflammation, an experimental animal model mimicking the pathological hallmarks of MS: neuroinflammatory demyelination and axonal degeneration. OBJECTIVE: Understanding the role of NOS2 in murine-ß-coronavirus-MHV-RSA59 demyelination. METHODS: Brain and spinal cords from mock and RSA59 infected 4-5-week-old MHV-free C57BL/6 mice (WT) and NOS2-/- mice were harvested at different disease phases post infection (p.i.) (day 5/6-acute, day 9/10-acute-adaptive and day 30-chronic phase) and compared for pathological outcomes. RESULTS: NOS2 was upregulated at the acute phase of RSA59-induced disease in WT mice and its deficiency resulted in severe disease and reduced survival at the acute-adaptive transition phase. Low survival in NOS2-/- mice was attributed to (i) high neuroinflammation resulting from increased accumulation of macrophages and neutrophils and (ii) Iba1 + phagocytic MG/Mφ mediated-early demyelination as observed at this phase. The phagocytic phenotype of CNS MG/Mφ was confirmed by significantly higher mRNA transcripts of phagocyte markers-CD206, TREM2, and Arg1 and double immunolabelling of Iba1 with MBP and PLP. Further, NOS2 deficiency led to exacerbated demyelination at the chronic phase as well. CONCLUSION: Taken together the results imply that the immune system failed to control the disease progression in the absence of NOS2. Thus, our observations highlight a protective role of NOS2 in murine-ß-coronavirus induced demyelination.

Post-Vaccination/Post-COVID Immune-Mediated Demyelination of the Brain and Spinal Cord: A Novel Neuroimaging Finding.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which not only produces respiratory symptoms but is known to involve almost every system, and its neuroinvasive properties have been well demonstrated throughout the pandemic. Also, to combat the pandemic, there was rapid development and induction of various vaccination drives, following which many adverse events following immunization (AEFIs) have been reported, which include neurological complications as well. Method: We present a series of three cases, post vaccination, with and without a history of COVID illness that showed remarkably similar findings on magnetic resonance imaging (MRI). Result: A 38-year-old male presented with complaints of weakness of the bilateral lower limbs with sensory loss and bladder disturbance a day after receiving his first dose of ChadOx1 nCoV-19 (COVISHIELD) vaccine. A 50-year-old male with hypothyroidism characterized by autoimmune thyroiditis and impaired glucose tolerance experienced difficulty in walking 11.5 weeks after being administered with COVID vaccine (COVAXIN). A 38-year-old male presented with subacute onset progressive symmetric quadriparesis 2 months after their first dose of a COVID vaccine. The patient also had sensory ataxia, and his vibration sensation was impaired below C7. All three patients had typical pattern of involvement of the brain and spine on MRI with signal changes in bilateral corticospinal tracts, trigeminal tracts in the brain, and both lateral and posterior columns in the spine. Conclusion: This pattern of brain and spine involvement on MRI is a novel finding and is likely a result of post-vaccination/post-COVID immune-mediated demyelination.

Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies.

Demyelinating diseases are a group of pathologies characterized by the alteration of myelin-that is, the coating that wraps around most of the nerve fibres of the central and peripheral nervous system, whose goal is the improvement of nerve conduction and the preservation of energy spent during action potential propagation [...].

Safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of central nervous system: A single center experience.

Introduction: Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS. Materials and methods: Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Results: We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms. Discussion: COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD.

Progressive multifocal leukoencephalopathy in a patient with B-cell chronic lymphocytic leukemia after Covid 19 vaccination, complicated with Covid-19 and mucormycosis: a case report (preprint)

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral demyelinating infectious disease of the central nervous system (CNS) which is rare & fetal. There is various clinical presenting symptoms for the disease. Case presentation: This paper presents a clinical case of PML in a patient with B-CLL in remission, previously treated with Chlorambucil that complicated later in disease course with Covid-19 and mucormycosis. Conclusion: like many other viruses, the more relevant immune-competent cells in host defense against JCV, appear to be T cells. This issue is recently also suggested in Covid 19 patients which a dissociation between severity and seroconversion has been reported. The case reported due to its rarity and multiple challenges in its diagnosis and treatment.

Demyelinating Disorders Following COVID-19 Vaccines, a VAERS-Based Study (preprint)

Introduction: The rapid emergence of COVID-19 as a global crisis has led to the approval of many vaccinations, which were unfortunately associated with high complication rates due to a lack of sufficient safety studies. Objectives: The following manuscript focuses on discussing the demyelinating disorders that were noticed after COVID vaccine administration. Methods: We conducted a retrospective study using anonymous medical records from the US vaccine adverse events reporting system, complications retrieved included Acute disseminated encephalomyelitis (ADEM), Guillain Barre syndrome (GBS), and Multiple sclerosis (MS), outcome parameters were age, sex and the dose after which this complication was observed. Patients younger than 18 years-old were excluded as some of the vaccines, namely Janssen (JNJ-78436735) is not yet approved below this age. Results: Our analysis showed that demyelinating disorders were more likely to occur in patients over the age of 50 compared to other age groups, regardless of the type of vaccination, except for MS and ADEM occurrences after the Jansen vaccine. In addition, demyelinating complications were more likely to occur after the first dose of vaccination. Conclusion: Further research and observation of demyelinating diseases in different vaccinations, as well as additional in vitro studies, are recommended to further explain the pathogenesis of demyelinating disorder occurrence.

CNS demyelinating disease following inactivated or viral vector SARS-CoV-2 vaccines: A case series.

BACKGROUND: Several reports have been documented in possible association with the administration of different severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccines and central nervous system (CNS)demyelinating disorders, specifically post mRNA vaccines. We report twelve cases of developing Multiple sclerosis (MS) or Neuromyelitis Optica spectrum disorders (NMOSD) following neither the first nor second dose of inactivated or viral vector COVID-19 vaccine. METHODS: We retrospectively compiled twelve patients' medical information with a new onset of MS or NMOSD in their first six weeks following a COVID-19 vaccine. RESULTS: We report twelve cases of MS (n = 9), clinically isolated syndrome (CIS)(n = 1), and NMOSD (n = 2) following COVID-19 inactivated vaccines (n = 11) or viral vector vaccines (n = 1), within some days following either the first (n = 3), second dose (n = 8), or third dose (n = 1). Their median age was 33.3 years, ranging from 19 to 53 years. Ten were women (83 %). All patients fully (n = 5) or partially (n = 2) recovered after receiving 3 doses of Corticosteroids. Common medications were Natalizumab, Teriflunomide, Dimethyl fumarate, and Rituximab. Also, Interferon beta 1-a was administered to one patient with severe symptoms of numbness. CONCLUSION: Our case series identifies the Sinopharm BBIBP-CorV and the AstraZeneca AZD1222 vaccines as potential triggers for CNS demyelinating diseases. Vaccine administration routines are not affected by these rare and coincidental events. However, these manifestations are not deniable and require serious attention. Further investigations are needed to clarify the actual mechanisms and real associations.

Sustained Infiltration of Neutrophils Into the CNS Results in Increased Demyelination in a Viral-Induced Model of Multiple Sclerosis.

Intracranial inoculation of the neuroadapted JHM strain of mouse hepatitis virus (JHMV) into susceptible strains of mice results in acute encephalomyelitis followed by a cimmune-mediated demyelination similar to the human demyelinating disease multiple sclerosis (MS). JHMV infection of transgenic mice in which expression of the neutrophil chemoattractant chemokine CXCL1 is under the control of a tetracycline-inducible promoter active within GFAP-positive cells results in sustained neutrophil infiltration in the central nervous system (CNS) that correlates with an increase in spinal cord demyelination. We used single cell RNA sequencing (scRNAseq) and flow cytometry to characterize molecular and cellular changes within the CNS associated with increased demyelination in transgenic mice compared to control animals. These approaches revealed the presence of activated neutrophils as determined by expression of mRNA transcripts associated with neutrophil effector functions, including CD63, MMP9, S100a8, S100a9, and ASPRV1, as well as altered neutrophil morphology and protein expression. Collectively, these findings reveal insight into changes in the profile of neutrophils associated with increased white matter damage in mice persistently infected with a neurotropic coronavirus.

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology (preprint)

Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, however, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1-/-) and the other with dampened IFN-I response (hACE2; Ifnar1-/-) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2; Irgm1-/- mice were resistant to lethal SARS-CoV-2 (including delta variant) infection with substantially reduced cytokine storm and immunopathology in the lungs and brain. In striking contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2; Ifnar1-/- mice. Additionally, hACE2; Ifnar1-/- mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2; Irgm1-/- Ifnar1-/- double knockout mice or hACE2; Irgm1-/- mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2; Irgm1-/- mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against COVID-19.

Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. METHODS: Wild-type (WT) and Trem2 deficient (Trem2-/-) mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. RESULTS: BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2-/- mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. CONCLUSIONS: Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.

Clinical onset of CNS demyelinating disease after COVID-19 vaccination: denovo disease?

BACKGROUND: Clinical onset of multiple sclerosis (MSpostvacc) and myelin-oligodendrocyte-glycoprotein-antibody-associated disease (MOGADpostvacc) has been reported in association with SARS-CoV-2-vaccination. There is uncertainty as to whether this is causality (denovo disease) or temporal coincidence (manifestation of a preexisting, subclinical neuroinflammation). OBJECTIVES: Comparing the clinical characteristics of MSpostvacc-patients versus patients with MS (PwMS) whose clinical onset occurred independently of vaccination (MSreference). METHODS: Consecutive patients with clinical onset ≤30 days after SARS-CoV-2-vaccination were included. Clinical data, cerebrospinal fluid (CSF) parameters and magnetic resonance imaging (MRI) as well as optical coherence tomography (OCT) data were compared to an age- and sex-matched MSreference-cohort. RESULTS: We identified 5 MSpostvacc and 1 MOGADpostvacc patients who developed their clinical onset ≤ 30 days after SARS-CoV-2-vaccination. Clinical characteristics, CSF, MRI and OCT parameters from MSpostvacc patients were comparable to the MSreference cohort and showed evidence of preexisting subclinical CNS disease. The single case with MOGADpostvacc clearly differed from PwMS in higher CSF cell counts, remission of MRI lesions during follow-up, and absence of oligoclonal bands. CONCLUSIONS: Our case series indicates that MSpostvacc patients showed a rather typical initial manifestation in temporal association with SARS-CoV-2-vaccination and harbored preexisting subclinical neuroinflammation. This argues against the denovo development of MS in this cohort.

Multiple Sclerosis Presenting as Intracranial Hypertension in the Setting of COVID-19 Infection (preprint)

Background Multiple sclerosis (MS) and Idiopathic Intracranial Hypertension (IIH) occur more commonly in women of childbearing age. There is cerebral spinal fluid (CSF) altered dynamics in both diseases causing them to have similar presentation at times. Coronavirus disease 19 (COVID-19) have also been reported to affect the Central Nervous System (CNS) of any age.Case Presentation: We report A-19-year-old male who initially presented with headaches, and fever and was diagnosed with COVID-19 infection. A few days later, he developed acute severe left eye pain, blurred vision, diplopia, and left ear tinnitus. The patient was found to have reduced visual acuity, left sixth nerve palsy, esotropia and asymmetric bilateral papilledema. Later, he developed left facial nerve palsy. MRI of the brain showed extensive demyelinating lesions. Lumbar puncture revealed significantly increased intracranial pressure (ICP) and positive oligoclonal bands.Conclusion This is a unique case of MS presenting with intracranial hypertension (IH) in the setting of COVID-19 infection that could have been the trigger for the MS clinical attack.

Real-World Data on the Incidence and Risk of Guillain-Barre Syndrome Following SARS-CoV-2 Vaccination: A Prospective Surveillance Study (preprint)

Increasing evidence suggests an association between SARS-CoV-2 vaccines and Guillain-Barré syndrome (GBS). Nevertheless, little is understood about the contributing risk factors and clinical characteristics of GBS post SARS-CoV-2 vaccination. In this prospective surveillance study of 38,828,692 SARS-CoV-2 vaccine doses administered from February 2021 to March 2022 in the Gyeonggi Province, South Korea, 55 cases of GBS were reported post vaccination. We estimated the incidence rate of GBS per million doses and the incidence rate ratio for the vaccine dose, mechanism, age, and sex. Additionally, we compared the clinical characteristics of GBS following mRNA-based and viral vector-based vaccinations. The overall incidence of GBS following SARS-CoV-2 vaccination was 1.42 per million doses. Viral vector-based vaccines were associated with a higher risk of GBS. Men were more likely to develop GBS than women. The third dose of vaccine was associated with a lower risk of developing GBS. Classic sensorimotor and pure motor subtypes were the predominant clinical subtypes, and demyelinating type was the predominant electrodiagnostic subtype. The initial dose of viral-vector based vaccine and later doses of mRNA-based vaccine were associated with GBS, respectively. GBS following SARS-CoV-2 vaccination may not be clinically distinct. However, physicians should pay close attention to the classic presentation of GBS in men receiving an initial dose of viral vector-based SARS-CoV-2 vaccines.

Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19.

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is still poorly understood. This review summarizes the current knowledge of neurological sequelae in post-COVID patients and discusses brain demyelination as a possible mechanism of these complications with a focus on neuroimaging findings. Numerous reviews, experimental and theoretical studies consider brain demyelination as one of the mechanisms of the central neural system impairment. Several factors might cause demyelination, such as inflammation, direct effect of the virus on oligodendrocytes, and cerebrovascular disorders, inducing myelin damage. There is a contradiction between the solid fundamental basis underlying demyelination as the mechanism of the neurological injuries and relatively little published clinical evidence related to demyelination in COVID-19 patients. The reason for this probably lies in the fact that most clinical studies used conventional MRI techniques, which can detect only large, clearly visible demyelinating lesions. A very limited number of studies use specific methods for myelin quantification detected changes in the white matter tracts 3 and 10 months after the acute phase of COVID-19. Future research applying quantitative MRI assessment of myelin in combination with neurological and psychological studies will help in understanding the mechanisms of post-COVID complications associated with demyelination.