Nervous system-related tropism of SARS-CoV-2 and autoimmunity in COVID-19 infection.

The effects of SARS-CoV-2 in COVID-19 on the nervous system are incompletely understood. SARS-CoV-2 can infect endothelial cells, neurons, astrocytes, and oligodendrocytes with consequences for the host. There are indications that infection of these CNS-resident cells may result in long-term effects, including emergence of neurodegenerative diseases. Indirect effects of infection with SARS-CoV-2 relate to the induction of autoimmune disease involving molecular mimicry or/and bystander activation of T- and B cells and emergence of autoantibodies against various self-antigens. Data obtained in preclinical models of coronavirus-induced disease gives important clues for the understanding of nervous system-related assault of SARS-CoV-2. The pathophysiology of long-COVID syndrome and post-COVID syndrome in which autoimmunity and immune dysregulation might be the driving forces are still incompletely understood. A better understanding of nervous-system-related immunity in COVID-19 might support the development of therapeutic approaches. In this review, the current understanding of SARS-CoV-2 tropism for the nervous system, the associated immune responses, and diseases are summarized. The data indicates that there is viral tropism of SARS-CoV-2 in the nervous system resulting in various disease conditions. Prevention of SARS-CoV-2 infection by means of vaccination is currently the best strategy for the prevention of subsequent tissue damage involving the nervous system.

Prevalence and Impact of Cerebral Microbleeds on Clinical and Safety Outcomes in Acute Ischaemic Stroke Patients Receiving Reperfusion Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Cerebral microbleeds (CMBs), a notable neuroimaging finding often associated with cerebral microangiopathy, demonstrate a heightened prevalence in patients diagnosed with acute ischemic stroke (AIS), which is in turn linked to less favourable clinical prognoses. Nevertheless, the exact prevalence of CMBs and their influence on post-reperfusion therapy outcomes remain inadequately elucidated. MATERIALS AND METHODS: Through systematic searches of PubMed, Embase and Cochrane databases, studies were identified adhering to specific inclusion criteria: (a) AIS patients, (b) age ≥ 18 years, (c) CMBs at baseline, (d) availability of comparative data between CMB-positive and CMB-negative groups, along with relevant post-reperfusion therapy outcomes. The data extracted were analysed using forest plots of odds ratios, and random-effects modelling was applied to investigate the association between CMBs and symptomatic intracerebral haemorrhage (sICH), haemorrhagic transformation (HT), 90-day functional outcomes, and 90-day mortality post-reperfusion therapy. RESULTS: In a total cohort of 9776 AIS patients who underwent reperfusion therapy, 1709 had CMBs, with a pooled prevalence of 19% (ES 0.19; 95% CI: 0.16, 0.23, p < 0.001). CMBs significantly increased the odds of sICH (OR 2.57; 95% CI: 1.72; 3.83; p < 0.0001), HT (OR 1.53; 95% CI: 1.25; 1.88; p < 0.0001), as well as poor functional outcomes at 90 days (OR 1.59; 95% CI: 1.34; 1.89; p < 0.0001) and 90-day mortality (OR 1.65; 95% CI: 1.27; 2.16; p < 0.0001), relative to those without CMBs, in AIS patients undergoing reperfusion therapy (encompassing intravenous thrombolysis [IVT], endovascular thrombectomy [EVT], either IVT or EVT, and bridging therapy). Variations in the level of association can be observed among different subgroups of reperfusion therapy. CONCLUSIONS: This meta-analysis underscores a significant association between CMBs and adverse postprocedural safety outcomes encompassing sICH, HT, poor functional outcome, and increased mortality in AIS patients undergoing reperfusion therapy. The notable prevalence of CMBs in both the overall AIS population and those undergoing reperfusion therapy emphasizes their importance in post-stroke prognostication.

Prospective analyses of alertness, sleep, and fitness to drive one year after de novo multiple sclerosis diagnosis.

BACKGROUND: The prevalence and functional burden of the chronic demyelinating disease multiple sclerosis (MS) are well documented; however, little is known about the initial clinical course of alertness, sleep, cognitive, and psychological symptoms. OBJECTIVES: This exploratory, prospective, longitudinal study multidimensionally investigated the development and progression of alertness, sleep, fitness to drive, and psychological symptoms in the first year after de novo MS diagnosis. METHODS: Twenty-five people with MS (pwMS) were assessed cognitively, psychologically, and using polysomnography soon after diagnosis and one year later, with outcomes compared to matched healthy controls. RESULTS: In the early stage of the disease, psychological symptoms of pwMS were comparable with those of controls, and patient conditions did not deteriorate within the first disease year. A small percentage of pwMS experienced increased levels of anxiety and depression after diagnosis. Alertness, sustained attention, and fitness to drive were comparable between both groups, and fatigue levels remained low over the course of the year. CONCLUSIONS: This study highlights patient experiences within the initial clinical course of MS in a small group of patients. Further research is needed to understand the progression of symptoms and impairments in MS over a longer period and in different stages of the disease.

Brain atrophy in acute ischaemic stroke patients treated with reperfusion therapy: a systematic review.

BACKGROUND: Brain atrophy (BA) may have a role in acute ischemic stroke (AIS) in mediating outcomes after reperfusion therapy. The extent of this association is not well understood. PURPOSE: : To examine the impact of pre-existing BA on functional outcome, survival, symptomatic intracerebral hemorrhage (sICH), and early neurological change in patients with AIS treated with intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). MATERIAL AND METHODS: PubMed, EMBASE, and the Cochrane library were searched for studies on BA in AIS receiving reperfusion therapy. Studies were included if: (i) patients were aged ≥18 years; (ii) patients had been diagnosed with AIS; (iii) patients received IVT and/or EVT; (iv) studies reported on BA; (v) studies reported on post-reperfusion outcomes; and (vi) studies had a sample size of >25 patients. RESULTS: A total of 4444 patients from eight studies were included. Four out of seven studies reporting on 90-day functional outcome found pre-existing BA to be significantly associated with poor functional outcome. Moreover, two out of four studies found BA to be a significant predictor of 90-day mortality. None of the included studies reported a significant association of BA with sICH or early neurological deterioration. CONCLUSION: This systematic review indicates a potential prognostic role of BA in AIS. Quantitative analysis of association of BA with outcomes in AIS is not possible given the heterogeneity in BA assessment and reporting across studies. Future studies using standardized BA assessment are warranted to clarify its association with clinical and safety outcomes in AIS.

Early remission in multiple sclerosis is linked to altered coherence of the Cerebellar Network.

BACKGROUND: The development of permanent disability in multiple sclerosis (MS) is highly variable among patients, and the exact mechanisms that contribute to this disability remain unknown. METHODS: Following the idea that the brain has intrinsic network organization, we investigated changes of functional networks in MS patients to identify possible links between network reorganization and remission from clinical episodes in MS. Eighteen relapsing-remitting MS patients (RRMS) in their first clinical manifestation underwent resting-state functional MRI and again during remission. We used ten template networks, identified from independent component analysis, to compare changes in network coherence for each patient compared to those of 44 healthy controls from the Human Connectome Project test-retest dataset (two-sample t-test of pre-post differences). Combining a binomial test with Monte Carlo procedures, we tested four models of how functional coherence might change between the first clinical episode and remission: a network can change its coherence (a) with itself ("one-with-self"), (b) with another network ("one-with-other"), or (c) with a set of other networks ("one-with-many"), or (d) multiple networks can change their coherence with respect to one common network ("many-with-one"). RESULTS: We found evidence supporting two of these hypotheses: coherence decreased between the Executive Control Network and several other networks ("one-with-many" hypothesis), and a set of networks altered their coherence with the Cerebellar Network ("many-with-one" hypothesis). CONCLUSION: Given the unexpected commonality of the Cerebellar Network's altered coherence with other networks (a finding present in more than 70% of the patients, despite their clinical heterogeneity), we conclude that remission in MS may result from learning processes mediated by the Cerebellar Network.

Upregulated Retinal Neurofilament Expression in Experimental Optic Neuritis.

In optic neuritis (ON), transient thickening of the macular retinal nerve fibre layer (RNFL) can be observed. This optical coherence tomography-based observation is not understood. The axonal diameter correlates with the neurofilament (Nf) protein content, but there are no data on the retinal tissue concentration of Nfs. The myelin-oligodendrocyte-glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) model was used to investigate the retinas of Brown Norway rats with (i) visual evoked potentials (VEP) confirmed ON, (ii) VEP confirmed absence of ON and (iii) control animals. Twenty retinas were collected from MOG-EAE and control rats 27 days after immunisation. Retinal tissue Nf concentrations per total protein (µg/mg) were significantly higher in MOG-EAE rats with ON (median 4.29, interquartile range [IQR] 3.41-5.97) compared with MOG-EAE rats without ON (1.14, IQR 1.10-1.67) or control rats (0.93, IQR 0.45-4.00). The data suggest that up-regulation of Nf expression in the retinal ganglion cells precedes development of RNFL atrophy and plausibly explains the transient increase of axonal diameter and RNFL thickening.

Leukoaraiosis severity and post-reperfusion outcomes in acute ischaemic stroke: A meta-analysis.

OBJECTIVES: Severity of leukoaraiosis may mediate outcomes after reperfusion therapy in acute ischaemic stroke (AIS) patients. However, the level of the association remains poorly understood. We performed a meta-analysis to investigate the impact of leukoaraiosis severity on functional outcome, survival, haemorrhagic complications, and procedural success in AIS patients treated with intravenous thrombolysis and/or endovascular thrombectomy. MATERIALS AND METHODS: PubMed, EMBASE and the Cochrane library were searched for studies on leukoaraiosis in AIS receiving reperfusion therapy. A random-effects meta-analysis was conducted for post-reperfusion outcomes in AIS patients with absent-to-mild leukoaraiosis and moderate-to-severe leukoaraiosis. The strength of association between moderate-to-severe leukoaraiosis and poor outcomes was quantified using odds ratios (OR). RESULTS: A total of 15 eligible studies involving 6460 patients (1451 with moderate-to-severe leukoaraiosis and 5009 with absent-to-mild leukoaraiosis) were included in the meta-analysis. Moderate-to-severe leukoaraiosis was significantly associated with poor 90-day functional outcome (OR 3.16; 95% confidence interval (CI) 2.69-3.72; p < .0001), 90-day mortality (OR 3.11; 95% CI 2.27-4.26; p < .0001) and increased risk of symptomatic intracerebral haemorrhage (OR 1.69; 95% CI 1.24-2.32; p = .001) after reperfusion therapy. Overall, no significant association of leukoaraiosis severity with haemorrhagic transformation (HT) and angiographic recanalization status were observed. However, subgroup analysis revealed a significant association of WML severity with HT in patients receiving EVT. CONCLUSION: Leukoaraiosis is a useful prognostic biomarker in AIS. Patients with moderate-to-severe leukoaraiosis on baseline imaging are likely to have worse clinical and safety outcomes after reperfusion therapy.

Emerging role of white matter lesions in cerebrovascular disease.

White matter lesions have been implicated in the setting of stroke, dementia, intracerebral haemorrhage, several other cerebrovascular conditions, migraine, various neuroimmunological diseases like multiple sclerosis, disorders of metabolism, mitochondrial diseases and others. While much is understood vis a vis neuroimmunological conditions, our knowledge of the pathophysiology of these lesions, and their role in, and implications to, management of cerebrovascular diseases or stroke, especially in the elderly, are limited. Several clinical assessment tools are available for delineating white matter lesions in clinical practice. However, their incorporation into clinical decision-making and specifically prognosis and management of patients is suboptimal for use in standards of care. This article sought to provide an overview of the current knowledge and recent advances on pathophysiology, as well as clinical and radiological assessment, of white matter lesions with a focus on its development, progression and clinical implications in cerebrovascular diseases. Key indications for clinical practice and recommendations on future areas of research are also discussed. Finally, a conceptual proposal on putative mechanisms underlying pathogenesis of white matter lesions in cerebrovascular disease has been presented. Understanding of pathophysiology of white matter lesions and how they mediate outcomes is important to develop therapeutic strategies.

Effects of Alemtuzumab on (Auto)antigen-Specific Immune Responses.

Alemtuzumab (anti-CD52 mAb) leads to a long-lasting disease activity suppression in patients with relapsing forms of multiple sclerosis (MS). In this study, we examined the change of the immune cell repertoire and the cellular reactivity after treatment with alemtuzumab. We analyzed the number of IFN-γ-secreting cells in presence of several peptides which had been eluted from the central nervous system (CNS) of MS patients and are possible targets of autoreactive T cells in MS. The patients showed a stabilized disease activity measured in clinical parameters and lesion formation after the treatment. We detected a reduction of the number of IFN-γ-secreting cells in the presence of every tested self-antigen. The number of IFN-γ-secreting cells was also reduced in the presence of non-self-antigens. We also found a clear change in the immune cell repertoire. After an almost complete depletion of all lymphocytes, the cell specificities showed different reconstitution patterns, resulting in different cell fractions. The percentage of CD4+ T cells was clearly reduced after therapy, whereas the fractions of B and NK cells were elevated. When we evaluated the number of IFN-γ-secreting cells in relation to the number of present CD4+ T cells, we still found a significant reduction. We conclude that the reduction of IFN-γ-secreting cells by alemtuzumab is not only due to a reduction of the CD4+ T cell fraction within the peripheral blood mononuclear cell (PBMC) compartment but might also be caused by functional changes or a shift in the distribution of different subtypes in the CD4+ T cell pool.

Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper.

Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.

The Effect of Coffee and Caffeine Consumption on Patients with Multiple Sclerosis-Related Fatigue.

Background: Coffee and caffeine are considered to have beneficial effects in patients with multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) that can lead to disability and chronic fatigue. Methods: In the present study the preference in terms of coffee and caffeine consumption in patients with MS was assessed. In total the opinions of 124 MS patients were explored with a questionnaire, which was developed to investigate the consumption behavior and associated beneficial and harmful effects of coffee and caffeine concerning symptoms of fatigue. Results: Our study showed that 37.1% of the included patients experience severe symptoms of fatigue. In our cohort, fatigue was not related to age, type of diagnosis or duration of the disease. The effects of coffee did not differ between MS patients with and without fatigue. Very few side effects linked to coffee consumption were reported, and we could demonstrate that coffee consumption had no negative impact on quality of sleep. A positive effect on everyday life was observed particularly among patients with a mid-level expanded disability status scale (EDSS). The strongest effects of coffee consumption were observed regarding a better ability to concentrate while fulfilling tasks, an expanded attention span and a better structured daily routine. Conclusions: Since coffee showed no severe side effects and in the absence of an effective fatigue therapy, coffee consumption might be a therapeutic approach for selected patients with MS-related fatigue.

Patients With Epileptic Seizures and Multiple Sclerosis in a Multiple Sclerosis Center in Southern Germany Between 2003-2015.

Background: So far, many studies have shown that the risk of developing seizures and epilepsy is higher among patients with multiple sclerosis (MS) than in the general population. However, the causal link between these two diseases is still unclear. In addition, it is not clearly understood whether and to what extent the manifestation of seizures and epilepsy in patients with MS affects the clinical course and the long-term prognosis of the disease. We aimed to retrospectively identify and describe patients with MS and with seizures and epilepsy which were seen at the Department of Neurology of the University of Regensburg in Germany between the years 2003-2015. Methods: With the help of the electronic documentation system of hospital admitted patients followed by scrutinizing medical records of patients with MS for evidence of seizures and epilepsy, we identified patients with MS and seizures or epilepsy. Results: We identified 22 individuals (1.74%) out of 1,267 patients with MS with seizures or epilepsy. 18 of these 22 individuals met criteria for epilepsy (1.42%). Nine MS patients (40.9%) suffered from relapsing-remitting MS (RRMS) whereas 11 MS patients (50.0%) showed a secondary progressive disease course (SPMS). Five of those (45.5%) converted from RRMS to SPMS before they acquired epilepsy. None of the identified patients with MS and seizures or epilepsy suffered from primary progressive MS (PPMS). Moreover, two MS patients (9.1%) had a history of seizures before MS onset. Seizures were of focal onset in 17 patients with MS (77.3%). Fourteen out of these 17 MS patients presented with focal to bilateral tonic-clonic seizures (82.4%). Five MS patients (22.7%) showed tonic clonic seizures of unknown onset. Status epilepticus was reported in three patients with MS (13%), for one patient the data was inconclusive. Conclusion: The occurrence of seizures and epilepsy was higher than in the general population, suggesting a causal relationship between both diseases. In most cases, seizures occurred after the first manifestation of MS. The high frequency of focal seizures supports the concept of cerebral lesions in patients with MS playing an important role in precipitation of seizures and epilepsy.

Functional Connectivity in Multiple Sclerosis: Recent Findings and Future Directions.

Multiple sclerosis is a debilitating disorder resulting from scattered lesions in the central nervous system. Because of the high variability of the lesion patterns between patients, it is difficult to relate existing biomarkers to symptoms and their progression. The scattered nature of lesions in multiple sclerosis offers itself to be studied through the lens of network analyses. Recent research into multiple sclerosis has taken such a network approach by making use of functional connectivity. In this review, we briefly introduce measures of functional connectivity and how to compute them. We then identify several common observations resulting from this approach: (a) high likelihood of altered connectivity in deep-gray matter regions, (b) decrease of brain modularity, (c) hemispheric asymmetries in connectivity alterations, and (d) correspondence of behavioral symptoms with task-related and task-unrelated networks. We propose incorporating such connectivity analyses into longitudinal studies in order to improve our understanding of the underlying mechanisms affected by multiple sclerosis, which can consequently offer a promising route to individualizing imaging-related biomarkers for multiple sclerosis.

The Impact of Coffee and Caffeine on Multiple Sclerosis Compared to Other Neurodegenerative Diseases.

Background: The literature concerning the effect of coffee and caffeine on Multiple Sclerosis (MS) with focus on fatigue is investigated in this review. Potentially clinically relevant effects were also assessed in studies concerning comparable neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Since the existing studies obtained very inconclusive results, we systematically reviewed these studies to summarize the evidence on the possible effects of coffee and caffeine on those disease entities. Previous studies suggested that coffee and caffeine intake is associated with a reduced risk of developing MS and other neurological diseases. Methods: The PubMed database was searched using the keywords "coffee" OR "caffeine" in combination with keywords for each of the different diseases. Besides the keyword search, we included studies by reference list search. Studies on the effects of coffee and caffeine on the single neurological diseases were included for this review. A total of 51 articles met our inclusion criteria. The reviewed articles assessed the impact of coffee and caffeine on the susceptibility for neurological diseases, as well as the effect of coffee and caffeine on disease progression and possible symptomatic effects like on performance enhancement. Results: Higher intake of coffee and caffeine was associated with a lower risk of developing PD. In some of the MS studies there, is evidence for a similar effect and experimental studies confirmed the positive impact. Interestingly in MS coffee and caffeine may have a stronger impact on disease course compared to effects on disease susceptibility. In ALS no such beneficial effect could be observed in the clinical and experimental studies. Conclusion: This literature assessment revealed that coffee and especially caffeine could have a preventative role in the development of several neurodegenerative diseases if provided in comparatively high doses. The systematic assessment indicates that coffee and caffeine intake must not be considered as a health risk. Additional clinical studies are needed to fully understand how far coffee and caffeine intake should be considered as a potential therapeutic approach for certain disease entities and conditions.