Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system which is associated with numerous comorbidities. These include cardiovascular disease, psychiatric and ...neurologic disturbances, restless leg syndrome, migraine, cancer, autoimmune diseases, and metabolic disorders. Comorbid disease is an important consideration for clinicians treating patients with MS; early presentation of comorbidities can obscure or delay MS diagnosis, as well as significantly impacting the disease course. Improved understanding of comorbidities and their emergence in MS populations is important for improving the quality of life and optimizing treatment for patients. Therefore, we evaluated published studies reporting epidemiologic data on comorbidities and their associated impact on disease progression in patients with MS (PwMS). The prevalence of neurologic, cardiovascular, metabolic, and autoimmune comorbidities was elevated in PwMS in general, and furthermore, this adversely affected a broad range of outcomes. Compared with PwMS, cancer rates in people without MS or the general population were lower, which should prompt further studies into the mechanisms of both diseases. Studies were under-represented in many regions owing to the latitudinal gradient of MS and possible underfunding of studies.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where immunopathology is thought to be mediated by myelin-reactive CD4+ T helper (TH) cells. The ...TH cells most commonly implicated in the pathogenesis of the disease are of TH1 and TH17 lineage, which are defined by the production of interferon-γ and interleukin-17, respectively. Moreover, there is emerging evidence for the involvement of TH17.1 cells, which share the hallmarks of TH1 and TH17 subsets. In this review, we summarise current knowledge about the potential role of TH17 subsets in the initiation and progression of the disease and put a focus on their response to approved immunomodulatory MS drugs. In this regard, TH17 cells are abundant in peripheral blood, cerebrospinal fluid and brain lesions of MS patients, and their counts and inflammatory mediators are further increased during relapses. Fingolimod and alemtuzumab induce a paramount decrease in central memory T cells, which harbour the majority of peripheral TH17 cells, while the efficacy of natalizumab, dimethyl fumarate and importantly hematopoietic stem cell therapy correlates with TH17.1 cell inhibition. Interestingly, also CD20 antibodies target highly inflammatory TH cells and hamper TH17 differentiation by IL-6 reductions. Moreover, recovery rates of TH cells best correlate with long-term efficacy after therapeutical immunodepletion. We conclude that central memory TH17.1 cells play a pivotal role in MS pathogenesis and they represent a major target of MS therapeutics.
•TH17 cells are abundant in patients with MS and further increase during relapses.•TH17.1 cells appear to have a pathogenic advantage over other TH cells.•Cells from the TH17 axis represent major targets of MS therapeutics.
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.
Cerebral venous thrombosis can happen in patients with severe acute respiratory syndrome coronavirus‐2 infection. Early diagnosis and proper management are paramount, as it is associated with high mortality.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). In recent years, vitamin D has gained attention, as low serum levels ...are suspected to increase the risk for MS. Cholecalciferol supplementation has been tested in several clinical trials, since hypovitaminosis D was linked to higher disease activity and may even play a role in long-term outcome. Here, we review the current understanding of the molecular effects of vitamin D beyond calcium homeostasis, the potential beneficial action in MS and hazards including complications of chronic and high-dose therapy. In clinical trials, doses of up to 40,000 IU/day were tested and appeared safe as add-on therapy for short-term periods. A recent meta-analysis of a randomized, double-blind, placebo-controlled clinical trial investigating vitamin D as add-on therapy in MS, however, suggested that vitamin D had no therapeutic effect on disability or relapse rate. We recognize a knowledge gap for chronic and high-dose therapy, which can lead to life-threatening complications related to vitamin D toxicity including renal failure, cardiac arrythmia and status epilepticus. Moreover, vitamin D toxicity may manifest as fatigue, muscle weakness or urinary dysfunction, which may mimic the natural course of progressive MS. Given these limitations, vitamin D supplementation in MS is a sensitive task which needs to be supervised by physicians. While there is strong evidence for vitamin D deficiency and the development of MS, the risk-benefit profile of dosage and duration of add-on supplementation needs to be further clarified.
Background
Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus‐disease‐2019 (COVID‐19) infection, but the available evidence is scattered. Here we sought to understand the ...acute and mid‐term effects of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection on cardiovascular autonomic function.
Methods
We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS‐CoV‐2 infection or post‐COVID‐19 condition. The clinical‐demographic characteristics of individuals in the acute versus post‐COVID‐19 phase were compared.
Results
We screened 6470 titles and s. Fifty‐four full‐length articles were included in the data synthesis. One‐hundred and thirty‐four cases were identified: 81 during the acute SARS‐CoV‐2 infection (24 thereof diagnosed by history) and 53 in the post‐COVID‐19 phase. Post‐COVID‐19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS‐CoV‐2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post‐COVID‐19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post‐COVID‐19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002).
Conclusions
There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID‐19. More data about the prevalence of autonomic disorders associated with a SARS‐CoV‐2 infection are needed to quantify its impact on human health.
The development of intracranial hemorrhage (ICH) in acute ischemic stroke is associated with a higher neutrophil to lymphocyte ratio (NLR) in peripheral blood. Here, we studied whether the predictive ...value of NLR at admission also translates into the occurrence of hemorrhagic complications and poor functional outcome after endovascular treatment (EVT).
We performed a retrospective analysis of consecutive patients with anterior circulation ischemic stroke who underwent EVT at a tertiary care center from 2012 to 2016. Follow-up scans were examined for non-procedural ICH and scored according to the Heidelberg Bleeding Classification. Demographic, clinical, and laboratory data were correlated with the occurrence of non-procedural ICH.
We identified 187 patients with a median age of 74 years (interquartile range IQR 60-81) and a median baseline National Institutes of Health Stroke scale (NIHSS) score of 18 (IQR 13-22). A bridging therapy with recombinant tissue-plasminogen activator (rt-PA) was performed in 133 (71%). Of the 31 patients with non-procedural ICH (16.6%), 13 (41.9%) were symptomatic. Patients with ICH more commonly had a worse outcome at 3 months (p = 0.049), and were characterized by a lower body mass index, more frequent presence of tandem occlusions, higher NLR, larger intracranial thrombus, and prolonged rt-PA and groin puncture times. In a multivariate analysis, higher admission NLR was independently associated with ICH (OR 1.09 per unit increase, 95% CI (1.00-1.20, p = 0.040). The optimal cutoff value of NLR that best distinguished the development of ICH was 3.89.
NLR is an independent predictor for the development of ICH after EVT. Further studies are needed to investigate the role of the immune system in hemorrhagic complications following EVT, and confirm the value of NLR as a potential biomarker.
Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological ...disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.
The high efficacy of natalizumab in the treatment of relapsing-remitting multiple sclerosis (MS) is without controversy. Indeed, effective disease control was not only demonstrated in the pivotal ...trials but has been corroborated impressively in real-world observations. This monoclonal IgG4 antibody blocks the α4β1 integrin-mediated leukocyte-endothelial interaction and thereby inhibits the migration of immune cells to the brain parenchyma. However, treatment with natalizumab carries the risk of progressive multifocal leukoencephalopathy (PML). This potentially lethal side effect is a significant limitation for treatment initiation and long-term therapy. Natalizumab is given intravenously or subcutaneously in the standard dose of 300 mg every 4 weeks, allowing drug concentrations at levels that ensure continuous α4β1 integrin receptor saturation on the surface of immune cells. Extended-interval dosing (EID) is an emerging treatment approach that aims to mitigate the natalizumab-related PML risk by prolonging the standard infusion intervals to 6 weeks or even more. This treatment approach may abrogate the PML risk due to improved immune surveillance within the central nervous system while maintaining clinical efficacy. Moreover, even an individual interval dosing can be envisioned based on the availability of a biomarker that is capable of monitoring both safety and efficacy aspects. This review summarizes the early and encouraging evidence for EID from observational and randomized-controlled trials and discusses current limitations and upcoming challenges for introducing a tailored treatment approach.
Abstract Multiple sclerosis (MS) is the most common acquired inflammatory demyelinating disorder of the central nervous system (CNS). Not unlike many inflammatory diseases with a presumed autoimmune ...pathogenesis, it has been established that there is a female preponderance in prevalence. While in the past it was shown that there are two women for every man with a diagnosis of MS, recent serial cross-sectional assessments provide compelling evidence for an increase of the female to male sex ratio in patients with relapsing–remitting MS over the last decades. An understanding of this phenomenon might provide key insights into the pathogenesis of the disease but also may have implications for health-care strategies and further research efforts. We review possible etiologies for the gender disparity in MS, and we discuss possible underlying causes. We determined that the biologically most plausible explanations for a disproportional increase of MS among women in some population may be the role of vitamin D in MS pathogenesis. Decreased sun exposure may be a critical factor in diminished vitamin D levels in many recent cohort studies. Vitamin D insufficiency or deficiency has been shown to affect T cell differentiation and regulation, which may affect cellular immune responses against autoantigens and pathogens that have been associated with the etiology of MS. Vitamin D also appears to impact B cell activation and differentiation, another cell type that has been implicated in the inflammatory cascade underlying CNS autoimmune disease.
Intracerebral hemorrhage and ischemic stroke are increasingly recognized complications of central nervous system (CNS) infection by herpes simplex virus (HSV).
To analyze clinical, imaging, and ...laboratory findings and outcomes of cerebrovascular manifestations of HSV infection.
Systematic literature review from January 2000 to July 2018.
We identified 38 patients (median age 45 years, range 1-73) comprising 27 cases of intracerebral hemorrhage, 10 of ischemic stroke, and 1 with cerebral venous sinus thrombosis. Intracerebral hemorrhage was predominantly (89%) a complication of HSV encephalitis located in the temporal lobe. Hematoma was present on the first brain imaging in 32%, and hematoma evacuation was performed in 30% of these cases. Infarction was frequently multifocal, and at times preceded by hemorrhage (20%). Both a stroke-like presentation and presence of HSV encephalitis in a typical location were rare (25% and 10%, respectively). There was evidence of cerebral vasculitis in 63%, which was exclusively located in large-sized vessels. Overall mortality was 21% for hemorrhage and 0% for infarction. HSV-1 was a major cause of hemorrhagic complications, whereas HSV-2 was the most prevalent agent in the ischemic manifestations.
We found a distinct pathogenesis, cause, and outcome for HSV-related cerebral hemorrhage and infarction. Vessel disruption within a temporal lobe lesion caused by HSV-1 is the presumed mechanism for hemorrhage, which may potentially have a fatal outcome. Brain ischemia is mostly related to multifocal cerebral large vessel vasculitis associated with HSV-2, where the outcome is more favorable.
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