Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ...‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. Effector T helper cells, mainly Th1 and Th17, cytotoxic T-cells, B-cells, macrophages, microglia, and ...the cytokines they secrete, are implicated in the initiation and maintenance of a deregulated immune response to myelin antigens and the ensuing immune-mediated demyelination. In this study, we investigated whether signature cytokines exist in MS patients at presentation to gain an insight into the underlying immunopathogenic processes at the early stage of the disease.
We collected serum and cerebrospinal fluid (CSF) samples from 123 patients at presentation, eventually diagnosed with MS or non-inflammatory (NIND) or inflammatory neurological diseases (IND) or symptomatic controls (SC). The levels of cytokines IFN-γ, TNF-α, TGF-β1, IL-2, IL-4, IL-6, IL-10 and IL-17 were measured, and cytokine ratios, such as Th1/Th2, Th1/Th17, and Type-1/Type-2, were calculated. All parameters were tested for their correlations with the intrathecal IgG synthesis.
Cytokine levels in CSF were lower than in serum in all the patients, with the exception of IL-6. Serum or CSF cytokine levels of MS patients did not differ significantly from NIND or SC, with the exception of serum IFN-γ and TNF-α that were significantly higher in NIND. IND patients presented with the highest levels of all cytokines in serum and CSF, with the exception of serum IL-10 and CSF IL-17. MS patients had a significantly lower serum Th1/Th2 ratio compared to the NIND and IND groups, and significantly lower serum Type-1/Type-2, IFN-γ/IL-10 and CSF Th1/Th17 ratios compared to IND patients. MS patients had a significantly higher CSF IL-17/IL-10 ratio compared to IND patients. The IgG index was higher in MS patients compared to the control groups; the differences reached statistical significance between the MS and the NIND and SC groups. Reiber-Felgenhauer analysis of the QIgG and QAlb indices revealed higher intrathecal IgG synthesis in MS patients, and higher blood-CSF barrier dysfunction in IND patients. The IgG index correlated with CSF IL-4 in MS patients only.
We found no signature cytokines or profiles thereof in MS patients at presentation. Only IND patients presented with a clear Th1 cytokine polarization in serum and CSF. The parameters that distinguished MS patients from patients with other neurological disorders were IgG intrathecal synthesis, the IgG index and its correlation with CSF IL-4 levels.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory ...symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. The most prominent clinical features include visual ...loss and sensorimotor symptoms and mainly affects those of young age. Some of the factors affecting its pathogenesis are genetic and/or environmental including viruses, smoking, obesity, and nutrition. Current research provides evidence that diet may influence MS onset, course, and quality of life of the patients. In this review, we address the role of nutrition on MS pathogenesis as well as dietary interventions that show promising beneficial results with respect to MS activity and progression. Investigation with large prospective clinical studies is required in order to thoroughly evaluate the role of diet in MS.
Summary Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for ...individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.
Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible ...neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA Structural Image Evaluation using Normalization of Atrophy). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.
Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases, proteins essential to the degradation of various tissue extracellular matrix proteins. Under normal conditions, MMPs participate ...in several physiological processes, both in the developing organism and the adult. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), affecting primarily young adults. Inflammatory infiltrations of the CNS parenchyma by autoreactive immune cells, that mediate myelin degradation in the form of the demyelination "plaque", are the pathological hallmark of the disease. Due to their capacity to orchestrate tissue penetration from various cells, MMPs have been elucidated in MS as mediators of blood-brain barrier disruption and CNS inflammation, thus contributing to the disease pathogenesis.
This review focuses on clinical and experimental evidence of MMPs' pathogenetic role in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
A MEDLINE search was performed for using the following terms: "metalloproteinases", "multiple sclerosis", "experimental autoimmune encephalomyelitis", "central nervous system" and "autoimmunity".
Expression patterns of MMPs and their specific inhibitor molecules at the sites of MS and EAE lesions, as well as by specific cell types of the immune system, provide evidence of MMPs' role in the pathogenesis of CNS autoimmunity. Clinical evidence suggests differential profile of MMPs' expression in serum and cerebrospinal fluid (CSF) between MS patients with various disease types and healthy adults, rendering MMPs potential biomarkers for disease incidence and activity.
MMPs' role in the processes of CNS inflammation, de- and remyelination, confers implications as therapeutic targets, either alone, or in relation with widely-used disease modifying treatments in MS.
Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction ...between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex.
We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse.
We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab.
In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4).
The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.
In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) ...transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.
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