Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications.

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62-62.23 vs. Mild 3.91 pg/mL CI 1.5-10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4-4.4 vs. Non-Pronounced 2.0, CI 1.4-2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.

Depression and anxiety in patients with multiple sclerosis treated with interferon-beta or fingolimod: Role of indoleamine 2,3-dioxygenase and pro-inflammatory cytokines.

Depression/anxiety (D/A) occurs in up to 50% of multiple sclerosis (MS) patients. Proinflammatory cytokines induce classical symptoms of depression. Activation of the inflammatory response also triggers production of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, the amino acid precursor of serotonin and melatonin. It has been suggested that IDO is the link between the immune and serotonergic systems. This study aimed to quantify the levels of IDO and pro-inflammatory and anti-inflammatory cytokines in patients with MS and depression, according to treatment with interferon-beta (IFN-ß) or fingolimod. The study inclusion criteria were age 18-60 years and a clinical and radiological diagnosis of MS. One hundred and thirty-two patients diagnosed by McDonald's criteria and followed up at Brasília District Hospital, Brazil, with relapsing-remitting MS were identified as potential study participants. Thirty-five of these patients were identified to be receiving treatment with fingolimod or IFN-ß and to have a diagnosis of D/A. IDO and pro-inflammatory and anti-inflammatory cytokine levels were compared between these 35 patients and 18 healthy controls. The level of IL-10 (an anti-inflammatory cytokine) was lower in both the fingolimod-treated (P â€‹< â€‹0.001) and IFN-ß-treated (P â€‹< â€‹0.01) patient groups than in the control group. IFN-ß-treated patients showed increased IDO expression and decreased inflammatory cytokine levels. In contrast, fingolimod-treated patients showed significantly decreased expression of IDO and significantly increased levels of proinflammatory cytokines produced by innate immune cells, including tumor necrosis factor-alpha and interleukin-6. The agents used to treat MS maintain symptoms of D/A in patients with MS via different mechanisms.

From Charcot's descriptions to the current understanding of neuropsychiatric symptoms in multiple sclerosis.

Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.

From Charcot's descriptions to the current understanding of neuropsychiatric symptoms in multiple sclerosis / Das descrições de Charcot à compreensão atual dos sintomas neuropsiquiátricos na esclerose múltipla

ABSTRACT Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.

RESUMO Os distúrbios neuropsiquiátricos na esclerose múltipla são conhecidos desde a descrição clínico-patológica original de Charcot no final do século XIX. Charcot nas últimas décadas de sua vida se envolveu no campo da neuropsiquiatria. Isso produziu uma batalha de escolas rivais na época que ainda ecoa até hoje. A intuição de Charcot, incluindo a linha de pensamento de Babinski, um de seus discípulos mais famosos, foi a teoria correta da conexão entre os transtornos do humor e muitas das doenças do sistema nervoso. A preocupação da Medicina em estabelecer uma relação entre transtornos do humor e doenças vem das idades antiga e média, com referências encontradas na doutrina hipocrática. No entanto, foi apenas na segunda metade do século XIX e início do século XX que, com as descobertas de Charcot essa discussão foi realizada de maneira estruturada, estabelecendo os fundamentos da neuropsiquiatria.

MRZH reaction increases sensitivity for intrathecal IgG synthesis in IgG Oligoclonal band negative Multiple Sclerosis patients.

Given the low detection rates of CSF IgG-Oligoclonal bands (IgG-OCB) in non-European Multiple Sclerosis (MS) patients and higher specificity of the MRZH-reaction, we evaluated whether associating MRZH-reaction to CSF IgG-OCB detection improved investigation of suspected MS. Paired CSF and sera were analyzed for IgG-OCB and polyspecific viral antibodies. IgG-OCB were detected in 72% of MS patients and an MRZH-reaction in 67%. Combining IgG-OCB and MRZH raised detection of IgG abnormalities to 97% of studied MS patients. Detection of IgG-OCB and/or ≥2 MRZH antibodies showed sensitivity of 88% and specificity of 92% for MS, versus 72% and 96% for IgG-OCB alone.

Impact of electroacupuncture on quality of life for patients with Relapsing-Remitting Multiple Sclerosis under treatment with immunomodulators: a randomized study.

BACKGROUND: Multiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS. METHODS: Thirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients. RESULTS: Electroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure. CONCLUSION: This paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly. TRIAL REGISTRATION: RBR-58yq52.

Interferon-beta modifies the peripheral blood cell cytokine secretion in patients with multiple sclerosis.

Immunotherapy with Interferon-beta (IFNbeta) results in remarkably beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. An investigation was made of the effects of IFNbeta on pro-inflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as in healthy controls. Results show a significant increase in the production of pro-inflammatory cytokines such as TNFalpha, IFNgamma and IL-12 in the plasma and in the supernatant of leukocyte cultures from MS patients with the untreated disease; IFNbeta administration significantly reduced the levels of TNFalpha and IFNgamma, with no changes in the level of IL-12. The Interferon-beta therapy also led to a significant increase in the production of IL-10, as well as a slight increase in that of TGFbeta. The reduction in pro-inflammatory cytokine production in the treated MS patient group, accompanied by a simultaneous increase in the production of anti-inflammatory cytokines and the reduction of relapse rates suggests that the beneficial effects of IFNbeta immunotherapy result, at least in part, from the modulation of cytokine patterns.

Intrathecal immunoglobulin G synthesis and brain injury by quantitative MRI in multiple sclerosis.

OBJECTIVES: It was the aim of this study to evaluate if the quantitative intrathecal immunoglobulin G (IgG) synthesis correlates with the brain atrophy and the total lesion volume (TLV) in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients. METHODS: A total of 50 patients with relapsing-remitting MS were included in this study. MRIs were performed and cerebrospinal fluid samples were collected during the diagnostic determination when patients were in remission without treatment. RESULTS: At study baseline, IgG index values were elevated in 36 patients (72%), and oligoclonal IgG bands were positive in 42 of 50 patients (84%). Brain MRI was abnormal in 94% of patients, and, compared with healthy controls, brain atrophy was observed in MS patients. A positive correlation among IgG index, cerebrospinal fluid leukocyte count and TLV was observed; the Expanded Disability Status Scale correlated positively with TLV and the number of lesions, although a significant relationship between disability and brain atrophy was not demonstrated. CONCLUSIONS: Although new parameters will be necessary in longitudinal studies to characterize the axonal injury in various stages of the disease, the data suggest that the high intrathecal IgG synthesis may predict a greater brain lesion burden.