CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation

Objective c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4(+)c-Met(+) T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Methods c-Met expression by CD4(+) T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4(+)c-Met(+) T cells was assessed in EAE. Results CD4(+)c-Met(+) T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin alpha 4 (Itg alpha 4). The adoptive transfer of Itg alpha 4-expressing CD4(+)V alpha 3.2(+)c-Met(+) T cells induces increased disease severity compared to CD4(+)V alpha 3.2(+)c-Met(-) T cells. Finally, CD4(+)c-Met(+) T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itg alpha 4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4(+) T lymphocytes associated with neuroinflammation

Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST" (Taper Or Abrupt Steroid STop) multicenter trial

BACKGROUND Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

BackgroundNeurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome.MethodsWe conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models.ResultsWe included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region.InterpretationNeurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome

Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters

Short-term glucocorticoid-related side effects and adverse reactions: a narrative review and practical approach

Glucocorticoids are the mainstay treatment of a variety of inflammatory and autoimmune disorders. Unfortunately, metabolic side effects, drug interactions and adverse reactions commonly lead to glucocorticoid-related side effects, thereby compromising their intended anti-inflammatory and immunosuppressive effects. The goal of this review is to help clinicians to monitor the broad spectrum of side effects of short-term systemic glucocorticoid administration, defined as glucocorticoid treatment shorter than 30 days. We review the various systems affected, with a focus on metabolic conditions and hyperglycaemia management

Physiopathologie de l’hypoxémie silencieuse dans le Covid-19

Une proportion significative de patients atteints de pneumopathie Covid-19 présente initialement une « hypoxémie silencieuse », désignant une absence de dyspnée et de signe de détresse respiratoire en présence d’une hypoxémie profonde. Le Covid-19 est multisystémique, le virus et la réaction immunitaire secondaire à l’infection se répandant par voie hématogène. Le cerveau n’est pas épargné par le Covid-19 avec le développement d’encéphalopathie ou d’autres complications. L’hypoxémie silencieuse représente une perte d’un signal d’alarme pour l’organisme, précédant parfois une rapide aggravation clinique avec issue fatale. Dans cet article, nous reprenons les bases physiologiques du contrôle de la ventilation et tentons d’élucider les différents mécanismes physiopathologiques qui sous-tendent le phénomène d’hypoxémie silencieuse

IL-8 as a potential biomarker in Guillain-Barre Syndrome

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis

Neuropathie des petites fibres dans les maladies autoimmunes systémiques

La neuropathie des petites fibres (NPF) implique une atteinte des fibres nerveuses de petit calibre : les fibres C non myélinisées et les fibres A-delta myélinisées. Elle se manifeste principalement par des troubles sensitifs : paresthésies, dysesthésies ou douleurs neuropathiques (brûlures) et déficits protopathiques, associés à des symptômes dysautonomiques. Les étiologies possibles des NPF sont variées : idiopathiques, toxiques, métaboliques, immunologiques, infectieuses et héréditaires. Nous présentons dans cet article la démarche diagnostique des NPF, les étiologies autoimmunes les plus fréquemment associées aux NPF, ainsi que des éléments de prise en charge thérapeutique

Serum neurofilament light chains in MS: Association with the Timed Up and Go

This cross-sectional study aims to assess the association between neuroaxonal damage assessed by serum neurofilament light chain (sNfL) and the Timed Up and Go (TUG)—a reliable and rapid measure of global neurologic disability—in patients with MS