An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

Comparative features and outcomes of major neurological complications of COVID-19.

BACKGROUND AND PURPOSE: The aim of this study was to assess the neurological complications of SARS-CoV-2 infection and compare phenotypes and outcomes in infected patients with and without selected neurological manifestations. METHODS: The data source was a registry established by the European Academy of Neurology during the first wave of the COVID-19 pandemic. Neurologists collected data on patients with COVID-19 seen as in- and outpatients and in emergency rooms in 23 European and seven non-European countries. Prospective and retrospective data included patient demographics, lifestyle habits, comorbidities, main COVID-19 complications, hospital and intensive care unit admissions, diagnostic tests, and outcome. Acute/subacute selected neurological manifestations in patients with COVID-19 were analysed, comparing individuals with and without each condition for several risk factors. RESULTS: By July 31, 2021, 1523 patients (758 men, 756 women, and nine intersex/unknown, aged 16-101 years) were registered. Neurological manifestations were diagnosed in 1213 infected patients (79.6%). At study entry, 978 patients (64.2%) had one or more chronic general or neurological comorbidities. Predominant acute/subacute neurological manifestations were cognitive dysfunction (N = 449, 29.5%), stroke (N = 392, 25.7%), sleep-wake disturbances (N = 250, 16.4%), dysautonomia (N = 224, 14.7%), peripheral neuropathy (N = 145, 9.5%), movement disorders (N = 142, 9.3%), ataxia (N = 134, 8.8%), and seizures (N = 126, 8.3%). These manifestations tended to differ with regard to age, general and neurological comorbidities, infection severity and non-neurological manifestations, extent of association with other acute/subacute neurological manifestations, and outcome. CONCLUSIONS: Patients with COVID-19 and neurological manifestations present with distinct phenotypes. Differences in age, general and neurological comorbidities, and infection severity characterize the various neurological manifestations of COVID-19.

COVID-19 Associated Guillain-Barré Syndrome: A Report of Nine New Cases and a Review of the Literature.

BACKGROUND: Guillain-Barré syndrome (GBS)-a rare condition characterized by acute-onset immune-mediated polyneuropathy-has been registered as a neurological manifestation of COVID-19, suggesting a possible link between these two conditions. METHODS: We report a case series of patients with COVID-19-related GBS hospitalized in the Neurology Department of Colentina Clinical Hospital, Bucharest, Romania, between March 2020 and March 2021. Several variables were analyzed, such as the mean interval between the onset of COVID-19 symptoms and neurological ones, clinical features, treatment course, and outcome. Further on, we conducted a thorough literature review based on the PubMed and ScienceDirect scientific databases. RESULTS: A total of 9 COVID-19 patients developed symptoms of GBS, out of which in 7, it manifested as an acute inflammatory demyelinating polyneuropathy (AIDP). Five patients presented respiratory failure, 2 requiring mechanical ventilation. All patients received a course of intravenous immunoglobulins, 2 additionally requiring plasma exchange. Upon discharge, all but 1 patient (who had not regained the ability to walk) had a positive outcome, and 1 died during admission. In the literature review, we analyzed the published sources at the time of writing. CONCLUSIONS: A link between COVID-19 and GBS might be possible; therefore, increased vigilance is required in the early identification of these cases for prompt diagnosis and treatment. Some notable differences such as an earlier onset of GBS symptoms, higher respiratory dysfunction, and higher mortality rates in COVID-19 patients have been observed between the presentation of GBS in the context of COVID-19 and GBS of other causes.

Short- and long-term outcome and predictors in an international cohort of patients with neuro-COVID-19.

BACKGROUND AND PURPOSE: Despite the increasing number of reports on the spectrum of neurological manifestations of COVID-19 (neuro-COVID), few studies have assessed short- and long-term outcome of the disease. METHODS: This is a cohort study enrolling adult patients with neuro-COVID seen in neurological consultation. Data were collected prospectively or retrospectively in the European Academy of Neurology NEuro-covid ReGistrY ((ENERGY). The outcome at discharge was measured using the modified Rankin Scale and defined as 'stable/improved' if the modified Rankin Scale score was equal to or lower than the pre-morbid score, 'worse' if the score was higher than the pre-morbid score. Status at 6 months was also recorded. Demographic and clinical variables were assessed as predictors of outcome at discharge and 6 months. RESULTS: From July 2020 to March 2021, 971 patients from 19 countries were included. 810 (83.4%) were hospitalized. 432 (53.3%) were discharged with worse functional status. Older age, stupor/coma, stroke and intensive care unit (ICU) admission were predictors of worse outcome at discharge. 132 (16.3%) died in hospital. Older age, cancer, cardiovascular complications, refractory shock, stupor/coma and ICU admission were associated with death. 262 were followed for 6 months. Acute stroke or ataxia, ICU admission and degree of functional impairment at discharge were predictors of worse outcome. 65/221 hospitalized patients (29.4%) and 10/32 non-hospitalized patients (24.4%) experienced persisting neurological symptoms/signs. 10/262 patients (3.8%) developed new neurological complaints during the 6 months of follow-up. CONCLUSIONS: Neuro-COVID is a severe disease associated with worse functional status at discharge, particularly in older subjects and those with comorbidities and acute complications of infection.

Prognostic Factors in COVID-19 Patients With New Neurological Manifestations: A Retrospective Cohort Study in a Romanian Neurology Department.

Introduction: The emerging Coronavirus Disease (COVID-19) pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious public health issue due to its rapid spreading, high mortality rate and lack of specific treatment. Given its unpredictable clinical course, risk assessment, and stratification for severity of COVID-19 are required. Apart from serving as admission criteria, prognostic factors might guide future therapeutic strategies. Aim: We aimed to compare clinical features and biological parameters between elderly (age ≥ 65 years) and non-elderly (age <65 years) patients with COVID-19 and new neurological symptoms/conditions. We also aimed to determine factors independently associated with all-cause in-hospital mortality. Methods: All consecutive patients with COVID-19 and new neurological symptoms/conditions admitted in our Neurology Department between April 1 and August 23, 2020 were enrolled in this observational retrospective cohort study. Patient characteristics such as demographic data, comorbidities, biological parameters, imaging findings and clinical course were recorded. All-cause in-hospital mortality was the main outcome, whereas COVID-19 severity, hospitalization duration and the levels of supplemental oxygen were the secondary outcomes. Results: One hundred forty-eight patients were included, out of which 54.1% were women. The average age was 59.84 ± 19.06 years and 47.3% were elderly, the majority having cardiovascular and metabolic comorbidities. In the elderly group, the most frequent neurological symptoms/manifestations responsible for hospitalization were stroke symptoms followed by confusion, whereas in the non-elderly, headache prevailed. The final neurological diagnosis significantly varied between the two groups, with acute cerebrovascular events and acute confusional state in dementia most commonly encountered in the elderly (65.71 and 14.28%, respectively) and secondary headache attributed to SARS-CoV-2 infection often experienced by the non-elderly (38.46%). The elderly had statistically significant higher median values of white blood cell (8,060 vs. 6,090/µL) and neutrophil count (6,060 vs. 4,125/µL), C-reactive protein (29.2 vs. 5.72 mg/L), ferritin (482 vs. 187 mg/dL), fibrinogen (477 vs. 374 mg/dL), D-dimer (1.16 vs. 0.42), prothrombin time (151.15 vs. 13.8/s), aspartate transaminase (26.8 vs. 20.8 U/l), creatinine (0.96 vs. 0.77 mg/dL), and blood urea nitrogen level (51.1 vs. 27.65 mg/dL), as well as lower median value of hemoglobin (13.05 vs. 13.9 g/dL) and lymphocyte count (1,245 vs. 1,670/µL). Moreover, advanced age was significantly associated with more extensive lung involvement (25 vs. 10%) and higher fatality rate (40 vs. 9%). Overall, the mortality rate was 23.6%. Age as well as neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels were independently associated with mortality. Conclusions: Older age, higher neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels are independent predictors of mortality in COVID-19 patients with new neurological manifestations/conditions at admission.