Since the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a growing body of evidence indicates that besides common COVID-19 symptoms, patients may develop various neurological manifestations affecting both the central and peripheral nervous systems as well as skeletal muscles. These manifestations can occur prior, during and even after the onset of COVID-19 general symptoms. In this Review, we discuss the possible neuroimmunological mechanisms underlying the nervous system and skeletal muscle involvement, and viral triggered neuroimmunological conditions associated with SARS-CoV-2, as well as therapeutic approaches that have been considered for these specific complications worldwide.
Our results demonstrate that seizure development in the acute phase is the most significant factor for development of remote seizure. Parenchymal lesions in the supratentorial area were also found to be associated with both acute and remote seizures. However, no factor was predictive of acute or remote seizures in a multivariate analysis.
Anti–aquaporin-4 (AQP4) autoantibody plays a key role in the pathogenesis of neuromyelitis optica (NMO). Studies have shown increased relapse rates in patients with NMO during pregnancy and postpartum. High estrogen levels during pregnancy can increase activation-induced cytidine deaminase expression, which is responsible for immunoglobulin production. Additionally, sex hormones may influence antibody glycosylation, with effects on antibody function. Estrogen decreases apoptosis of self-reactive B cells, through upregulation of antiapoptotic molecules. Furthermore, high estrogen levels during pregnancy can boost B-cell activating factor and type 1 interferon (IFN) production, facilitating development of self-reactive peripheral B cells in association with increased disease activity. Elevated levels of estrogen during pregnancy decrease IFN-γ generation, which causes a shift toward T helper (Th) 2 immunity, thereby propagating NMO pathogenesis. Women with NMO have an elevated rate of pregnancy complications including miscarriage and preeclampsia, which are associated with increased Th17 cells and reduction of T-regulatory cells. These in turn can enhance inflammation in NMO. Increased regulatory natural killer cells (CD56−) during pregnancy can enhance Th2-mediated immunity, thereby increasing inflammation. In the placenta, trophoblasts express AQP4 antigen and are exposed to maternal blood containing anti-AQP4 antibodies. Animal models have shown that anti-AQP4 antibodies can bind to AQP4 antigen in placenta leading to complement deposition and placental necrosis. Reduction of regulatory complements has been associated with placental insufficiency, and it is unclear whether these are altered in NMO. Further studies are required to elucidate the specific mechanisms of disease worsening, as well as the increased rate of complications during pregnancy in women with NMO.
Exposure to heavy metals has been associated to a higher incidence of multiple sclerosis. In this work, we present a possible relationship between serum mercury levels and development of multiple sclerosis in Isfahan, the third largest city in Iran. Seventy-four patients affected by multiple sclerosis were retrieved from multiple sclerosis (MS) clinic in Isfahan, Iran. By matching sex and age, 74 healthy volunteers were chosen as control group. Blood samples were collected and serum mercury content was determined. Serum mercury level in MS patients was significantly higher than controls (9.6 ± 10.17 vs. 5.7 ± 8.6, P = 0.037). Concerning all MS patients, serum mercury value was significantly higher than the mercury concentration founded in control subjects {odd ratio: 2.39 (CI, 1.96-2.94), P = 0.00}. Serum mercury level is higher in MS patients with odd ratio equal to 2.39 compared with healthy individuals. It may reveal that high mercury levels in serum might help MS development in susceptible individuals. More studies with larger sample size are needed to confirm this hypothesis.
Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.
Objective: We conducted a longitudinal prospective study to evaluate the long-term effect of pregnancy on the progression of multiple sclerosis (MS). Method: Parous female MS patients were extracted from the database of Isfahan Multiple Sclerosis Society (IMSS). Through comparing the annual relapsing rate during a mean of 4 years before pregnancy versus a mean of 6 years after delivery, MS progression influenced by the pregnancy was analyzed. Result: 102 female patients were included in our study. The mean annual relapsing rate 4 years prior to pregnancy was significantly higher than at the subsequent 6 years after delivery (1.06 vs. 0.45, p < 0.001). In addition, the annual relapsing rate in years prior to pregnancy was significantly higher than each trimester of gestation (p < 0.001). Furthermore, there was a 2.2-fold increased risk of having a relapse in individuals who had experienced more relapses prior to pregnancy, and a 0.8-fold decreased in the risk of having more relapses with older age at the onset of MS. Conclusion: Although the course of MS was deteriorated 3 months after delivery, it was not statistically significant comparing annual relapsing rates during the years prior to pregnancy. Moreover, the rate of disease progression slowed down in the 6-year period monitored after delivery.
Since the coronavirus disease 2019 (COVID-19) pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, accumulating evidence indicates that SARS-CoV-2 infection may be associated with various neurological manifestations, including acute cerebrovascular events (i.e., stroke and cerebral venous thrombosis). These events can occur prior to, during and even after the onset of COVID-19’s general symptoms. Although the mechanisms underlying the cerebrovascular complications in patients with COVID-19 are yet to be fully elucidated, the hypercoagulability state, inflammation and altered angiotensin-converting enzyme 2 (ACE-2) signaling in association with SARS-CoV-2 may play key roles. ACE-2 plays a critical role in preserving heart and brain homeostasis. In this review, we discuss the current state of knowledge of the possible mechanisms underlying the acute cerebrovascular events in patients with COVID-19, and we review the current epidemiological studies and case reports of neurovascular complications in association with SARS-CoV-2, as well as the relevant therapeutic approaches that have been considered worldwide. As the number of published COVID-19 cases with cerebrovascular events is growing, prospective studies would help gather more valuable insights into the pathophysiology of cerebrovascular events, effective therapies, and the factors predicting poor functional outcomes related to such events in COVID-19 patients.
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