Neuromyelitis optica spectrum disorder (NMOSD) is a rare chronic, relapsing, demyelinating, autoantibody-mediated disease of the central nervous system (CNS), also known as Devic disease. The classical presentation of this disease involves transverse myelitis, optic neuritis, area postrema syndrome (bouts of intractable vomiting and hiccoughs), and acute brainstem syndrome. Approximately 75% of patients with NMOSD have antibodies against aquaporin-4 (AQP4), a water channel expressed on astrocytes. In this theoretical article, the authors from the United States conducted a systematic review of the published literature to investigate the de novo onset or relapse of NMOSD after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination.
BNT162b2 (Pfizer- BioNTech) and mRNA 1273 (Moderna) vaccines were the first messenger RNA (mRNA)-based vaccines ever approved. In both vaccines, a mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 spike (S) glycoprotein. Previous studies reported the occurrence of new-onset autoimmune phenomena after COVID-19 vaccination, including immune thrombotic thrombocytopenia, autoimmune liver diseases, IgA nephropathy, rheumatoid arthritis, and systemic lupus erythematosus. Also, many previous case reports have linked the SARS-CoV-2 infection with CNS diseases such as transverse myelitis, acute demyelinating encephalomyelitis, multiple sclerosis, and NMSOD. https://discovermednews.com/acute-demyelinating-disease-of-the-cns-acute-disseminated-encephalomyelitis-associated-with-sars-cov-2-infection-or-anti-sars-cov-2-vaccination/
https://discovermednews.com/sars-cov-2-infection-is-associated-with-optic-neuritis/
About the study
In this review article, the authors conducted a Boolean medical literature search utilizing Medline, Cochrane Library, Embase, Trip Database, Clinicaltrials.gov, Scopus, and Web of Science databases. All case reports and case series that met the study criteria, and reported NMOSD that developed after acute SARS-CoV-2 infection or COVID-19 vaccination were included in this review. The review comprises articles indexed in the peer-reviewed literature. Poster and symposium abstracts, non-peer-reviewed publications, and clinical trials were excluded. Articles reporting other demyelinating disorders were also excluded. After removing articles based on exclusion criteria, 34 articles were analyzed.
Results
The study included 41 patients diagnosed with NMSOD associated with SARS-CoV-2 infection or COVID-19 vaccination. 76% of participants were women. Out of 41 cases, 15 developed de novo onset of NMOSD after SARS-CoV-2 infection, 21 developed de novo onset of NMOSD after COVID-19 vaccination, three patients diagnosed with NMOSD experienced a relapse after COVID-19 vaccination, and two patients had presumed diagnosis of multiple sclerosis that was manifested as NMOSD after COVID-19 vaccination.
Cases who developed NMOSD after acute SARS-CoV-2 infection
This group included 15 patients, 73% of whom were women. The cases came from twelve countries. The median age of the patients was 37.5 years, with a range of 7.5–71 years. Two patients (13%) had a previous history of an immune-mediated condition, one had juvenile arthritis, and the other had an episode of suspected acute demyelinating encephalomyelitis.
The median time between the first symptoms of SARS-CoV-2 infection and the first symptoms of NMOSD was 14 days (range 3–120 days).
The most common neurological clinical presentation was transverse myelitis, which was diagnosed in 67% of patients (10 cases). Optic neuritis was diagnosed in 47% of patients (7 cases), and area postrema syndrome in 13% of patients (two cases), manifested as intractable nausea, vomiting, or hiccoughs that persisted for at least 48 hours. 33% of patients (5 cases) had the brain stem involvement.
The examination of cerebrospinal fluid (CSF) showed a pleocytosis in 5 patients (33%), while two patients (13%) had normal white blood cell count. Two patients (13%) had high protein levels, ten patients (67%) tested positive for AQP4 antibody, while four patients (27%) were AQP4 antibody-negative.
Almost all patients (92%) were initially treated with intravenous methylprednisolone. In addition to methylprednisolone, patients were treated with plasmapheresis and intravenous immunoglobulins. 84% (11 of 13 patients) recovered fully or partially after the treatment, whereas 15% (2 of 13 patients) died. The first patient died from multiorgan failure and sepsis secondary to the SARS-CoV-2 infection, and the second patient died from respiratory insufficiency and lymphopenia after cyclophosphamide treatment.
Cases who developed NMOSD following COVID-19 vaccination
This group included 26 patients. The median age was 50 years, ranging from 19 to 80 years. The cases came from 13 countries. Eight patients (31%) had a history of an immune-mediated condition and four patients (15%) had a family history of an immune-mediated condition.
Out of 26 patients, 21 developed de novo onset of NMOSD, whereas three patients with known NMOSD experienced a relapse after the vaccination. Two patients had presumed multiple sclerosis that was manifested as NMOSD after the vaccination. Notably, one patient with a previous diagnosis of NMOSD was stable and relapse-free for eight years before he experienced a relapse triggered by vaccination.
The median interval between anti-SARS-CoV-2 vaccination and the onset of the first symptoms of NMOSD was 10 days (range one to 97 days).
Out of the 26 cases, 58% (15 patients) experienced their first neurological symptoms after the first dose of the vaccine, 23% (6 patients) after the second dose, and two patients (8%) after the third dose of the vaccine. One patient did not specify which dose induced neurological symptoms.
In total, 54% (14/26) of cases received mRNA vaccine, 31% (8/26) received a viral vector vaccine, and 15% (4/26) received an inactivated COVID-19 vaccine.
35% of NMOSD cases (nine patients) occurred after receiving the BNT162b2 mRNA (Pfizer-BioNTech) vaccine, 23% (six patients) after ChAdOx1 nCoV-19 (Oxford–AstraZeneca) viral vector vaccine, 19% (5 patients) after mRNA-1273 vaccine (Moderna), 15% (four patients) after the Sinovac or Sinopharm inactivated COVID-19 vaccine and one case (4%) after Sputnik V adenovirus viral vector vaccine.
The most common neurological clinical presentation was transverse myelitis, diagnosed in 65% (17 patients). Optic neuritis was diagnosed in 19% (in five patients), area postrema syndrome in three patients (12%), and brainstem syndrome in three patients (12%).
The CSF examination showed pleocytosis in 55% (11 of 20 patients), and elevated CSF protein levels in 45% (9 of 20 cases). 88% (22 patients) tested positive for AQP4 antibodies, while three patients (12%) were AQP4 antibody-negative.
Almost all patients (96%) were initially treated with intravenous methylprednisolone. In addition to methylprednisolone, patients were treated with plasmapheresis and intravenous immunoglobulins. The maintenance immunotherapy included rituximab, azathioprine, cyclophosphamide, eculizumab, and mycophenolate mofetil. 88% (22 patients) recovered fully or partially after treatment, two patients (8%) did not have any improvement, and one patient (4%) died.
Conclusion
This review article has shown that SARS-CoV-2 infection and COVID-19 vaccination are associated with de novo onset or relapse of NMSOD. The authors also discussed possible pathological mechanisms underlying NMOSD associated with COVID-19 or vaccination. As evidence suggests that SARS-CoV-2 may cross the blood-brain barrier, neuroinvasion by SAR-CoV-2 or its antigens may release CNS antigens such as AQP-4 into the systemic circulation, triggering the bystander immune cascade. Other mechanisms include the activation of toll-like receptors or the autoantibody production against myelin via molecular mimicry.
Although causation cannot be proven, cases with a short latency (less than 28 days) are less likely to be coincidental. NMOSD manifestations may be coincidental in cases with a longer latency (more than 28 days after the exposure). The authors concluded that the observed findings of NMOSD after acute SARS-CoV-2 infection or COVID-19 vaccination require further research in a larger population.
This article was published in Frontiers in Neurology.
Journal Reference
Harel T, et al. New onset or relapsing neuromyelitis optica temporally associated with SARS-CoV-2 infection and COVID-19 vaccination: a systematic review. Front. Neurol. 22 June 2023. Sec. Multiple Sclerosis and Neuroimmunology. Volume 14 – 2023. (Open Access) https://doi.org/10.3389/fneur.2023.1099758
