The objective of this article by the US authors was to conduct a systematic review of the published literature in order to evaluate the potential association between SARS-CoV-2 infection or anti-SARS-CoV-2 vaccination and de novo onset or relapse of neuromyelitis optica spectrum disorder (NMOSD).
SARS-CoV-2 is capable to dysregulate the host immune system. Many case reports have linked the SARS-CoV-2 infection with an array of autoimmune demyelinating disorders of the central nervous system (CNS) such as transverse myelitis, acute demyelinating encephalomyelitis, multiple sclerosis, and neuromyelitis optica spectrum disorder.
NMOSD is a rare chronic, relapsing, demyelinating, autoantibody-mediated disease of the 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 have antibodies against aquaporin-4 (AQP4), a water channel expressed on astrocytes.
About the study
In this review article, the authors conducted a Boolean search of the medical literature utilizing Medline, Cochrane Library, Embase, Trip Database, Clinicaltrials.gov, Scopus, and Web of Science databases. The literature review included all case reports and case series that met the study criteria and involved NMOSD following either the SARS-CoV-2 infection or the COVID-19 vaccination. The review included only articles indexed in the peer-reviewed literature. Poster and symposium abstracts, non-peer reviewed publications, and clinical trials were excluded. The articles that addressed peripheral nervous system demyelinating diseases or CNS demyelinating disorders other than NMOSD were also excluded. A total of 702 articles were imported for screening. After removing 352 duplicates and 313 articles based on exclusion criteria, a total of 34 articles were analyzed.
The study included a total of 41 NMOSD cases, and 76% of them were female. 15 patients developed de novo onset of NMOSD following a SARS-CoV-2 infection, 21 patients developed de novo onset of NMOSD following COVID-19 vaccination, 3 patients with known NMOSD experienced a relapse following vaccination, and 2 patients had presumed multiple sclerosis that was manifested as NMOSD post-vaccination.
1. The group that developed NMOSD following the SARS-CoV-2 infection
This group included 15 patients, 11 (73%) of them were women, 3 (20%) of them were men. For one patient, the gender remained unknown (7%). The cases came from 12 countries. The median age of the patients was 37.5 years, with a range of 7.5–71 years. 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).
Two patients (13%) had a history of an immune-mediated condition. One patient had juvenile arthritis, and the other had a past episode of suspected acute demyelinating encephalomyelitis.
Transverse myelitis was the most common neurological clinical presentation, occurring in 10 patients (67%). The optic neuritis was found in 7 patients (47%). Two patients (13%) were found to have area postrema syndrome, manifested as intractable nausea, vomiting, or hiccoughs that persisted for at least 48 h. In 5 patients (33%), brain stem involvement was found.
The analysis of cerebrospinal fluid revealed a pleocytosis in 5 patients (33%) while 2 patients (13%) had normal white blood cell count. 2 patients (13%) had high protein levels. Ten patients (67%) tested positive for AQP4 antibody, while 4 patients (27%) were AQP4 antibody-negative (one case not reported).
All but one patient (92%) were initially treated with intravenous methylprednisolone. In addition to methylprednisolone, patients were treated with plasmapheresis and intravenous immunoglobulins. 11/13 (84%) patients recovered fully or partially after treatment, whereas 2/13 (15%) 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, lymphopenia, and a fever after being treated with cyclophosphamide.
2. The group of patients who developed NMOSD after anti-SARS-CoV-2 vaccination
This group included 26 patients, 21 of them developed de novo onset of NMOSD following COVID-19 vaccination, 3 patients with known NMOSD experienced a relapse following vaccination, and 2 patients had presumed multiple sclerosis that was manifested as NMOSD post-vaccination. It is worth noting that one patient with a previous diagnosis of NMOSD had been stable and relapse free for 8 years before he experienced relapse triggered by vaccination.
The median age was 50 years, with a range from 19 to 80 years. The cases came from 13 countries. The median interval between anti-SARS-CoV-2 vaccination and onset of the first symptoms of NMOSD was 10  days (range 1 to 97  days). Out of the 26 cases, 15 patients (58%) experienced their first neurological symptoms following the first dose of the vaccine, 6 patients (23%) after the second dose, and 2 patients (8%) after the third dose of the vaccine. One patient did not specify which dose induced neurological symptoms.
9 cases (35%) occurred after receiving the Pfizer-BioNTech BNT162b2 mRNA vaccine, 6 cases (23%) following the Oxford–AstraZeneca ChAdOx1 nCoV-19 viral vector vaccine, 5 cases (19%) following the Moderna mRNA-1273 vaccine, 4 cases (15%) after the Sinovac or Sinopharm inactivated COVID-19 vaccine, and 1 case (4%) after the Sputnik V adenovirus viral vector vaccine. 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.
8 patients (31%) had a history of an immune-mediated condition and 4 patients (15%) had a family history of an immune-mediated condition.
Transverse myelitis was the most common neurological clinical presentation, occurring in 17 patients (65%). Optic neuritis was found in 5 patients (19%), area postrema syndrome in 3 patients (12%) and brainstem syndrome in 3 patients (12%).
The CSF results showed pleocytosis in 11/20 (55%) patients, 9/20 (45%) had elevated CSF protein levels. 22 patients (88%) tested positive for AQP4 antibodies, while 3 patients (12%) were AQP4 antibody-negative.
All but one patient (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. 22 patients (88%) recovered fully or partially after treatment, 2 patients (8%) did not have any improvement, and 1 patient (4%) died.
Afterward, the authors discussed theories about the pathological mechanism underlying NMOSD induced by the COVID-19 vaccine or the SARS-COV-2 infection. Evidence suggests that SARS-CoV-2 crosses the blood brain barrier along with other cytokines. After the SARS-CoV-2 has accessed the CNS, various pathological mechanisms have been proposed. Neuroinvasion by SAR-CoV-2 or its antigens may result in the release of CNS antigens such as AQP-4 peptides into the systemic circulation, triggering the bystander immune cascade. Other mechanisms include activation of toll-like receptors and production of antibodies against myelin via molecular mimicry.
In conclusion, this review article showed that there is association between SARS-CoV-2 infection or anti-SARS-CoV-2 vaccination and de novo onset or relapse of neuromyelitis optica spectrum disorder. Although causation cannot be proven, the authors stated that cases with a short latency (less than 28 days) are less likely to be coincidental. NMOSD manifestations may be coincidental in cases with a long latency (more than 28 days after the exposure). The observed correlation requires further investigation utilizing quantitative epidemiological assessments in a larger population to more accurately quantify the risk.
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