Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) following COVID-19 vaccines: A systematic review

Abstract

Background

The global COVID-19 pandemic began in March 2019, and given the number of casualties and adverse effects on the economy, society, and all aspects of the health system, efforts have been made to develop vaccines from the beginning of the pandemic. Numerous vaccines against COVID-19 infection have been developed in several technologies and have spread rapidly. There have been reported multiple complications of the COVID-19 vaccines as with other vaccines. A number of studies have reported multiple sclerosis (MS ) and neuromyelitis optica spectrum disorder (NMOSD) as complications of COVID-19 vaccines.

Methods

First, we found 954 studies from 4 databases (PubMed, Embase, Scopus, and Web of Science) from inception to March 1^st, 2022. Next, duplicate articles were eliminated, and 476 studies remained. Then 412 studies were removed according to inclusion and exclusion criteria. After obtaining the full text of 64 articles, 12 studies were selected finally.

Results

The data were extracted from included studies in a table. Our data includes demographic data, comorbidities, vaccines information and side effects, NMOSD and MS symptoms, laboratory and cerebrospinal fluid (CSF) findings, magnetic resonance imaging (MRI) results, treatment, and outcome of all cases.

Conclusion

MS and NMOSD are two neuroinflammatory disorders that arise in the CNS. Cases of MS and NMOSD have been reported following COVID-19 vaccination. Nevertheless, more studies with more subjects are needed to assess any possible relationship between the COVID-19 vaccine and central nervous system demyelination.

1. Introduction

Multiple sclerosis (MS) is a common inflammatory and demyelinating disorder of the central nervous system (CNS) with axonal damage in young adults. Although the pathophysiology of MS is not clear, some of the risk factors that develop MS include genetics, Epstein-Barr virus (EBV), smoking, and vitamin D deficiency [1], [2].

Unlike MS, neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune demyelination disease. Pathophysiology of NMOSD is related to a specific antibody against the aquaporin-4 (AQP4) water channel. Moreover, lesions associated with NMOSD are developed in AQP4-enriched areas as area postrema(AP) and involve optic nerves and the spinal cord [3], [4].

In late 2019 the world witnessed the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has out broken from Wuhan, China, to the rest of the world in a short period, and as of February 03, 2022, 448 million confirmed cases and 6 million deaths have been reported worldwide [5], [6]. During the spread of the virus to 210 countries, in March 2020, the World Health Organization (WHO) declared the infection a pandemic [7]. Given the similarity in features of other viruses in this family, similar symptoms are expected in exposure to SARS-CoV-2, which has spread worldwide since 2019. Case histories reported complications of COVID-19 infection in patients including anosmia [8], ageusia [9], seizure [10], cerebral hemorrhage [11], [12], [13], ischemic stroke [14], acute encephalopathy [15], acute transverse myelitis [16], optic neuritis(ON) [17], MS [18] and NMOSD [19].

The number of quarantines, psychological effects, activity restriction, hospitalizations, deaths, and most importantly, mutation of the virus (which occurs mainly in the spike protein (S-protein), responsible for binding and entering the host cell and increasing the risk of transmission and severity), have let to efforts in many countries to develop the COVID-19 vaccine [20], [21], [22], [23], [24], [25]. The first vaccine against COVID-19 infection was the BNT162b2 vaccine (ClinicalTrials.gov Identifier: NCT04368728), which its clinical trials began in April 2020 [26], [27], [28]. Other vaccines made by various companies and research institutes also have been approved [29].

In the wake of the approval of COVID-19 vaccines, these vaccines have been administered throughout the world. Despite the immunization of vaccines, cases of local and systemic side effects of vaccination have been reported [30], [31]. Whereas further serious complications after COVID-19 vaccine injection have been noted as well. According to the reports, COVID-19 vaccines may cause many disorders, but not limited to the CNS, and lead to neurological disorders [32]. Mainly, COVID-19 infection is able to cross the blood-brain barrier (BBB) and lead to inflammation in the CNS. The cytokine storm begins with the arrival of immune cells, and the inflammation peaks [33]. However, the similar mechanism of the vaccine in causing inflammation in the CNS is unknown. Likewise, there are reports of triggering post-COVID-19 vaccination MS and NMOSD [34], [35].

In this study, we systematically reviewed the MS and NMOSD cases as complications of post-COVID-19 vaccination to date. In addition, we described the clinical and laboratory features of all cases and discussed the possible risk of MS and NMOSD following COVID-19 vaccination.

2. Methods

2.1. Literature search

Initially, we searched four databases containing PubMed (Medline), Scopus, Web of Science, and Embase from inception to March 1st, 2022. The gray literature (references of the articles and review studies, and conference abstracts) was also searched. Our search strategy was based on the MeSH term that was customized for each database and included: ((“Multiple Sclerosis*”) OR (Sclerosis* AND “Multiple”) OR (Sclerosis* AND “Disseminated”) OR (“Multiple Sclerosis*” AND “Acute Fulminating”) OR (“Disseminated Sclerosis*”) OR (“NMO Spectrum Disorder*”) OR (Disorder AND “NMO Spectrum*”) OR (“Neuromyelitis Optica Spectrum Disorder*”) OR (Disorder AND “Neuromyelitis Optica Spectrum*”) OR (“Devic Neuromyelitis Optica*”) OR (Devic AND “Neuromyelitis Optica*”) OR (“Devic Disease*”) OR (Disease AND Devic) OR (Devic) OR (“Neuromyelitis Optica*”)) AND (“COVID 19 Vaccin*” OR (Vaccin* AND COVID-19) OR “COVID-19 Virus Vaccin*” OR (Vaccin* AND “COVID-19 Virus”) OR (“Virus Vaccin*” AND COVID-19) OR “COVID-19 Virus Vaccin*” OR “COVID 19 Virus Vaccin*” OR (“Virus Vaccin*” AND COVID-19) OR “COVID19 Virus Vaccin*” OR (Vaccin* AND “COVID19 Virus”) OR (“Virus Vaccin*” AND COVID19) OR “COVID19 Vaccin*” OR (Vaccin* AND COVID19) OR “SARS-CoV-2 Vaccin*” OR “SARS CoV 2 Vaccin*” OR (Vaccin* AND SARS-CoV-2) OR “SARS2 Vaccin*” OR (Vaccin* AND SARS2) OR “Coronavirus Disease 2019 Vaccin*” OR “Coronavirus Disease 2019 Virus Vaccin*” OR “Coronavirus Disease-19 Vaccin*” OR (Vaccin* AND “Coronavirus Disease-19”) OR “Coronavirus Disease 19 Vaccin*” OR “COVID 19 Vaccin*” OR (Vaccin* AND “COVID 19”) OR “2019-nCoV Vaccin*” OR “2019 nCoV Vaccin*” OR (Vaccin* AND 2019-nCoV) OR “2019 Novel Coronavirus Vaccin*” OR “2019-nCoV Vaccin*” OR “2019 nCoV Vaccin*” OR (Vaccin* AND 2019-nCoV) OR “COVID-19 Vaccin*” OR “SARS Coronavirus 2 Vaccin*”).

2.2. Inclusion and exclusion criteria

The inclusion and exclusion criteria of our review study were determined according to the following information. All case reports of MS and NMOSD patients following the COVID-19 vaccine were included in our inclusion criteria. Also, the exclusion criteria were composed of non-English articles, insufficient data on patients with COVID-19, and no definite diagnosis of MS or NMOSD.

2.3. Study selection and data extraction

The process of study selection of all articles was carried out by two researchers (OM) and (RP) separately, and any disagreement was resolved by the third researcher (VS). After selecting the desired articles, related data was extracted by (SV) and (RP) in Table 2 Table 1 . The table encompassed not only the demographics, symptoms, and tests of patients but also the vaccine and treatment type.

Table 1.

Quality assessment based on JBI tool.

Year	Author	1	2	3	4	5	6	7	8
2021	Ariana	Y	Y	Y	Y	Y	N	Y	Y
2021	Khayat-Khoei	U	N	Y	Y	Y	Y	U	Y
2021	Havla	U	N	Y	Y	Y	Y	U	Y
2021	Watad	N	N	N	U	Y	N	N	N
2021	Fujimori	Y	U	Y	Y	U	N	N	Y
2021	Fujikawa	Y	Y	Y	Y	Y	Y	U	Y
2021	Badrawi	Y	Y	Y	Y	N	N	U	U
2021	Chen	N	N	Y	Y	Y	N	U	U
2021	Mathew	N	N	N	N	Y	N	Y	U
2022	Toljan	U	N	Y	Y	Y	Y	U	Y
2022	Anamnart	U	N	Y	Y	Y	Y	U	Y
2022	Caliskan	Y	Y	Y	Y	U	U	U	Y

Y: yes; N: no; U: unclear; NA: not applicable.

2.4. Quality assessment

The quality of all studies was assessed with Joanna Briggs Institute (JBI) tool, a checklist for evaluating systematic reviews [36]. Two researchers (EM) and (SV) conducted the quality assessment of all case reports, and the senior researcher (OM) solved any disagreement. The evaluation was based on “Yes”, “NO”, “Unclear”, and “Not applicable”. In addition, the “Yes” answers were summed from 0 to 8. The articles lower than score 4 were presumed to be low quality, and those higher than score 4 were considered high quality (Table 1).

3. Results

The selection process of the studies was carried out according to the inclusion and exclusion criteria and using the PRISMA flow chart (Fig. 1 ). Accordingly, 954 articles were collected from the databases. After the elimination of duplicates, 476 articles remained. The articles were screened, 64 articles remained, and 412 studies were eliminated. Full-text articles were gathered, and 12 articles were included in our study based on our interest data.

Fig. 1.

PRISMA flow diagram: the PRISMA diagram includes details our search and selection.

Table 2 contains demographic information of 19 patients, their comorbidities, COVID-19 tests, vaccine information received, type of MS or NMOSD, symptoms at onset, laboratory investigations, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings, treatment, and outcome. In all 19 cases, 14 (73.6%) patients were female, and the mean (SD) of their age was 37.8 (10.1) years. Also, the mean (SD) of the interval time between injection of the COVID-19 vaccination and the first symptoms of MS or NMOSD in 1st and 2nd doses were 7.5 (4.8) and 15.1 (12.8) days, respectively. 89.4% of patients received intravenous methylprednisolone (IVMP), and 26.3% conducted plasma exchange (PLEX). Finally, all available data demonstrated that all patients recovered. Six out of eight NMOSD patients tested positive for AQP4, whereas none of the four MS patients tested positive for AQP4.

Table 2.

Demographic and clinical features of MS and NMOSD patients following COVID-19 vaccination.

Author	Age/gender	Comorbidities	Name of vaccine	Time interval/dose	MS/NMOSD	Vaccine side effects	MS/NMO first signs and symptoms	Laboratory findings	CSF findings	MRI/radiology	Acute treatment	Main treatment	Outcome
Tagliaferri et al. [37]	32/F	None	Pfizer-BioNTech (BNT162b2)	1 week/1st	MS	Left arm Soreness at the site of injection Fevers Chills	Motor weakness in the right hand Word slurring Gait instability Diffuse right-sided weakness in the upper and lower extremities	WBC count: 11.3 109/liter ESR: 24 mm/hour CRP: normal Vitamin D: 12.2 nmol/liter	Myelin basic protein: 13.3 pg/mL OCB: (0–3)	Brain CT: Normal Brain MRI: Multiple round hyperintensities in the white matter with restricted diffusion in the left pons MRA: Normal MRV: Normal	IVMP 1g for 3 days Prednisone 60mg for 11 days	NR	Recovered
Fujimori et al. [35]	40/F	Left peripheral facial nerve palsy	Pfizer-BioNTech (BNT162b2)	2 weeks/2nd	MS	Fever	Numbness and sensory Disturbance in the right hand and shoulder	AQP4 Ab: negative MOG Ab: negative	Leukocytes: elevated Protein level: normal Glucose level: normal OCB: positive Myelin basic protein: 146 pg/mL IL-6 level: 2.4 pg/mL	Brain MRI: Several periventricular or subcortical T2 Hyperintense white matter lesions Spinal MRI: T2 Hyperintense right lesion with Gd enhancement at the level of C5/C6	IVMP 1g for 3 days	NR	Recovered
Badrawi et al. [34]	34/M	None	Sputnik V (Gam-COVID-Vac)	3 weeks/2nd	NMOSD	NR	Confusional state Imbalance Headache dizziness	AQP4 Ab: positive SARS-CoV-2 Abs (IgG): detected	Normal	Brain MRI: Extensive periventricular and/or peri-ependymal signal changes around the ventricles, along with periaqueductal gray matter, Signal changes in the optic chiasma, thalamus, and corpus callosum Spinal MRI: normal	PLEX for 5 sessions	NR	Recovered
Fujikawa et al. [38]	46/F	Vitamin B12 deficiency	Moderna (mRNA-1273)	10 days/1st	NMOSD	NR	Pain in shoulder Bilateral lower-extremity weakness Urinary retention	AQP4 Ab: Negative	Normal	Brain MRI: normal Cervical spine MRI: Increased, Non-expansile intramedullary signal involving the central gray matter at C6-T2 without enhancement Thoracic spine: normal	IVMP 1g for 3 days Prednisone	NR	Recovered
Havla et al. [39]	28/F	NR	Pfizer-BioNTech (BNT162b2)	6 days/1st	MS	NR	Left abdominal neuropathic pain Sensory impairment Hypoesthesia of right abdominal wall and genital regions Left leg paresis	SARS-CoV-2 Abs (IgG): Detected	Mild pleocytosis: 7 cells/μL OCB: positive	Brain MRI: Multiple lesions (>20) Partially confluent lesions with spatial dissemination but without enhancement Spinal MRI: Contrast-enhancing lesion at T6 level T2 hyperintense lesion at level T6 and T7 Contrast enhancement after application of gadolinium is consistent with an active lesion	IVMP 1g for 5 days, followed by the second cycle of IVMP 2g for 5 days PLEX	NR	Recovered
Watad et al. [40]	45/F	Hypothyroidism	Pfizer-BioNTech (BNT162b2)	1 week/1st	MS	NR	Left leg weakness Lower limbs distal numbness	CBC: Normal	OCB: Positive	Brain MRI: Multiple PV white matter changes	IVMP 1g for 5 days Prednisolone 60 mg daily	NR	Recovered
Khayat-Khoei et al. [32]	26/F	NR	Moderna (mRNA-1273)	2 weeks/2nd	MS	None	Mild blurring Pain with eye movement OD	ANA: negative C-ANCA: negative Lyme titer: negative SARS-CoV-2 Abs (IgG): detected	Cell count: elevated IgG index: elevated OCB: negative	Brain MRI: Multiple T2 hyperintense periventricular, subcortical, and posterior fossa Spinal MRI: T2 hyperintense focal lesions at C1-2 After gadolinium administration, the spinal cord lesion at C4-5 enhanced	IVMP 1g for 5 days	NR	Recovered
	33/M	None	Pfizer-BioNTech (BNT162b2)	1 day/2nd	NMO	Arm pain	Unilateral painless blurring of vision	AQP4 Ab: negative	OCB: positive IgG index: Elevated	Brain MRI: Periventricular and juxtacortical T2 lesions, one of the lesions ring-enhances with GD Multiple T2 hyperintense white matter lesions with a single gadolinium-enhancing lesion consistent with an active demyelinating process Spinal MRI: A T2 hyperintense lesion, no cervical spinal cord enhancing lesions were seen	IVMP 1g for 3 days Prednisone	NR	Recovered
	64/M	Sjogren's disease	Pfizer-BioNTech (BNT162b2)	18 days/1st	NMOSD	None	Pain Paresthesia Numbness Weakness Sphincter dysfunction Balance/gait difficulty	AQP4 Ab: positive	AQP4 Ab: positive OCB: negative	Brain MRI: T2 white matter signal abnormalities in the corpus callosum with extension into the left frontal and parietal white matter Multiple T2 white matter signal abnormalities in the corpus callosum with extension into the left frontal and parietal white matter Spinal MRI: Minimally expansile central spinal cord T2 hyperintensity extending from the cervical cord to the conus, with patchy areas of Gd enhancement, consistent with longitudinally extensive transverse myelitis	IVMP 1g for 3 days PLEX	Rituximab	Recovered
Chen et al. [41]	NA/F	None	NR	3 days/1st	NMOSD	Fever Vomiting Diarrhea Cough Dizziness	Dizziness Unsteady walking Weakened pharyngeal reflex Weakness in limb muscle	AQP4 Ab: positive ANA: positive SSA: positive SSB: positive, Ro52: positive p-ANCA Abs: positive	WBC count: 31 per million	Brain MRI: Area postrema and bilateral hypothalamus lesions without Gd enhancement on FLAIR sequence Optic MRI: normal Spinal MRI: normal	IVMP 500 mg for 5 days	NR	Recovered
Mathew et al. [42]	24/F	History of left facial numbness, left upper limb weakness	AstraZeneca (ChAdOx1 nCoV-19)	5 days/2nd	MS	NR	Paresthesia in left upper and lower limbs Lhermitte's sign	NR	NR	Brain MRI: Two lesions Spinal MRI: One lesion with enhancement	IVMP 1g for 5 days	NR	Recovered
Toljan et al. [43]	29/F	Migraine	Pfizer-BioNTech (BNT162b2)	1 day/1st	MS	NR	Weakness and numbness in left leg Paresthesia in right arm	NR	IgG index: elevated OCB: unmatched bands Pleocytosis (8 leukocytes/μL)	Brain MRI: Several periventricular and juxtacortical white matter lesions with one enhancing lesion in the right centrum semiovale Brain: T2-weighted hyperintensities T1-weighted hypointense lesion which showed contrast enhancement	IVMP 1g for 5 days	Ocrelizumab	Recovered
	37/M	None	Pfizer-BioNTech (BNT162b2)	3 days/1st	MS	NR	Left hand paresthesia	AQP4 Ab: negative, MOG Ab: negative	NR	Brain MRI: Multiple periventricular non-enhancing T2/FLAIR hyperintensities Spinal MRI: A C3-C4 cord T2 and STIR hyperintense lesion T2/FLAIR hyperintensities on axial and sagittal projections, as well as T2- Weighted hyperintense lesions, compatible with multifocal demyelination	Prednisone 600mg for 3 days	NR	NR
	41/M	None	Moderna (mRNA-1273)	30 days/2nd	MS	NR	Bilateral foot numbness	AQP4 Ab: negative, MOG Ab: negative	IgG index: elevated OCB: positive Pleocytosis (104 leukocytes/μL)	Brain MRI: Multiple intracranial periventricular and juxtacortical T2/FLAIR hyperintensities, with most lesions demonstrating contrast enhancement Spinal MRI: Multifocal enhancing and non-enhancing T2 and STIR dorsal cord hyperintensities Prominent T2/FLAIR hyperintensities with contrast enhancement are seen on axial projection, with additional multifocal STIR hyperintensities on sagittal image	IVMP 1g for 5 days PLEX for 5 sessions Prednisolone	NR	Recovered
	46/F	History of unilateral optic neuritis	Moderna (mRNA-1273)	NR/1st	MS	NR	Right leg numbness	AQP4 Ab: Negative, MOG Ab: Negative	IgG index: Elevated Pleocytosis (8 leukocytes/μL)	Brain MRI: periventricular and juxtacortical intracranial lesions with enhancement of the periventricular lesion Spinal MRI:Multiple enhancing lesions Sagittal T2/FLAIR sequence projection demonstrates typical MS lesions with associated contrast enhancement and accompanying spinal cord lesions seen on T2-weighted sequence	IVMP for 5 days	NR	NR
	43/F	NR	Pfizer-BioNTech (BNT162b2)	35 days/2nd	MS	NR	Weakness in right arm Numbness in right periorbital and palatal	Cell count: Normal	OCB: Positive	Brain MRI: Enhancing and non-enhancing temporal and callosal periventricular ovoid lesions, and enhancement of the proximal right trigeminal nerve Axial T2/FLAIR sequence demonstrated multiple periventricular and juxtacortical lesion	IVMP for 3 days	Rituximab	Recovered
Anamnart et al. [44]	26/F	None	Sinovac (CoronaVac)	10 days/1st	NMOSD	Watery diarrhea Fatigue	Weakness in left leg Numbness in left arm and leg	AQP4 Ab: positive	OCB: negative	Brain MRI: normal Spinal MRI: Focal intramedullary swelling with T2 hyperintense signal and heterogeneous enhancement of left-sided cervical cord at C4-C5 levels	IVMP PLEX	Rituximab	Recovered
	46/F	None	AstraZeneca (ChAdOx1 nCoV-19)	10 days/1st	NMOSD	None	Weakness in right leg Hypoesthesia in right side	AQP4 Ab: Positive	OCB: Negative	Brain MRI: Abnormal T2 hyperintense signals and corresponding T1 hypointense signals with inhomogeneous gadolinium enhancement at the right lateral aspect of the medulla and the subependymal periventricular area along the right lateral ventricle Spinal MRI: Focal intramedullary T2 hyperintense signal with heterogeneous enhancement of right-sided cervical cord at C2-C3 levels	IVMP for 5 days Prednisolone	Azathioprine	Recovered
Caliskan et al. [45]	43/F	None	Pfizer-BioNTech (BNT162b2)	1 day/2nd	NMOSD	NR	Blurred vision Movement-associated pain in the right eye	AQP4 Ab: positive MOG Ab: negative	OCB: positive Mononuclear leukocytes Protein: elevated Glucose: normal Atypical cells: none	Brain MRI: right optic neuritis Spinal MRI: normal	IVMP for 10 days	Rituximab	Recovered

EDSS: expanded disability status scale, CSF: cerebrospinal fluid, MRI: magnetic resonance imaging, F: female, M:male, mRNA: messenger ribonucleic acid, MOG: myelin oligodendrocyte glycoprotein, WBC: white B cell, ESR: erythrocyte sedimentation rate, CRP: c-reactive protein, IVMP: IV methylprednisolone, RAPD: relative afferent pupillary defect, PLEX: Plasmapheresis, ANA: antinuclear antibodies, ANCA: antineutrophil cytoplasmic antibodies, OCB: oligoclonal band, IL: interleukin, OD: oculus dextrus, MRA: Magnetic Resonance, Angiography, MRV: Magnetic Resonance Venography, PV: Partial volume, GAD + Gd: gadolinium, NR: not reported, TPE: therapeutic plasma exchange, STIR: Short-tau inversion recovery. Normal ranges of: WBC: 4.5-11 × 103, ESR: 0-20, Vitamin D: 30–100 ng/mL.

4. Discussion

Viral infection and vaccination have been essential discussions in eliciting immune responses [[46], [47]]. Finding a way to prevent infections and their complications has always been a human desire, and vaccination is that unique finding. Nonetheless, vaccination sometimes has various complications [[48], [49], [50], [51]]. This paper reviews case reports that describe MS and NMOSD cases following COVID-19 vaccination.

4.1. COVID-19 vaccines in the CNS and their mechanisms

Genetic susceptibility and the type of vaccine may determine immunity to vaccines. Vaccines and adjuvants can induce autoimmunity because structure-related host proteins react with those in the vaccine [52]. Immune reactions vary according to the type of vaccine. The adenovirus vector induces the pathogenesis of vector-based vaccines. On the other hand, the pathogenesis of mRNA vaccines is related to the production of the S-protein by the host cells.

Additionally, inactivated vaccines are also capable of molecular mimicry since they have unique properties and are capable of causing disease [[52], [53]]. Pathogenesis of demyelinating autoimmune diseases may involve interactions between host proteins and COVID-19 S-protein antibodies or immunological interactions with myelin basic protein. ACE-2 receptors are also found in the endothelium of the BBB and in nervous tissue, and their interactions with viral S-proteins are able to induce inflammation [52].

Each vaccine triggers a different set of signaling pathways. Regarding innate immunity, vector-based vaccines elicit Toll-like receptor (TLR) 9, the major dsDNA sensor, and mRNA vaccines elicit TLR7 and MDA5, the major RNA sensor [54]. In microglia, macrophages, plasmacytoid dendritic cells, monocytes, and B lymphocytes, TLR 7 (upregulated in experimental autoimmune encephalomyelitis (EAE)) can detect single-stranded RNA. By triggering TLR7, naive T cells are induced to secrete IL-1, IL-6, and IL-12 and differentiate into Th1 and Th17 cells, which may release IL-17 and IFN-gamma [[54], [55]]. Vector-based vaccines activate TLR9 to cause the production of IFN-B, which modulates IL-17 production and suppresses T-cell activity. Therefore, the vaccination may have exacerbated a relapse in these patients. Due to this contrast with TLR9 signaling by vector-based vaccines, this vaccine is characterized by a relatively low occurrence of severe relapses [[54], [56]].

On the other hand, Neutralizing antibodies are generated when the S-protein is produced by dendritic cells in response to mRNA and vector-based vaccinations. Also, these vaccines lead to the triggering of innate immunity which stimulates IFN-B and inflammatory cytokines production. Relapse and triggering of MS are the possible consequences of systemic side effects and possibly the modulation of ongoing inflammation [54]. During MS, immune cells identify vaccine-related antigens, activating other immune cells, including T cells, plasma cells, neutrophils, and macrophages. In the process, they generate inflammatory cytokines that result in cytokine storms, demyelination, and degeneration in neurons [57]. Besides the cytokine storm and the invocation of immune cells, the produced AQP4 IgG enters the CNS and binds to the feet of the astrocytes. Inflammatory mediators in the complement system detect them, resulting in damage to astrocytes (Fig. 2 ) [58].

Fig. 2.

Following injection of the vaccine, the produced proteins or inactivated viruses cross the BBB (as in the SARS-CoV-2) with molecular mimicry properties in the CNS, causing inflammation. Also, the production of S-protein by vector-based and mRNA vaccines causes activation of innate and adaptive immunity. In MS, immune cells identify vaccine-related antigens, invoking other immune cells, including T-cells, plasma cells, neutrophils, and macrophages. Afterward, they generate inflammatory cytokines that lead to cytokine storms, demyelination, and degeneration in neurons. In NMOSD, in addition to the cytokine storm and the invocation of immune cells, produced AQP4 IgG enters the CNS and binds to astrocytes’ feet. Complement mediators detect them, eventually causing astrocyte damage by inflammatory actions. Created with BioRender.com.

In the case reports included in our study, the MRI of the brain and spine revealed a wide variety of lesions, including enhanced or non-enhanced lesions in the brain or spine. In the spine MRIs, the involvement was in the cervical or thoracic regions. The lesions found in brain MRI of MS patients were located in periventricular, subcortical, and posterior fossa regions. Further, lesions extending from the intramedullary and other spine areas in spinal MRI were contained. However, spinal MRI was normal in some studies. Regarding the NMOSD MRI, brain lesions ranged from normal [[38], [44]] to periventricular [[32], [34], [44]] and juxtacortical [32] involvement. There was also a spectrum of spine MRI results from normal [[34], [41], [45]] to intramedullary [[38], [44]] and longitudinally extensive transverse myelitis (LETM) [44].

4.2. Side effects of COVID-19 vaccines

After the COVID-19 vaccine injection, there have been cases complaining of adverse vaccination effects. Injection site pain, redness, and swelling belong to local side effects. Meanwhile, systemic side effects have been headaches, fatigue, myalgia, fever, chills, and joint pain [[59], [60], [61]]. The clinical presentation of each patient in this study was different. Numbness and weakness were the most common symptoms in both MS and NMOSD patients, and blurred vision was also found in the third place.

4.3. Complications following vaccines injection

Subsequent to receiving various vaccines, some cases have multiple complications. ON has been reported following vaccinations against hepatitis A, B, and yellow fever [[62], [63]]. In a review written by Silver et al., the varicella vaccine was associated with postherpetic neuralgia [64]. Guillian-Barré Syndrome (GBS) also has been reported in a case report after the Influenza and polio vaccine [[65], [66]]. In another report, the rabies vaccine had neurological complications that contained encephalitis, radiculitis, and polyradiculoneuropathy in 3 cases [67]. Moreover, varicella, HBV, and measles, mumps, and rubella vaccine (MMR) vaccines cause mainly neurological syndromes, rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopenia, acute arthritis or arthralgia, chronic arthritis, thrombocytopenia, respectively [66].

Severe complications of COVID-19 vaccines were reported incorporating thrombotic thrombocytopenia [68], anaphylaxis [69], myopericarditis [70], and myocardial infarction (MI) [[71], [72]]. The neurological complications possess GBS [73], small fiber neuropathy [74], cognitive impairment [75], acute transverse myelitis [76], anxiety [77], dizziness [78], seizures [75], cerebellar ataxia [79], Bell's palsy [80], cerebral venous sinus thrombosis (CVST) [81], Intracerebral hemorrhage [81], delirium [82], myasthenia gravis [83], NMOSD [41], and MS [37]. The incidence of side effects in neurovirulence is more significant than the vaccine complications [[84], [85], [86], [87], [88], [89], [90]].

4.4. MS and NMOSD following vaccines injection

There is ample evidence that vaccines may alter the risk of MS.

Within three years after HBV or Human papillomavirus (HPV) vaccination, the risk of CNS demyelinating illness was examined in a case-control study. As a consequence, immunologically induced CNS demyelinating illness was associated with vaccination during the first 30 days of life in younger groups [52]. Vaccines for influenza, diphtheria, tetanus, and pertussis are most commonly associated with a weakened immune system [[52], [91], [92], [93]]. This study concluded that since 3 of 24 individuals had a family history of MS or another systemic autoimmune disorder, the vaccine only accelerated the symptoms of demyelination under pre-existing disease conditions [52].

An investigation conducted in Manitoba, Canada involved 341,347 people vaccinated with Arepanrix H1N1 (AS03-adjuvanted H1N1 pandemic influenza vaccine) during the 2009 pandemic and 485,941 persons who were not vaccinated. The incidence of MS was 17.7 cases per 100,000 person-years in the cohort that had received vaccination and 24.2 cases per 100,000 in the cohort that had not. Also, a hazard ratio of 0.92 was calculated [94]. In conclusion, these studies have shown that vaccination is not only not associated with an increased risk of MS, but rather lower risk of MS. According to a study by Isai et al., GBS was the most common adverse event following flu vaccination, not MS or NMOSD [94]. In the same sense as the Williams et al. study, the most frequent diagnoses associated with the flu vaccine were GBS (37%) and seizure (11%) [66]. According to a case report, the early weeks following H1N1 vaccination are also associated with higher relapse risk in patients with MS [95]. Besides, a randomized trial revealed that the researchers did not find evidence that influenza vaccination leads to an increase in exacerbations in patients with MS post-vaccination or a change in disease course after the vaccination [66].

Human antigens and SARS-CoV-2 molecules can exhibit similar molecular properties, causing autoimmune diseases in those who receive the vaccine [96]. Twenty-one human tissue antigens are cross-reactive with SARS-CoV-2 antibodies. This could explain the cause of autoimmunity resulting from COVID-19 infections and SARS-COV-2 mRNA vaccines affecting the gastrointestinal tract system, cardiovascular system, nervous system, and connective tissues [96]. In addition, mRNA vaccines may trigger a cascade of immune responses that lead to aberrant activation of acquired and innate immunity [97]. Furthermore, certain adjuvants can cause self-reactive T cells to differentiate, causing tissue damage to the host [98]. Activating pattern recognition receptors (PRRs) is one way adjuvants induce innate immunity. It is for this reason that vaccines contain them in order to stimulate the production of immunity against antigens [99]. Compared to previous vaccines, SARS-CoV-2 adjuvanticity acts as an agonist for TLR-7/8 or TLR-9. There is a possibility that this is a new pathogenic mechanism responsible for human immune-mediated diseases [100]. Meanwhile, the activation of adaptive immunity in response to vaccines is also governed by TLR pathways. As a result of these findings, it is evident that TLRs play a significant role in vaccine efficacy as well as the pathogenesis of MS and NMOSD [[101], [102]].

In the case described by Chen et al., the female patient presented with symptoms of weakness 3 days after the first dose of an inactivated COVID-19 vaccine and was diagnosed with NMOSD following performing MRIs and observation of area postrema and bilateral hypothalamus lesions without gadolinium enhancement [41]. This may be because, following increasing the permeability of the BBB, molecular mimicry is performed by the vaccine (as in the SARS-CoV-2), and triggering the immune cells leads to inflammation, and eventually, NMOSD occurs. According to another study by Fujimori et al., a patient with a prior inflammatory background in CNS following mRNA COVID-19 vaccine injection developed MS [35]. Notably, this subject previously had a brain lesion, uptook steroids, and there was an appropriate environment to contract other neurological disorders in her CNS. A case reported by Caliskan et al. developed NMOSD one day after the second dose of an mRNA COVID-19 vaccine [45]. An issue that needs to be addressed is the pre-vaccine titer of the AQP4 antibody. This is because the person may have a high antibody titer before the vaccine and be prone to developing autoimmunity. All these factors must be investigated for a definite statement that vaccination may trigger MS or NMOSD, but until then, the cause-and-effect relationship is unclear.

In this systematic review, we comprehensively assessed all case reports on MS and NMOSD patients following COVID-19 vaccination with various platforms. Although this is the first systematic review in this regard, we had some limitations composed of the low number of cases which shows it is not able to represent the population and the lack of available data for all vaccines.

5. Conclusion

In conclusion, MS and NMOSD are neuroinflammatory diseases that occur in the CNS. Cases of MS and NMOSD have been reported following recent vaccination against COVID-19 infection worldwidehave been reported in our systematic review. In order to assess a possible causal relationship between the COVID-19 vaccine and MS and NMOSD, more studies with more cases and various study designs are required.

Funding

None.

Disclosure of interest

The authors declare that they have no competing interest.