The association between SARS-CoV-2 vaccines and transverse myelitis: A review

In late 2019, the emergence of a new viral strain, later referred to as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) took the shape of a global pandemic, affecting millions of lives and deteriorating economies around the globe. Vaccines were developed at an exceptional rate to combat the viral desolation, all of them being rolled out once they displayed sufficient safety and efficacy. However, assorted adverse events came into attention, one of them being Transverse Myelitis (TM), an infrequent, immune-mediated, focal disease of the spinal cord. This disorder can lead to severe neurological complications including autonomic, sensory, and motor deficits. The literature aims to shed light on TM and its various etiologies, specifically in line with the vaccine, and a comprehensive treatment plan. Discussing and reducing the number of vaccines related adverse events can help succor in bringing down the vaccine hesitancy and ultimately combatting the pandemic.


Introduction
The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which originated in Wuhan, China towards the end of 2019, was declared a pandemic by the World Health Organization (WHO) in March 2020 following its drastic spread [1]. To date, December 26, 2021, 276.4 million confirmed cases have been reported and 5.4 million deaths have occurred worldwide due to the virus [2]. Other than healthcare consequences, the detrimental economic implications of the pandemic have rendered numerous unemployed and financial markets and global economies unstable [3]. Furthermore, according to the United Nations Educational, Scientific and Cultural Organization (UNESCO), lockdowns and closures disrupted over half of the student population worldwide [4].
To overcome the debilitating effects of the virus, worldwide efforts led to the development of several COVID-19 vaccines within the first year of the pandemic. The currently authorized vaccines include can (i) The viral vector vaccines comprising AstraZeneca, Sputnik, and Janssen incorporating spike protein gene into the Adenovirus DNA, which then induces the synthesis of anti-spike protein antibodies. (ii)modern technology-based RNA vaccines including Pfizer and Moderna directly delivering the messenger RNA code for spike protein [5]. The DNA and RNA vaccines use immunologic liposomes as delivery vehicles to obtain maximum antigen levels within the target cells [6,7]. (iii) Sinopharm and Sinovac which makes use of live attenuated virus to stimulate a protective immune response [8]. These vaccines employ adjuvants like Aluminum hydroxide to enhance their effects [6,9].
Despite having different modes of action, these vaccines were approved after rigorous trials and demonstrated an adequate safety profile [10]. As of December 26, 2022, 8.6 billion doses have been administered [2]. Injection site pain, headache, fever, chills, myalgias, and fatigue constitute the commonly reported adverse effects following vaccine administration. All these effects are mild, short-lived, and self-limited [11]. However, a few serious adverse events including tinnitus [12], vaccine-induced thrombotic thrombocytopenia (VITT) [13], myocarditis [14], uveitis [15], Guillain Barre Syndrome (GBS) [16] have also been reported. Although the current literature evidence the beneficial effects of COVID-19 vaccines in reducing hospital admissions and severe outcomes [17,18], rare side effects and spread of misinformation significantly continue to contribute toward vaccine hesitancy [19].
More recently, several cases of transverse myelitis have been reported following COVID-19 vaccination. According to Vaccine Adverse Event Reporting System (VAERS), 593 cases of TM following COVID-19 vaccination have been reported [20]. Although the incidence of these cases is rare, that is compared to the total vaccine doses administered (11.7 billion) [21]. Although the incidence of these cases is rare, understanding the precise pathophysiology, predispositions and management are integral towards countering vaccine hesitancy. In this review, we evaluate the currently available literature to highlight the potentially involved mechanisms and management of such cases.

Transverse myelitis: what we know about it?
Transverse myelitis (TM) is an infrequent, immune-mediated, focal disease of the spinal cord that may involve one or more levels, in the absence of a compressive lesion [22]. This form of acute inflammation leads to morbid changes in the spinal cord segments [23]. Around 1.8 million people are affected by this disease every year around the globe with maximal incidence reported between 20 and 40 years of age [24]. It is estimated that 3 in every 100,000 people suffer from this illness and about 66% of these have some degree of residual disability [25].
While the disease can result from a broad spectrum of etiologies, the most prevalent causes include demyelinating illnesses such as multiple sclerosis and neuromyelitis optica. It is also associated with infections like Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), Epstein Barr Virus (EBV), and Cytomegalovirus (CMV), immunizations, neoplastic lesions, and connective tissue diseases [24]. Furthermore, numerous cases have been reported in individuals with systemic autoimmune conditions like systemic lupus erythematosus (SLE), Sjogren's syndrome, etc [24,26]. Lastly, the cause of TM is unknown in up to 30% of cases [27]. It is clinically defined by the onset of acute or sub-acute motor, sensory, and autonomic dysfunction [24,28].
This disorder is known to cause neurological symptoms including autonomic, sensory, and motor deficits [23]. Paresthesia and numbness are initial symptoms among adults. Patients also complain of pain in the spinal region, extremities, and abdomen. Weakness is characterized by expeditious development of ascending paraparesis, starts in the lower limbs and then rapidly involves the upper extremities. The genitourinary system is greatly affected with diseased experiencing urinary incontinence, difficulty in voiding, increased urgency, erectile dysfunction, ejaculatory disorders, and markedly decreased lubrication in females. Pudendal nerve lesion diminishes the sensations in both men and women which makes orgasm arduous and causes sexual impairment. Involuntary bowel movements and constipation are the usual manifestations of the gastrointestinal system [29].
This disorder is classified based on the area and extent of the lesion, and the diagnosis is made using spinal cord imaging particularly magnetic resonance imaging (MRI) [30] and lumbar puncture with microscopic analysis of the cerebrospinal fluid (CSF) which identifies inflammatory markers, oligoclonal bands, specific proteins, and enzymes [31]. Longitudinally extensive transverse myelitis (LETM) is a type of TM that involves three or more vertebral segments and is associated with serious morbidity and increased risk for recurrence [32].

Literature search and data extraction
Three authors (FNN, SFSH, MDR) independently conducted a thorough literature search over PubMed and google scholar from inception till November 25, 2021. The following key terms separated by BOOL-EAN Operators 'OR' and 'AND' were employed: "SARS-CoV-2 vaccine", "Coronavirus vaccine", "COVID-19 vaccine", "transverse myelitis", "spinal cord inflammation", "longitudinally extensive transverse myelitis", "LETM". Grey literature and bibliographies of the relevant articles were also screened without any restriction of location and language. Any discrepancies were resolved by discussion with a fourth author (SW). The results of the literature search are shown in Fig. 1. Following a comprehensive literature search, the retrieved full-length articles were screened and recruited for inclusion in this review. After study selection, two authors (SHA, TGS) independently tabulated all the   Table 1.

Demographics
11 studies, comprising data from 11 vaccinated patients (6 females, 5 males) with a mean age 49.27 ± 5.47 were short-listed for the review. Fig. 2 illustrates the geographical distribution of reported cases included in this review [23,24,[33][34][35][36][37][38][39][40][41]. Literature suggests that TM affects women and men, equally in general [42], and minor to no indifference is discerned in the occurrence pattern between Euro/American-born and Afro/Asian-born populations [43], which also appears to be valid for the included cases in this review. However, despite a diverse geographical location, any potential connection among ethnicities, races, or environmental factors that led to TM in a group of people post-vaccination, while sparing others, who got their shots requires exploration. To reach a submissive conclusion and establish missing links, it is pivotal that while conducting trials, geographical links must be investigated critically.

Transverse myelitis following previous vaccines
Vaccines are probably one of the greatest achievements in the public health sector reducing the number of deaths and illnesses associated with it [44]. Despite being able to significantly reduce mortality and morbidity, vaccines share wavering public confidence due to safety concerns [45]. One such complication of post-vaccination, although very rare, is the manifestation of neurological conditions, including the TM, which is mostly immune mediated [46].
There are several vaccines, along with SARS-CoV-2 vaccines, that are associated with TM. One such example is the recombinant hepatitis B vaccine which was approved in 1986 [47]. An article published in Lupus 2009 has reported 13 cases of TM following HBV vaccination since 1982 making it the most common vaccine associated with TM [46] during the above-mentioned period.
Another example is the live attenuated oral polio vaccine (OPV) which is widely used globally to battle poliovirus but very rarely it can cause poliovirus which itself is associated with TM. The Institute of Medicine of the National Academies of the United States in 1993 mentioned a casual relation between TM and OPV vaccine [46]. Primarily because of this along with several other disadvantages, many countries have shifted to inactivated poliovirus vaccine (IPV) [48].
Other vaccines, including DPT, Influenza, and rabies vaccination may also result in neurological complications including the TM [46]. Prolonged periods between vaccination and the onset of symptoms are another debatable topic and might point towards other underlying complications, genetic predisposition, and environmental triggers. The exact cause and the mechanism behind vaccine-induced TM are not clear but it is proposed that since the host's response to the vaccine is similar to the response by an infective agent and can cause auto-immunity, it could be assumed that the recombinant or live attenuated vaccines may trigger TM through the same mechanism [49].

Transverse myelitis following SARS-CoV-2 vaccines
As summarized in the table below (Table 1), most of the cases presented with varied neurological manifestations of sensory, motor, and autonomic dysfunction. Clinical presentations of the majority cases included pain and weakness of lower limbs [33,40,41] along with paresthesia [23,34] and numbness [24,38,39,41]of lower limbs. Some cases also presented with autonomic symptoms such as urinary retention [24,35,40,41], urinary incontinence [39], and fecal retention [41] accompanying sensory and motor deficits of limbs. Cerebrospinal fluid (CSF) analyses of most of the cases revealed elevated proteins and white blood cells (WBC), and relatively normal glucose. MRI spine of these patients revealed abnormal hyperintense signals from the level of the cervical spine down to the thoracic spine indicating acute inflammation of the spinal cord. The combination of the high abnormal CSF protein test and acute inflammation of the spine observed from the MRI findings were confirmed evidence of acute transverse myelitis [33] after the administration of the SARS-CoV-2 vaccine in the cases under review.

Pathophysiology
Usually, TM's pathogenesis involves an atypical immune response causing injury to the spinal cord. At times, infections result in the transcription of a protein that mimics the self-antigen which stimulates T-lymphocytes against the body's own tissue, resulting in immunemediated destruction. Similarly, the administration of vaccines can also induce the same response. When the body's immune system cannot distinguish between foreign antigens and host antigens, it triggers autoimmunity which leads to the destruction of host cells [23,46,49]. The following mechanisms may induce autoimmunity in a person:

A. Molecular Mimicry
The concept of molecular mimicry implied to post-infection neurological disorder could be possible pathogenesis eliciting TM after SARS-CoV-2 vaccination. The proposed mechanism of the post-infection "Molecular Mimicry" suggests that microorganism epitope shares a similar structure to the host's antigen. The cross-reaction between the epitope and self-antigen activates B lymphocyte and the bystander activation of T cells, which induces an immune response. This mechanism appears to be the explanation for vaccines with viral antigen adjuvants, which may mediate immune responses targeting spinal cords [23,24,29,37,50]. AZD1222 and Johnson & Johnson COVID-19 vaccines, both contain adenovirus antigens, thus may induce acute TM by the same pathogenesis [24,51].
The mRNA vaccine consists of spike glycoprotein sequencing as their main target [52], hence the proposed mechanism of molecular mimicry in such vaccines can be cross-reactivity with a structurally similar host protein causing an acute autoimmune reaction [34,46]. A study reported massive commonality between the SARS-CoV-2 glycoprotein and human proteomes, thereby further supporting molecular mimicry as a possible pathogenesis mechanism [53].

B. Interaction between Spike Protein Antibody and Host Protein
The Moderna COVID-19 (mRNA-1273) vaccine is composed of an mRNA encoding the pre-fusion spike protein encapsulated in lipid nanoparticles, with no adjuvants [54]. Therefore, other mechanisms might be involved in the development of autoimmunity in such cases. A study suggested that the immunological reaction between the SARS-CoV-2 spike protein antibody and tissue proteins, such as myelin basic protein, maybe a plausible cause for the occurrence of demyelinating autoimmune diseases [36,55].

C. Role of Angiotensin-converting Enzyme 2 Receptors
It can be speculated that post-vaccination spike protein elicits a similar response in the body, as that of post-SARS-CoV-2 infection resulting in the development of TM via interaction of spike protein and angiotensin-converting enzyme 2 (ACE-2) receptors.
The mechanism by which COVID-19 causes ATM is not well comprehended but has been presumed to be that of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). SARS-CoV-1 was thought to cause extra-pulmonary manifestations through its functional receptor; ACE-2, which is abundantly expressed on the endothelial layer of blood vessels of all organs. Entrance to the nervous system can take place through two pathways: directly or indirectly. The direct pathway is via trans-synaptic transmission from the peripheral nervous system or by hematogenous spread into the blood-brain barrier (BBB) through ACE-2 [56]. Whilst the indirect pathway is through a systemic immune   response that prompts the release of a cytokine storm, especially interleukin-6 (IL-6) [57,58]. Therefore, the inflammatory response triggered by the interaction between spike proteins and angiotensin-converting enzyme 2 (ACE-2) receptors present in endothelial cells of the blood-brain barrier or spinal neurons may be another possible mechanism of demyelination [36,51,59].

D. Factors predisposing to the development of Autoimmunity
The fact that not all individuals receiving the SARS-CoV-2 vaccine developed TM suggests a plausible role of predisposing factors in the development of autoimmunity. Following are some of the reported and suggested factors.

i. Genetic Predisposition
Individuals developing the SARS-CoV-2 vaccine-associated TM may have certain genetic mutations thereby making them susceptible to autoimmunity development [60,61]. A mutation in VPS37A has been reported in individuals with idiopathic transverse myelitis [62]. Similarly, post-vaccination TM may be associated with certain genetic mutations. However, further research is required to identify the genetic role.
ii. Environmental Triggers Autoimmune diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause [60]. In a few discrete illnesses such as reactive arthritis, rheumatic fever, or hepatitis B virus (HBV) associated vasculitis, the inciting microbial agent is relatively well defined. Similarly, viral vaccines can be implicated as an environmental trigger or factor associated with the development of autoimmunity [63,64].
ii. Comorbidities An underlying chronic disease or chronic inflammatory process can be correlated to the autoimmunity development in some individuals. Some of the cases reviewed in this study had chronic diseases including hypothyroidism, chronic kidney disease, coronary artery disease, pulmonary sarcoidosis, neuropathy, and atopic dermatitis. Moreover, two cases had a history of diabetes mellitus (DM) should not be ignored as a coincidence. However, the establishment of a potential link between DM and the development of the SARS-CoV-2 vaccine-associated TM needs more evidence and can be elucidated in future research.
However, further investigations are crucial to identify complex interactions between specific predisposing factors and underlying chronic diseases for TM development. Moreover, strong exploration is vital to establish links between the interaction of spike protein with ACE-2 receptors. Lastly, the development of transverse myelitis regardless of viral vector or mRNA vaccine supports the idea of spike protein as the key pathogenesis of SARS-CoV-2 vaccine-associated TM which can be elucidated further in future studies.

Diagnostic criteria
Owing to a broad differential for TM, reaching a terminating conclusion may be tricky. Hence, physicians are advised to search and devise a cost-effective strategy. This can be done via an extensive patient's clinical history, thorough examination, CSF pleocytosis and magnetic resonance imaging (MRI) findings [65].
The Brighton Collaboration Encephalomyelitis guideline can be utilized to confirm whether the inflammation is of post-vaccine etiology. The Collaboration group designed a set case definition and diagnostic criteria for encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM), exemplified in Fig. 3, which can be applied in diverse health care settings and different geographical areas [66].

A. Glucocorticoids
Transverse myelitis (TM) is an inflammatory disorder for which the first-line therapy is the administration of intravenous glucocorticoid [67]. They act by altering the gene expression of inflammatory mediators, thereby reducing their levels in the body, and suppressing the inflammation [68]. Nine of the included studies reported the administration of glucocorticoids, such as methylprednisolone, followed by oral prednisone in three of the studies [36,39,41]. The remaining two studies [33,38] did not report the treatment. Administration through intramuscular and intravenous routes is of great advantage as it surpasses the liver biotransformation and gastrointestinal symptoms that occur when given orally [69]. Five of the included studies reported the administration of intravenous methylprednisolone [23,36,[39][40][41]. This route might also be preferred due to rapid action (onset of action is 1 h) in  emergency situations [69]. However, the use of glucocorticoids needs to be strictly regulated as the high dosage and long-term use of these drugs leads to several adverse effects such as resistance of insulin, hypertension, Cushing-like symptoms, and hyperglycemia [70]. In addition, the use of these drugs is contraindicated in the situations such as uncontrolled medical disorders, administration of live vaccines, and systemic infections [68].

B. Plasma Exchange
The plasma exchange can also be initiated if the management by corticosteroids is not optimum [67]. It is the procedure to remove the abnormally located substances from the body such as the removal of cytokines or viral load from the body in COVID-19 [71]. This can be seen in 3 of the included studies [23,24,39], where this line of treatment was started after methylprednisolone. However, the plasma exchange is associated with anaphylactic shock and disruption of electrolytes such as calcium and magnesium [71]. Most of the symptoms occurring are minor with urticaria and pruritus being the most common [72]. Hence, plasma exchange can be used safely with appropriate monitoring.

C. Other medications
The patients should be started with antibiotics if the cerebrospinal fluid (CSF) study shows elevated proteins and an abundance of neutrophils [67]. Consequently, in two of the studies [35,40], antibiotics were administered due to the elevated protein levels in CSF examination in both of the studies and increased granulocytes in Pagenkopf et al. [35]. The common antibiotic given in both studies was ceftriaxone, which is a third-generation drug of cephalosporins and inhibits the synthesis of bacteria's cell walls [73].
Patients with TM can be given rituximab or immunomodulatory therapy such as cyclophosphamide to prevent the resistant TM [22,74]. Rituximab or immunomodulatory therapy helps by decreasing the attacks of diseases such as transverse myelitis or preventing the occurrence of neuromyelitis optica, which is an inflammatory central nervous disease [75,76]. None of the studies, included in this review, reports the usage of these medications. This might be because of different presentations in each case and different genetic factors such as age and co-morbidities.

Other neurological manifestations
A wide spectrum of neurological manifestations, ranging from mild to moderate, following COVID-19 vaccines has been reported in the literature. Severe adverse events following immunization included facial nerve palsy [77,78], thrombotic complications [79], ischemic stroke [80], Guillain-Barre Syndrome [81], and cerebral venous thrombosis [82], among many others. Some of the numerous manifestations witnessed post-COVID-19 vaccination are illustrated in Fig. 4. Despite several case reports, the fact that COVID-19 vaccines are the causative agents of all the manifestations is yet to be proven, suggesting the potential need for large-scale collaborative trials and studies to determine the exact relationship between the vaccines and neurological manifestation.

Conclusion
This review highlights the potential pathophysiology and management of SARS-CoV-2 vaccine-induced transverse myelitis in light of the currently available literature. Despite a rare incidence, it is integral to elucidate its precise pathogenesis that may help redefine vaccine administration criteria to eliminate incidence. While corticosteroids remained the mainstay of treatment, there is an overwhelming need to evaluate other treatment options in terms of both short and long-term effects. Further research must emphasize on investigating the genetic and environmental predispositions, risk populations, economic diagnostic measures, and potential treatments options in order to combat vaccine hesitancy and ensure the success of the global vaccination program.

Ethical approval
Not required.

Author contributions
F⋅N⋅N and S⋅F⋅S⋅H conceived the idea, F⋅N⋅N, S⋅F⋅S⋅H, M.D.R and S⋅W, retrieved the data, did write up of letter, and finally, S⋅H.A and T.G. S reviewed and provided inputs. All authors approved the final version of the manuscript.

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Declaration of competing interest
N/A.