Introduction

Coronavirus Disease 2019 (COVID-19) is a contagious disorder caused by the novel coronavirus which belongs to the Betacoronavirus genera [1]. The first case of unusual viral pneumonia caused by SARS-CoV-2 was described in Wuhan, China, in December 2019. Despite the restrictions, a growing number of infections that spread worldwide resulted in the declaration of a pandemic within three months [1]. To date (October 2022), 615 million laboratory-confirmed cases of the disease and 6.5 million deaths have been reported worldwide [2].

Autoimmune diseases (AIDs) are caused by impairment of the immune system, which results in the production of antibodies against one’s own tissues. This leads to clinical damage or impairment of their function [3]. At the time of the COVID-19 pandemic, patients affected by AIDs may be exposed to a more severe course of infection due to the failure of the immune system. Moreover, the use of immunosuppressants may also increase susceptibility to COVID-19.

We reviewed the literature to describe the impact of the pandemic on the course of neuroimmune diseases. The aim of our study was to assess the severity of COVID-19, the response to treatment, and the impact of COVID-19 infection on the course of the underlying diseases in patients with autoimmune diseases of the nervous system.

Figure 1. Similarities in pathophysiology of neuroimmune diseases and SARS-CoV-2. Both COVID-19 and AIDs activate immune system, which results in cytokine and antibody overproduction. Another mechanism of viral penetration is direct invasion of central nervous system by SARS-CoV-2. Due to molecular mimicry in cases with COVID-19, production of antibodies may lead to de novo occurrence of AIDs. AIDs — autoimmune diseases; CNS — central nervous system; IS – immune system

Material and methods

This paper assesses and compares research on autoimmune diseases of the nervous system at the time of the COVID-19 pandemic. We reviewed the systematic literature, including our own papers on selected neuroimmune diseases and COVID-19. We searched PubMed, Scopus and Google Scholar using the phrases: ‘COVID-19’ and ‘SARS-CoV-2’ together with ‘autoimmune’, ‘neuroimmune’, ‘multiple sclerosis’, ‘NMOSD’, ‘myasthenia gravis’, ‘Guillain-Barré syndrome’ and ‘ADEM’. As a result, relevant articles were selected. All the papers included in this review were published between 2020 and 2022.

Similarities in pathogenesis of SARS-CoV-2 infection and neuroimmune diseases

In AIDs and in SARS-CoV-2 infection, the inflammatory process affects various locations. Symptoms can occur in many organs and systems, such as the cardiovascular system, nervous system, lungs, kidneys, skin, or digestive tract [4]. Excessive production of cytokines and the activation of immune cells lead to the production of antibodies and organ failure in AIDs and SARS-CoV-2 infection. Overproduction of the proinflammatory molecules (IL-1, IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, CXCL10, CCL2) results in cytokine storm [5]. Another similarity between AIDs and COVID-19 is that cells of the innate immune response (macrophages, monocytes, mast cells, neutrophils) are over-activated. Furthermore, dysregulation between the levels of B-cells and T-cells has been reported with reduced T-cell levels [4].

Furthermore, in some patients with COVID-19, the presence of autoantibodies characteristic of neuroimmune diseases has been found. Halpert and Shoenfeld reported infected cases with antibodies characteristic of Guillain-Barré syndrome (ANA, antinuclear antibodies), Miller-Fisher syndrome (aCL, anti-cardiolipin antibodies), neuromyelitis optica [anti-phosphatidylserine antibodies (IgM/IgG)], NMDA-receptor encephalitis [antiannexin V (IgM/IgG)], and myasthenia gravis (anti-GD1b antibodies) [6]. AIDs can also occur secondarily to COVID-19. Infection with the SARS-CoV-2 virus can lead to the activation of autoimmune processes due to molecular mimicry [7]. There is another hypothesis of direct viral invasion of the central nervous system. PCR-positive cerebrospinal fluid (present in several cases) seems to confirm this [8]. The above mechanisms are shown in Figure 1.

Course of neuroimmune disorders and impact on SARS-CoV-2 infection

In our review, we have selected the most common AIDs of the nervous system, which are presented below. Detailed information on the study groups, the course of the infection, treatment and clinical outcomes is given in Table 1.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease that affects the central nervous system. It is usually diagnosed between 20 and 40 years of age. It is characterised by remissions and exacerbations, which gradually lead to disability [9]. Due to the autoimmune nature of the disease and the immunomodulatory therapies, it was important to determine the impact of COVID-19 on the course of MS. In most studies, the existence of MS has not been shown to significantly increase the risk of COVID-19 infection [10]. However, some reports have indicated that MS patients are more susceptible to it [11]. Older obese patients and subjects with higher disability scores were found to be more at risk of a worse course of SARS-CoV-2 [12]. However, in some cases, younger, less disabled patients could be more vulnerable because of their more frequent social interactions [13]. COVID-19 infection can also contribute to the exacerbation of the underlying disease. There have been some reports related to COVID-19-induced relapse and failure of the applied treatment due to the viral invasion [8, 9].

Most studies have found no significant correlation between disease-modifying therapy (DMT) and a more severe course of COVID-19 [4, 5, 7]. Alonso et al. showed that patients on rituximab were more at risk of death from SARS-CoV-2 [18]. Additionally, Barzegar et al. [19] demonstrated that one patient who was administered rituximab had a critical course of disease. Some data has suggested that anti-CD20 therapies could contribute to a higher probability of infection and a severe course of COVID-19 [20]. Another cross-sectional study showed that natalizumab was related to a higher risk of infection. Treatment in hospital settings has also been reported to be connected to higher susceptibility as opposed to home-based drug administration [21]. However, all these findings should be interpreted with caution because of the different conclusions made by the various authors.

Neuromyelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory demyelinating disease affecting the optic nerves and the spinal cord. It is characterised by the presence of IgG autoantibodies against aquaporin 4 (AQP4) [22]. Due to increased susceptibility to bacterial and viral infections following immunosuppressive therapies, it was crucial to determine the impact of SARS-CoV-2 on the course of the disease. Several studies found no increased risk of infection due to NMOSD [4, 14]. In their meta-analysis, Barzegar et al. [24] showed that the prevalence of COVID-19 in patients with NMOSD was 1.2%, while the mortality rates ranged from 0 to 31.3%. In terms of immunosuppressive treatment, no risk of drug administration has been reported during the pandemic. However, patients should follow the restrictions and observe social distancing [10].

Studies showed that the administration of rituximab and the presence of comorbidities could be risk factors for COVID-19 [24]. Studies also found that patients on rituximab were more likely to develop gastrointestinal manifestations of COVID-19 infection and a worse course of the disease that required hospitalisation (60%) [25]. Research showed an increased risk of relapse during the pandemic, not only due to COVID-19 infection, but also to the accompanying chronic stress [23].

There are some reports on NMOSD following COVID-19 infection or vaccination. Based on 11 reports, Mirmosayyeb et al. [26] showed that a first episode of NMOSD could occur after SARS-CoV-2 infection. Furthermore, some cases of NMOSD with the presence of MRI lesions and AQP4 IgG after COVID-19 vaccination have also been reported [14–16]. Despite the rising concerns, resolving this issue would require further investigation and long-term surveillance of such patients.

Myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. It is characterised by the presence of IgG antibodies against the nicotinic acetylcholine receptor (nAChR) [30]. Patients with MG are more susceptible to SARS--CoV-2, particularly those with a higher Myasthenia Gravis Foundation of America (MGFA) clinical class [31]. Well-controlled MG and the absence of comorbidities has been shown to correlate positively with a milder course of COVID-19 infection [32]. Interestingly, according to a Polish study, COVID-19 infection does not necessarily worsen MG severity as assessed by the MGFA classification [33]. Exacerbation of the disease caused by COVID-19 occurred in 10–15% of patients with MG. Rodrigues et al. described eight patients with MG exacerbation and myasthenic crisis during the viral infection. The main risk factors for a worse prognosis and death included long-term corticosteroid use, older age, cancer, and rituximab use [34]. Patients with MG could be more vulnerable to a severe course of COVID-19. However, there is some evidence that immunosuppressive therapy may have a protective effect [35]. The type of treatment does not influence the occurrence of SARS-CoV-2. Patients should continue their therapy during the pandemic [31]. Studies have shown that azathioprine, mycophenolate mofetil, and cyclophosphamide do not significantly affect the outcomes. Large doses of corticosteroids and the administration of rituximab could be related to higher mortality rates [34]. However, corticosteroids may actually play a protective effect in moderate and severe COVID-19 [32].

SARS-CoV-2 infection may not only exacerbate the disease, but also contribute to the development of a new episode of MG. This unexpected neurological manifestation suggests that the virus could induce the production of antibodies. However, further studies are warranted in this regard [26, 27].

Guillain-Barré syndrome

Guillain-Barré Syndrome (GBS) belongs to the most common acquired demyelinating polyneuropathies. The exact cause of the disease is unknown. Nerve damage is associated with autoimmune processes [38]. The onset of GBS is usually preceded by an infection, mostly of the lower respiratory tract. The pathogens that could be aetiological factors of GBS include Campylobacter jejuni, Haemophilus influenzae, Mycoplasma pneumoniae, the Zika virus, etc. Since 2020, new cases of GBS secondary to SARS-CoV-2 have been reported [39].

Filosto et al. [40] observed a significant increase in GBS during the pandemic. Moreover, COVID-19-associated GBS had a more severe course than non-COVID-19 GBS. The first manifestation of GBS usually occurs 5–21 days after infection. The highest incidence is among older men (aged 60+ years), yet the mean age before the pandemic was 40 years [41]. The red flags that may indicate the occurrence of GBS in the course of infection include anosmia, ageusia, cranial neuropathies and lymphocytopenia. Early diagnosis and the initiation of treatment are essential. The primary therapeutic methods are IVIg and plasma exchange [42]. In COVID-19-related and non-related GBS, the response to treatment is similar [40]. Li et al. [43] made a systematic review describing patients with Miller-Fisher syndrome, a variant of GBS, after SARS-CoV-2 infection. These unusual manifestations of the viral infection underline the importance of follow-up and neurological examination in COVID-19 patients [44].

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a demyelinating autoimmune disease with sudden episodes of inflammation in the brain and the spinal cord [45]. It can occur at any age, although most cases are seen in children [46]. ADEM is usually triggered by infection or vaccination. There is limited data on the COVID-19 course in patients with pre-existing ADEM. Hussein et al. [47] showed a case of Coxsackie-induced ADEM exacerbated by SARS-CoV-2 infection. Treatment with steroids and plasmapheresis resulted in a favourable outcome. Zelada-Ríos et al. [48] published a systematic synthesis of worldwide cases of ADEM secondary to COVID-19 (Tab. 1). They found that the prevalence of this condition was higher among adult men than in children. The mean time from the onset of infection to the development of ADEM was 23.2 days (4–60 days). Another meta-analysis showed the existence of acute haemorrhagic leukoencephalitis (AHLE) in the course of SARS-CoV-2 infection, with high rates of brain haemorrhage on MRI (30%) [49]. In most patients, steroid therapy, IVIg and plasmapheresis are effective methods of treatment [35,38]. Unfortunately, ADEM in the course of COVID-19 contributes to more frequent hospitalisation in intensive care units, higher mortality, and long-term neurological deficits [50].

Other autoimmune diseases

Cases of other neuroimmune disorders secondary to COVID-19 have also been reported. Autoimmune encephalitis is brain inflammation with the production of antibodies against self-antigens [51]. Anti-NMDAR, anti-MOG, anti--GAD, anti-GD1a and anti-CASPR2 are significant molecules that play a role in its origin [52]. There is limited data on AE and COVID-19. Payus et al. [8] demonstrated that most COVID-19-associated cases (77%) occurred during the acute phase of the infection. Thirty percent of patients presented with neurological symptoms before developing fever and respiratory symptoms. Apart from typical infectious symptoms, the most common presentations are as follows: psychomotor agitation, hallucinations, seizure, anxiety, thought disorganisation, persecutory delusions and insomnia [8]. Treatment with corticosteroids, IVIg, plasma exchange and antiseizure medications is effective in most cases. Limbic encephalitis (LE) may be another complication of SARS-CoV-2. This is a form of encephalitis limited to the medial temporal lobes and is caused by autoimmunity [53]. It is characterised by the production of auto-antibodies, such as anti-Hu, anti-Ma2 and anti-NMDAR [54]. It is mainly diagnosed as a paraneoplastic phenomenon. There are some reports of LE associated with SARS-CoV-2 [39–42]. The mean age of patients was 73.8 years (66–80 years), as reported by Pizzanelli et al. The most common symptoms included seizures, neuropsychiatric symptoms, confusion and amnesia. Typical lesions in medial temporal lobes were present on brain MRI. In all described cases, the disease resolved after treatment with corticosteroids, IVIg, or plasma exchange [58].

Effects of treatment of neuroimmune diseases on SARS-CoV-2 infection

The use of immunosuppressants and adhering to the principles of social distancing seem to be safe in most cases, and do not increase susceptibility to COVID-19 infection. Some drugs used in neuroimmune diseases have been tested for their effectiveness in COVID-19 [59].

Glucocorticoids, which are widely used in AIDs, reduce mortality from severe COVID-19. However, some data has indicated that high doses during AID treatment could worsen the prognosis and be associated with a higher risk of hospitalisation and death [60].

In our previous review, we included some immunomodulatory drugs (interferons, teriflunomide and leflunomide) used in MS that were tested in SARS-CoV-2 infection [59]. Rabie et al. [61] showed that the use of teriflunomide in patients with COVID-19 reduced the cytokine storm. Other studies showed that leflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, was associated with faster hospital discharge or reduction in C-reactive protein (CRP) levels in COVID-19 cases [61, 62]. IMU-838 is another promising candidate from this group. It has shown antiviral properties in patients infected with SARS-CoV-2 [64]. Yousefi et al. [65] assessed fingolimod as one of the potential drugs that could stop the virus from invading the CNS. However, the above studies did not consider lymphopenia to be a significant indicator in patients. The National Institutes of Health suggests the use of IL-6 inhibitors (tocilizumab, sarilumab and siltuximab) during SARS-CoV-2 infection. IL-6 inhibitors are also in the research phase related to NMOSD. In COVID-19, they may contribute to the reduction of the cytokine storm [66]. Another meta-analysis showed the efficacy of IVIg in the course of COVID-19 infection [67]. Plasmapheresis is a different method worthy of consideration. Both of them should be used within 14 days of the onset of infection, which may reduce mortality and shorten hospitalisation [68]. A reduction in proinflammatory cytokine levels and the immune response was also observed in patients with acute respiratory distress syndrome (ARDS) after plasmapheresis [69].

However, all these studies have their limitations due to the pandemic’s dynamics and the insufficient number of results confirming treatment efficacy. Therefore, further studies are warranted.

COVID-19 vaccination in patients with neuroimmune disorders

There have been concerns raised about the efficacy and safety of vaccines against COVID-19 in patients with AIDs. In MS patients, vaccination did not increase the risk of relapse or vaccine ineffectiveness [70]. Nevertheless, DMTs can significantly affect the development of the humoral response. Kulikowska et al. [71] revealed that vaccination in MS patients treated with dimethyl fumarate, interferon beta and glatiramer acetate significantly induces the production of IgG and IgA against S protein (p < 0.0001). Patients treated with the above-mentioned drugs can efficiently produce antibodies against SARS-CoV 2. In the case of therapies with anti-CD20 antibodies, alemtuzumab and natalizumab, it is recommended to plan the vaccination date individually depending on the last drug administration [70]. In fingolimod-treated patients, attention should be paid to the presence of lymphopenia [72]. In NMOSD patients, vaccination is also safe and not associated with disease progression [73]. Patients treated with rituximab showed a poorer response, and could be at risk of infection despite vaccination [74]. In MG cases, vaccination theoretically may cause disease exacerbation, but patients with MGFA I and II should not avoid vaccination [73, 74]. Qualification for vaccination in other cases should be done on an individual basis, bearing in mind that the benefits outweigh the risks in most patients [77]. The occurrence of COVID-19 had a worse effect on MG than vaccine administration [76]. In patients with a previous episode of GBS not associated with COVID-19, vaccination is recommended. However, age and risk factors must be considered [78, 79]. We found no data about the safety or efficacy of SARS-CoV-2 vaccines in patients with a history of ADEM. Some reports have shown cases of MG, GBS, NMOSD and ADEM following vaccination against SARS-CoV-2 [77–81, 84–86]. Nevertheless, this should be interpreted with caution. Only single cases of such phenomena are usually reported. According to Kaulen et al. [81], severe neurological complications after COVID-19 vaccination are extremely rare (< 0.1%).

Conclusions

Overall, the pathogenesis and immune response in AIDs and COVID-19 share many common features. Both are heterogeneous conditions in which immune-mediated mechanisms can lead to multiple organ failure. The main concern for patients with AIDs is whether the infection is associated with a worse prognosis or an exacerbation of the underlying disease.

In most of the above studies, the presence of AIDs did not significantly affect the infection course. In patients with many comorbidities and advanced disease, the need for hospitalisation and the mortality rate may be higher. The approach to patients with AIDs should be individual because many issues remain unresolved despite the long-lasting pandemic. There is a lack of comprehensive research into specific topics.

However, we hope that our review contributes to a better understanding of the connections between neuroimmune diseases and COVID-19.

Conflict of interests: None.

Funding: None.

References

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