The Occurrence of Acute Disseminated Encephalomyelitis in SARS-CoV-2 Infection/Vaccination: Our Experience and a Systematic Review of the Literature

Background: The neurological complications of coronavirus disease 2019 (COVID-19) infection and the side effects of vaccination include immune-mediated diseases of the central nervous system (CNS) such as acute disseminated encephalomyelitis (ADEM). It is an acute-onset demyelinating disease that involves a rapid evolution and multifocal neurological deficits that develops following a viral or bacterial infection or, less frequently, following vaccination. Acute hemorrhagic leukoencephalitis (AHLE) is the hemorrhagic variant of ADEM that presents a more severe evolution which can be followed by coma and death. The objectives of this study consist in evaluating the diagnosis, clinical characteristics, imaging and laboratory features, evolution, and treatment of ADEM and AHLE following COVID-19 infection or vaccination. Methods: We performed a systematic review of the medical literature according to PRISMA guidelines that included ADEM cases published between 1 January 2020 and 30 November 2022 following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination and also included our own clinical experience regarding this pathology. Results: A total number of 74 patients were diagnosed with ADEM, 45 following COVID-19 infection and 29 after a SARS-CoV-2 vaccine. A total of 13 patients (17.33%) presented AHLE. The moderate form of COVID-19 presented a positive correlation with AHLE (r = 0.691, p < 0.001). The existence of coma and AHLE was correlated with poor outcomes. The following more aggressive immunomodulatory therapies applied in severe cases were correlated with poor outcomes (major sequelae and death): therapeutic plasma exchange (TPE) treatment (r = 382, p = 0.01) and combined therapy with corticosteroids and TPE (r = 0.337, p = 0.03). Conclusions: Vaccinations are essential to reduce the spread of the COVID-19 pandemic, and the monitoring of adverse events is an important part of the strategic fight against SARS-CoV-2. The general benefits and the overall good evolution outweigh the risks, and prompt diagnosis is associated with a better prognosis in these patients.


Introduction
Coronaviruses are well-known pathogens that affect humans and animals, being responsible for respiratory tract infections. In 2019, a mutated form of a coronavirus, which resulted in a worldwide pandemic considered as the most tragic in our history, was first identified in Wuhan, China. Respiratory symptoms were initially identified as prominent, but soon after, the involvement of different systems and organs was reported following coronavirus disease 2019  infection, including neurological complications [1]. The most common neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include immune-mediated diseases; encephalopathy and encephalomyelitis; ischemic stroke; neuromuscular disorders; and smell and taste disorders [1,2]. Some of these complications-such as neuromuscular diseases, Guillain-Barre syndrome (GBS), stroke, and acute disseminated encephalomyelitis (ADEM)-appear at the onset or during active infection, while others appear after a latent period; these include autoimmune encephalitis and post-COVID-19 neurological syndrome (characterized by brain frog and cognitive dysfunction; sleep disorders; mood disorders; and smell and taste disorders) [3].
ADEM is an acute-onset demyelinating disease of the central nervous system (CNS) that affects the cerebral hemispheres, cerebellum, brainstem, or spinal cord with rapidly evolutive, multifocal neurological deficits, and usually evolves in a monophasic way and develops following a viral or bacterial infection (usually involving the upper respiratory tract) or less frequently following vaccination [4][5][6][7].
Case reports of a rising number of patients with ADEM following viral infection or SARS-CoV-2 vaccination have been published.
The objectives of this study consist in providing an overview on the diagnosis, clinical characteristics, imaging and laboratory features, evolution, and treatment of ADEM following COVID-19 infection or vaccination. We also wanted to evaluate if acute hemorrhagic leukoencephalitis (AHLE) appears more frequently postvaccination or postinfection and if there are evolutionary differences compared with the classic form.

General Incidence of ADEM
Children and adolescents are most commonly affected, but cases have also been reported in adults and elderly patients [8]. The incidence of ADEM in childhood is 0.5/100,000 patients [9]. The annual global incidence of ADEM is 1 in 125,000-250,000 individuals per year, and according to some reports it seems to be more common in males than in females [10]. Other studies also revealed a similar global incidence, estimated at 0.8/100,000 [8,11].

Etiology
The appearance of ADEM is considered secondary to viral exposure, or less often (in 5% of cases) following vaccination [12,13]. Infections by various pathogens have been reported to result in ADEM-especially herpes simplex, coronaviruses, influenza, Epstein-Barr virus, cytomegalovirus, and measles [14,15]. Many vaccines have been associated over time with side effects like GBS and transverse myelitis. In young people, narcolepsy was reported after they received the influenza vaccine [16,17]. Postvaccinal ADEM is described especially after influenza, varicella, measles, mumps, rabies, hepatitis B, diphtheria, and tetanus immunization [5,18]. Isolated case reports and case series in the current context of the last 3 years show a relationship between SARS-CoV-2 virus and ADEM, with both postviral and postvaccinal cases being described, secondary to the efforts made to combat Vaccines 2023, 11,1225 3 of 38 the pandemic [12,13]. Until now, there have been no large population studies to evaluate the incidence of these cases.

Materials and Methods
We performed a systematic review of the medical literature according to PRISMA guidelines (Preferred Reporting Items for Systematic Review and Meta-Analyses) (http:// www.prisma-statement.org/, accessed on 30 November 2022) using articles available in the PubMed database, and a predefined combination of search terms: "acute disseminated encephalomyelitis" or "ADEM" and "COVID-19" or "SARS-CoV-2" or "SARS-CoV-2 vaccine" or "COVID-19 vaccine". The literature research was performed by 2 independent reviewers (AS and RC) and all articles with relevant titles published between 1 January 2020 and 30 November 2022 were subjected to a systematic analysis and included in the review if the content was relevant to the current study. An evaluation was solicited from a third reviewer (MS) if there were discrepancies or doubts regarding the relevance of some articles.
Inclusion criteria: age of the reported patient(s) was over 18 years; confirmed ADEM diagnosis after COVID-19 or administered SARS-CoV-2 vaccine; magnetic resonance imaging (MRI) performed; presence of relevant information regarding the collected data; and a clear description of the cases. Only papers in English were considered.
Exclusion criteria: duplicate articles; reports published only as abstracts; reports published in a language other than English; studies that contained insufficient data; general reviews; and neurologic disease other than ADEM.
For the association between vaccination and ADEM, a total of 193 articles met the criteria using our defined keyword search. The number of articles increased by 12 after we screened and analyzed the reference lists of found articles and discovered additional case series and case reports. Duplicate records were removed (n = 55) and 150 articles were screened and analyzed. There were 120 publications that were eliminated because they were written in a language other than English, they did not include information on COVID-19 infection or immunization status, or the patients were children. In addition, 6 studies were excluded due to inadequate data for our analysis. Finally, 24 publications fulfilled the inclusion and exclusion criteria and were included in the review. From these, we identified 28 patients who developed postvaccinal ADEM. We added our own case to the total number of patients when we performed the statistics. The flow chart of the research strategy is illustrated in Figure 1. The following data were extracted from the selected articles: age, gender, type of administered vaccine, reverse transcription-polymerase chain reaction (RT-PCR) test swab (performed/not performed), the onset latency for neurological symptoms after vaccine, neurological symptoms, brain and spine MRI, cerebrospinal fluid (CSF) analysis, other lab tests carried out, treatment, and outcome.
For the association between infection and ADEM, a total of 221 articles met the criteria according to the searched keywords. Another 17 articles with additional case series and case reports were discovered after we screened and analyzed reference lists. Duplicate records were removed (n = 42) and 179 articles were screened and analyzed. A total of 114 articles were eliminated because they were written in a language other than English, the patients had no history of COVID-19 infection, or the patients were under the age of 18. Another 30 research articles were also eliminated because of inadequate data for our study. In the end, 35 publications fulfilled the inclusion and exclusion criteria and were finally included in the review. We identified 45 patients reported in the included articles that developed postinfectious ADEM. The flow chart of the research strategy is illustrated in Figure 2. The following data were extracted from the selected articles: age, gender, RT-PCR test swab (performed/not performed), the onset latency for neurological symptoms after infection, neurological symptoms, brain and spine MRI, CSF analysis, other lab tests carried out, treatment, and outcome. Data from all the articles and the characteristics of the patients included in the review are compiled in two tables (Tables 1 and 2).

Our Clinical Experience
A previously healthy, 33-year-old male presented at the emergency room and was admitted to the neurology clinic in July 2021 with a 3-day history of fever, headache, nausea and vomiting, decreased muscle strength of the limbs with a predominance in the lower limbs, paresthesia, and urinary difficulties with urinary retention-symptoms that started 14 days after receiving his first dose of the Johnson & Johnson vaccine.
On neurological examination, he was aware and fully alert to the place, time, and person; negative for nuchal rigidity; and had cranial nerves in normal limits. The examination of muscle strength as assessed by Medical Research Council (MRC) grading revealed spastic tetraparesis, grade 4+/5, in the upper limbs and 4/5 in the lower limbs; increased deep tendon reflexes in the lower limbs; bilateral Babinski signs; and acute urinary retention. He had no significant personal history of previous diseases and had no family history suggestive of autoimmune disease, but he was overweight. He had no contact with SARS-CoV-2-positive cases and the RT-PCR swab test was negative.
Upon admission, laboratory tests revealed the following: white blood cells ( The CSF had normal pressure and was clear and colorless. The CSF analyses revealed the following values: glucose: 93 mg/dL; proteins: 469 mg/dL; RBC: 0/uL; and WBC: 650/uL (95% lymphocytes, but no lymphoid cells suggestive of lymphoma were present in the CSF). The CSF examination did not reveal other abnormalities or bacterial, fungal, or Mycobacterium tuberculosis infection; and an immunoelectrophoretic exam of serum and CSF revealed no oligoclonal bands. Serology for SARS-CoV-2 in CSF was not performed. The patient underwent a thoracoabdominal-pelvic computed tomography scan that was within normal limits, ruling out neoplasia.
Informed consent was obtained from the patient for the publication of his data and his accompanying MRI images. To the best of our knowledge, this is the first case of postvaccinal ADEM reported in Romania in the context of the COVID-19 pandemic.  The spine MRI revealed hyperintense areas in T2 and FLAIR images that occurred in the cervical region at C2, C4-C5, and C7, without contrast enhancement (Figure 4).
Empiric therapy with antibiotics and acyclovir was started first. Based on these clinical, imaging, and CSF results, and taking into account the temporal relationship with the administration of the Johnson & Johnson vaccine, we concluded that the diagnosis was ADEM postviral vector vaccination and continued with intravenous methylprednisolone (IV MP). The patient received 1 gr of IV MP for 5 days with marked improvement in the symptomatology, and he was discharged on oral steroids with a tapering regime. A repeated brain MRI on day 40 following the initial examination showed a significant reduction in the diameter of the demyelinating lesions, without any new lesions.
Our patient met the diagnostic criteria for ADEM according to the International Pediatric Multiple Sclerosis Study Group 2007, and the correlation between neurological clinical presentations, lab tests, and MRI findings led to the diagnosis of ADEM. An association with the vaccine was suspected based on the temporal relationship between vaccine administration and the onset of neurologic disease. After pathogen-induced encephalitis was excluded, the presence of pleocytosis and the absence of intrathecal oligoclonal band synthesis pointed to the diagnosis of ADEM. Although the connection between the vaccine and the neurological disease may be coincidental, there is still the possibility of a secondary neuroinflammatory syndrome.
The positive diagnosis is supported by the following: (1) The temporal association between the infection/vaccine and disease; Informed consent was obtained from the patient for the publication of his data and his accompanying MRI images. To the best of our knowledge, this is the first case of postvaccinal ADEM reported in Romania in the context of the COVID-19 pandemic.

Literature Review
A total number of 74 patients were diagnosed with ADEM, 45 patients (60.81%) after COVID-19 infection and 29 (39.19%) after a SARS-CoV-2 vaccine. A total of 13 patients (17.33%) out of the total number of patients presented AHLE (22.22% after infection and 10% after vaccine), without a statistically significant difference (p = 0.18).
The average time between infection with SARS-CoV-2 and the onset of ADEM was 19.53 days, and the average time between the vaccine administration and the onset of ADEM was 12.34 days (p = 0.04). In the postinfectious group, a statistically significant correlation was not found between the severity of COVID-19 and the outcome; however, there was a positive correlation between the moderate form of COVID-19 and AHLE (r = 0.691, p < 0.001). Brain MRIs were performed on 73 patients (98.64%) and spine MRIs on 21 patients (28.37%). Contrast enhancement was reported in 27 cases (36.48%), without a significant difference between the groups.
Oligoclonal bands (OCB) were present in 12 cases (16%), and anti-MOG antibodies were present in 1 case. Moreover, SARS-CoV-2 RT-PCR from CSF was positive in four patients (8.89%) from the postinfectious group, with the precise result that only two patients were positive at the time of the PCR swab test.
The most frequent immunosuppressive therapy administered was corticosteroid therapy (87.83%), alone or in combination with other therapies, followed by IVIg (32.43%), plasmapheresis (17.56%), and rituximab (5.40%). No statistically significant relationship was observed between the administered therapy and the clinical evolution of the disease, with all the administered classes seeming to have similar clinical efficiency. Regarding the  The average time between infection with SARS-CoV-2 and the onset of ADEM was 19.53 days, and the average time between the vaccine administration and the onset of ADEM was 12.34 days (p = 0.04). In the postinfectious group, a statistically significant correlation was not found between the severity of COVID-19 and the outcome; however, there was a positive correlation between the moderate form of COVID-19 and AHLE (r = 0.691, p < 0.001). Brain MRIs were performed on 73 patients (98.64%) and spine MRIs on 21 patients (28.37%). Contrast enhancement was reported in 27 cases (36.48%), without a significant difference between the groups.

Literature Review
Oligoclonal bands (OCB) were present in 12 cases (16%), and anti-MOG antibodies were present in 1 case. Moreover, SARS-CoV-2 RT-PCR from CSF was positive in four patients (8.89%) from the postinfectious group, with the precise result that only two patients were positive at the time of the PCR swab test.
The most frequent immunosuppressive therapy administered was corticosteroid therapy (87.83%), alone or in combination with other therapies, followed by IVIg (32.43%), plasmapheresis (17.56%), and rituximab (5.40%). No statistically significant relationship was observed between the administered therapy and the clinical evolution of the disease, with all the administered classes seeming to have similar clinical efficiency. Regarding the combined treatment, in the postvaccination group we see a higher incidence of corticosteroid and plasmapheresis therapy (p = 0.04). The rest of the combined therapies and their incidences are presented in Table 3. In terms of the therapy used (Table 4) and clinical outcome, for the Spearman correlation we have a positive correlation between monotherapy (regardless the administrated therapy), corticosteroid monotherapy, and full recovery (r = 0.352, p = 0.003; and r = 0.384, p = 0.001) for all patients, as well as for postvaccination ADEM patients (r = 0.493, p = 0.007; and r = 0.529, p = 0.003), but not for the postinfection COVID-19 patients. The italic shows the significant values.
In contrast, in terms of poor outcomes (major sequelae and death), as seen in Table 5, we have a positive correlation between the TPE treatment (r = 0.382, p = 0.01), combined therapy with corticosteroids and TPE (r = 0.337, p = 0.03), and the abovementioned endpoint in all patients. Moreover, the presence of coma (r = 0.501, p < 0.001) and AHLE (r = 0.314, p = 0.006) is correlated with poor outcomes. For the postinfection group, TPE therapy (r = 0.314, p = 0.04) and coma (r = 0.389, p = 0.008) presented a positive correlation with poor outcomes. Furthermore, for the postvaccination patients, AHLE (r = 0.665, p < 0.001) and coma (r = 0.449, p = 0.01) were associated with poor outcomes. The italic shows the significant values.

Pathophysiology of ADEM
The relationship between infection/vaccination and the occurrence of demyelinating diseases is not fully understood, being attributed to an exaggerated autoimmune reaction of the body to viral or vaccine antigens [73].
Experimental autoimmune encephalomyelitis in animal models can be triggered after immunization with CNS homogenate with myelin peptides emulsified in complete Freud's adjuvant, and this is used to study the mechanisms underlying ADEM with inflammatory demyelinating lesions in the brains and spinal cords of experimental animals [8,74].
Additionally, Theiler proposed in the 1930s a murine encephalomyelitis model as a model to study the pathogenic infectious mechanisms of the disease, consisting in inoculation of susceptible mouse strains in the cerebral hemisphere with the Theiler murine encephalomyelitis virus. The disease seems to be triggered by cluster of differentiation (CD)8+ T cells, while ongoing inflammation is sustained by CD4+ T cells which infiltrate the CNS and recruit additional mononuclear cells and lymphocytes to cross the blood-brain barrier (BBB), finally producing inflammation and demyelination [8,75]. Based on animal model research, two theories have been developed: (a) The concept of molecular mimicry is based on the similarity of an amino-acid sequence (epitope) between myelin proteins of the host and invading pathogens [75,76]. The antigen-presenting cells (dendritic cells) process the pathogen, activating T cells which in turn activate B cells. Both of these cell types are able to enter into the central compartment during the process of immune surveillance and can be reactivated by local antigen-presenting cells (microglia), producing a local inflammatory immune reaction [8,75]. The injection of CD4+ T lymphocytes from immunized animals that recognize myelin-associated protein can initiate the disease in healthy animals [75,77]. (b) CNS infection with a pathogen results in nervous tissue damage with the penetration of autoantigens in systemic circulation through a disrupted BBB. These autoantigens reach the lymphatic organs, where they are processed and initiate a self-reactive T-cell response with nonspecific activation of an autoreactive T-cell clone [8,75].
The proposed postinfectious and postvaccinal mechanisms are molecular mimicry, bystander activation, epitope spreading, and polyclonal B-cell activation [3,78]. In the context of inflammation that produces increased vascular permeability in the CNS, molecular mimicry between viral proteins and myelin antigens is followed by a cross-reaction driven by a T-cell-mediated autoimmune response directed against myelin basic protein [32,34]. Talbot et al. reported human coronavirus myelin-T-cell cross-reactivity in patients with multiple sclerosis (MS) [79]. Postvaccinal ADEM generally appears after between 1 and 14 days, especially after the first dose of the vaccine, and rarely after revaccination [34,80].
Postinfectious ADEM is characterized from a morphopathological point of view by the existence of perivenous demyelinating lesions, lymphocytic and macrocytic infiltrates along with endothelial swelling, perivascular edema, and hemorrhages, followed in late stages by foci of fibrillary fibrosis [75].

Pathophysiology of ADEM after SARS-CoV-2 Infection
Currently, it is clear that SARS-CoV-2 is a neurotrophic virus and that the neurological damage directly involves viral lesions of the glial cells and neurons, neuroinflammation, hypercoagulability, and endothelial dysfunction [49,81]. SARS-CoV-2 penetrates the CNS, producing neurological complications. The most common methods of penetration mentioned are the following: (1) Systemic circulation can contribute to the distribution of the virus in the cerebral blood flow and from here, due to sluggish blood flow in the context of inflammation, viral neuroinvasion is facilitated [82]. (2) The virus crosses the BBB due to increased permeability in the context of a cytokine storm [9]. (3) The virus is carried by the infected immune cells-leukocytes [9]-that function as a viral reservoir and can infiltrate the brain tissue through the glymphatic (glial-lymphatic) system-the so-called Trojan horse mechanism [1,82,83]. (4) The spike protein of the virus binds to cell-surface angiotensin-converting enzyme type 2 (ACE2) receptors found in various tissues and infects the endothelial cells of the BBB or the epithelial cells of the blood-CSF barrier at the level of the choroid plexus-mediating cellular entry of the virus towards the central compartment (brain and brainstem-the nucleus of the solitary tract and the paraventricular nuclei) [1,35,83].
(5) Penetration occurs via a neuronal route by retrograde axonal transport from the peripheral nerves towards the CNS through synaptic connections (olfactory nerves) [1,84].
Viral agents, including SARS-CoV-2, can disrupt the immunomodulatory mechanism due to a transient immunosuppression in the periphery with lymphopenia and an aberrant immune reconstitution that leads to perturbed immunoregulation, breakdown of self-tolerance, and reactivation of self-reactive lymphocytes even in the absence of epitopes common to self-antigens [77]. The generation of a systemic inflammatory response (SIRS) causes the excessive production of proinflammatory cytokines (interleukins: IL-6, IL-12, IL-15, TNF-α), resulting in a cytokine storm that also affects the CNS. The BBB is compromised by the cytokine storm with increased permeability, which triggers an innate local immune response in resident cells with activation of glial cells in the CNS compartment, and infiltration of cytotoxic T lymphocytes in brain parenchyma. This induces a powerful proinflammatory state and initiates autoimmunity [1,84]. A recent study found a compartmentalized response when analyzing the blood and the CSF of patients with COVID-19 with CNS-specific T-cell and B-cell activation and antineuronal reactivity [85].
Neurological disease can occur early in the evolution of COVID-19 as the result of virus invasion, which could explain, in some cases, the early onset of neurological symptoms after diagnosis with COVID-19. Alternatively, it can occur in the recovery phase through a postinfectious, immune-mediated mechanism: the virus induces an autoimmune reaction after a latent period following acute infection. This is explained by the hypothesis of molecular mimicry between viral and self-antigens [83]. Not much is known about the immune-mediated diseases of the CNS secondary to SARS-CoV-2 infection. In most cases with neurological involvement in the context of COVID-19, the presence of the virus in CSF was not highlighted, probably due to reduced viremia or a rapid viral clearance, and there were only isolated cases that reported a RT-PCR test of CSF [3].
Generally, vaccines stimulate a strong pathogenic response from T cells, with an increase in the level of proinflammatory cytokines-as demonstrated in the case of the ChAdOx1 nCoV-19 vaccine [86,87]. The antigens contained in the vaccine are recognized as potential pathogens by the peripheral circulating immune cells (macrophages and monocytes) and induce the transcription of the target genes with increased synthesis of inflammatory and pyrogenic cytokines (IL-1, IL-6, tumor necrosis factor [TNF] α). These enter into the bloodstream, creating a response that is similar to infection. Phagocytosis is then initiated and stimulated in the immune system with further release of inflammatory mediators-including cytokines, chemokines, activation of the complement system, and cellular recruitment. Inflammatory mediators released into the circulation can induce systemic side effects including microglia activation and neuroinflammation, depending on the immunogenetic background [86,88,89]. Several pathogenic mechanisms, like molecular mimicry, aberrant immune responses with immune cell activation and infiltration, maladaptive immune responses, an inflammatory cascade, and direct neurotoxicity, have been used to explain the association between vaccines and neurological manifestations [16,17]. In molecular mimicry, systemic or intrathecal antibody synthesis against some myelin proteins (myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein) with which the virus shares antigenic properties leads to a cross-reaction of the antibodies produced by infection or following vaccination [15]. The molecular analyses of anti-SARS-CoV-2 antibodies demonstrated a cross-reaction of antibodies directed against the viral spike protein with some human antigens, including neurofilament proteins [90]. The autoimmune reaction and increased central system blood vessel permeability can explain the favorable effect of anti-inflammatory therapy [49,91,92].

ADEM Diagnosis
Diagnostic criteria were developed for the pediatric population by the International Pediatric Multiple Sclerosis Society Group in 2007 and were updated in 2013. However, there are no clearly defined criteria for the adult population [27].
(1) Multifocal damage of CNS at first manifestation due to an inflammatory demyelinating cause. (2) Encephalopathy that cannot be explained by a rise in fever.
(3) Lack of other clinical events or new lesions on MRI in the 3 months following onset. (4) Brain and/or spine MRI shows lesions in the acute phase (3 months). (5) Brain lesions on MRI are diffuse and poorly demarcated and have the following characteristics: (a) Large-size lesions of 1-2 cm that mainly affect the white matter.
(c) Lesions may also be present in deep gray matter [27,93].

General Considerations on Postinfectious and Postvaccinal ADEM in the Context of COVID-19
From December 2020, vaccination started being approved worldwide as a safe solution designed to protect individuals from the virus and to prevent progression to the severe form of the disease [20,94]. Although studies carried out so far indicate that the vaccines against SARS-CoV-2 have a high safety profile, and none of the currently approved vaccines use live attenuated viruses, postvaccination neurological complications including ADEM have nevertheless been reported [53]. The full spectrum of complications for these vaccines is not yet fully known.
Current vaccines used against COVID-19 include the following: (1) mRNA-based vaccines in which human cells are stimulated to produce SARS-CoV-2 proteins and express the viral spike protein on their surface by means of genetically transferred information. The human body then initiates a defensive response against it. (2) Viral vector-based vaccines in which an adenovirus is used to deliver fragments of the SARS-CoV-2 genome to human cells. (3) Inactivated viral vaccines in which a dead SARS-CoV-2 virus triggers the immune response after inoculation [16,17].
The vaccine developed by Johnson & Johnson (COVID-19 Vaccine Janssen) uses a nonreplicating viral vector to deliver a fragment of SARS-CoV-2 genetic information to host cells. This genetic information is necessary for the synthesis of the SARS-CoV-2 spike protein that subsequently acts as an antigenic protein. The viral vector used is an adenovirus without replicative capacity, which is considered safe for immunocompromised patients [53].
ChAdOx1n COV-19 contains an adenoviral vector that encodes the spike protein of SARS-CoV-2 [95]. Both vector-based vaccines and mRNA vaccines encode and stimulate the production of the SARS-CoV-2 spike protein [33]. Messenger RNA is recognized by cytosolic and endosomal toll-like receptors (TLR3, TLR7), while the vector-based vaccines contain elements of the virus particle that are recognized by pattern recognition receptors (TLR9) [33]. The ChAdOx vaccine elicits a strong T-cell response based on a Th1-phenotype [96]. Infection and vaccination trigger a strong immune response with increased expression of T lymphocytes and proinflammatory cytokines. Viral or vaccine antigens are recognized by peripheral circulating immune cells (monocytes, macrophages) through surface receptors, resulting in an increase in the expression of many target genes, increased synthesis of inflammatory cytokines, complement activation, and phagocytosis initiation with further cell recruitment [86,87].
The neutralizing antibodies compete with ACE2 for the receptor-binding domain of SARS-CoV-2, and it is suggested that postinfection and postvaccinal antibodies could show an aberrant affinity for endogenous ACE2-receptors, increasing the risk of autoimmune reactions in the areas of the brain rich in ACE2 receptors (periventricular lesions) [35,97,98]. This would also explain the impaired function of ACE2 receptor-rich endothelial cells belonging to the cerebral microvasculature that leads to increased BBB permeability with demyelination, like in ADEM [35].
Additional factors belonging to the host, like cell-surface proteins including neutrophilin-1 (very well expressed in the olfactory nerve and human brain with an important role in endothelial function, neuronal development, and modulation of innate immune responses), are presumed to facilitate virus entry into cells [35,99,100]. The alteration of neutrophilin-1 expression correlates with endothelial and BBB dysfunctions, neuroinflammation from experimental autoimmune encephalomyelitis, and the severity of immune responses produced by COVID-19 [35,101,102].
The incidence of ADEM after SAR-CoV2 vaccines has not yet been reported worldwide, but some data from India show an incidence of 3 cases/8.19 million ChAdOx1 vaccines, so without a statistically significant increase, this might raise questions about the safety of these vaccines [30]. Messenger RNA vaccines are a new type of vaccine, but as of 26 May 2021, 9442 adverse reactions were reported to the Vaccines Event Reporting System (VAERS) database, including some rare neurological complications and six cases of ADEM [103]. Until the end of March 2022, more than 170 patients with postvaccinal ADEM were reported to the Eudra Vigilence database of the European Medicine Agency (91 patients after the BioNTech Pfizer Vaccine, 46 after the AstraZeneca vaccine, 27 after the Moderna vaccine, and 8 following the Johnson & Johnson vaccine) [33]. Different institutions collect data regarding adverse reactions that occur after administration of COVID-19 vaccines. For example, the National Institute of Public Health of Quebec (INSPQ) reported 67 side effects in Quebec for each 100.000 doses administered, for all types of vaccines. The proportion is higher for AstraZeneca, with 182.5 reported cases per 100.000 doses, but most of them were labeled as "without gravity" [86]. The European Medicine Agency (EMA) reported only 10 cases of ADEM between 20/01/21 and 10/06/21, after almost 46 million doses of the CgAdOx1 nCoV-19 vaccine were administered-so its protective effects far outweigh any side effects [1,104]. Cases of ADEM are more frequently reported after SARS-CoV-2 infection than postvaccination [14].
The published literature reveals a constellation of manifestations in patients, suggestive of multifocal CNS involvement. The first case of COVID-19-associated ADEM was reported by Zhang et al. in a 40-year-old woman [105]. Shortly thereafter, more case reports or case series appeared.
In ADEM, pathological findings on MRI are multifocal, bilateral, sometimes with confluent T2/FLAIR hyperintensities, often asymmetrical and bilateral, sometimes tumefactive, and with poorly defined borders on T2-weighted and FLAIR images. The lesions are situated in the cortical peripheral gray matter, subcortical gray matter, and white matter junction but also in the basal ganglia, thalami, brainstem, and cerebellum, with a variable enhancement pattern. Unlike in MS, the corpus callosum is spared [49,73]. MRI findings in ADEM may overlap with MS, but the latter is characterized by periventricular white matter, corpus callosum, and subcortical U fiber involvement [12,106]. Usually, the plaque borders in ADEM are not clearly defined. While in MS the lesions are permanent, in ADEM there is a nonspecific gliosis with no myelin loss, and axons are also generally preserved, which explains the clinical evolution with total recovery in some cases [107]. The involvement of gray matter, the lack of periventricular lesions and of T1-black holes, and the absence of Dawson finger configuration are helpful in distinguishing ADEM from MS [108,109]. A particularity of COVID-19-associated ADEM is the presence of a linear perivascular enhancement that correlates with the changes highlighted in the biopsy with perivenous inflammation and inflammatory infiltrates of lymphocytes and macrophages [49].
Acute hemorrhagic leukoencephalitis (AHLE) is a hyperacute and more severe subtype of ADEM. It is much rarer, with a poor prognosis and a more severe course that can rapidly progress to coma and death. This variant was first described by Hurst in 1941 [110] and can occur at any age, but predominates in children and young adults. AHLE is characterized by the presence of T2 and FLAIR hyperintense lesions and edema in the deep white matter and subcortical areas, as well as T1 hypointense lesions with microhemorrhages in susceptibility-weight images (SWI) [9]. The histological characteristics of AHLE are necrotizing vasculitis of the venules with perivascular hemorrhages and infiltrates with polymorphonuclear cells [75]. Hemorrhagic lesions have been reported in postvaccinal and COVID-19-associated ADEM [66]. Brain MRI investigation, when the clinical context is suggestive, is essential to identify inflammatory lesions and a hemorrhagic component [1,111]. The MRI reveals larger white matter lesions, accompanying edema, and multifocal hemorrhages [112], with a poorer prognosis compared with the classical presentation, despite early intensive treatment [33]. The cerebellar and brainstem involvement, and the presence of gross hemorrhage with mass effect, is correlated with poor prognosis [9]. Reports of patients with AHLE show more elevated levels of inflammatory cytokines and inflammatory markers (CRP, D-dimers, procalcitonin, and serum ferritin) compared with those with classical ADEM [113]. These patients are critically ill, with encephalopathy that deteriorates rapidly to coma and sometimes death. The survivors remain afflicted with significant neurological sequelae [9]. AHLE must be differentiated from posterior reversible encephalopathy syndrome (PRESS), which also presents with parieto-occipital white matter lesions (some of them hemorrhagic) and has also been reported in relation to COVID-19 [35,114].
Lumbar puncture (LP) and CSF can reveal changes in 50-80% of patients-with slightly elevated proteins and lymphocytic pleocytosis, increased pressure, raised levels of myelin basic protein, and, rarely, oligoclonal bands of IgG [32,75,115]. CSF can be normal in up to 60% of cases of ADEM [4,7].
The treatment is symptomatic and etiologic, supportive and immunomodulatory, and intended to reduce the morbidity and mortality of ADEM [49]. Intravenous corticosteroids suppress inflammation and aberrant immune responses, and remain the recommended first line of treatment: 1-2 g/day for 3-5 days followed by oral tapering. The response to corticosteroids is favorable in two thirds of cases, and it shortens the duration of the disease and stops further progression. In case of inadequate response, and in refractory cases, therapeutic plasma exchange or IVIg (0.4/kg/body weight) can be recommended according to the protocol applied in other autoimmune neurological diseases [12,117,[120][121][122].
Nowadays, in general, the prognosis of ADEM patients is favorable with treatment, with an average recovery period between 1 and 6 months. However, it can result in permanent neurological disability that can burden a patient for the rest of their life [8]. Deaths have been reported in COVID-19-associated ADEM and recovery seems to be incomplete [66]. Sequelae after the initial attack include cognitive impairment, as well as motor and sensory deficits [109]. Mortality is higher among adults compared with the pediatric population [49]. The most important prognostic factors for poor outcomes seem to be the following: the association of COVID-19; ADEM with hemorrhagic features; extensive lesions and brainstem involvement; and the admission to an intensive care unit due to respiratory distress or consciousness impairment [49]. The majority of cases with postvaccinal ADEM have a good evolution with favorable outcomes towards full recovery, as in the case we treated. Only eight reported deaths were found by us in this review (five after infection, three after vaccination). In general, the disease follows a monophasic course, but the evolution towards another demyelinating disease or another multiphasic disease cannot be ruled out; it remains to be seen what the future holds [15].
Despite the increasing number of reported cases of ADEM and AHLE in patients with SARS-CoV-2 infection, this type of neurological complication remains low considering the total number of infections. Numbers of postvaccination cases are even lower. We cannot exclude the possibility that the incidence of adverse postvaccination effects may be slightly higher, as a mild presentation of the disease may remain unreported. In the majority of cases, it is hard to establish if vaccination and the onset of ADEM are coincidental or not, but increasing numbers of vaccinated subjects may support this supposition. A clear link between a certain type of vaccine and increased incidence of ADEM was not observed. Most cases of reported postvaccinal ADEM had a good clinical evolution, even with complete recovery. The absence of encephalopathy seems to be associated with better clinical outcomes in both groups, and its presence is associated with a poor prognosis. The new technology used in the production of vaccines against the SARS-CoV-2 virus, the factors involved in the occurrence of ADEM, the existing gaps in the pathogenic mechanisms, and the lack of clinical studies encourage cautious analyses of cases suspected to be SARS-CoV-2-vaccination-related ADEM. Vaccination is essential for reducing the morbidity and mortality associated with the infection, and additional prospective data are needed for a definite conclusion.
Overall, this study has some limitations: the small sample size with limited published data for some cases (paraclinical investigations, clinical evolution); the retrospective analyses of published reports; and the short follow-up period. In addition, the potential influence of publication bias cannot be excluded, and conclusions may not be representative of the entire population. Another limitation of the study is that not all the patients among those reported with postvaccinal ADEM were tested for SARS-CoV-2. Tests may have become negative after a few weeks and serological tests were not always performed, potentially leading to an underestimation of association between ADEM and COVID-19.
Evidence of immune or immune-mediated CNS damage suggests that neuroinflammation may occur as a long-term consequence of SARS-CoV-2 infection or vaccination, and larger studies with epidemiological and pooled data are needed to check causality.

Conclusions
The COVID-19 pandemic greatly affects not only the healthcare system, but also the entire socioeconomic system. It is already evident that COVID-19 is a global threat as well as a threat to the CNS, due to its multifactorial pathogenic mechanisms. Attempts to solve this issue have led to the development of different ways to approach the disease, and great effort was made in the development of different vaccines to prevent severe cases of the disease, especially in high-risk categories. Vaccinations are essential to reducing the spread of the COVID-19 pandemic, and the monitoring of adverse events is an important part of the strategic fight against SARS-CoV-2.
In the era of COVID-19, it is mandatory that clinicians should be aware of and remain vigilant to these rare but potential complications following SARS-CoV-2 infection or vaccination, in a suggestive clinical context. A prompt diagnosis and treatment are associated with better prognoses for patients. Although the association between the vaccine and neurologic disease could be coincidental, there is the possibility of a postvaccination neuroinflammatory syndrome given the time sequence of events.
So far, experience suggests that SARS-CoV-2 vaccination is safe. The scarcity of postvaccinal ADEM case reports, and the overall good evolution, should emphasize that the general benefits of vaccination outweigh the risks, and that vaccination programs should continue to be recommended.  Informed Consent Statement: Written informed consent was obtained from the patient to publish this paper. Data Availability Statement: Data are available based on the request from corresponding author.