Post-COVID-19 Vaccination CNS Magnetic Resonance Imaging Findings: A Systematic Review

Objective This systematic review aims to synthesize and analyze the available literature on central nervous system (CNS) magnetic resonance imaging (MRI) findings in individuals who have received COVID-19 vaccinations. Our objective is to enhance understanding of potential neurological side effects, inform clinical practice, and guide future research on the neurological implications of COVID-19 vaccination. Methods In this systematic review, we conducted a comprehensive search in PubMed, Scopus, and Web of Science from January 2020 to April 2023, using terms related to COVID-19 vaccination and CNS MRI findings. We evaluated the quality of the study, extracted relevant data, and included 89 eligible studies that covered various vaccines, demographics of patients, symptoms, and MRI findings to provide a thorough understanding of SARS-CoV-2 vaccination-related CNS problems. Results We investigated CNS MRI findings following COVID-19 vaccination across various vaccine types. Common diseases associated with post-vaccination CNS MRI findings included cerebral venous sinus thrombosis (CVST), vaccine-induced immune thrombotic thrombocytopenia (VITT), acute disseminated encephalomyelitis (ADEM), acute myelitis, autoimmune encephalitis (AE), and others. Patients presented with diverse onset symptoms and neurological manifestations. Abnormalities identified in CNS MRI findings included white matter (WM) hyperintensity. Our analysis offers a comprehensive overview of the current literature on post-vaccination CNS MRI findings. Discussion. We highlight a range of post-COVID-19 vaccination CNS MRI findings, including CVST, with a higher incidence in individuals receiving the ChAdOx1 (AstraZeneca) vaccine. Other notable observations include cases of ADEM, myelitis or transverse myelitis (TM), Guillain–Barré syndrome (GBS), and acute encephalopathy following COVID-19 vaccination. The incidence of these neurological complications is extremely rare, and the benefits of vaccination outweigh the risks. The reviewed studies were primarily case reports or case series, and thus large-scale epidemiological studies and controlled clinical trials are needed to better understand the underlying mechanisms and risk factors associated with these neurological complications following COVID-19 vaccination.


Introduction
Te coronavirus disease 2019  pandemic, caused by the coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2), has had a profound impact on global public health and resulted in signifcant morbidity and mortality rates [1][2][3][4][5]. Te disease, initially recognized for its respiratory manifestations, has demonstrated multiorgan involvement, including the central nervous system (CNS). In order to mitigate the pandemic's devastating efects, vaccination programs have been implemented worldwide, aiming to reduce morbidity and mortality and ultimately achieve herd immunity. Various SARS-CoV-2 vaccines have been developed, with clinical trials demonstrating their efcacy in preventing severe COVID-19 infection [3,6,7].
Te implementation of vaccination programs is crucial for controlling the spread of COVID-19 and protecting public health. Understanding potential side efects related to vaccines is essential for both healthcare providers and the general population. Common adverse efects following vaccination include pain, swelling, localized erythema at the injection site, fever, chills, fatigue, myalgia, muscle pain, vomiting, arthralgia, and lymphadenopathy [2,6,[8][9][10]. In addition, some individuals have reported mild neurological symptoms, such as headaches, dizziness, myalgia, muscle spasticity, and paresthesia. A limited number of case reports have documented more serious side efects, including generalized seizures, Guillain-Barré syndrome (GBS), and transverse myelitis (TM). Other neurological symptoms, such as facial nerve palsy, acute disseminated encephalomyelitis, and stroke, have been reported [6,8,11,12].
Magnetic resonance imaging (MRI) is one of the most crucial, extensively utilized, and powerful imaging modalities that ofer numerous advantages, such as high spatial resolution, unrestricted tissue depth penetration, multiplanar imaging, and soft tissue functionality [13][14][15]. MRI has been used in various medical aspects and biomedical applications, including diagnosis, therapy, follow-up, and treatment assessment; cancer imaging; infammation detection and perfusion imaging; and targeted MRI-guided drug delivery, among others. In light of the increasing number of COVID-19 vaccinations administered worldwide and the potential neurological side efects, understanding and characterizing the CNS MRI fndings post-vaccination is crucial [6,[16][17][18][19].
In this study, our objective was to systematically review the existing literature on CNS MRI fndings after COVID-19 vaccination. By providing a comprehensive analysis of the current evidence, we seek to contribute to the understanding of the potential neurological implications of COVID-19 vaccination and inform clinical practice and future research.

Search Strategy and Inclusion and Exclusion Criteria.
Te Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) fowchart is a structured and transparent approach to identifying, screening, and selecting studies for inclusion in a systematic review or meta-analysis [20,21]. We designed a comprehensive search strategy to identify studies that examined post-COVID-19 vaccination CNS MRI fndings. Our search was performed in three databases: PubMed, Scopus, and Web of Science, and covered the period from January 2020 to April 2023. Te main search terms were as follows: ((COVID-19) AND (magnetic resonance imaging)) AND (vaccination) AND (Brain) and ((COVID-19) AND (magnetic resonance imaging)) AND (Vaccination) AND (spinal cord). Two reviewers (SG and SM) independently screened the search results. Primary research publications that present the implications of post-COVID-19 vaccination CNS MRI fndings were included according to the inclusion criteria. Studies were excluded if they did not involve MRI imaging. Articles in all languages were considered for inclusion.
In addition to the database search, we reviewed existing reviews and checked their reference lists to identify any relevant studies that might have been missed during the initial search. Trough this comprehensive search and selection process, we aimed to ensure that only relevant studies were included in our analysis.

Quality Assessment and Data Extraction.
After the initial screening, articles were identifed for further analysis based on the inclusion and exclusion criteria. To assess the quality of the selected studies, both reviewers independently evaluated the methodologies and results presented in each article. Discrepancies between the reviewers were resolved through discussion and consensus. Data extraction was performed using a standardized data extraction form. Te extracted information included frst author (year), vaccine, past medical history, gender/age, diseases, symptoms, and MRI fndings. Te data were then inserted into Table 1 for further analysis.

Characteristics of Eligible Studies.
Te 89 eligible studies included in our systematic review investigated the implications of post-COVID-19 vaccination CNS MRI fndings ( Figure 1). To be included, studies needed to investigate the MRI modality simultaneously in conjunction with post-COVID-19 vaccination. Te selected studies covered a diverse range of vaccines, patient demographics, clinical symptoms, and MRI fndings, providing a comprehensive overview of the potential adverse efects and mechanisms of SARS-CoV-2 vaccination-related problems in the CNS.

Overview of Results.
Our systematic review included 89 eligible studies, which consisted of case reports, case series, and an original article by Nistri et al. [64]. Studies investigated the CNS MRI fndings following COVID-19 vaccination, covering various vaccine types, including Pfzer-BioNTech, Ad26.COV2.S (Jcovden), ChAdOx1 (AstraZeneca), Johnson & Johnson, BIBP-CorV (Sinopharm), Sinovac-CoronaVac, mRNA-1273 (Moderna), and others. Te medical history of patients in the included studies most commonly involved hypertension (HTN) and diabetes mellitus (DM). Te gender distribution was approximately equal between men and women, and the age range of the patients spanned from 12 to 88 years.

Discussion
MRI is commonly used as a diagnostic approach for both short-term and long-term neurological diseases that may be caused by vaccine injection because of its excellent soft tissue contrast resolution. Te primary objective of this systematic review was to provide a comprehensive analysis of the literature on CNS MRI fndings following COVID-19 vaccination. Our search strategy identifed 89 eligible studies, which revealed a wide range of vaccines, patient demographics, clinical symptoms, and MRI fndings. Te following discussion will focus on the key fndings and implications of these studies.
It is important to note that the incidence of CVST following COVID-19 vaccination is still relatively low, and the benefts of vaccination in preventing severe COVID-19 infection and its complications far outweigh the risks associated with rare adverse events such as CVST [111]. Clinicians should remain vigilant for the early signs and symptoms of CVST in patients who have recently received a COVID-19 vaccine, as prompt diagnosis and treatment are essential for optimal patient outcomes [112].
CVST and VITT with CVST varied in symptoms, ranging from headache and abdominal pain to more severe manifestations such as visual loss, seizures, or encephalopathy [34,35]. As with other cases of CVST postvaccination, MRI and MRV were able to detect the thromboses as well as secondary complications like venous infarction or hemorrhage. Tese fndings further highlight the need for clinicians to maintain a high index of suspicion of CVST and associated conditions in patients who present with neurological symptoms after COVID-19 vaccination, especially with the ChAdOx1 vaccine. Our analysis demonstrates that CVST and VITT with secondary CVST may be potential complications of COVID-19 vaccination requiring vigilance and early recognition. In particular, the risk of CVST appears to be higher following the ChAdOx1 vaccine compared to other vaccine platforms [34,35].
A notable observation in our analysis was the prevalence of ADEM as a reported neurological complication after The total number of studies included in the database searches N=89 14 Canadian Journal of Infectious Diseases and Medical Microbiology COVID-19 vaccination. ADEM is an autoimmune infammatory demyelinating disease of the CNS that usually occurs after viral infection or vaccination [43,45]. In our review, several ADEM cases were reported following vaccination with diferent COVID-19 vaccines such as mRNA-1273 (Moderna) [43], Pfzer-BioNTech [44,47,48], ChA-dOx1 (AstraZeneca) [35,45,50], and BIBP-CorV (Sinopharm) [46]. Te onset of symptoms varied from a few days to several weeks after vaccination, and the MRI fndings showed multiple hyperintense lesions in diferent brain regions and spinal cord on T2-w and FLAIR sequences [43-48, 50, 103]. Another interesting fnding in our review was the presence of MOG antibody-associated disorder (MOGAD) in two cases following COVID-19 vaccination [50,51]. MOGAD is a rare autoimmune demyelinating condition that afects the optic nerves, spinal cord, and brain. In both cases, patients developed neurological symptoms after receiving a COVID-19 vaccine, and their MRI fndings revealed hyperintense lesions in diferent brain regions with MOG-antibody positivity [50,51]. Tis raises the question of whether COVID-19 vaccination can trigger MOGAD in susceptible individuals, which warrants further investigation.
Some of the included studies reported cases of myelitis or TM following COVID-19 vaccination, suggesting a possible association between vaccination and the development of these conditions. For instance, Dams et al. [52] reported a case of MOG-antibody-associated longitudinally extensive transverse myelitis (LTEM) following the ChAdOx1 (AstraZeneca) vaccine. Similar fndings were reported by Sepahvand et al. [53], Miyaue et al. [54], Esechie et al. [55], and Erdem et al. [56] in patients who received the BIBP-CorV (Sinopharm), Pfzer-BioNTech, mRNA-1273 (Moderna), and Sinovac-CoronaVac vaccines, respectively. Tese cases suggest that various COVID-19 vaccines may be associated with the development of myelitis or TM, warranting further investigation to better understand the underlying mechanisms and potential risk factors. ATM was also reported in several cases following COVID-19 vaccination. Hirose et al. [57] and Eom et al. [58] described cases of ATM following mRNA-1273 (Moderna) and Pfzer-BioNTech vaccination, respectively. Alabkal et al. [59] reported a case of TM following the Pfzer-BioNTech vaccine, while Chen et al. [60] described a concurrent vasculitis in vertebral bodies and partial TM in a patient whose vaccine type was not specifed. Tese cases add further evidence to the potential association between COVID-19 vaccination and the development of ATM or TM.
Neuromyelitis optica spectrum disorder (NMOSD) was reported in two cases following COVID-19 vaccination. Chen et al. [62] described a case of NMOSD in a middleaged female following an inactivated virus vaccine, while Umezawa et al. [63] reported a case of NMOSD in a patient with a history of GBS who received the Pfzer-BioNTech vaccine. Tese cases suggest that COVID-19 vaccination might be associated with the development of NMOSD in certain individuals, particularly those with a history of autoimmune or demyelinating disorders. A rare case of vaccine-associated herpes simplex encephalitis was reported by Chen et al. [61] in a patient who received the Pfzer-BioNTech vaccine. Tis fnding highlights the importance of considering the potential for atypical neurological complications following COVID-19 vaccination and underscores the need for further research to better understand the possible underlying mechanisms.
Some studies included demyelinating diseases, GBS, and anti-NMDAR encephalitis. Demyelinating diseases, particularly multiple sclerosis (MS) and clinically isolated demyelinating syndrome, were observed in several cases [65,66]. Te majority of these patients had a history of MS or other demyelinating disorders, suggesting that the COVID-19 vaccination might have induced an exacerbation of the pre-existing condition. Interestingly, the vaccines involved in these cases were mRNA-based (Moderna and Pfzer-BioNTech) and inactivated virus-based (Sinopharm). Tis observation indicates that the potential of inducing or exacerbating demyelinating diseases might not be limited to a specifc vaccine type.
GBS was another neurological condition identifed in post-vaccination CNS MRI fndings [68][69][70][71][72]. GBS is an immune-mediated disorder characterized by rapidly developing muscle weakness and, in some cases, paralysis. Te cases involved patients who received either the ChAdOx1 (AstraZeneca), Pfzer-BioNTech, or Ad26.COV2.S (Janssen) vaccines. Tese results suggest that GBS might be a potential neurological complication of COVID-19 vaccination, although the incidence remains rare. It is worth noting that GBS has been previously associated with other vaccines, including infuenza and other viral vaccines [113,114].
One case reported by Etemadifar et al. [65] described a patient who developed anti-NMDAR encephalitis, an autoimmune disorder, after receiving the Sinopharm BIBP-CorV vaccine. Te patient presented with various symptoms, including myalgia, ataxia, and dizziness, and the MRI fndings revealed multiple new plaques in the periventricular, juxtacortical, and cortical areas. Tis case highlights the potential for post-vaccination neurological complications related to autoimmunity.
Kobayashi et al. [73] reported a case of AE following Pfzer-BioNTech vaccination, presenting with acute-onset diplopia and a lesion on the dorsal pons across the midline on brain MRI. Similarly, Rastogi et al. [74] observed acute encephalopathy in a patient who received ChAdOx1 (AstraZeneca) and mRNA-1273 (Moderna) vaccines, with multiple focal, poorly defned regions of contrast enhancement in the cerebral cortex, deep grey matter, brainstem, and cerebellum on brain MRI. Tese cases suggest that acute encephalopathy may be a potential neurological manifestation of COVID-19 vaccination.
Vences et al. [75,76] reported two cases of AE following COVID-19 vaccination. In the frst case, a patient with DM and HTN developed neurological symptoms after receiving the Pfzer-BioNTech vaccine. MRI revealed hyperintense lesions in various brain regions that evolved between the frst and second doses of the vaccine. In the second case, a patient developed neurological symptoms after receiving the BIBP-CorV (Sinopharm) vaccine. MRI showed small hyperintense non-specifc demyelinating lesions in several brain regions, with some lesions evolving over time. Tese fndings may suggest a possible link between COVID-19 vaccination and the development of acute encephalopathy or demyelinating lesions in some individuals. Zhang et al. [77] described a case of AE following BIBP-CorV (Sinopharm) vaccination, with abnormal signals in the splenium of the corpus callosum on brain MRI. Tis case adds to the growing body of evidence suggesting that COVID-19 vaccination may be associated with various CNS manifestations, although further studies are needed to confrm this association and to understand the underlying mechanisms.
Huang and Huang [78] reported a case of autoimmune encephalopathy following ChAdOx1 (AstraZeneca) vaccination. Te patient presented with acute-onset amnesia, language disturbance, and seizure, and brain MRI revealed a subacute infarction at the right internal capsule and irregular vascular contour. Tis case highlights the potential for autoimmune encephalopathy to occur following COVID-19 vaccination.
Some reviewed studies consistently reported the presence of cytotoxic lesions of the corpus callosum (CLOCCs) following vaccination. Youn and Yang [79] reported a case of a 22-year-old male presenting with febrile sensation and headache around the eyes and forehead after receiving the Pfzer-BioNTech vaccine. Te MRI fndings showed restricted difusion in the corpus callosum, characterized by low ADC values and lack of contrast-mediated enhancement. Similar fndings were observed by Poussaint et al. [80], who described a 12-year-old male with Lyme disease experiencing severe headache and visual hallucinations following vaccination. In this case, the MRI revealed T2-w prolongation and lower difusivity in the splenium of the corpus callosum.
Procaccini et al. [81] described a 51-year-old woman who presented with fever, weakness, headache, palpitations, malaise, and AMS after receiving the Pfzer-BioNTech vaccine. MRI fndings revealed a single oval-shaped lesion located in the splenium of the corpus callosum with hyperintense signal on T2-w and FLAIR, as well as restricted difusivity on DWI. Interestingly, this study also provided follow-up MRI data, which showed complete resolution of the lesion in the splenium after 17 days and the persistence of small round-shaped WM hyperintensities on T2-w and FLAIR after 67 days. Lastly, Ohara et al. [82] reported two cases of CLOCCs in patients with diferent medical histories after receiving the Pfzer-BioNTech vaccine. Both patients exhibited similar MRI features, including restricted difusion in the splenium with low ADC values and high signal intensity lesions on FLAIR images. All the CLOCC cases reviewed here involved the Pfzer-BioNTech vaccine, and further research is needed to determine whether similar MRI fndings occur following other COVID-19 vaccines.
CNS-related events, such as ischemic stroke, spinal cord ischemia, acute hemorrhagic encephalomyelitis (AHEM), intracerebral bleeding, and others, were reported. Blauenfeldt et al. [83] described a case of acute ischemic stroke in a 60-year-old woman with a history of Hashimoto's thyroiditis and HTN following the ChAdOx1 (AstraZeneca) vaccine. Similarly, Elaidouni et al. [84] reported a case of acute ischemic stroke in a 36-year-old man after receiving the BIBP-CorV (Sinopharm) vaccine. In both cases, the patients presented with neurological symptoms, such as headache, numbness, and weakness, and their brain MRI fndings confrmed the presence of ischemic stroke.
Cases of prolonged migraine aura resembling ischemic stroke have also been reported following the Sinovac-CoronaVac vaccine [85,86]. Both patients were young females (24 years old) with neurological symptoms, including visual disturbance, tingling, and numbness. Brain MRA fndings in both cases revealed mild irregularities of the intracranial arteries. Yoshida et al. [87] reported a case of cardioembolic stroke in an 83-year-old woman with atrial fbrillation and osteoarthritis following the Pfzer-BioNTech vaccine. Te patient experienced left hemiplegia and left hemispatial neglect, and brain MRI fndings showed acute infarction in the left insular cortex and corona radiates, as well as occlusion of the left middle cerebral artery (MCA). After the second dose of the vaccine, the patient developed another ischemic stroke, with acute infarction in the right insular cortex, caudate, and corona radiate, and occlusion of the right MCA. Spinal cord ischemia was reported by Fotiadou et al. [88] in a 59-year-old man following the Pfzer-BioNTech vaccine. Te patient presented with right lower limb weakness, abdominal pain, and paraplegia. Spine MRI fndings revealed T2-w hyperintensities extending from the T6 level to the conus medullaris and bilaterally symmetric circular high signal foci in the anterior horn cells of the spinal cord.
AHEM has been described in three cases following the ChAdOx1 (AstraZeneca) vaccine [89]. Te patients exhibited various neurological symptoms, including fever, headache, seizures, back pain, weakness, nausea, and dizziness. Brain and spine MRI fndings in these cases showed FLAIR hyperintense lesions with hemorrhagic involvement in diferent regions of the CNS, such as the basal ganglia, WM, and spinal cord. Kits et al. [90] reported a case of AHEM in a 53-year-old man with rheumatoid arthritis following the Pfzer-BioNTech vaccine. Te patient presented with confusion, unconsciousness, agitation, and snoring. Brain MRI fndings showed multiple cortical and subcortical lesions with high T2-w and FLAIR signal and ubiquitous petechial hemorrhages. Repeated MRI demonstrated the development of widespread lesions in various CNS regions and cortical laminar necrosis. Lastly, Finsterer and Korn [91] reported a case of intracerebral bleeding in a 52-year-old man with a history of myocardial infarction, hypertension, hyperlipidemia (HLP), and nephrolithiasis following an mRNA-based SARS-CoV-2 vaccine. Te patient experienced sudden-onset difculties with reading and speaking (aphasia), and cerebral MRI fndings showed intracerebral bleeding in the left temporal lobe.
We observed a wide range of neurological manifestations following COVID-19 vaccination in the included studies. Tese manifestations included optic neuropathy [93], infammatory demyelinating polyneuropathy [94], acute small fber neuropathy [95], unilateral multiple cranial neuropathy [96], cranial nerve palsies [97], Bell's palsy [98], ischemic stroke [99], and polyneuritis cranialis [100]. Te onset symptoms varied across studies but commonly involved pain, sensory changes, and motor defcits. In the majority of the cases, the reported MRI fndings were consistent with the clinical presentation of the patients. For example, Elnahry et al. [93] reported signifcant enhancement of the left optic nerve in a patient with optic neuropathy, while Bagella et al. [94] found enhancement of the facial nerves and cauda equina in a patient with infammatory demyelinating polyneuropathy. Similarly, other studies reported abnormal enhancement of cranial nerves in patients presenting with cranial neuropathies [96][97][98]100] or ischemic lesions in a patient with ischemic stroke [99]. In some cases, the MRI fndings were less specifc or incidental, such as the multiple perineural cysts found in a patient with acute small fber neuropathy [95].
Finally, in recent literature, there have been several case reports describing concerns about potential neurological complications [101][102][103][104][105][107][108][109]. Tese fndings include cerebral infarctions [101], demyelinating diseases [102][103][104], hemorrhagic events [105], and infections [107], among others. While these case reports suggest a potential association between COVID-19 vaccination and neurological complications, it is important to note that the rarity of these events and the presence of confounding factors, such as preexisting medical conditions, necessitate further investigation to establish causality. Te development of multi-systemic infammatory syndromes and the exacerbation of hereditary neuropathies after COVID-19 vaccination have also been reported in the literature [107,109]. Recent case reports have documented a variety of CNS MRI fndings following COVID-19 vaccination, raising questions about potential neurological complications [101][102][103][104][105][107][108][109]. Tese fndings encompass cerebrovascular events, demyelinating processes, hemorrhagic events, infections, and infammatory processes, among others. While these cases suggest a potential association between COVID-19 vaccination and neurological complications, it is crucial to consider that the rarity of these events and the presence of confounding factors, such as pre-existing medical conditions, require additional research to establish causality.
In sum, one of the important frameworks is the World Health Organization (WHO) causality assessment framework for adverse events following immunization (AEFI). Te WHO has developed protocols and algorithms to determine the causality relationship between vaccine administration and AEFI in a standardized manner. Tese protocols consider factors such as the temporal relationship between vaccination and the event, alternative explanations, past medical history, laboratory tests, and outcomes upon rechallenge. By following the WHO framework, researchers can evaluate the likelihood of a true causal association between vaccination and AEFI on a six-point scale from "very likely" to "unlikely." Implementing the WHO causality assessment framework would strengthen future studies examining post-COVID-19 vaccination CNS MRI fndings. First, it allows for objective and standardized determinations of causality that can be compared across studies. Second, it facilitates the detection of possible safety signals by distinguishing events that are very likely or likely due to vaccination from those that are indeterminate or unlikely to be causally related. Tird, for events categorized as very likely or likely due to vaccination, the WHO framework guides the recommendation of further epidemiological study to confrm or refute the signal [115,116].
However, limited data and lack of control groups in the included case reports and case series in this review highlight the challenges of conducting a full WHO causality assessment. Large, rigorous epidemiological studies on events that appear potentially related to vaccination based on existing cases are needed to enable comprehensive causality determinations. While case reports play an important role in initial signal detection, controlled observational studies and randomized trials remain the gold standard evidence required for policy decision making regarding vaccine safety.

Conclusion
Tese fndings highlight the importance of MRI as a diagnostic tool in identifying potential neurological complications following COVID-19 vaccination. It is important to note that the incidence of these neurological complications is extremely rare and the overall benefts of COVID-19 vaccination in preventing severe illness and death far outweigh the risks. It is important to note that the reviewed studies were case reports or case series, and the number of reported cases with post-vaccination CNS MRI fndings is relatively small compared to the millions of COVID-19 vaccine doses administered worldwide. Terefore, the incidence of these neurological complications following COVID-19 vaccination remains unclear. Comprehensive and systematic investigations, including large-scale epidemiological studies and controlled clinical trials, are crucial to understanding the underlying mechanisms and risk factors associated with these neurological complications and informing public health recommendations.

Data Availability
Te data used to support the fndings of this study are included within the article. Any further inquiries should be forwarded to the corresponding author.