Despite the unknown causal relationship, several studies have reported that the first manifestation or relapse of multiple sclerosis (MS) is temporally associated with coronavirus disease 2019 (COVID-19) vaccination or infection.12345678910111213141516 Recently, we encountered an autopsy case of a young Korean male with undiagnosed MS of which possible flare-ups were preceded by both COVID-19 vaccination and infection. Herein, we present the detailed clinical and histopathological findings of an autopsy case and review the literature.

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On the morning of March 22, 2022, a 19-year-old male soldier was found dead in the barrack. The body was located in a sleeping bag under the bed. The deceased’s posture was supine, with his head slightly turned to the right and his right arm raised. The sleeping bag was wet with urine. During the last few days before his sudden death, he had been suffering from left finger numbness at night and because of this, he asked his company commander for exemption from night duty. One day before the sudden death, the deceased said to his colleague “I cannot sleep well these days and I feel like I'm having a seizure at night.”

The medical history of the deceased is summarized in Fig. 1. About 4 years before death, he had been diagnosed with unilateral ON. Demyelinating disease was suspected in the brain magnetic resonance imaging (MRI), but he was lost to further follow up after his vision recovered. Six months before death, he had received the second dose of the COVID-19 vaccine (Pfizer-BioNTech), and 3 months later, he started experiencing epileptic seizures during sleep and was admitted to an outside hospital. Since the first seizure, he presented with 5 more generalized tonic-clonic seizures within a week. Besides seizures, he presented with no other symptoms or signs of meningeal irritation. Cerebrospinal fluid (CSF) analysis including culture and viral polymerase chain reaction revealed no abnormalities except for mild pleocytosis. Oligoclonal band and aquaporin-4 antibodies were not detected in the CSF and serum. Brain MRI performed 1 day after the seizure revealed T2 hyperintensities in the periventricular region, subcortical white matter, and left basal ganglia, raising a suspicion of demyelinating disorder, and leptomeningeal enhancement of cerebral convexities. Additional brain MRI performed 8 days after the first seizure revealed diffuse dural thickening and venous sinus engorgement with focal cortical venous thrombosis, which were suggestive of cerebral venous thrombosis (CVT) due to intracranial hypotension. Under the clinical impression of epilepsy, meningoencephalitis and focal cortical venous thrombosis, he was treated with empirical antiviral/antibiotic medications, anticonvulsant and anticoagulant for 3 weeks and was discharged after symptom improvement. Seizures seemed to be controlled with medication management. During regular follow-up, he suffered Stevens-Johnson syndrome (SJS). As a cause, an anticonvulsant (lamotrigine) was suspected and replaced with lacosamide. No recurrence of epileptic seizure was observed after the change of anticonvulsant. Seventeen days before his death, he developed a sore throat without fever, and tested positive for COVID-19 while he was on leave, being with his family. Eight days before his death, he returned to duty after conservative follow-up on home isolation. Additional brain MRI was not performed during this follow-up period.

An autopsy was conducted 1 day after death. External examination revealed diffuse dyschromic macules on trunk and limbs which were suspected to be old sequelae of SJS. Teeth imprints on both ventral and dorsal sides of the tongue were present. The brain weighed 1,550 g (age-matched normal value: 1,450 ± 20 g) and showed no gross abnormalities, including hemorrhage or meningitis. No intravascular or venous sinus thrombi were identified. Coronal sections of the brain showed multifocal, relatively well-circumscribed, gray-tan, irregular-shaped discoloration in the periventricular areas, cerebral deep white matter (frontal, parietal, and temporal lobes), internal capsule, and corpus callosum (Fig. 2). Cerebellum and brainstem were grossly unremarkable. Histologically, multifocal white matter lesions exhibited loss of myelin with Luxol fast blue and relatively preserved neuropils by immunostaining for phosphorylated neurofilaments, consistent with demyelinated plaques (Figs. 3 and 4). Active plaques characterized by abundant myelin-containing macrophages and perivenous lymphocytic infiltrates were mostly identified in the cerebral white matter and internal capsule. Inactive plaques characterized by reactive gliosis, sharply demarcated demyelination, and virtually no macrophages were mainly located in the periventricular areas, optic nerve, and corpus callosum. Microglial cell proliferation was noted in the peri-plaque and distant normal-appearing cerebral cortex and white matter. Perivascular lymphocytic cuffing in the parenchyma was frequently observed, and immunostaining for CD20, CD4, and CD8 demonstrated a mixed population of B- and T-lymphocytes, with CD8+ T-lymphocytes predominance. Additionally, multifocal lymphocytic infiltration was observed in the subarachnoid space of the cerebrum and was associated with subpial cortical band-like vacuolation, which was suspected to be cortical demyelination. Demyelinated plaques were not observed in cerebellum and brainstem. The other major organs including heart and lungs were unremarkable in both macroscopic and microscopic examination.

Toxicological examination revealed positive results for anticonvulsant (lacosamide) and anticoagulant (warfarin) within the therapeutic range.

Based on autopsy, histologic, and toxicological findings and medical records, the cause of death was determined to be MS with suspected exacerbation.

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The pathological hallmark of MS is spatially and temporally disseminated inflammatory demyelinating lesions in the central nervous system (CNS).1718 Although there is no single definite diagnostic test for MS, identification of the typical clinical presentations supported by MRI findings and CSF analysis can lead to an early and accurate diagnosis of MS.1819 However, in cases of atypical clinical presentation, the diagnosis of MS can be challenging.

ON is the initial manifestation in approximately one-fifth of patients with MS and may occur at least once in approximately half of them.20 ON with “typical” features tend to show unilateral involvement, spontaneous visual recovery within a month, favorable prognosis, and no deterioration after steroid withdrawal. The presence of white matter lesions found on T2-weighted brain MRI, even in asymptomatic patients, was strongly associated with an MS diagnosis in patients with ON.181921 Four years before death, the deceased had a history of unilateral ON and the brain MRI revealed T2 hyperintense lesions in the periventricular white matter at that time. Therefore, ON might have been the first manifestation of MS.

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the CNS that may occur in young adults after viral infection or vaccination, which is the most important differential diagnosis in this case.17 Multiple demyelinated plaques centered on venules and inflammatory infiltrates including myelin-laden macrophages are supportive findings for ADEM. However, the presence of demyelinated plaques of different stages supports the diagnosis of MS, while ADEM is a monophasic inflammatory demyelinating process.

In addition to the MS lesion, brain MRI after his first seizure attack revealed slight leptomeningeal enhancement, which was suspected to be meningoencephalitis. As both acute meningoencephalitis and its long-term sequelae can induce epileptic seizures, the brain was thoroughly examined during autopsy for meningoencephalitis; however, leptomeninges were grossly unremarkable. Histologically, multifocal lymphocytic infiltration of the subarachnoid space, and perivascular lymphocytic cuffing in the parenchyma were identified, which can be seen in meningoencephalitis; however, typical pathological findings of viral encephalitis including microglial nodules and neuronophagia were absent. In fact, lymphocytic meningitis is another feature of particularly active MS.

An increased frequency of seizures has been noted in patients with MS. Clinically, the occurrence of epileptic seizures in MS does not correlate with the disease duration or severity.22 Although the underlying pathological mechanism of seizures in MS remain unelucidated, advanced imaging techniques suggest that cortical lesions are responsible for epileptogenesis.22 Multifocal leptomeningeal lymphocytic infiltration with subpial vacuolation in this case suggests cortical demyelination; however, confirmation by immunohistochemistry for myelin basic protein was not available. Whenever exacerbated, MS may have resulted in recurrent seizures via either inflammatory infiltration or suspected cortical demyelination.

Increased risk of epileptic seizure following CVT has been noted.23 However, in this case, the onset of seizure preceded the identification of CVT via brain MRI. A few cases of CVT without thrombocytopenia after receiving the COVID-19 mRNA vaccine have been reported although most post-vaccination thrombotic events occurred after the administration of viral vector-based vaccines, and an alternative explanation of the thrombotic event such as intracranial hypotension should be considered in this case.2425

The deceased’s death occurred unexpectedly in the benign circumstances. The deceased had a history of epilepsy, and the occurrence of terminal epileptic seizure is suspected, although his death was unwitnessed. No other structural abnormality except MS with suspected exacerbation is identified in the autopsy. From a forensic pathologist’s perspective, seizure in MS does matter because sudden unexpected death in epilepsy (SUDEP) is one of the most important direct causes of death in epilepsy patients.26 SUDEP is a heterogeneous category of death with many possible explanations for death including fatal arrhythmia or laryngospasm.27 Additionally, the occurrence of status epilepticus, an exclusion criterion for SUDEP, would be another possible explanation for his death. Suffocation due to positional impediment seems less likely considering the given situational information.28

Infection has long been recognized as etiologic factor for MS.29 Vaccines are designed to stimulate immune response against pathogen, but occasionally trigger autoimmune response. Since the COVID-19 pandemic, several cases of MS temporally associated with COVID-19 vaccination have been published. Cases reporting the first manifestation or relapse of MS after COVID-19 vaccination or infection are listed in Tables 1 and 2, respectively. Neither epileptic seizure as a symptom nor death as a clinical outcome has been documented in the previous reports. In this case, the initial onset of epileptic seizure is 96 days after the second dose of mRNA vaccination. Multifocal active demyelinated plaques may explain the onset of seizure and would be a manifestation of MS flare-up. Thus, relatively longer duration than previous reports would not completely exclude the possible causality between the vaccination and MS flare-up. Additionally, the deceased tested positive for COVID-19, 176 days after the second dose of the vaccine, and that is where “vaccine-induced immunity” could come in. Deterioration of previously well-controlled seizure might be another MS flare-up which occurred 17 days after the possible activation of vaccine-induced immunity.

The underlying pathogenic mechanism of the flare-up of MS after COVID-19 vaccination or infection remains unclear due to small number of reported cases. Both COVID-19 vaccination and infection can induce certain immune responses and may consequently trigger the exacerbation of the preexisting MS. In addition, vaccination against COVID-19 and infection may cause rise in core body temperature for some time, which may modify the structural and physiologic conditions of the demyelinated axons of the CNS, leading to worsening of the neurological function of the MS patient. Further studies with larger cohort on the effect of COVID-19 infection and vaccines on MS pathology are needed.

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