Autoimmune seronegative limbic encephalitis following ChAdOx1‐S/nCoV‐19 vaccination in a patient with ankylosing spondylitis

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Autoimmune LE after vaccination against COVID‐19 is a rare entity, and its incidence has yet to be defined in the current literature. Here we describe the case of a 59‐year‐old male who presented with acute confusional syndrome and amnesia. He had ankylosing spondylitis but no other previous neurological history. He reported first dosage of vaccination was with the adenovector viral ChAdOx1‐S/nCoV‐19 vaccine (AZD1222; AstraZeneca) 15 days before symptom onset, which is a recombinant replication‐deficient adenoviral vector vaccine against coronavirus disease (COVID‐19), which expresses the SARS‐CoV‐2 spike protein gene, and generates an immune response retaining information in the memory immune cells. No other concurrent triggers such as infection or medication changes were identified. He also had no history of exposure to any patient with COVID‐19 infection.

He was completely healthy until 2 days before admission. At neurologic evaluation he was disoriented with no focal or lateralizing signs. The MMSE score was 23. The emergency laboratory tests including blood gases, complete blood count, sedimentation, liver and kidney functions, electrolytes, CRP, nasopharyngeal swab PCR and rapid SARS‐CoV‐2 antigen test were negative. Thyroid functions were within normal limits. Thyroid peroxidase and thyroglobulin antibodies were also negative.

The Electroencephalogram was normal. A Magnetic resonance imaging (MRI) of the brain including diffusion‐weighted MRI together with apparent diffusion coefficient scans did not reveal any acute ischemic lesions on the day of admisson. The repeated MRI images of the following day were nonspecific. Lumbar puncture showed cerebrospinal fluid (CSF) with normal protein and cytology and it was also negative for the presence of neoplastic cells. The search for viral panel on CSF was negative (including Enterovirus, Herpes simplex 1 and 2, Human herpesvirus 6, Human parechovirus, Cytomegalovirus, Varicella zoster virus, Adenovirus). Furthermore, a panel of antibodies related to autoimmune and paraneoplastic encephalitis was negative in plasma and CSF (e.g., anti GAD, AMPA1, AMPA2, CASPR2, NMDAr, GABA B1, GluR3 A/B, Caspr 2, anti‐Hu, anti‐Yo, anti‐Ri, anti‐Ma‐1, anti‐Ma‐2, anti‐CV2 [CRMP‐5], anti‐Amphiphysin, anti‐Zic‐4, anti‐Sox 1, anti‐Tr, anti‐GAD, and anti‐DPPX). HIV and treponemal serology testing were negative.

The differential diagnosis of metabolic encephalopathies, viral encephalitis, cerebral venous sinus thrombosis, arterial infarction or hemorrhage and nonconvulsive status epilepticus were ruled out with these investigations. The patient improved completely after 5‐day pulse intravenous methylprednisolone and the MMSE scores improved rapidly from 23 to 30.

In a recent single‐centre prospective case series evaluating neurological autoimmune diseases following vaccinations against SARS‐CoV‐2 one case of limbic encephalitis (LE) was reported. ¹ In another study from India, 5 cases of autoimmune CNS adverse events and one case of LE were reported. ² A recent interesting case of prion‐like rapidly progressive dementia with asymmetric rigidity and akinetic mutism was also reported from India. ³

Patients with autoimmune diseases were excluded from the initial vaccine clinical trials. ⁴ In previous studies it was postulated that vaccines containing SARS‐CoV‐2 antigens may enhance autoimmunity by polyclonal or bystander activation, epitope spreading or molecular mimicry. Alternatively, the inflammatory stimulus posed by vaccination may unmask existing or asymptomatic autoimmunity in predisposed patients, by driving pre‐existing autoimmune pathways similar to immune related adverse events following the administration of immune checkpoint inhibitors. ⁵ , ⁶ Another proposed mechanism is the cross reaction of human anti‐SARS‐Cov‐2 spike protein antibody with neurofilament protein, mitochondrial antigen GAD‐65 and nuclear antigens which are the targets in neural tissues. ⁷

LE was also reported during asymptomatic infection or mild infection without respiratory disease. According to a recent cohort study providing data on the neurological symptoms of hospitalized COVID‐19 patients, nine cases of LE were reported, suggesting an immune‐mediated response and the release of proinflammatory cytokines. ⁸

The presented case had pre‐existing ankylosing spondylitis. According to a cohort study by Kaur et al. ⁹ including health care workers with a history of COVID‐19 vaccination, persisting health issues were more common among those with immune‐mediated inflammatory arthritis.

The spectrum of autoimmune LE is very broad including many different mechanisms and conditions. Although a temporal link existed between the vaccination and disease onset in the presented case, definite causal association needs to be confirmed further in larger prospective clinical studies. Factors like a previous autoimmune condition, possible exacerbations of the primary disease or possible severe SARS‐CoV‐2 during primary infection should be considered while evaluating the benefit‐risk ratio of vaccines.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

ETHICS STATEMENT

Informed consent was taken from the patient.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.