Sir,

Adverse events following immunization (AEFI) with the adenovector viral (AVV) ChAdOx1 vaccine (AZD1222) (AstraZeneca) are rare and include the thrombocytopenia with thrombosis syndrome (TTS) and Guillain-Barré syndrome [1, 2]. Only one series of post-vaccinal encephalitis after ChAdOx1 vaccination has been reported [3].

We report a series of seronegative autoimmune central nervous system (CNS) AEFI following ChAdOx1 (AstraZeneca) vaccination. CSFA acute encephalitis panel, serum paraneoplastic antibodies, serum, and CSF autoimmune encephalitis panel, NMDA and VGKC antibodies (Eurommun AG, immunofluorescence (IFA) assay) were performed in all cases.

Case 1

A 64-year-old man presented with 2 days’ history of fever and drowsiness 10 days after the first dose of ChAdOX1 vaccination. MRI brain showed features of limbic encephalitis and middle cerebellar peduncle hyperintensities (Fig. 1, panels A and B). CSF showed lymphocytic pleocytosis. Elevated systemic inflammatory markers were noted (ESR, CRP, d-dimer, ferritin). Post-vaccination seronegative limbic encephalitis was considered, and IV methylprednisolone 1 g/day × 5 days and plasmapheresis were initiated. Eight weeks after vaccination, 1 g rituximab was administered, and he was discharged without deficits.

Fig. 1
figure 1

A FLAIR hyperintensities in the mesial temporal lobe. B FLAIR hyperintensities in both middle cerebellar peduncles (left > right). C T2-weighted MRI hyperintensities extending from the perirolandic cortex along the corona radiata, via the corticospinal tracts. D T2-weighted sagittal spine MRI images showing a D9–10 short segment linear hyperintensity. E, F Axial FLAIR and post-contrast T1-weighted images showing right temporal lobe edema and an irregular contrast enhancing lesion (white arrows)

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Case 2

A 65-year-old man developed behavioral changes 10 days after the 2nd dose of ChAdOX1 vaccination. Over the next 3 weeks, he developed jerky movements. Examination revealed an opsoclonus myoclonus ataxia syndrome (OMAS). CSF showed mild pleocytosis (TC 10 cells). A diagnosis of post-vaccination OMAS was considered, and he was started on IVIg and IVMP 1 g/day × 5 days, with remarkable improvement.

Case 3

A 64-year-old man started developing ascending paresthesias in the legs which progressed up to an epigastric band-like sensation, leg stiffness, and hand paresthesias. These started 20 days after the 2nd dose of ChAdOX1 vaccine. On examination, he had a brisk jaw jerk, spastic quadriparesis with grade 3/5 power in the upper limbs, grade 0/5 power in the lower limbs, and loss of posterior column sensations till the T6 level. MRI showed multifocal cord hyperintensities and bilateral hemispheric corticospinal tract hyperintensities (Fig. 1, panel C). He improved to grade 4/5 motor strength in the upper and lower limbs after 5 days of IVIg and IVMP. Post-vaccination acute disseminated encephalomyelitis (ADEM) was considered. At 1 month, he was administered rituximab 1 g IV and continued to improve. A repeat MRI at 1 month showed stabilization of the lesions and no new contrast enhancement.

Case 4

A 46-year-old man presented with urinary complaints, progressive lower limb weakness (grade 0/5 MRC score), and numbness 4 days after his first dose of ChAdOX1 vaccination. MRI brain and spine showed extensive supratentorial, infratentorial, and long segment spinal cord hyperintensities (Fig. 1, panel D). Thrombocytopenia and increased LDH were noted (Table 1). He received a 2nd course of IVMP followed by plasma exchange, after which he improved significantly and was able to ambulate independently. Post-vaccination ADEM was considered.

Table 1 Clinical and laboratory parameters of our cases
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Case 5

A 42-year-old woman started developing severe daily headache and photophobia, 5 days after the 1st dose of ChAdOX1 vaccination. On examination, she had papilledema. The CSF opening pressure was elevated, but other parameters were normal (Table 1). As a contrast MRI showed leptomeningeal enhancement, a seronegative autoimmune meningeal process was suspected and oral steroids were administered for 15 days. She recovered and steroids were stopped. Two days later, her headache recurred. An MRI on day 25 showed a large irregular right temporal lobe enhancing lesion (Fig. 1, panels E and F). Brain biopsy was suggestive of tumefactive demyelination. Her headache remitted spontaneously after the excision biopsy.

We describe seronegative autoimmune CNS AEFI following ChAdOX1 vaccination, which included post-vaccination encephalitis (PVE) and post-vaccination ADEM (PV-ADEM). One of our cases satisfied a level 1 Brighton criterion level 1, and four other cases reached level 2 of diagnostic certainty for post-vaccination AEFI [4].

Our cases occurred within 20 days (range 5–20 days) after vaccination. All patients showed a response to immunosuppressive therapy or spontaneous resolution, and 80% had imaging findings suggestive of inflammatory CNS demyelination. As of November 19, 2021, over 1.15 billion doses of ChAdOx1 had been administered in India [5]. In two districts of Kerala, where our cases were detected, over 9.1 million doses had been administered, of which more than 90% were the ChAdOx1 vaccine (8.19 million).

To understand the impact of these AEFI, the incidence of community-acquired encephalitis (CAE) and community-acquired ADEM (c-ADEM) can be compared with that of PVE and PV-ADEM. The crude annual incidence of CAE in India is 8.35–10 per million, and the worldwide crude annual incidence of c-ADEM is 3.2–4 per million (Indian data is lacking) [6].

Comparatively, the incidence of PVE is estimated at 0.4–0.8 per million doses after ChAdOX1 vaccination and 0.2 per million with the mRNA vaccine (BNT162b2) [3, 7]. Our population showed a calculated crude incidence of PVE of ~ 0.24 cases per million (2 cases per 8.19 million vaccinees), similar to that for mRNA vaccines.

PV-ADEM has not yet been reported; however, our cohort had a calculated crude incidence of 0.36 cases per million (3 cases per 8.19 million vaccinees).

The incidence of post-vaccination CNS AEFI (PVE and PV-ADEM) was 10–20-fold less than the incidence of CAE and c-ADEM. While this emphasizes the safety of ChAdOX1 vaccination, it is important to recognize these syndromes early, to initiate appropriate immunosuppressive therapy. Delayed recognition of these CNS AEFI may lead to a futile search for other etiologies and increased morbidity.