Central nervous system immune-related disorders after SARS-CoV-2 vaccination: a multicenter study

Abstract

Background: COVID-19 vaccines have been approved due to their excellent safety and efficacy data and their use has also permitted to reduce neurological complications of SARS-CoV-2. However, clinical trials were underpowered to detect rare adverse events. Herein, the aim was to characterize the clinical spectrum and immunological features of central nervous system (CNS) immune-related events following SARS-CoV-2 vaccination.

Methods: Multicenter, retrospective, cohort study (December 1, 2020-April 30, 2022). Inclusion criteria were (1) de novo CNS disorders developing after SARS-CoV-2 vaccination (probable causal relationship as per 2021 Butler criteria) (2); evidence for an immune-mediated etiology, as per (i) 2016 Graus criteria for autoimmune encephalitis (AE); (ii) 2015 Wingerchuk criteria for neuromyelitis optica spectrum disorders; (iii) criteria for myelitis.

Results: Nineteen patients were included from 7 tertiary referral hospitals across Italy and France (one of them being a national referral center for AE), over almost 1 year and half of vaccination campaign. Vaccines administered were mRNA-based (63%) and adenovirus-vectored (37%). The median time between vaccination and symptoms onset was 14 days (range: 2-41 days). CSF was inflammatory in 74%; autoantibodies were detected in 5%. CSF cytokine analysis (n=3) revealed increased CXCL-10 (IP-10), suggesting robust T-cell activation. The patients had AE (58%), myelitis (21%), acute disseminated encephalomyelitis (ADEM) (16%), and brainstem encephalitis (5%). All patients but 2 received immunomodulatory treatment. At last follow-up (median 130 days; range: 32-540), only one patient (5%) had a mRS>2.

Conclusion: CNS adverse events of COVID-19 vaccination appear to be very rare even at reference centers and consist mostly of antibody-negative AE, myelitis, and ADEM developing approximately 2 weeks after vaccination. Most patients improve following immunomodulatory treatment.

Keywords: COVID-19; SARS-CoV-2; neurologic adverse events; neurological complications; vaccination; vaccine.

Figure 1

Cerebrospinal fluid cytokine levels in patients with CNS immune-mediated disorders after SARS-CoV-2 vaccination The CSF samples of 3 patients developing CNS disorders after SARS-CoV-2 vaccination were analyzed. Data refer to Case #1 (AE), Case #2 (ADEM) and Case #7 (AE). All samples were taken during the acute stage (first admission to the hospital, before immunotherapy administration). Dashed lines = reference values.

Figure 2

Neuroimaging findings in patients with CNS immune-mediated disorders after SARS-CoV-2 vaccination Autoimmune encephalitis phenotype (Case #7): axial fluid-attenuated inversion recovery (FLAIR) (A, B), turbo spin echo (TSE) T2 weighted (C, D), diffusion weighted (E, F) and Vibe T1 weighted after gadolinium administration (G, H) showing two different continuous lesions with restricted diffusion and patchy enhancement involving the left hippocampus and splenium of the corpus callosum. Myelitis phenotype (Case #4): sagittal short tau inversion recovery (STIR) (I), TSE T2 weighted (J), diffusion weighted (K) sequences and axial TSE T2 weighted (L, M) sequences of the cervical and upper thoracic spine showing a hyperintense cord lesion that extends over four contiguous vertebral segments. The lesion is characterized by restricted diffusion and involves the dorsal columns of the spinal cord. Acute disseminated encephalomyelitis (ADEM) phenotype (Case #2): coronal (N) and axial FLAIR (O), axial TSE T2 weighted (P) and diffusion weighted imaging (Q) sequences showing two different hyperintense lesions also with restricted diffusion (Q) involving the left superior cerebellar peduncle and white matter of centrum semiovale.

Figure 3

Electroencephalography findings in patients with CNS immune-mediated disorders after SARS-CoV-2 vaccination Electroencephalography (EEG) findings in two representative patients with autoimmune encephalitis ensuing after SARS-CoV-2 vaccination. Case #1: intermittent diffuse slowing (delta activity) was present at onset. During hospital stay, EEG slowing persisted mostly on the anterior (frontal) regions. At last follow-up, the patient had a normal EEG examination and clinically recovered. Case #19: mild slowing (theta activity) was present at onset, mostly over the left temporal region. During hospital stay, epileptic discharges (spike and wave complexes) were present over the left temporal region and the patient experienced focal (temporal) seizures. At last follow-up, the patient had a normal EEG examination but was still treated with antiseizure medications due to the persistence of focal seizures.