Neuronal-surface antibodies are uncommon in patients with a final diagnosis of sporadic Creutzfeldt-Jakob disease: a systematic review and meta-analysis

Abstract

Neuronal antibodies detected during evaluation of rapidly progressive dementia may indicate treatable autoimmune encephalitis or incidental seroreactivity in prion disease. We estimated their frequency in sporadic Creutzfeldt-Jakob disease (sCJD), separately from diagnostic yield in suspected CJD. Under a registered protocol (PROSPERO CRD420261458659), MEDLINE/PubMed, Embase and CENTRAL were searched on 12 July 2026 and with expanded antibody terms on 13 September 2026. Screening, extraction and JBI appraisal were performed independently in duplicate with third-reviewer adjudication. The primary outcome was neuronal-surface/synaptic antibody positivity in datasets with standardized testing. We report the aggregate proportion with an exact 95% confidence interval and model-based summaries from logistic-normal GLMM and beta-binomial models, which estimate different quantities. Forty-three reports were retained, including six independent datasets with 241 tested patients. All four low-level positives arose in one cohort: aggregate 4/241 (1.66%; 95% CI 0.45–4.19), GLMM 0.36% (lower bound <0.01%, upper bound 3.38%), and beta-binomial 1.21% (0.07–19.67). Restricting positivity to an identified neuronal-surface antigen gave 3/241 (1.24%; 0.26–3.59). Excluding two datasets at high risk of bias gave 4/154 (2.60%; 0.71–6.52); excluding the dataset with inseparable diagnostic-certainty groups gave 4/220 (1.82%; 0.50–4.59). No antibody was detected in 51 pathologically confirmed patients with directly linkable testing results from two non-overlapping datasets (0/51; exact upper 95% bound 7.0%). This selected subset does not encompass all pathologically confirmed patients or exclude antibody positivity in confirmed disease. Neuronal-surface antibodies were uncommon on the assays used, but estimates depend on antibody definition, denominator composition and model assumptions. Frequency in sCJD does not establish the probability of autoimmune disease after a positive antibody result. Interpretation requires the antibody identity, specimen, assay confirmation, phenotype and strength of prion evidence; autoimmune encephalitis and sCJD can coexist. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261458659 , identifier CRD420261458659.