Validation of a risk score to differentiate autoimmune and viral encephalitis: a Nationwide Cohort Study in Denmark

Abstract

Background: A score to differentiate autoimmune (AE) and viral encephalitis (VE) early upon admission has recently been developed but needed external validation. The objective of this study was to evaluate the performance of the score in a larger and more diagnostically diverse patient cohort.

Methods: We conducted a retrospective nationwide and population-based cohort study including all adults with encephalitis of definite viral (2015-2022) or autoimmune aetiology (2009-2022) in Denmark. Variables included in the score-model were extracted from patient records and individual risk scores were assessed. The performance of the score was assessed by receiver-operating characteristics (ROC) curve analyses and calculation of the area under the curve (AUC).

Results: A total of 496 patients with encephalitis [AE n = 90, VE n = 287 and presumed infectious encephalitis (PIE) n = 119] were included in the study. The score was highly accurate in predicting cases of AE reaching an AUC of 0.94 (95% CI 0.92-0.97). Having a score ≥ 3 predicted AE with a PPV of 87% and an NPV of 91%. The risk score was found to perform well across aetiological subgroups and applied to the PIE cohort resulted in an AUC of 0.88 (95% CI 0.84-0.93).

Conclusion: The excellent performance of the score as reported in the development study was confirmed in this significantly larger and more diverse cohort of patients with encephalitis in Denmark. These results should prompt further prospective testing with wider inclusion criteria.

Keywords: Autoimmune encephalitis; Encephalitis; Risk score; Validation; Viral encephalitis.

Fig. 1

Flow diagram of the inclusion process

Fig. 2

Bar charts comparing median score values and interquartile ranges of the AE and VE cohorts. A Compares the median score values between the AE and the VE cohort and B depicts the median score values by aetiological subgroups of the AE (light gray) and VE (dark gray), with fill patterns indicating individual diagnosis

Fig. 3

Receiver operating characteristics (ROC) curves and area under the curve (AUC) for the performance of the risk score to differentiate the AE from the VE cohort (A) and ROC curves for the comparison of the score performance for each of the different viral aetiological subgroups (B) as well as for each of the different autoimmune aetiological subgroups (C)

Fig. 4

Bar chart comparing the score distribution in the AE and the VE cohorts by accumulated score values A and score elements B

Fig. 5

Bar chart comparing the score distribution by score elements for each of the diagnostic subgroups. HSV1 herpes simplex virus 1, VZV varicella zoster virus, TBE tick-borne encephalitis, HSV2 herpes simplex virus 2, HIV human immunodeficiency virus, EBV Epstein-Barr virus, NMDAR N-methyl-d-aspartate-receptor, LGI1 leucine-rich glioma-inactivated 1, GABA-B γ-aminobutyric acid type B, AMPAR alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, CCI