# Mimics and Diagnostic Pitfalls of Anti‐Adenylate Kinase 5 Limbic Encephalitis

## TL;DR

This study finds that most cases initially diagnosed as anti-AK5 limbic encephalitis are actually mimics, often due to psychiatric symptoms and low antibody levels.

## Contribution

The study identifies common diagnostic pitfalls in anti-AK5 encephalitis and highlights the high frequency of misdiagnosis.

## Key findings

- Only 14% of patients had definite anti-AK5 limbic encephalitis, while 86% were classified as mimics.
- Psychiatric symptoms and low antibody titers were the most common reasons for misdiagnosis.
- Objective clinical improvement after immunotherapy suggests a need to reconsider the diagnosis.

## Abstract

The clinical understanding of limbic encephalitis associated with antibodies against adenylate kinase 5 (AK5) remains limited. Misinterpretation of antibody test results may lead to diagnostic errors and inappropriate management. We aim to assess the frequency of anti‐AK5 encephalitis overdiagnosis and identify common diagnostic pitfalls.

Cases of confirmed and mimicking anti‐AK5 limbic encephalitis from January 2021 to July 2024 using established criteria for autoimmune encephalitis (AE) were reviewed. AK5 mimics were defined as patients initially suspected of AE with a positive AK5 autoantibody result, but who ultimately received an alternative final diagnosis.

A total of 21 patients were included (57.1% female; median age 34 years; range 14–82). Only 3 patients (14%) were diagnosed with definite anti‐AK5 limbic encephalitis, while 18 patients (86%) were classified as AK5 mimics. Serum autoantibodies were predominantly of the IgG3 subclass, with titers ranging from 1:10 to 1:100. The mimics included primary psychiatric disorders (22%), central nervous system (CNS) infections (22%), other inflammatory disorders (28%), epilepsy (16%), neurodegenerative diseases (6%) and metabolic encephalopathy (6%). The most frequent confounding factor in misdiagnosis was the presence of prominent psychiatric and behavioral symptoms, seen in 50% (9 of 18) of AK5 mimics. The second most common confounder was the presence of low serum antibody titers or isolated serum positivity without corresponding cerebrospinal fluid (CSF) findings (< 1:100), observed in 94% (17 of 18) of mimics.

Mimics of anti‐AK5 encephalitis are common and that misdiagnosis is often driven by non‐specific symptoms and clinically irrelevant antibody results.

Mimics of anti‐AK5 encephalitis are common and that misdiagnosis is often driven by non‐specific symptoms and clinically irrelevant antibody results. The absence of cognitive impairment as a major symptom, prominence of psychiatric and behavioral symptoms, isolated from serum positivity or low CSF antibody titers (< 1:100), and objective clinical improvement following immunotherapy should prompt reconsideration of the diagnosis. The figure was drawn by Figdraw.