Neurological Manifestations in Whipple's Disease: A Scoping Review of Clinical Features, Laboratory Findings, and Neuroimaging Characteristics of 111 Cases

Abstract

Background

Whipple disease (WD) is a rare, potentially fatal infection caused by Tropheryma whipplei (TW). Central Nervous System involvement (CNS-WD) is a severe complication of WD with a challenging diagnosis, due to limited data integrating neurological features, imaging, cerebrospinal fluid analysis, PCR, and intestinal histopathology. Prompt recognition and treatment are essential to improve patient outcomes.

Methods

A scoping review of the literature from 2000 to 2025 was conducted, including all CNS-WD case reports and series, to outline its clinical spectrum and diagnostic workup.

Results

Included studies were 89, accounting for 111 CNS-WD cases. Most patients were male (79.8%), with a mean age of 53.6 years. Notably, 13.2% presented with CNS involvement in the absence of systemic WD. Pathognomonic signs were rare (13/111, 11.7%). Most patients (82.9%, 92/111) presented with two or more neurological symptoms, the most frequently reported being altered mentation, followed by ataxia, eye movement abnormalities, and other movement disorders. CSF was abnormal in 74.7% (56/75) of patients and TW PCR was positive in 75% (48/64); 64% (55/86) of cases showed intestinal histopathology consistent with WD. TW PCR on gastrointestinal biopsies was positive in 67.9% (19/28) cases. CNS imaging revealed abnormalities in 85.4% (82/96) of patients, with no distinctive pattern.

Conclusions

CNS-WD diagnosis remains challenging due to nonspecific symptoms, variable imaging, and occasional discordance among CSF, TW PCR or biopsy findings. Our review suggests that CNS-WD should be considered in the differential diagnosis of unexplained neurological syndromes, even in patients with atypical clinical or radiological profiles, supporting broader indications for TW testing.