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

backgroundWhipple 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.

methodsA 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.

resultsIncluded 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.

conclusionsCNS-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.