To describe a rare presentation of CNS Whipple’s Disease and highlight the novel use of Karius testing in its diagnosis.

Tropheryma whipplei is a gram-positive bacillus that causes Whipple’s Disease, a multi-system infection most often affecting middle-aged males. The organism is ubiquitous in soil, water, and human secretions. Typical symptoms include weight loss, arthralgia, diarrhea, and abdominal pain. Neurological manifestations occur in 10-40% of cases and may present with dementia, ophthalmoplegia, or myoclonus. Diagnosis is traditionally made via small bowel biopsy with PAS staining, though PCR is now available. Neuroimaging and CSF findings are nonspecific.

Case presentation 

A 57-year-old male presented to the emergency department with obstructive hydrocephalus of unclear etiology. Past medical history included seronegative RA, chronic diarrhea, and iron deficiency anemia. At the time, he was being treated for these conditions with TNF-alpha inhibitors and steroids. Extensive workup, including CSF gram stain and small bowel biopsies, was negative. On hospital day seven, Karius plasma microbial cell-free DNA sequencing suggested CNS Whipple’s Disease, later confirmed with CSF PCR. 

CNS Whipple’s Disease is a rare, complex disease that can mimic malignancy, autoimmune conditions, and infections. This case illustrates diagnostic challenges: presentation with obstructive hydrocephalus, prior misdiagnosis of seronegative rheumatoid arthritis, and negative small bowel biopsies despite systemic disease. CNS involvement lacks consistent neuroimaging or CSF findings, limiting reliance on standard modalities. Importantly, although diagnosis has classically required small bowel biopsy, this patient’s negative biopsies conflicted with positive Karius results. Obstructive hydrocephalus is a rarely reported manifestation; more common neurologic features include cognitive changes, ophthalmoplegia, oculomasticatory myorhythmia, and myoclonus. This case represents the first reported use of Karius testing to identify CNS Whipple’s Disease, suggesting a potential role for plasma microbial cell-free DNA sequencing in improving early recognition of this elusive condition.