Dipeptidyl-peptidase–like protein 6 (DPPX) antibody–associated encephalitis is a rare syndrome that includes weight loss, painful gastrointestinal symptoms, cognitive dysfunction, and CNS hyperexcitability. We describe a case of anti-DPPX encephalitis in a patient with painful GI symptoms and cognitive decline who underwent an extensive evaluation prior to diagnosis and treatment.

A 53 year old male presenting with recurrent emergency room visits with multiple seemingly unrelated symptoms. Symptoms occurred following a cruise and included skin discoloration, myalgias, and dyspnea. Respiratory symptoms resolved with standard bronchospastic treatment. He later developed dysesthesias, abdominal discomfort, and sixty pound weight loss. An extensive gastrointestinal evaluation was unremarkable. Persisting symptoms included anxiety and cognitive decline including apathy, memory impairment, and a persistent child-like demeanor, as well as exaggerated startle response. He underwent an inpatient psychiatric stay. His anxiety and depression slightly improved with psychotropic medications, however he did not return to his baseline positive demeanor. Symptoms of dysautonomia included episodic flushing and diaphoresis. Staring spells and unintelligible speech did not correlate with any simultaneous EEG recording. CSF resulted normal cell count and minimal increased protein (65 mg/dL). A lack of specific diagnosis and progressive decline prompted serum autoimmune antibody testing. Surprisingly, a positive anti-DPPX titer of 1:61440 was detected. Referred to oncology, the patient was treated sequentially with plasmapheresis and steroids, rituximab, and mycophenylate mofetil with a slight improvement in mental status over a period of weeks.

Dipeptidyl-peptidase–like protein 6 (DPPX) is expressed in the hippocampus, cerebellum, striatum, and myenteric plexus, resulting in the unique presentation of DPPX antibody–associated encephalitis. This syndrome should be considered in patients with a triad of gastrointestinal symptoms, cognitive decline, and evidence of CNS hyperexcitability. Practitioners caring for patients with unknown CNS syndromes should have a low threshold for ordering CSF and serum CNS encephalitis panels, prompting earlier diagnosis.