To report the 66^th published case of dipeptidyl-peptidase–like protein 6 (DPPX) antibody–associated encephalitis, describe the clinical and radiological trajectory, and therapeutic response to plasmapheresis followed by rituximab.

Anti-DPPX encephalitis is a rare autoimmune condition often manifesting with gastrointestinal symptoms, CNS hyperexcitability, and cognitive dysfunction. Although non-FDA approved immunosuppressive agents have been used, the impact on clinical outcomes and longitudinal radiological measures is not well-understood.

Not applicable.

A 27-year-old African American woman presented with altered consciousness, generalized weakness, gastrointestinal distress, and aphasia within a 12-week period. Her prior diagnoses included systemic lupus erythematosus and multiple sclerosis (MS). Initial radiological findings of multi-focal regions of high-signal abnormality in the genu and splenium of the corpus callosum and multiple regions of contrast enhancement were atypical for MS, prompting further investigation that resulted in the diagnosis of DPPX encephalitis.

Seizures, occurring monthly, were identified. Tolerability complaints related to prescribed anticonvulsants (levetiracetam, zonisamide), compounded by neuropsychiatric symptoms, including persistent irritability and unfiltered verbal expressions, contributed to treatment non-compliance and repeated hospitalizations.

Plasmapheresis followed by rituximab use, led to partial symptom control and improvement in clinical stability. Post-treatment, MRI findings demonstrated persistent multifocal signal abnormalities in white matter, with reduced edema and without new and/or enlarging lesions. However, progressive atrophy, cavitation, and persistent encephalomalacia was observed in the frontal and temporal lobes, suggesting selective vulnerability. The results from longitudinal global and regional volumetric analyses of brain MRI will be presented.

Accurate diagnosis of DPPX encephalitis, in contrast to other autoimmune disorders, may rely on identifying selectively vulnerable regions of the CNS, which can manifest clinically as neuropsychiatric symptoms. Due to the neuroanatomical changes that may affect treatment adherence, offering more durable treatment options, even if not FDA-approved, may be essential for effective long-term disease management.