S5210 Brain Fog in Patients With Juvenile Polyposis Syndrome: Clinical Pearls

Introduction: Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has emerged as an alternative treatment modality in juvenile polyposis syndrome (JPS). We uniquely describe the development of neurologic symptoms potentially due to sirolimus use in 2 patients with JPS. Case Description: The first patient is a 28-year-old man with JPS, Cowden's syndrome, duodenal cancer status post-Whipple’s procedure, and hypothyroidism who was initiated on sirolimus therapy in February 2024. One month after the initial sirolimus starting dose of 1 mg daily, the patient developed leukopenia. One month after dose reduction to 0.5 mg daily, leukopenia resolved, but 2 months thereafter, the patient developed brain fog, fatigue, intermittent confusion, and mild anhedonia. Sirolimus trough level at the time of neurologic symptoms was 1.9 ng/mL (normal range 3-20 ng/mL). Endoscopy revealed significant reduction in gastric and small bowel polyposis after 6 months of sirolimus therapy. Bloodwork revealed no electrolyte abnormalities and well-managed hypothyroidism on levothyroxine. The patient subsequently stopped sirolimus in July 2024, after which he had resolution of his neurologic symptoms. The second patient is a 35-year-old man with JPS and postural orthostatic tachycardia syndrome on sirolimus therapy since 2021 with significant endoscopic reduction in initially observed massive gastric polyposis. The patient was noted to have tolerated sirolimus until July 2024, when he developed worsening fatigue and brain fog. Sirolimus trough level in December 2024 was 2.4 ng/mL. The patient is without any electrolyte abnormalities and is currently not on any other notable medications. Sirolimus was discontinued in May 2025 with referral to neurology for work-up with a magnetic resonance imaging of his brain. Discussion: These cases highlight potential neurotoxicity that arises from sirolimus use. Side effects of sirolimus include dyslipidemia, cytopenia, nephrotoxicity, and to a lesser extent, neurotoxicity. Neurotoxicity mostly includes cognitive impairment or posterior reversible encephalopathy syndrome which commonly manifests as brain fog. Sirolimus-induced neurotoxicity is scarcely reported, with most cases being related to dose-independent toxicity. As such, we encourage clinicians to be aware of neurotoxicity in patients with JPS managed with sirolimus to allow for timely recognition and appropriate management with serial lab monitoring, imaging, discontinuation of therapy, and co-management with neurology.