The safety profile of intrathecal administration of the immune checkpoint inhibitor (ICI) nivolumab is not yet well-established, although preliminary data from phase I clinical trials show it is relatively safe. Cerebral microhemorrhages have not been reported as adverse events in those trials. Herein we describe a case of a melanoma patient with metastatic brain lesions who developed diffuse bilateral cerebral microhemorrhages following intrathecal nivolumab administration. 

 A 41-year old male with stage III melanoma, previously completed nivolumab monotherapy in 2018 followed by ipilimumab plus nivolumab reinduction due to recurrence, developed predominately left-sided, non-hemorrhagic metastatic brain lesions with leptomeningeal disease in 2023 while on nivolumab maintenance therapy. He was subsequently rechallenged with ipilimumab plus nivolumab before transitioning to encorafenib plus binimetinib with brain radiation. Intrathecal nivolumab was initiated due to worsening disease burden and progressive functional decline on targeted combination therapy. Several days after receiving intrathecal nivolumab, the patient became encephalopathic and developed generalized tonic-clonic seizures. MRI brain revealed new scattered bilateral cortical and deep gray matter microhemorrhages across the anterior cerebral artery territories, basal ganglia, cerebellum and temporal lobes, which were not previously seen on MRI brain obtained one month prior to intrathecal nivolumab administration. The patient was started on IV methylprednisolone for ICI neurotoxicity but unfortunately rapidly declined and was intubated due to respiratory distress. Cerebrospinal fluid analysis was positive for varicella-zoster virus, though favored to be nonconclusive due to absence of skin lesions and other systemic findings. Unfortunately, his metastatic disease burden worsened as he developed extensive hemorrhagic metastatic lesions within the posterior fossa that lead to tonsillar herniation. He was ultimately transitioned to hospice care in accordance with family wishes and passed away shortly after.

Intrathecal administration of immune checkpoint inhibitors, specifically nivolumab, may be associated with diffuse cerebral microhemorrhages in patients with metastatic melanoma.