To highlight the diagnostic challenges of cryptococcal meningitis (CM) in patients with sarcoidosis, emphasizing the clinical and radiological overlap with neurosarcoidosis.

CM is a life-threatening opportunistic infection, particularly in immunocompromised individuals. Sarcoidosis increases susceptibility to cryptococcal infection due to immune dysregulation. Both CM and neurosarcoidosis can present with similar neurological symptoms and imaging findings, complicating diagnosis and management.

A 50-year-old African-American man with stage IV pulmonary sarcoidosis presented with headaches, neck pain, left facial nerve weakness, and frequent falls. He had a prior history of cryptococcal meningitis and was recently evaluated for both neurosarcoidosis and CM. Initial workup at an outside hospital revealed a right parietal ring-enhancing brain lesion, leptomeningeal enhancement, and positive CSF cryptococcal antigen. Despite antifungal therapy, clinical improvement was limited. Upon transfer, repeat imaging and CSF analysis showed persistent lesions, positive serum and CSF cryptococcal antigen, but low titers and negative cultures. Due to ongoing diagnostic uncertainty and incomplete response to therapy, a brain biopsy was performed, confirming cryptococcal infection histopathologically. The case underscores the difficulty in distinguishing CM from neurosarcoidosis based on clinical, laboratory, and imaging findings alone.

This case illustrates the significant diagnostic challenge posed by overlapping features of CM and neurosarcoidosis in sarcoidosis patients. Standard CSF and imaging studies may be inconclusive, necessitating brain biopsy for definitive diagnosis. Accurate differentiation is critical, as management strategies for CM and neurosarcoidosis diverge substantially.