Neuroinvasive Free-Living Amoebae Pathogenesis, Neuroinflammation and Therapeutic Challenges.

Neuroinvasive free-living amoebae (FLA), particularly Naegleria fowleri and Acanthamoeba spp., are responsible for rare but devastating infections of the central nervous system (CNS). Approximately 480 cases of primary amoebic meningoencephalitis (PAM) and fewer than 200 well-documented cases of Acanthamoeba-associated granulomatous amoebic encephalitis (GAE) have been reported worldwide. Mortality rates frequently exceed 90%. PAM typically develops following exposure to warm freshwater contaminated with N. fowleri and progresses rapidly in otherwise healthy individuals. In contrast, GAE usually follows a more indolent course and occurs predominantly in immunocompromised hosts. Despite their distinct clinical courses, both infections are characterized by CNS invasion, amoeba-mediated tissue destruction, blood-brain barrier (BBB) disruption, and host inflammatory responses. These processes drive neuroinflammation, neuronal injury, and neurological deterioration. Early diagnosis remains challenging because clinical manifestations are nonspecific and disease progression can be either fulminant or initially subtle. Therapeutic management is hindered by poor CNS drug penetration, limited efficacy of currently available therapies, treatment-related toxicity, and the absence of standardized treatment protocols or controlled clinical trials. This narrative review critically synthesizes current evidence on CNS invasion, neuroinflammation, neuropathology, diagnostic challenges, and therapeutic strategies in neuroinvasive FLA infections. It also highlights key translational priorities, including earlier diagnosis, standardized treatment protocols, stronger clinical evidence, and improved CNS-targeted drug delivery.