Naegleria Fowleri: The Emerging Threat to the Human Brain

Abstract— Naegleria fowleri, the so-called "brain-eating amoeba," is a thermophilic free-living amoeboflagellate protozoan that causes Primary Amoebic Meningoencephalitis (PAM) — one of the deadliest human infectious diseases ever documented, with a case fatality rate exceeding 97%. Despite six decades of scientific investigation since its first characterisation in 1965, PAM remains therapeutically refractory, with fewer than ten globally documented survivors. This comprehensive review synthesises current knowledge across all dimensions of N. fowleri biology and clinical science: its taxonomy within the phylum Percolozoa; the morphology and functional roles of its trophozoite, flagellate, and cyst forms; its thermophilic ecology and widening environmental distribution; global and Indian epidemiology, including the unprecedented 2024–2025 Kerala outbreak; the molecular mechanisms of olfactory nerve invasion and central nervous system destruction; an expanded catalogue of virulence factors (naegleriapores, Nfa1, cysteine proteases, matrix metalloproteinases); the host innate and adaptive immune response; clinical staging from prodrome to coma; and diagnostic strategies encompassing cerebrospinal fluid (CSF) microscopy, culture, polymerase chain reaction (PCR), and neuroimaging. Therapeutic coverage includes the pharmacological profiles of amphotericin B and miltefosine, CDC-recommended combination regimens, the fundamental challenge of blood–brain barrier penetration, and an appraisal of emerging drug candidates (auranofin, nitroxoline, berberine, and nanotechnology-based delivery systems). The review also evaluates prevention strategies at individual, institutional, and governmental levels, including guidelines from the CDC, WHO, and ICMR. The article concludes with a critical assessment of future research priorities: point-of-care diagnostics, climate-integrated surveillance, paediatric pharmacokinetics, and vaccine development. Given the organism's escalating global epidemiological footprint against a backdrop of climate-driven