Primary Amebic Meningoencephalitis

name: Primary Amebic Meningoencephalitis
creation_date: "2026-11-03T17:00:00Z"
description: >-
  Primary amebic meningoencephalitis is a fulminant central-nervous-system
  infection caused by Naegleria fowleri after nasal water exposure. The ameba
  crosses the cribriform plate along olfactory nerves, invades the brain, and
  produces rapidly progressive meningoencephalitis with neutrophilic CSF
  inflammation, cerebral edema, necrosis, herniation, and high mortality.
category: Infectious Disease
disease_term:
  preferred_term: primary amebic meningoencephalitis
  term:
    id: MONDO:0000290
    label: primary amebic meningoencephalitis
parents:
- Protozoal infection
synonyms:
- Primary amoebic meningoencephalitis
notes: >-
  Scoped to primary amebic meningoencephalitis caused by Naegleria fowleri.
  Granulomatous amebic encephalitis from Acanthamoeba or Balamuthia follows a
  slower clinical course and is outside this entry.
review_notes: >-
  Deliberately lumped. This entry records Naegleria fowleri PAM across genotype,
  country, and water-source strata because global clinical summaries stratify
  exposure sources, geography, and confirmation status without defining
  mechanistically separate disease entities below the N. fowleri species level.
infectious_agent:
- name: Naegleria fowleri
  infectious_agent_term:
    preferred_term: Naegleria fowleri
    term:
      id: NCBITaxon:5763
      label: Naegleria fowleri
  description: >-
    Thermophilic free-living ameboflagellate whose trophozoites enter through
    the nose and invade the central nervous system in PAM.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Primary amebic meningoencephalitis (PAM) is a rapidly progressive and
      often fatal condition caused by the free-living ameba Naegleria fowleri.
    explanation: >-
      Identifies N. fowleri as the causal free-living ameba for PAM.
agent_life_cycle:
  description: >-
    Naegleria fowleri alternates among trophozoite, cyst, and transitory
    flagellate forms in the environment. Trophozoites are the only reproductive,
    feeding, and infective form; humans are incidental clinical hosts after
    nasal exposure, with no recognized insect vector or human carrier state.
  hosts:
  - preferred_term: Homo sapiens
    role: incidental clinical host
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  life_cycle_stages:
  - name: Trophozoite stage
    life_cycle_stage_term:
      preferred_term: trophozoite stage
      term:
        id: OPL:0000057
        label: trophozoite stage
    description: >-
      The motile, feeding trophozoite is the active environmental and host-entry
      form of N. fowleri and is the only stage documented to reproduce and cause
      infection.
    evidence:
    - reference: PMID:34572533
      reference_title: >-
        Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
        and Treatments.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The trophozoites are the only form of N. fowleri that can reproduce,
        feed, encyst, and cause infection in other organisms.
      explanation: >-
        Supports trophozoites as the replicative and infective N. fowleri stage.
  - name: Environmental cyst stage
    description: >-
      Dormant cysts allow N. fowleri to persist through hostile environmental
      conditions and reseed trophozoites when conditions become favorable.
    evidence:
    - reference: PMID:34572533
      reference_title: >-
        Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
        and Treatments.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        When conditions become too hostile, the amoeba transforms into a
        metabolically inactive cyst, described as a spherical structure that
        measures from 7 to 12 µm in diameter, with a thick endocyst, a thin
        ectocyst, and some mucoid-plugged pores
      explanation: >-
        Describes the resistant cyst form used outside the human host.
  - name: Transitory flagellate stage
    description: >-
      N. fowleri can transform into a short-lived flagellate in water under
      non-nutritive conditions.
    evidence:
    - reference: PMID:34572533
      reference_title: >-
        Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
        and Treatments.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        When the amoeba faces non-nutritive conditions but is in the presence of
        water, it transforms into a transitory flagellate.
      explanation: >-
        Supports flagellate transformation as a water-associated life-cycle form.
  evidence:
  - reference: PMID:36098909
    reference_title: Amebic infections of the central nervous system.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These ameba are unique from other protozoa in that they are free-living,
      have no known insect vector, do not result in a human carrier state, and
      are typically unassociated with poor sanitation.
    explanation: >-
      Supports the free-living ecology, absence of a known vector, and absence
      of a human carrier state for free-living amebae that invade the CNS.
transmission:
- name: Nasal exposure to warm fresh water
  description: >-
    PAM follows contaminated water entering the nose during swimming, diving,
    bathing, water sports, or nasal irrigation; trophozoites then attach to the
    nasal mucosa and enter the olfactory route to the brain.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Of the 247 cases with reported water activities thought to result in N.
      fowleri exposure, the most common activities were swimming/diving (58%),
      bathing (16%), water sports (eg, waterskiing, wakeboarding, jet skiing;
      10%), and nasal irrigation (9%; Table 1).
    explanation: >-
      Global case aggregation identifies activities that introduce contaminated
      water into the nose.
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      More than 90% of infections by N. fowleri occur when people submerge,
      dive, or splash in warm water bodies, allowing the amoeba’s trophozoites
      to enter the body through the nasal cavity
    explanation: >-
      Supports nasal entry of trophozoites after warm-water exposure.
environmental:
- name: Nasal exposure to N. fowleri-contaminated warm freshwater
  description: >-
    Warm freshwater or poorly disinfected water entering the nasal cavity during
    swimming, diving, bathing, water sports, nasal irrigation, or similar water
    contact is the environmental route that brings N. fowleri trophozoites to
    the olfactory epithelium.
  exposure_term:
    preferred_term: nasal exposure to Naegleria-contaminated warm freshwater
  presence: PRESENT
  effect: HARMFUL
  notes: >-
    ECTO was searched for "freshwater exposure" and "recreational water
    exposure"; it currently offers generic exposure to water and exposure to
    contaminated water terms, but no term for freshwater entering the nasal
    cavity during recreation, bathing, or nasal irrigation. The exposure is
    deliberately left unbound until ECTO has a more specific nasal-water
    exposure class.
  influences_mechanisms:
  - target: Nasal-Olfactory Amebic Neuroinvasion
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Trophozoites in warm or contaminated water must be introduced through the
      nose before they can attach to olfactory mucosa and migrate toward the
      olfactory bulb.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Of the 247 cases with reported water activities thought to result in N.
      fowleri exposure, the most common activities were swimming/diving (58%),
      bathing (16%), water sports (eg, waterskiing, wakeboarding, jet skiing;
      10%), and nasal irrigation (9%; Table 1).
    explanation: >-
      Identifies water activities that introduce N. fowleri-contaminated water
      to the nose in global PAM cases.
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
prevalence:
- population: Published and CDC-reported global PAM cases through 2018
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A global review of literature and CDC surveillance records identified 381
    PAM cases through 2018; only 7 reported survivors met confirmed laboratory
    criteria, patients were predominantly male (75%), and case-fatality was 92%
    overall, 96% among confirmed cases, and 98% among US cases.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A total of 381 PAM cases were identified. Seven reported survivors were
      classified as confirmed.
    explanation: >-
      Reports the worldwide literature and CDC-surveillance case count and the
      confirmed-survivor count through 2018.
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The overall case-fatality rate was 92% with 32 reported survivors; however,
      only 7 survivors met laboratory criteria for confirmed classification.
    explanation: >-
      Quantifies the historically high case-fatality rate and distinguishes all
      reported survivors from confirmed survivors.
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Patients were predominantly male (75%), with a median age of 14 years
      (range, 1 month–85 years; Table 2).
    explanation: >-
      Supports the male predominance recorded for the global case aggregation.
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The case-fatality rate differed between confirmed and suspect cases (96%
      vs 77%; P < .001; Table 2) and between US cases and non-US cases (98% vs
      87%; P < .001; Supplementary Table 3).
    explanation: >-
      Supports the confirmed-case and US-case fatality rates included in the
      prevalence notes.
progression:
- phase: Early flu-like prodrome after water exposure
  incubation_days: 5 days
  notes: >-
    PAM may initially present with vague flu-like symptoms before recognizable
    CNS involvement; in the global review, the median incubation was 6 days
    overall and 5 days among confirmed cases.
  evidence:
  - reference: PMID:26582886
    reference_title: >-
      Diagnosis, Clinical Course, and Treatment of Primary Amoebic
      Meningoencephalitis in the United States, 1937-2013.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Patients were categorized into the early (ie, flu-like symptoms) or late
      (ie, central nervous system signs) group on the basis of presenting
      clinical characteristics.
    explanation: >-
      Supports the early prodromal versus later CNS-involvement structure used
      for PAM clinical staging.
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The median incubation period for cases was 6 days (range, 1–30; Table 2).
      The incubation period was shorter for confirmed cases (median, 5 days;
      range, 1–12) compared with suspect cases (median, 7 days; range, 1–30; P <
      .001).
    explanation: >-
      Quantifies the water-exposure-to-symptom interval in reported global and
      confirmed cases.
- phase: Fulminant central-nervous-system disease
  duration_days: 5 days
  notes: >-
    Patients commonly reach healthcare after signs of CNS involvement and then
    progress over days to edema, herniation, coma, and death unless diagnosed
    and treated unusually early.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the overall median time from onset of symptoms to death was 5 days (range,
      1–65).
    explanation: >-
      Supports the rapid terminal course in fatal PAM cases.
pathophysiology:
- name: Nasal-Olfactory Amebic Neuroinvasion
  role: trigger
  biological_scale: TISSUE
  description: >-
    N. fowleri trophozoites introduced into the nasal cavity attach to olfactory
    mucosa and migrate along olfactory nerves across the cribriform plate into
    the olfactory bulb and central nervous system.
  locations:
  - preferred_term: olfactory epithelium
    term:
      id: UBERON:0001997
      label: olfactory epithelium
  - preferred_term: olfactory bulb
    term:
      id: UBERON:0002264
      label: olfactory bulb
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  downstream:
  - target: Contact-Dependent Trophozoite Cytotoxicity
    causal_link_type: DIRECT
    description: >-
      Trophozoites that reach neural tissue attach to and ingest host cells with
      amoebastome food cups.
  - target: Contact-Independent Secreted Cytolysis
    causal_link_type: DIRECT
    description: >-
      Trophozoites that have reached target tissues also release virulence
      factors and extracellular vesicles that injure host cells without direct
      phagocytic contact.
  - target: Anosmia
    causal_link_type: DIRECT
    description: >-
      Amebae moving through the olfactory neuroepithelium and olfactory nerves
      can disrupt early smell perception as they cross toward the olfactory
      bulb.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      PAM occurs upon accidental introduction of N. fowleri into the nose, after
      which the ameba invades the central nervous system (CNS) through the
      cribriform plate and olfactory nerves
    explanation: >-
      Identifies nasal exposure and olfactory-cribriform invasion as the route
      into the CNS.
  - reference: PMID:10701563
    reference_title: >-
      A light microscopy study of the migration of Naegleria fowleri from the
      nasal submucosa to the central nervous system during the early stage of
      primary amebic meningoencephalitis in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Focal inflammation and amebas were observed in the submucosal nerve
      plexus, olfactory nerves penetrating the cribriform plate, and the
      olfactory bulb of the brain as early as 24 hr postinoculation.
    explanation: >-
      Intranasal mouse infection directly localizes amebae along the early
      olfactory route into the brain.
- name: Contact-Dependent Trophozoite Cytotoxicity
  role: mechanism
  biological_scale: CELLULAR
  description: >-
    Attached N. fowleri trophozoites damage host neural cells through contact
    mechanisms including adhesion, amoebastome food cups, and phagocytosis.
  biological_processes:
  - preferred_term: cell adhesion
    term:
      id: GO:0007155
      label: cell adhesion
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
  downstream:
  - target: Fulminant Necrotizing Meningoencephalitis
    causal_link_type: DIRECT
    description: >-
      Contact cytotoxicity contributes to the tissue destruction and necrosis of
      PAM.
  evidence:
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Thus far, two pathogenic mechanisms have been recognized in N. fowleri:
      Contact-dependent mechanisms related to adhesion and phagocytic food-cups
      and contact-independent mechanisms involving cytolytic molecules secreted
      by the amoeba
    explanation: >-
      Separates adhesion and food-cup-mediated cytotoxicity from secreted
      cytolytic mechanisms.
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In addition to adhesion, amoebas cause severe tissue destruction through
      contact-dependent phagocytosis, where they use their amoebastomes to
      gradually engulf neuronal cells
    explanation: >-
      Supports phagocytic amoebastome ingestion as a direct neural-cell injury
      mechanism.
- name: Contact-Independent Secreted Cytolysis
  role: mechanism
  biological_scale: MOLECULAR
  description: >-
    N. fowleri trophozoites secrete extracellular vesicles carrying proteases,
    pore-forming naegleriapores, and other virulence cargo that can increase host
    membrane permeability, lyse cells, and induce necrosis without direct
    amoebastome-mediated ingestion.
  biological_processes:
  - preferred_term: exocytosis
    term:
      id: GO:0006887
      label: exocytosis
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
  downstream:
  - target: Fulminant Necrotizing Meningoencephalitis
    causal_link_type: DIRECT
    description: >-
      Secreted vesicles and proteases add contact-independent epithelial and
      neural injury to the direct trophozoite cytotoxic mechanisms driving PAM
      tissue necrosis.
  evidence:
  - reference: PMID:39432113
    reference_title: >-
      Analysis of virulence factors in extracellular vesicles secreted by
      Naegleria fowleri.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      N. fowleri secretes a wide variety of vesicle sizes ranging from 0.2
      to > 2 μm, and these EVs were recognized by antibodies anti-Naegleropore B,
      anti-19 kDa polypeptide band, anti-membrane protein Mp2CL5,
      anti-protease cathepsin B, and anti-actin.
    explanation: >-
      Shows that trophozoites secrete extracellular vesicles carrying multiple
      virulence-associated cargo proteins.
  - reference: PMID:40312759
    reference_title: >-
      Advances in the study of extracellular vesicles of Naegleria fowleri and
      their role in contact-independent pathogenic mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      EVs exhibited haemolytic activity in erythrocytes as well as increased
      ionic permeability and necrosis in MDCK cells 24 h postinteraction.
    explanation: >-
      Demonstrates contact-independent host-cell injury caused by isolated
      N. fowleri extracellular vesicles.
- name: Protease-Mediated Extracellular Matrix Disassembly
  role: mechanism
  biological_scale: MOLECULAR
  description: >-
    N. fowleri trophozoites secrete matrix metalloproteinases that degrade
    extracellular matrix between the nasal cavity and olfactory bulb.
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
  downstream:
  - target: Nasal-Olfactory Amebic Neuroinvasion
    causal_link_type: DIRECT
    description: >-
      Matrix degradation facilitates movement from nasal chambers toward the
      olfactory bulb, enabling subsequent CNS invasion.
  evidence:
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The results of this study suggest that N. fowleri secretes these MMPs and
      degrades the ECM, simplifying its passage from the nasal chambers into the
      olfactory bulb
    explanation: >-
      Supports MMP-mediated extracellular-matrix degradation as an invasion
      mechanism.
- name: Microglial Cytokine and Oxidant Activation
  role: mechanism
  biological_scale: CELLULAR
  description: >-
    Trophozoites and parasite-damaged tissue activate CNS innate immune cells,
    especially microglia, to release inflammatory cytokines and reactive oxygen
    and nitrogen species that can amplify neurotoxicity.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: positive regulation of cytokine production
    term:
      id: GO:0001819
      label: positive regulation of cytokine production
  downstream:
  - target: Fever
    causal_link_type: DIRECT
    description: >-
      IL-1β, IL-6, TNF-α, and other inflammatory mediators released by activated
      CNS innate immune cells provide a route from local trophozoite sensing to
      fever.
  - target: Fulminant Necrotizing Meningoencephalitis
    causal_link_type: DIRECT
    description: >-
      Microglial cytokine and oxidant release can add immunopathologic injury
      to direct amoebic cytolysis.
  evidence:
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In vitro, N. fowleri trophozoites activate microglial cells inducing the
      production of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, ROS,
      and RNS
    explanation: >-
      Supports activation of microglia and inflammatory mediator release by
      trophozoites.
- name: Fulminant Necrotizing Meningoencephalitis
  role: outcome
  biological_scale: TISSUE
  description: >-
    Direct amoebic cytolysis and host inflammation converge on an acute
    necrotizing CNS infection with edema, necrosis, and herniation.
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  downstream:
  - target: Raised Intracranial Pressure and Herniation
    causal_link_type: DIRECT
    description: >-
      Necrotizing meningoencephalitis produces destructive edema that can raise
      intracranial pressure and progress to herniation.
  - target: Headache
    causal_link_type: DIRECT
    description: >-
      Meningoencephalitic inflammation and edema generate severe headache during
      the acute CNS phase.
  - target: Nausea and vomiting
    causal_link_type: DIRECT
    description: >-
      Acute meningoencephalitis and intracranial-pressure elevation account for
      the frequent vomiting-predominant presentation.
  - target: Nuchal rigidity
    causal_link_type: DIRECT
    description: >-
      Meningeal inflammation produces meningismus and neck stiffness.
  - target: Altered mental status
    causal_link_type: DIRECT
    description: >-
      Diffuse necrotizing encephalitis disrupts cortical and subcortical
      function, producing encephalopathy.
  - target: Seizure
    causal_link_type: DIRECT
    description: >-
      Necrotizing cortical inflammation and edema lower the seizure threshold in
      fulminant PAM.
  - target: Neutrophilic cerebrospinal-fluid pleocytosis
    causal_link_type: DIRECT
    description: >-
      The acute CNS inflammatory response spills into CSF as
      neutrophil-predominant pleocytosis.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Invasion of the CNS results in cerebral edema, necrosis, herniation, and,
      in most cases, death
    explanation: >-
      Supports destructive CNS disease as the terminal tissue-level consequence
      of olfactory-route invasion.
- name: Raised Intracranial Pressure and Herniation
  role: outcome
  biological_scale: TISSUE
  description: >-
    PAM-related cerebral edema raises intracranial pressure; uncontrolled
    pressure and swelling can culminate in herniation with brainstem compression,
    coma, and death.
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  downstream:
  - target: Coma
    causal_link_type: DIRECT
    description: >-
      Brain swelling, herniation, and brainstem compression explain the rapid
      transition from meningoencephalitis to coma in advanced PAM.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Invasion of the CNS results in cerebral edema, necrosis, herniation, and,
      in most cases, death
    explanation: >-
      Places cerebral edema and herniation on the causal route to fatal PAM.
  - reference: PMID:25667249
    reference_title: >-
      Successful treatment of an adolescent with Naegleria fowleri primary
      amebic meningoencephalitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient's survival most likely resulted from a variety of factors:
      early identification and treatment, use of a combination of antimicrobial
      agents (including miltefosine), and management of elevated intracranial
      pressure based on the principles of traumatic brain injury.
    explanation: >-
      Identifies elevated intracranial pressure as a clinically actionable
      complication in a confirmed PAM survivor.
phenotypes:
- name: Fever
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  frequency: 88% at presentation in 256 classifiable global cases
  description: >-
    Fever is the most common presenting symptom in reported PAM cases.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the most common symptoms on presentation were fever (88%),
      headache (82%), nausea/vomiting (57%), altered mental status (50%), and
      nuchal rigidity (35%).
    explanation: >-
      Global case review quantified fever among patients with sufficient
      presentation details.
- name: Headache
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  frequency: 82% at presentation in 256 classifiable global cases
  description: >-
    Headache is a frequent early manifestation of Naegleria
    meningoencephalitis.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the most common symptoms on presentation were fever (88%),
      headache (82%), nausea/vomiting (57%), altered mental status (50%), and
      nuchal rigidity (35%).
    explanation: >-
      Global case review quantified headache among patients with sufficient
      presentation details.
- name: Nausea and vomiting
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  frequency: 57% at presentation in 256 classifiable global cases
  description: >-
    Nausea and vomiting occur in the acute meningoencephalitic presentation of
    PAM.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the most common symptoms on presentation were fever (88%),
      headache (82%), nausea/vomiting (57%), altered mental status (50%), and
      nuchal rigidity (35%).
    explanation: >-
      Global case review quantified nausea and vomiting among patients with
      sufficient presentation details.
- name: Nuchal rigidity
  phenotype_term:
    preferred_term: Nuchal rigidity
    term:
      id: HP:0031179
      label: Nuchal rigidity
  frequency: 35% at presentation in 256 classifiable global cases
  description: >-
    Meningeal inflammation produces nuchal rigidity in a subset of PAM
    presentations.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the most common symptoms on presentation were fever (88%),
      headache (82%), nausea/vomiting (57%), altered mental status (50%), and
      nuchal rigidity (35%).
    explanation: >-
      Global case review quantified nuchal rigidity among patients with
      sufficient presentation details.
- name: Altered mental status
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  frequency: 50% at presentation in 256 classifiable global cases
  description: >-
    Altered mental status is a common sign that PAM has progressed from a
    nonspecific prodrome into central-nervous-system involvement.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the most common symptoms on presentation were fever (88%),
      headache (82%), nausea/vomiting (57%), altered mental status (50%), and
      nuchal rigidity (35%).
    explanation: >-
      Global case review quantified altered mental status among patients with
      sufficient presentation details.
- name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: 41.6% at presentation in a 24-patient India systematic review
  description: >-
    Seizures occur in a substantial subset of PAM presentations as acute
    necrotizing meningoencephalitis injures the brain.
  evidence:
  - reference: PMID:42764041
    reference_title: >-
      Naegleria fowleri-associated primary amoebic meningoencephalitis in
      India: A systematic review and individual patient-level analysis of
      reported cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Fever (79.2%), headache (58.3%), and seizures (41.6%) were the most common
      presenting features.
    explanation: >-
      Quantifies seizure at presentation in a systematic review of reported
      Indian PAM cases.
- name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  frequency: 13% at presentation in 256 classifiable global cases
  description: >-
    Advanced PAM can already be severe enough to cause coma at initial
    healthcare presentation.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Thirty-four patients (13%) presented in an advanced state with coma.
    explanation: >-
      Global case review quantified coma at presentation as an advanced state.
- name: Anosmia
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  description: >-
    Loss of smell can accompany PAM and reflects involvement of the olfactory
    route that N. fowleri uses to enter the central nervous system from the nose.
  evidence:
  - reference: PMID:42109965
    reference_title: >-
      Primary Amebic Meningoencephalitis Mimicking Acute Bacterial Meningitis:
      Survival Following Early Empirical Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Neurological examination revealed meningeal signs (Brudzinski and Kernig)
      and anosmia, suggestive of olfactory nerve (cranial nerve I) involvement.
    explanation: >-
      Documents anosmia on neurologic examination in a presumptive PAM case
      following warm-lake-water nasal ablution.
- name: Neutrophilic cerebrospinal-fluid pleocytosis
  phenotype_term:
    preferred_term: CSF pleocytosis
    term:
      id: HP:0012229
      label: CSF pleocytosis
  frequency: Median CSF WBC 1238/µL with median 82% neutrophils in 237 reported cases
  description: >-
    PAM cerebrospinal fluid commonly shows a neutrophil-predominant pleocytosis
    that can mimic bacterial meningitis.
  diagnostic: true
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      White blood cell counts were also elevated (median, 1238 cells/μL; range
      0–30 000); these were predominantly neutrophils (median, 82%; range,
      0%–100%).
    explanation: >-
      CSF profiles in the global case review support neutrophil-predominant
      CSF inflammation.
diagnosis:
- name: CSF or brain-tissue ameba microscopy
  description: >-
    Direct visualization of motile amebae in cerebrospinal fluid or brain
    tissue can provide a presumptive PAM diagnosis when compatible acute
    meningoencephalitis follows nasal water exposure.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A presumptive diagnosis of N. fowleri infection can be made by microscopic
      examination of the cerebrospinal fluid (CSF) or brain tissue
    explanation: >-
      Supports microscopy of CSF or brain tissue as a presumptive diagnostic
      method.
- name: Naegleria confirmatory immunostaining or PCR detection
  description: >-
    Immunohistochemistry, indirect immunofluorescence, and PCR can confirm
    Naegleria fowleri infection in CSF or tissue.
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      a definitive diagnosis can be made by immunohistochemistry (IHC),
      indirect immunofluorescence (IIF)
    explanation: >-
      Supports immunostaining as a definitive diagnostic method for N. fowleri
      infection.
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Of 85 cases diagnosed by PCR (61 antemortem diagnosis, 21 postmortem
      diagnosis, and 3 with unknown diagnostic timing), 72 (85%) used the CDC
      multiplex real-time PCR assay for simultaneous detection of Acanthamoeba
      spp., Balamuthia mandrillaris, and Naegleria fowleri
    explanation: >-
      Documents PCR-confirmed PAM diagnoses in the global case review and the
      multiplex assay used for most PCR-confirmed cases.
- name: CSF chemistry profile
  description: >-
    PAM CSF typically resembles bacterial meningitis, with high opening
    pressure, neutrophilic pleocytosis, elevated protein, and low glucose.
  markers: CSF opening pressure; CSF white blood cell count; CSF protein; CSF glucose
  evidence:
  - reference: PMID:26582886
    reference_title: >-
      Diagnosis, Clinical Course, and Treatment of Primary Amoebic
      Meningoencephalitis in the United States, 1937-2013.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cerebrospinal fluid analysis resembled bacterial meningitis with high
      opening pressures, elevated white blood cell counts with predominantly
      neutrophils (median, 2400 cells/μL ...), low glucose levels (median, 23
      mg/dL ...), and elevated protein levels (median, 365 mg/dL ...).
    explanation: >-
      Defines the characteristic CSF pressure and chemistry profile in US PAM
      cases.
- name: Amoeba culture and flagellation testing
  description: >-
    CSF-derived amebae can be cultured on non-nutrient agar or transformed in
    distilled water to demonstrate pear-shaped flagellated forms, helping
    distinguish N. fowleri from other free-living amebae.
  evidence:
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      solid non-nutrient agar is the standard method for growing N. fowleri
    explanation: >-
      Supports culture on non-nutrient agar for N. fowleri growth.
  - reference: PMID:35020127
    reference_title: >-
      Real-Time PCR Confirmation of a Fatal Case of Primary Amoebic
      Meningoencephalitis in Turkey Caused by Naegleria fowleri or Brain-Eating
      Amoeba.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The CSF sample collected was taken into distilled water considering the
      possibility of transformation of trophozoites to intermediate form and
      incubated at 37 °C for 1 to 2 h, and pear-shaped non-permanent flagellated
      forms were observed in the direct microscopic examination
    explanation: >-
      Documents a clinical flagellation test used to support N. fowleri
      diagnosis.
treatments:
- name: Multidrug PAM pharmacotherapy
  description: >-
    Reported survivors with confirmed PAM received early intravenous
    amphotericin B and commonly also intrathecal amphotericin B, an azole,
    rifampicin, azithromycin, miltefosine, and dexamethasone.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amphotericin B
      term:
        id: CHEBI:2682
        label: amphotericin B
    - preferred_term: miltefosine
      term:
        id: CHEBI:75283
        label: miltefosine
    - preferred_term: fluconazole
      term:
        id: CHEBI:46081
        label: fluconazole
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:32369575
    reference_title: >-
      Epidemiology and Clinical Characteristics of Primary Amebic
      Meningoencephalitis Caused by Naegleria fowleri: A Global Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the following medications were used for treatment: intravenous
      amphotericin B (7/7), intrathecal amphotericin B (5/7), azoles (6/7),
      rifampin (6/7), azithromycin (4/7), miltefosine (4/7), and dexamethasone
      (5/7).
    explanation: >-
      Summarizes the multidrug regimens used among confirmed PAM survivors in
      the global review.
  - reference: PMID:34572533
    reference_title: >-
      Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis
      and Treatments.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      PAM is a rare, acute, and fulminating infection characterized by very low
      morbidity and a very high mortality rate, two factors that complicate the
      development of a treatment
    explanation: >-
      Explains why PAM drug evidence comes from case reports and preclinical
      studies rather than randomized clinical trials.
- name: Neurocritical intracranial-pressure control
  description: >-
    Survivors have been managed with aggressive control of elevated intracranial
    pressure, including traumatic-brain-injury-style neurocritical care,
    cerebrospinal-fluid diversion by ventricular shunt, and therapeutic
    hypothermia alongside anti-amebic pharmacotherapy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Raised Intracranial Pressure and Herniation
    treatment_effect: INHIBITS
    description: >-
      ICP-directed neurocritical care attempts to prevent edema-driven
      herniation while anti-amebic drugs clear the trophozoite infection.
  evidence:
  - reference: PMID:25667249
    reference_title: >-
      Successful treatment of an adolescent with Naegleria fowleri primary
      amebic meningoencephalitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient's survival most likely resulted from a variety of factors:
      early identification and treatment, use of a combination of antimicrobial
      agents (including miltefosine), and management of elevated intracranial
      pressure based on the principles of traumatic brain injury.
    explanation: >-
      Supports aggressive elevated-intracranial-pressure management as part of
      a confirmed PAM survivor's regimen.
  - reference: PMID:27525348
    reference_title: >-
      Naegleria fowleri: Diagnosis, Pathophysiology of Brain Inflammation, and
      Antimicrobial Treatments.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Successful treatment of PAM started with a rapid diagnosis, extensive
      antimicrobial therapy including an investigational medication miltefosine,
      supportive care, an intraventricular shunt, and hypothermia.
    explanation: >-
      Identifies CSF diversion and hypothermia in the multimodal management of a
      North American survivor.

animal_models:
- name: Intranasal mouse olfactory-invasion model
  species: Mus musculus
  genotype: Wild type
  publication: PMID:10701563
  description: >-
    Intranasal N. fowleri inoculation in mice recapitulates the early olfactory
    route into the brain, with amebae and focal inflammation appearing in the
    nasal submucosal nerve plexus, olfactory nerves, and olfactory bulb within
    24 hours.
  associated_phenotypes:
  - Olfactory-nerve amebae
  - Olfactory-bulb inflammation
  modeled_mechanisms:
  - target: Nasal-Olfactory Amebic Neuroinvasion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Intranasal challenge directly reproduces the route from nasal mucosa,
      across cribriform olfactory nerves, and into the olfactory bulb.
    evidence:
    - reference: PMID:10701563
      reference_title: >-
        A light microscopy study of the migration of Naegleria fowleri from the
        nasal submucosa to the central nervous system during the early stage of
        primary amebic meningoencephalitis in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Focal inflammation and amebas were observed in the submucosal nerve
        plexus, olfactory nerves penetrating the cribriform plate, and the
        olfactory bulb of the brain as early as 24 hr postinoculation.
      explanation: >-
        Localizes the model's amebae along the same olfactory-cribriform route
        that defines human PAM entry into the CNS.
- name: BALB/c active-immunization intranasal-challenge model
  species: Mus musculus
  genotype: Wild type
  background: BALB/c
  publication: PMID:646016
  description: >-
    BALB/c mice immunized with live N. fowleri by intraperitoneal injection were
    challenged intranasally and tested for protection against experimental
    amebic meningoencephalitis.
  associated_phenotypes:
  - Intranasal N. fowleri challenge
  - Survival after immunization
  modeled_mechanisms:
  - target: Nasal-Olfactory Amebic Neuroinvasion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The challenge enters through the nasal route used in human PAM, while the
      prior intraperitoneal immunization is an experimental protective
      perturbation rather than natural human immunity.
    evidence:
    - reference: PMID:646016
      reference_title: >-
        Protective immunity to Naegleria fowleri in experimental amebic
        meningoencephalitis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Intranasal inoculation of N. fowleri in mice produces an infection
        similar to human disease.
      explanation: >-
        Supports intranasal mouse inoculation as an experimental PAM model.