What are the clinical features, diagnosis, and treatment of Primary Amoebic Meningoencephalitis (PAM)?

Primary Amoebic Meningoencephalitis: Clinical Features, Diagnosis, and Treatment

Primary Amoebic Meningoencephalitis (PAM) requires immediate aggressive combination therapy including intravenous and intrathecal amphotericin B, along with miltefosine and other agents, as early diagnosis and treatment are critical for survival in this nearly always fatal disease. 1

Clinical Features

PAM is a fulminant, rapidly progressive infection of the central nervous system caused by the free-living amoeba Naegleria fowleri, often referred to as the "brain-eating amoeba." The clinical presentation typically follows this timeline:

• Early symptoms (2-5 days after exposure):

  • Change in taste or smell
  • Headache
  • Fever
  • Nasal congestion
  • Vomiting 2, 1

• Late symptoms (3-4 days after initial symptoms):

  • Stiff neck (meningismus)
  • Confusion and abnormal behavior
  • Seizures
  • Papilledema
  • Nystagmus
  • Cranial nerve abnormalities
  • Ataxia
  • Loss of balance and body control
  • Progression to coma and death 2, 1, 3

The disease predominantly affects children and young adults (median age 14 years), with males representing 75% of cases 4. Death typically occurs within 5 days of presentation due to cerebral edema 2.

Epidemiology

• Most cases occur after exposure to warm freshwater bodies (lakes, ponds, reservoirs) during summer months 2, 4
• Historically concentrated in southern US states, but cases are now being reported in northern regions, possibly due to climate change 2
• Alternative transmission routes include:
  • Municipal water supplies
  • Sinus irrigation with contaminated water (neti pots)
  • Ritual nasal ablution
  • Water slides 2

Diagnosis

Early diagnosis is critical but challenging, with only 27% of cases diagnosed pre-mortem 5. The diagnostic approach includes:

1. CSF analysis (resembles bacterial meningitis):

   • Elevated opening pressure
   • Neutrophilic pleocytosis (median 2400 cells/μL)
   • Low glucose concentration (median 23 mg/dL)
   • Elevated protein levels (median 365 mg/dL) 1, 5

2. Direct microscopy of CSF:

   • Identification of motile trophozoites (cornerstone of diagnosis) 1, 6

3. PCR testing:

   • Available from CDC and reference laboratories 1

4. Neuroimaging:

   • MRI may show frontal lobe involvement
   • Abnormal in approximately 75% of patients but not diagnostic for amoebic infection 1, 5

Treatment

The mortality rate exceeds 95%, but recent treatment advances have improved survival 2. The recommended treatment regimen includes:

1. Amphotericin B:

   • Administered both intravenously AND intrathecally (essential for reaching effective CSF concentrations)
   • Close monitoring of renal and cardiac function required due to nephrotoxicity 1

2. Miltefosine:

   • Now commercially available in the USA
   • Critical component of successful treatment regimens in survivors 2, 3

3. Additional agents (combination approach is critical):

   • Rifampin
   • Azithromycin
   • Sulfisoxazole or miconazole
   • Voriconazole (used in recent successful treatment) 1, 3

Prevention

• Avoid swimming in warm freshwater during periods of high water temperature and low water levels
• Use nose clips or avoid submerging the head when swimming in freshwater lakes or rivers
• Maintain minimum 15 ppm chlorine residual in water systems
• Use filtration through 0.1-0.2 μm filters
• Regular cleaning and disinfection of water storage tanks and distribution systems
• Avoid dead-end pipes, unused branches, and joints in water systems 1

Key Clinical Pitfalls

• PAM is often misdiagnosed as bacterial meningitis, delaying appropriate treatment 7
• Standard empiric antibiotics for bacterial meningitis are ineffective against N. fowleri 7
• Clinicians should include PAM in the differential diagnosis for any patient with meningitis symptoms and recent freshwater exposure
• Contact CDC immediately (770-488-7100) for diagnostic testing and treatment guidance if PAM is suspected 5

The survival of recent patients treated with regimens including miltefosine demonstrates that early diagnosis and aggressive combination therapy can improve outcomes in this otherwise devastating disease 2, 3.