How to confirm a diagnosis of leptospirosis affecting the central nervous system (CNS)?

Diagnosing Leptospirosis with CNS Involvement

To confirm a diagnosis of leptospirosis affecting the central nervous system (CNS), a combination of clinical features, serological testing, and CSF analysis is required, with serological confirmation being the most definitive approach. 1

Clinical Presentation Suggestive of Neuroleptospirosis

• Leptospirosis typically follows a biphasic course with an initial bacteremic phase with flu-like symptoms lasting 4-7 days, followed by an immune phase characterized by fever, myalgia, and potential organ involvement 1
• CNS involvement occurs in approximately 10-15% of leptospirosis cases, with presentations ranging from aseptic meningitis to encephalitis 2
• Key clinical features suggesting neuroleptospirosis include:
  • Fever with chills and rigors, headache, and vomiting 2
  • Altered sensorium (seen in up to 81% of neuroleptospirosis cases) 2
  • Conjunctival suffusion (redness without exudate) - a highly suggestive clinical sign 1, 3
  • Evidence of hepatorenal dysfunction (jaundice, elevated liver enzymes, renal impairment) 1, 2
  • History of exposure to contaminated water or animals, particularly in endemic areas 4, 5

Diagnostic Testing Algorithm

1. Initial Laboratory Investigations

• Complete blood count (may show polymorphonuclear leukocytosis, thrombocytopenia, anemia) 1
• Liver function tests (elevated bilirubin with mild elevation of transaminases) 1
• Renal function tests (may show evidence of renal failure) 1
• Urinalysis (may show proteinuria and hematuria) 1

2. Serological Testing (Most Important)

• Collect blood for serological testing as early as possible 1, 3
• IgM ELISA - earliest positives appear 6-10 days after symptom onset 1
  • An IgM titer >1:320 is considered suggestive of leptospirosis 1
  • A titer of 1:80 to 1:160 is consistent with early infection but may be due to cross-reactions 1
• Microscopic Agglutination Test (MAT) - the gold standard for confirmation 1, 3
  • Collect convalescent serum >10 days after symptom onset 1
  • A fourfold or greater increase in titer between acute and convalescent specimens confirms the diagnosis 3
  • A single MAT titer ≥1:200 supports a probable case classification 3

3. CSF Analysis (Critical for CNS Involvement)

• Perform lumbar puncture if no contraindications exist 1
• Typical CSF findings in neuroleptospirosis:
  • Pleocytosis with lymphocytic predominance (mean 50 cells/μL) 2
  • Elevated protein levels (mean 115.5 ± 67.5 mg%) 2
  • Normal glucose 1
• Send CSF for:
  • Leptospira antibody testing - positive in some cases of neuroleptospirosis 2
  • PCR for Leptospira - if available and within first 5 days of illness 1, 6
  • Other tests to exclude differential diagnoses (Gram stain, bacterial culture, viral PCRs) 1

4. Blood Culture

• Collect aerobic blood cultures within the first 5 days of onset, before antibiotics 1
• Keep blood cultures at room temperature prior to dispatch to reference laboratory 1
• Note: Urine is not a suitable sample for isolation of leptospira 1

5. Neuroimaging

• MRI is preferred over CT for evaluation of CNS infections 1
• In neuroleptospirosis, neuroimaging may be normal in majority of cases (67%) 2
• When abnormal, diffuse cerebral edema is the most common finding (26%) 2

Diagnostic Criteria for Confirmation

• Confirmed case: A clinically compatible case with one of the following 3:

  • Isolation of Leptospira from a clinical specimen
  • Fourfold or greater increase in Leptospira agglutination titer between acute and convalescent serum specimens
  • Demonstration of Leptospira in clinical specimen by immunofluorescence

• Probable case: A clinically compatible case with supportive serologic findings (Leptospira agglutination titer ≥200 in one or more serum specimens) 3

Important Considerations and Pitfalls

• Deep altered sensorium at presentation and raised CSF protein are poor prognostic indicators 2
• Pathological mechanisms in neuroleptospirosis include direct invasion, immune-mediated processes, and vasculitis 2, 7
• Consider leptospirosis in patients with aseptic meningitis, especially with history of water exposure or animal contact 5
• Treatment should be initiated upon clinical suspicion without waiting for laboratory confirmation, as early treatment improves outcomes 1, 3
• Differential diagnosis should include other tropical infections that can cause CNS manifestations 7