What is the recommended treatment for histoplasmosis with central nervous system (CNS) involvement presenting with double vision?

Treatment of Histoplasmosis with CNS Involvement Presenting with Double Vision

For histoplasmosis with central nervous system involvement presenting with double vision, liposomal amphotericin B (5.0 mg/kg daily for 4-6 weeks) followed by itraconazole (200 mg 2-3 times daily for at least 12 months) is the recommended treatment regimen. 1

Diagnosis Considerations

When a patient presents with double vision and suspected CNS histoplasmosis:

• Evaluate for other neurological symptoms: headache, confusion, mental status changes, seizures, or focal neurological deficits 1
• CSF analysis typically shows:
  • Lymphocytic pleocytosis
  • Elevated protein
  • Hypoglycorrhachia (low glucose) 1
• Diagnostic testing should include:
  • CSF culture (gold standard but only positive in 20-60% of cases) 1
  • CSF Histoplasma antigen testing (positive in 40-70%) 1
  • CSF antibody testing (positive in 70-90%) 1
  • Urine and serum Histoplasma antigen testing 2
  • Brain MRI to identify single or multiple enhancing lesions 1

Treatment Algorithm

Initial Phase (Induction Therapy)

• Liposomal amphotericin B at 5.0 mg/kg daily IV for 4-6 weeks 1, 2
  • Preferred over amphotericin B deoxycholate due to better CNS penetration 1
  • Liposomal formulation achieves higher concentrations in the brain than other formulations 1

Maintenance Phase (Consolidation Therapy)

• Itraconazole 200 mg 2-3 times daily for at least 12 months 1, 2
  • Loading dose: 200 mg three times daily for first 3 days 1
  • Maintenance: 200 mg twice daily thereafter 1
  • Monitor serum levels to ensure concentration >1.0 μg/mL 1, 3

Alternative Regimens

• If patient cannot tolerate liposomal amphotericin B:

  • Amphotericin B deoxycholate 0.7-1.0 mg/kg daily may be used 1, 4
  • Total cumulative dose should be at least 35 mg/kg 1

• If patient cannot take itraconazole:

  • Fluconazole 800 mg daily can be used, though it's less effective 1
  • Note that fluconazole has a 74% response rate compared to higher rates with itraconazole 3

Monitoring During Treatment

• Monitor for amphotericin B toxicity:

  • Renal function
  • Electrolytes (particularly potassium and magnesium)
  • Complete blood count 4

• For itraconazole:

  • Check serum levels after 2 weeks of therapy 3
  • Target trough level >1.0 μg/mL 1, 3
  • Monitor liver enzymes before therapy and at 1,2, and 4 weeks, then every 3 months 3
  • Be aware of numerous drug interactions 5

• Monitor Histoplasma antigen levels:

  • During therapy and for 12 months after completion 1
  • Decline in antigen levels indicates response to therapy 1
  • Failure to decline suggests treatment failure 1
  • Rising levels (>2-4 units) after decline suggests relapse 1

Special Considerations

• CNS histoplasmosis has a poorer outcome compared to other forms:

  • 20-40% mortality despite treatment 1
  • Up to 50% relapse rate after therapy is discontinued 1

• Risk factors for poor outcomes:

  • Age ≥54 years 2
  • Immunocompromised status 2
  • AIDS (particularly with poor medication adherence) 2

• For patients who relapse:

  • Consider chronic fluconazole maintenance therapy at 800 mg daily 1
  • Consider lifelong suppressive therapy in immunocompromised patients 1

Important Caveats

• Double vision (diplopia) in CNS histoplasmosis may result from cranial nerve involvement or focal brain lesions
• Treatment should be initiated promptly as CNS histoplasmosis is progressive and fatal if untreated 1
• Neither amphotericin B nor its lipid formulations achieve detectable concentrations in CSF, but clinical response is still observed 1
• Itraconazole does not enter CSF well but is still effective as maintenance therapy 1
• Intrathecal or intraventricular therapy has not been encouraging and is discouraged except as a last resort 1

The aggressive approach with liposomal amphotericin B followed by long-term itraconazole is warranted due to the high mortality and relapse rates associated with CNS histoplasmosis 2, 6.