Table of Contents
- Introduction
- Pathophysiology
- Etiology
- Table 1: Common Fungi associated with meningitis
- Risk Factors
- Clinical Manifestations
- Differential Diagnosis
- Diagnosis and Management
- Laboratory tests
- Table 2: Cerebrospinal fluid analysis
- Specific laboratory tests
- Cryptococcal meningitis
- Histoplasma meningitis
- Coccidioides meningitis
- Blastomycosis meningitis
- Candida meningitis:
- Sporothrix meningitis:
- Table-3: Overview of drugs for fungal infections of the CNS
- Complications
- Prevention
- Further Reading
- Bibliography
Primary Category
Neuroinfectious
P-Category
Secondary Category
S-Category
Introduction
- Meningitis is defined as the inflammation of the fluid and membranes (meninges) surrounding the brain and spinal cord.
- The causes of meningitis may be infectious or non-infectious
- Infectious causes include viral, bacterial, fungal, or parasitic
- The worldwide incidence of cryptococcal meningitis alone in HIV/AIDS patients was estimated at 223,100 cases per year worldwide, resulting in 181,100 annual deaths in 2014
Pathophysiology
- In most cases, fungal spores are inhaled during breathing which causes initial pulmonary infection.
- The subsequent seeding of infection to the brain or spinal cord causes meningitis.
- Candida is normal body flora, and it can cause meningitis in certain individuals with immunodeficiency,
- It can be also directly inoculated into CNS during neurosurgical procedures.
- It is not contagious from person to person
Etiology
The most common causative organisms, areas of distribution, and primary source of infection are given in Table 1.
Table 1: Common Fungi associated with meningitis
Common Fungi associated with meningitis
Type of Fungus
Area of Distribution
Source of Infection
Primary Site of Infection
Tropical and Subtropical Regions
Soil and Decaying vegetation
Paranasal Sinuses, Direct Seeding
Risk Factors
- Immunodeficiency
- Solid-organ transplantation
- Stem cell transplantation
- Steroids
- TNF inhibitors
- AIDS
- Diabetes Myelitis
- Low-birth-weight neonates
- Post-neurosurgery patients
- Alcoholics
- Malignancies
Clinical Manifestations
- Fever
- Headache
- Neck Rigidity
- Nausea and Vomiting
- Confusion
- Photophobia
- Seizures
- Muscle aches
- Dry cough
- CN palsies
- Lethargy and Coma
- Ataxia
- Other focal neurologic deficits
Differential Diagnosis
Fungal meningitis must be differentiated from other diseases like
- Bacterial Meningitis
- Viral Meningitis
- Tubercular Meningitis
- Encephalitis
- Brain abscess
- Syphilis
- Malignancies
Diagnosis and Management
- Fungal meningitis needs an extensive workup for diagnosis
Laboratory tests
- Blood work may show peripheral leukocytosis, lymphocytosis, and increased inflammatory markers like ESR and CRP.
- Lumbar puncture shows increased opening pressure usually greater than 200mm of H2O.
- Typical CSF findings in fungal meningitis are shown in Table 2
Table 2: Cerebrospinal fluid analysis
Cerebrospinal fluid analysis
CSF Parameters
Bacterial Meningitis
Viral Meningitis
Fungal Meningitis
Tuberculous Meningitis
1000—10,000
Range <100—20,000
<300
Range <100—1000
20—500
Variable, dependent upon fungus
50—500
Range 50—4000
Specific laboratory tests
The specific laboratory tests, imaging studies, and treatment plans are in accordance with causative agent
Cryptococcal meningitis
Diagnosis
- CSF cryptococcal antigen testing by latex agglutination has a sensitivity and specificity of >90%.
- CSF culture is also positive after 5-7 days.
- Cryptococcal antigen testing is the gold standard
Treatment
- Induction therapy: Amphotericin B 0.7–1.0 mg/kg per day intravenously combined with flucytosine 100mg/kg/day for 2 weeks.
- Consolidation phase: Fluconazole 400 – 800 mg/day for at least 8 weeks.
- Maintenance therapy: Fluconazole 200 mg/day for ≥1 year from initiation of therapy.
Complications
- Immune reconstitution inflammatory syndrome (IRIS): Seen in HIV-infected individuals
Histoplasma meningitis
Diagnosis
- Histoplasma antigen is positive in the urine of >90% of the patients while in serum of 50%.
- A fourfold increase in antibody level during serial antibody testing suggests active infection.
- Complement fixation against Histoplasma antigen in CSF diagnoses the Histoplasma meningitis even if the culture is negative.
- Methenamine silver staining of histopathological tissue shows oval narrow-based budding yeast.
Treatment
- Induction therapy: Liposomal amphotericin B 5 mg/kg intravenously daily for four to six weeks.
- Consolidation phase: Oral itraconazole, 200 mg two to three times a day for ≥12 months
Coccidioides meningitis
Diagnosis
- CSF analysis is of prime importance in the diagnosis and management of coccidiosis. Eosinophils, if present, are highly suggestive of coccidioides meningitis.
- Complement fixation antibody in CSF is the most reliable test.
- The skin lesions, if present, are the important source of histopathology
Treatment
- Fluconazole 400 to 800 mg daily is the preferred treatment regimen
- If treatment fails, itraconazole or intrathecal Amphotericin B can also be used.
- Suppression therapy: Lifelong, especially in immunocompromised individuals
Complications
- Hydrocephalus: Managed by VP shunts
Blastomycosis meningitis
Diagnosis
- Biopsy of extracranial lesion of skin, bone, or lung shows broad-based budding yeast.
Treatment
- Induction therapy: Lipid formulation of amphotericin B 5 mg/kg per day for 4 to 6 weeks,
- Consolidation phase: Oral azole for about 12 months.
- Suppression therapy: Lifelong, especially in an immunocompromised individual
Candida meningitis:
Diagnosis
- CSF culture may be helpful in some cases
Treatment
- Induction therapy: Liposomal amphotericin B 5 mg/kg intravenously once daily with or without flucytosine 25 mg/kg orally four times daily for several weeks.
- Consolidation phase: Fluconazole 400 to 800 mg 6 to 12 mg/kg oral daily as a step-down therapy
Sporothrix meningitis:
Diagnosis
- Culture is the most sensitive and gold standard test.
- Skin lesion biopsy is used for histopathological diagnosis.
- Beta D-glucan essay is also positive in different types of invasive fungal infection.
Treatment
- Induction therapy: Liposomal amphotericin B 3 to 5 mg/kg/day
- Consolidation phase: Itraconazole 200 mg twice daily for 12 months
Table-3: Overview of drugs for fungal infections of the CNS
Overview of drugs for fungal infections of the CNS
Drug
Indications
Usual dose
Cryptococcal meningitis, systemic candidias, histoplasmosis
Oral/IV: 400mg daily
Oral: 200mg daily for prophylaxis
Blastomycosis, aspergillosis resistant to/intolerant of amphotericin B
Oral: 400–800mg daily, then 400mg daily
Candidal and cryptococcal infection, blastomycosis, histoplasmosis
Oral: 600mg daily × 3 days, then 200mg daily
Invasive aspergillosis, Fusarium, Scedosporium, apiospermum and candidaemia
IV loading: 6 mg/kg q12h × two doses; maintenance: 4 mg/kg q12h
Oral loading: 400mg q12h × two doses; maintenance: 200mg q12h
Patients <40kg oral loading: 200mg q12h × two doses; maintenance: 100mg q12h
Prophylaxis against candidiasis and aspergillus in severely immunocompromised hosts
Invasive aspergillosis resistant to or patients intolerant of other therapies, zygomycoses, dematiaceous fungi, candida
Oral: 200mg four times daily or 400mg twice daily (prophylaxis dose is 200mg every 3 hours)
Aspergillosis, blastomycosis, candidiasis, coccidiomycosis, cryptococcus, histoplasmosis, severe fungal infections of the CNS
IV: typically 1.0–1.5 mg/kg/day, although dose may vary slightly with indication; ocassionally intrathecal.
Aspergillosis, candidiasis, cryptococcus in refractory cases or when intolerance or renal impairment precludes use of conventional amphotericin B, cryptococcus in HIV patients
Invasive fungal infections in refractory cases or when patients are intolerant of amphotericin B
IV: 3–5 mg/kg/day; has been used in dosages up to 7.5–10 mg/kg/day
IV: 5 mg/kg/day; has been used in dosages up to 10 mg/kg/day
Invasive aspergillosis; esophageal candidiasis; Fusarium, Scedosporium/Pseudallescheria resistant to, or patients intolerant of other agents, Zygomycosis, histoplasmosis, blastomycosis and dematiaceous fungal infections
IV: 5 mg/kg/day
Aspergillosis when renal impairment or unacceptable toxicity precludes, or when refractory to, conventional amphotericin B
IV: 3–4 mg/kg/day; maximum 7.5 mg/kg/day
Derived from: Góralska, K., Blaszkowska, J., & Dzikowiec, M. (2018). Neuroinfections caused by fungi. Infection, 0(0), 1–17. https://doi.org/10.1007/s15010-018-1152-2
Complications
CT scan and MRI with contrast done to rule out the complications
- Hydrocephalus
- Cranial nerve palsies
- Brain abscesses
- Frequent relapses
Prevention
For Prevention, the immunocompromised individual must take the following measures,
- Avoid construction or excavation sites, especially when there is a risk for dust exposure.
- Limit outdoor activity during dust and wind storms
- Avoid gardening, landscaping.
- Take prophylactic antifungal medication when recommended.
Further Reading
- Góralska, K., Blaszkowska, J. & Dzikowiec, M. Neuroinfections caused by fungi. Infection 46, 443–459 (2018). https://doi.org/10.1007/s15010-018-1152-2
- Pagliano P, Esposito S, Ascione T, Spera AM. Burden of fungal meningitis. Future Microbiol. 2020;15:469-472. doi:10.2217/fmb-2020-000
- Raman Sharma R. Fungal infections of the nervous system: Current perspective and controversies in management. International Journal of Surgery. 2010;8(8):591-601.
Bibliography
- Abassi, M., Boulware, D. R., & Rhein, J. (2015). Cryptococcal Meningitis: Diagnosis and Management Update. Current tropical medicine reports, 2(2), 90–99. https://doi.org/10.1007/s40475-015-0046-y
- Fungal Meningitis. Cdc.gov. https://www.cdc.gov/meningitis/fungal.html. Published 2021. Accessed August 26, 2021.
- Charles P. Davis, MD, PhD. Fungal Meningitis. Medicinenet.com. https://www.medicinenet.com/fungal_meningitis/article.htm#fungal_meningitis_facts. Published 2021. Accessed August 30, 2021.
- Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Clinicalinfo.hiv.gov. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines. Published 2021. Accessed August 30, 2021.
- Kauffman, MD C, Marr, MD K, Baron, MD, DTMH E. Candida infections of the central nervous system. Uptodate.com. https://www.uptodate.com/contents/candida-infections-of-the-central-nervous-system. Published 2021. Accessed August 25, 2021.
- Mayo Clinic Staff. Valley fever - Symptoms and causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/valley-fever/symptoms-causes/syc-20378761. Published 2020. Accessed August 25, 2021.
- Rajasingham, R., Smith, R. M., Park, B. J., Jarvis, J. N., Govender, N. P., Chiller, T. M., Denning, D. W., Loyse, A., & Boulware, D. R. (2017). Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. The Lancet. Infectious diseases, 17(8), 873–881. https://doi.org/10.1016/S1473-3099(17)30243-8
- Salardini A, Biller J. The Hospital Neurology Book. McGraw-Hill Education, Inc.; 2016:92-96.
- Slavoski LA, Tunkel AR. Therapy of fungal meningitis. Clin Neuropharmacol. 1995 Apr;18(2):95-112. doi: 10.1097/00002826-199504000-00001. PMID: 8635178.
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