Fungal Meningitis

Authors:

Hafiz Muhammad Waqas Siddique MD,

Talha Nazir MD,

Junaid Kalia MD

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

Table 1: Common Fungi associated with meningitis

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

• 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

Specific laboratory tests

Cryptococcal meningitis

• 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

• 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.

• Immune reconstitution inflammatory syndrome (IRIS): Seen in HIV-infected individuals

Histoplasma meningitis

• 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.

• 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

• 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

• 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

• Hydrocephalus: Managed by VP shunts

Blastomycosis meningitis

• Biopsy of extracranial lesion of skin, bone, or lung shows broad-based budding yeast.

• 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:

• CSF culture may be helpful in some cases

• 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:

• 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.

• 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

Complications

• Hydrocephalus

• Cranial nerve palsies

• Brain abscesses

• Frequent relapses

Prevention

• 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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