Fungal meningitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

Fungal meningitis results from the infection of the meninges by fungi, most commonly cryptococcus. While cryptococcal meningitis occurs worldwide, other fungal meningitis are endemic to specific regions of the world.^[1] Fungal meningitis usually affects immunocompromised patients like HIV patients and transplant recipients on chronic immunosuppression medications. The course of the disease is progressive and may lead to complications if a high dose long term treatment with antifungals are not initiated.^[2]

The first report of human cryptococcosis was published by Busse and Busckhe more than 100 years ago; 10 years later, it was identified as the cause of human meningitis. Cryptococcus neoformans, an encapsulated basidiomycetous yeast, represents one of the most common CNS pathogens encountered in clinical practice today. In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis. In 1891, Heinrich Quincke provided an early analysis of CSF by introducing a new technique of lumbar puncture. Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with Exophiala dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant severe complications.^[3][4][5] The 1980s witnessed an increase in the number of cases of cryptococcus meningitis in the United States and certain African countries largely due to HIV infection

Fungal meningitis is usually classified according to the causative organism if identified. It may also be additionally classified according to the severity and duration of the disease as mild, moderate, severe, acute, subacute, chronic and recurrent fungal meningitis.^{[6][7][8][9][10][11][12][13][14]}

The pathophysiology of fungal meningitis is not very well studied however, it is known to have a lot of similarities with bacterial meningitis. Fungal meningitis usually occurs in immunocompromised patients. The initial step in fungal meningitis is the pulmonary exposure to the fungi by the inhalation of airborne fungal spores. The pulmonary infection is usually self limited and maybe asymptomatic. Fungal infections are not contagious so they do not spread from one person to another.With an associated impaired immune response the fungus may disseminate. For instance in cryptococcal infection, the fungus may remain dormant in the lungs until the immune system weakens and then can reactivate and disseminate to the CNS. Cryptococcus has predilection for CNS dessimination. Although this remains unclear, the presence of a receptor on glial cells for a ligand on the organism has been suggested to enhance its invasion.^[15] Cryptococcal meningitis is most common due to the virulence factors of the organism that enhancing invasion of the blood brain barrier. These factors include: polysaccharide capsule which makes the organism withstand phagocytosis and host immune system, melanin production, ability to thrive at mammalian body temperatures, urease production and phospholipase production.^{[16][17][18][19][20][21][22][23][24]} Once the fungi cross the blood brain barrier they cause an inflammation of the meninges and arachnoid space. The inflammation promotes cytokine release mainly tumor necrosis factor (TNF), interleukin 1, interleukin 2 , interleukin 6, interleukin 12, colony-stimulating factors, and interferon-λ.^[25][26][27] The cytokines lead to modulation of host system resuting in fever, increase in the permeability of the blood brain barrier and subsequent cerebral edema and increase in the intracranial pressure. The increase in the permeability of the blood brain barrier is the cause of the observed elevation of the protein level in the cerebral spinal fluid.^[28]

Fungal meningitis is initially caused by the inhalation of airborne fungal spores. The pulmonary infection is usually self limiting and can be asymptomatic. The most common cause of fungal infection is cryptococcus neoformans which is usually found in soil and bird excreta.^[29] Other common causes of fungal meningitis include; Aspergillus spp., Blastomyces dermatitidis, Coccidioides immitis, Candida spp., Histoplasma capsulatum and Sporothrix schenckii.^{[30][31][32][2][33]} Rarely, fungal meningitis may be caused by Xylohypha (formerly Cladosporium) trichoides, Curvularia, Mucor, Arthrographis kalrae, Pneumocystis jirovecii,^[34][35] Cryptococcus albidus,^[36], Alternaria spp,^[37], Rhodotorula spp, ^[38] Acremonium spp,^[39] Dreschlera spp,^[40] Malassezia spp,^[41] Scedosporium spp,^[42] Arthrographis spp,^[43] Blastoschizomyces,^[44][45] Paecilomyces,^[46][47] Aureobasidium,^[48] Clavispora,^[49] Ustilago,^[50] Exophiala (Wangiella)^[51] and Exserohilum^[5]

The differential diagnosis of fungal meningitis includes a range of medical conditions that can be broadly classified into infectious and non infectious. The cerebrospinal fluid analysis and radiological findings help distinguishing fungal meningitis from other causes of meningitis example bacterial meningeal infection, protozoal meningeal infection, viral meningeal infection, and non infectious causes.

While cryptococcus and candida infections occur worldwide, other fungal infections tend to cluster in specific geographical regions.^[52][2] There is an increasing trend of fungal meningitis. This has been attributed to enlarging population of high-risk immunosuppressed patients, more successful pharmacological immunosuppression and chemotherapies, increase in numbers of patients living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS), migration of susceptible persons into hyperendemic areas and aging of the population.^[2][53] Cryptococcal meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of HIV is high.^[28] The incidence of cryptococcal meningitis is almost the same as in meningococcal meningitis^[54] with an incidence of one case per 100,000 persons.^[54] Prior to the introduction of highly active antiretroviral therapy (HAART) in the United States, yearly incidence rate of cryptococcal meningitis was on ascendancy with incidence of 6600 cases per 100,000 persons with AIDS^[55] The incidence has decreased with the advent of HAART ^[56] although cases are still reported.^[57] The worldwide incidence of cryptococcal meningitis is pegged at 1,000,000 annually according to an estimate by Centers for Disease Control and Prevention CDC in 2009^[58] with approximately half of these resulting in death.^[58] The prevalence of fungal meningitis does not vary with gender.^[59] Non-Caucasian race have a higher prediclection to developing fungal meningitis especially coccidioidal meningitis^[60] The prevalence of fungal meningitis does not vary with age.^[59] The major factor accounting for age predilection has to do with the clinical state of the patient and the immune response. For example candida meningitis may occur in older children^[61][62] and in adults with neutropenia, often presenting with brain abscesses rather than meningitis.^[63] Children with certain conditions have higher incidence of fungal meningitis example myeloperoxidase deficiency,^[64][65] chronic granulomatous disease of childhood^[66][67] and chronic mucocutaneous candidiasis.^[68]

It is recommended that patients with CD4 counts ≤ 100 cells/μl, should have routine cryptococcal antigen screening. Patients with positive result are offered preemptive anti-fungal therapy.^[69][70]

Fungal meningitis rarely occurs in otherwise healthy individuals. Co-existing medical conditions, immunosuppression and travel history to areas where specific fungi are endemic are risk factors for fungal meningitis. ^{[30][31][32][2][53][71][72][73]}

If left untreated, neurological complications might occur. Fungal meningitis may be complicated by abscesses, bone invasion, fluid collections, neurological deficits, ocular invasion, papilledema, neurodevelopmental delays in children, and seizures^{[74][75][76][77][78]} The mortality associated with fungal meningitis is high. Better prognosis is associated with early diagnosis, early initiation of the treatment and compliance of patients with medications.

Fungal meningitis can occur in two main clinical pictures: subacute meningitis and chronic meningitis. Chronic meningitis is characterized by the presence of symptoms for more than four weeks. Commonly, patients with fungal meningitis have a history of one or more of the following chronic sinusitis, Granulocytopenia, chronic renal failure, Diabetes, Pregnancy, persons with diabetes, IV drug abuse, prolonged intravenous therapy, exposure history example travel to or residence inendemic regions of the pathogen, immune suppression examples systemic neoplasia, organ transplantation, Human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), water aspiration as in a case of Pseudoallescheria boydii and traumatic inoculation as in a case of Sporothrix schenckii.^{[13][52][30][31][32][2][53][71][72][73][79]}On presentation patients may have the following symptoms, Headache, Neck stiffness, fever, Fatigue, Night sweats, cranial nerves involvement,^[28] Hydrocephalus, cranial neuropathy, Radiculopathy and cognitive and personality changes.^[28]

As in the case of any disease, a complete physical exam must be done on the patient looking for positive and negative symptoms. The clinical presentation of fungal meningitis is usually obscure as are the findings on physical exam. The pertinent findings are low grade fever and possible neurological signs like focal weakness, loss of sensation and cranial nerves involvement. Physical exam findings, including presence of rashes, lymphadenopathy, hepatomegaly, pulmonary disease, ocular pathology (eg, endophthalmitis, vitritis, chorioretinitis, uveitis, optic nerve involvement), and cranial nerve (CN) palsies, may narrow the differential. Papilledema and abducens nerve palsy suggest the presence of increased intracranial pressure (ICP). Kernig’s sign and brudzinski’s sign are not typically present in fungal meningitis.

A lumbar puncture is essential for the diagnosis of fungal meningitis and initiation of the appropriate treatment. The cerebrospinal fluid (CSF) of a patient having fungal meningitis is distinguished by the presence of lymphocytosis, low glucose level and high proteins level. Specific CSF stains and cultures as well as serologies help in determining the specific nature of the causative fungi. Biopsy of skin lesions, chest radiography, ophthalmologic examination, computed tomography or MRI of the brain, in addition to cultures of CSF, blood, and sputum, may provide essential diagnostic clues.

The diagnosis of fungal meningitis mainly relies on the results of the cerebrospinal fluid (CSF) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased intracranial pressure to prevent brain herniation.

The diagnosis of fungal meningitis mainly relies on the results of the cerebrospinal fluid (CSF) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased intracranial pressure to prevent brain herniation. Also, MRI can detect meningeal enhancement, tumors and para-meningeal infections (brain abscess).^[28]

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure^[80].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

The first report of human cryptococcosis was published by Busse and Busckhe more than 100 years ago; 10 years later, it was identified as the cause of human meningitis. Cryptococcus neoformans, an encapsulated basidiomycetous yeast, represents one of the most common CNS pathogens encountered in clinical practice today. In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis. In 1891, Heinrich Quincke provided an early analysis of CSF by introducing a new technique of lumbar puncture. Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with Exophiala (Wangiella) dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant severe complications.^[1][2][3] The 1980s witnessed an increase in the number of cases of cryptococcus meningitis in the United States and certain African countries largely due to HIV infection

The major advancements in the history of meningitis may be summarized as follows:^{[4] [5]}

• Cryptococcus neoformans, an encapsulated basidiomycetous yeast, represents one of the most common CNS pathogens encountered in clinical practice today.
• The first report of human cryptococcosis was published by Busse and Busckhe more than 100 years ago; 10 years later, it was identified as the cause of human meningitis.

• In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis.
• In 1891, Heinrich Quincke provided an early analysis of CSF by introducing a new technique of lumbar puncture.
• In early 19th century, detailed profile of CSF analysis in meningitis was explained by William Mestrezat, and H. Houston Merritt.
• Advancements regarding the treatment of meningitis was given by Georg Joachmann in Germany and Simon Flexnor in USA in 18th and 19th century respectively
• Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with Exophiala (Wangiella) dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant severe complications.^[1][2][3]
• Between 1960s and 1970s, data from some United States hospitals showed an increase in the incidence of systemic fungal infections, including cryptococcosis.^[6]
• The 1980s witnessed an increase in the number of cases of cryptococcus meningitis in the United States and certain African countries largely due to HIV infection.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Fungal meningitis is usually classified according to the causative organism if identified. It may also be additionally classified according to the severity and duration of the disease as: mild, moderate, severe, acute, subacute, chronic and recurrent fungal meningitis.^{[1][2][3][4][5][6][7][8][9]}

Although fungal meningitis has no formal classification system, it is usually classified according to the causative organism if identified. It may however be additionally classified according to the severity and duration of the disease as shown below:^{[1][2][3][4][5][6][7][8][9]}

The common causes of fungal meningitis may be classified into two subgroups.

All of these may cause CNS infections. These include; Cryptococcus neoformans,^[10][11] Coccidioides immitis,^[12][13] Blastomyces dermatitidis,^[14][15] Paracoccidioides brasiliensis,^[16][17] Sporothrix schenckii,^[18][19] Histoplasma capsulatum,^[20][21] Pseudallescheria boydii (scedosporium apiospermum),^[22][23] dematiaceous fungi,^[24]

The second group is considered opportunistic, which take advantage of significant immune defects in the host. This group includes: Candida species,^[25][26][27] Aspergillus species,^{[28][29][29][30]} mucormycosis,^[31] and Trichosporon species.^[32][33]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

The pathophysiology of fungal meningitis is not very well studied however, it is known to have a lot of similarities with bacterial meningitis. Fungal meningitis usually occurs in immunocompromised patients. The initial step in fungal meningitis is the pulmonary exposure to the fungi by the inhalation of airborne fungal spores. The pulmonary infection is usually self limited and maybe asymptomatic. Fungal infections are not contagious so they do not spread from one person to another.With an associated impaired immune response the fungus may disseminate. For instance in cryptococcal infection, the fungus may remain dormant in the lungs until the immune system weakens and then can reactivate and disseminate to the CNS. Cryptococcus has predilection for CNS dessimination. Although this remains unclear, the presence of a receptor on glial cells for a ligand on the organism has been suggested to enhance its invasion.^[1] Cryptococcal meningitis is most common due to the virulence factors of the organism that enhance invasion of the blood brain barrier. These factors include: polysaccharide capsule which makes the organism withstand phagocytosis and host immune system, melanin production, ability to thrive at mammalian body temperatures, urease production and phospholipase production.^{[2][3][4][5][6][7][8][9][10]} Once the fungi cross the blood brain barrier they cause an inflammation of the meninges and arachnoid space. The inflammation promotes cytokine release mainly tumor necrosis factor (TNF), interleukin 1, interleukin 2 , interleukin 6, interleukin 12, colony-stimulating factors, and interferon-λ.^[11][12][13] The cytokines lead to modulation of host system resuting in fever, increase in the permeability of the blood brain barrier and subsequent cerebral edema and increase in the intracranial pressure. The increase in the permeability of the blood brain barrier is the cause of the observed elevation of the protein level in the cerebral spinal fluid.^[14]

The steps involved in the pathogenesis of fungal meningitis is a complex process. Majority of cases result from an imbalance between the host immune response and virulence factors of pathogen causing infection. Outlined below are the steps explaining the underlying process in a comprehensive way.^[15][16][17]

• The initial step in fungal meningitis is the pulmonary exposure to the fungi by the inhalation of airborne fungal spores.
• Inflammation results leading to a primary pulmonary and lymph node focus limiting the inhaled organism from further spread.^[15]
• The pulmonary infection is usually self limited and maybe asymptomatic.

• With an associated impaired immune response the fungus may disseminate. For instance in cryptococcal infection, the fungus may remain dormant in the lungs until the immune system weakens and then can reactivate and disseminate to the CNS. Cryptococcus has predilection for CNS dessimination. Although this remains unclear, the presence of a receptor on glial cells for a ligand on the organism has been suggested to enhance its invasion.^[1]

• Fungal infections are not contagious so they do not spread from one person to another.
• In most cases of fungal meningitis, the fungi undergo hematogenous spread.
• Patients with immunosuppression are the most vulnerable to fungal meningitis.
• Fungal meningitis may uncommonly occur In patients with no underlying immunosuppression. This usually is as a result of predisposing factors for instance some medical conditions such as pregnancy, certain lymphoreticular malignancies, iron chelation therapy, and diabetes impair host immune responses. These permit dissemination of even low-virulent pathogens.

• Cryptococcal meningitis is most common due to the virulence factors of the organism that enhancing invasion of the blood brain barrier. These factors include:^{[2][3][4][5][6][7][8][9][10]}
  • Polysaccharide capsule which makes the organism withstand phagocytosis and host immune system.
  • Melanin production
  • Ability to thrive at mammalian body temperatures
  • Urease production
  • Phospholipase production
• Once the fungi cross the blood brain barrier they cause an inflammation of the meninges and arachnoid space.
• The inflammation promotes cytokine release mainly tumor necrosis factor (TNF), interleukin 1, interleukin 2 , interleukin 6, interleukin 12, colony-stimulating factors, and interferon-λ.^[11][12][13]

• • The cytokines cause the fever observed in meningitis
  • The cytokines promotes an increase in the permeability of the blood brain barrier and subsequent cerebral edema and increase in the intracranial pressure
• Cerebral edema leads to decreased blood flow to the brain and hypoxia
• The glucose level in the cerebral spinal fluid (CSF) will decrease due to a decreased transport of glucose coupled to an increased use of glucose by the fungi
• The increase in the permeability of the blood brain barrier is the cause of the observed elevation of the proteins level in the cerebral spinal fluid.^[14]

• Stimulation of the nociceptive fibers by inflammatory processes:
  • Headache, neck pain, back pain
• Cerebral edema and obstructive of the cerebral spinal fluid‘s pathway:
  • Hydrocephalus
• Increased intracranial pressure:
  • Headache, vomiting, gait disturbance
• Vascular damage:
  • Cognitive and behavioral changes, seizures, stroke, myelopathy
• Seeding of inflammatory processes by the cerebral spinal fluid to the brainstem and cranial nerves (CN):
  • Vision loss (CN II), facial weakness (CN VII), hearing loss (CN VIII), diplopia (CN III, IV, V), other cranial nerves involvement
• Injury to spinal motor and sensory roots:
  • Radiculopathy with associated radicular pain, sensory loss, motor weakness^[18]

Homozygous neutrophil dependent mutation of caspase recruitment domain 9 (CARD9) have been discovered to predispose to invasive chronic candida infections, especially of the central nervous system.^[19]

On gross pathology, there is cerebral edema.

The image below is a microscopic pathology showing fungal component (multiple yellow arrow) in a section of brain tissue.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

Fungal meningitis is initially caused by the inhalation of airborne fungal spores. The pulmonary infection is usually self limiting and can be asymptomatic. The most common cause of fungal infection is cryptococcus neoformans which is usually found in soil and bird excreta.^[1] Other common causes of fungal meningitis include; Aspergillus spp., Blastomyces dermatitidis, Coccidioides immitis, Candida spp., Histoplasma capsulatum and Sporothrix schenckii.^{[2][3][4][5][6]} Rarely, fungal meningitis may be caused by Xylohypha (formerly Cladosporium) trichoides, Curvularia, Mucor, Arthrographis kalrae, Pneumocystis jirovecii,^[7][8] Cryptococcus albidus,^[9], Alternaria spp,^[10], Rhodotorula spp, ^[11] Acremonium spp,^[12] Dreschlera spp,^[13] Malassezia spp,^[14] Scedosporium spp,^[15] Arthrographis spp,^[16] Blastoschizomyces,^[17][18] Paecilomyces,^[19][20] Aureobasidium,^[21] Clavispora,^[22] Ustilago,^[23] Exophiala (Wangiella)^[24] and Exserohilum^[25]

Life-threatening conditions may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of fungal meningitis.

The most common cause of fungal meningitis is:^[26][27][5]

• Cryptococcus neoformans

Common causes of fungal meningitis include:^{[2][3][4][5][6]}

• Aspergillus sp.
• Blastomyces dermatitidis
• Coccidioides immitis
• Candida spp.
• Histoplasma capsulatum
• Sporothrix schenckii

The common causes of fungal meningistis may be classified into two subgroups.

All of these may cause CNS infections. These group include:

• Cryptococcus neoformans^[28][29]

• Coccidioides immitis^[30][31]

• Blastomyces dermatitidis^[32][33]

• Paracoccidioides brasiliensis^[34][35]

• Sporothrix schenckii^[36][37]

• Histoplasma capsulatum^[38][39]

• Pseudallescheria boydii (Scedosporium apiospermum)^[40][41]

• Dematiaceous fungi^[42]

The second group is considered opportunistic, which take advantage of significant immune defects in the host. This group includes:

• Candida species^[43][44][45]

• Aspergillus species^{[46][47][47][48]}

• Mucormycosis^[49]

• Trichosporon species^[50][51]

There are some rare causes of fungal meningitis. Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with Exophiala (Wangiella) dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant severe complications.^[52][53][25]

Some of the rare causes include the following:^{[54][16][7][8][9]}

• Xylohypha (formerly Cladosporium) trichoides and other dark-walled (demateaceous) fungi such as Curvularia and Drechslera
• Mucor
• Arthrographis kalrae
• Pneumocystis jirovecii^[7][8]
• Cryptococcus albidus^[9]

• Alternaria spp^[10]

• Rhodotorula spp ^[11]

• Acremonium spp.^[12]

• Dreschlera spp^[13]

• Malassezia spp^[14]

• Scedosporium spp^[15]

• Arthrographis spp^[16]

• Blastoschizomyces^[17][18]

• Paecilomyces^[19][20]

• Aureobasidium^[21]

• Clavispora^[22]

• Ustilago^[23]

• Exophiala (Wangiella)^[24]

• Exserohilum^[25]
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

The differential diagnosis of fungal meningitis includes a range of medical conditions that can be broadly classified into infectious and non infectious. The cerebrospinal fluid analysis and radiological findings help distinguishing fungal meningitis from other causes of meningitis example bacterial meningitis, protozoal meningeal infection, viral meningeal infection, and non-infectious causes.

Fungal meningitis must be differentiated from other causes of meningeal irritation as shown below:

• Meningeal infection
  • Bacterial meningitis
  • Protozoal meningeal infection
  • Helminthic meningeal infection
  • Viral meningeal infection
• Non infectious causes
  • Behçet’s syndrome
  • Chronic benign lymphocytic meningitis
  • Chemical meningitis
  • Drug hypersensitivity
  • Isolated granulomatous angiitis of the nervous system
  • Granulomatosis with polyangiitis (Wegener’s)
  • Malignancy
  • Mollaret’s meningitis
  • Sarcoidosis
  • Systemic lupus erythematosus
  • Vogt-Koyanagi-Harada syndrome^[1]

Fungal meningitis may be differentiated from other causes of meningitis by cerebrospinal fluid examination as shown below:^{[12][13][14][15][16]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

While cryptococcus and candida infections occur worldwide, other fungal infections tend to cluster in specific geographical regions.^[1][2] There is an increasing trend of fungal meningitis. This has been attributed to enlarging population of high-risk immunosuppressed patients, more successful pharmacological immunosuppression and chemotherapies, increase in numbers of patients living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS), migration of susceptible persons into hyperendemic areas and aging of the population.^[2][3] Cryptococcal meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of HIV is high.^[4] The incidence of cryptococcal meningitis is almost the same as in meningococcal meningitis^[5] with an incidence of one case per 100,000 persons.^[5] Prior to the introduction of highly active antiretroviral therapy (HAART) in the United States, yearly incidence rate of cryptococcal meningitis was on ascendancy with incidence of 6600 cases per 100,000 persons with AIDS^[6] The incidence has decreased with the advent of HAART ^[7] although cases are still reported.^[8] The worldwide incidence of cryptococcal meningitis is pegged at 1,000,000 annually according to an estimate by Centers for Disease Control and Prevention CDC in 2009^[9] with approximately half of these resulting in death.^[9] The prevalence of fungal meningitis does not vary with gender.^[10] Non-Caucasian race have a higher prediclection to developing fungal meningitis especially coccidioidal meningitis^[11] The prevalence of fungal meningitis does not vary with age.^[10] The major factor accounting for age predilection has to do with the clinical state of the patient and the immune response. For example candida meningitis may occur in older children^[12][13] and in adults with neutropenia, often presenting with brain abscesses rather than meningitis.^[14] Children with certain conditions have higher incidence of fungal meningitis example myeloperoxidase deficiency,^[15][16] chronic granulomatous disease of childhood^[17][18] and chronic mucocutaneous candidiasis.^[19]

There is an increasing trend of fungal meningitis. This has been attributed to the following: ^[2][3]

• Enlarging population of high-risk immunosuppressed patients
• More successful pharmacological immunosuppression and chemotherapies
• Increase in numbers of patients living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS)
• Migration of susceptible persons into hyperendemic areas
• Aging of the population

• It is the most common cause of fungal meningitis.^[20][21][2]

• Cryptococcus meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of HIV is high.^[4]
• It is a common opportunistic infection in patients with HIV and it is considered as an AIDS defining lesion. ^[22]

The incidence of cryptococcal meningitis in is almost the same as in meningococcal meningitis^[5] with an incidence of one case per 100,000 persons.^[5] Prior to the introduction of highly active antiretroviral therapy (HAART) in the United States, yearly incidence rate of cryptococcal meningitis was on ascendancy with incidence of 6600 cases per 100,000 persons with AIDS^[6] The incidence has decreased with the advent of HAART ^[7] although cases are still reported.^[8]

The worldwide incidence of cryptococcal meningitis is pegged at 1,000,000 annually according to an estimate by Centers for Disease Control and Prevention (CDC) in 2009^[9] with approximately half of these resulting in death.^[9]

The predominate species involved is cryptococcus neoformans, although there have been recent reports of incidence with Cryptococcus gattii Canada, Vancouver and the Pacific Northwestern United States^[23][24]

The incidence of Histoplasma meningitis is estimated to be 2.3 per 100,000 persons.^[3]

The incidence of Blastomyces meningitis is estimated to be 0.2 per 100,000 persons.^[3]

• Coccidioidomycosis is only prevalent in the Western Hemisphere, especially in the southwestern United States and northwestern Mexico.
• The annual incidence of the disease is not known.

The prevalence of fungal meningitis does not vary with age.^[10] The major factor accounting for age predilection has to do with the clinical state of the patient and the immune response.

For example candida meningitis may occur in older children^[12][13] and in adults with neutropenia, often presents with brain abscesses rather than meningitis.^[14]

The prevalence of fungal meningitis does not vary with gender.^[10]

• Non-Caucasian race have a higher predilection to developing fungal meningitis especially coccidioidal meningitis^[11]

The geographical distribution of endemic fungi causing meningitis are shown below:^[25]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

It is recommended that patients with CD4 counts ≤ 100 cells/μl, should have routine cryptococcal antigen screening. Patients with positive result are offered preemptive anti-fungal therapy.^[1][2]

Screening is recommended in some types of fungal meningitis. Cryptococcal meningitis commonly affects patients with CD4 count are ≤ 100 cells/μl. It is responsible for major cause of mortality and morbidity in HIV individuals. It is recommended that patients with CD4 counts ≤ 100 cells/μl, should have routine cryptococcal antigen screening. Patients with positive result are offered preemptive anti-fungal therapy.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

Fungal meningitis rarely occurs in otherwise healthy individuals. Co-existing medical conditions, immunosuppression and travel history to areas where specific fungi are endemic are risk factors for fungal meningitis. ^{[1][2][3][4][5][6][7][8]}

Risk factors in the development of fungal meningitis include:^{[9][10][1][2][3][4][5][6][7][8][11]}

• Aspergillus sp.
  • Sinusitis
  • Granulocytopenia
  • Immunosuppression
  • Chronic renal failure
  • Diabetes
• Blastomyces dermatitidis
  • Travel to or residence in midwestern and southeastern USA
  • Systemic infection
  • Abscesses
  • Draining sinus
  • Ulcers
• Coccidioides immitis
  • Exposure history
  • Travel to or residence in southwestern United States
  • Dark-skinned races
  • Elderly individuals
  • Income of < $15,000 per year
  • Pregnancy
  • Persons with diabetes and
  • Smoking
• Candida sp.
  • IV drug abuse
  • Post surgery
  • Prolonged intravenous therapy
  • Disseminated candidiasis
• Cryptococcus neoformans
  • Human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS)
  • Immune suppression (examples systemic neoplasia and organ transplantation)
  • Pigeon exposure
  • Skin and other organ involvement due to disseminated infection
• Histoplasma capsulatum
  • Exposure history
  • Travel to or residence in Ohio and central Mississippi River Valley
  • Human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS)
  • Mucosal lesions
• Pseudallescheria boydii
  • Water aspiration
• Sporothrix schenckii
  • Traumatic inoculation
  • IV drug use
  • Ulcerated skin lesion^[12]

Children with the following conditions have higher incidence of fungal meningitis:

• Myeloperoxidase deficiency^[13][14]

• Chronic granulomatous disease of childhood^[15][16]

• Chronic mucocutaneous candidiasis^[17]

• White blood cell defects^[15][16]

• Severe combined immunodeficiency SCID^[18]

• Advanced HIV^[19]

• Direct extension via trauma ^[20]

• Post ventriculostomy placement, or ventricular shunts, especially after antibacterial therapy^[21][22]

• Use of bischloroethylnitrosourea polymer wafers implanted for local therapy of CNS malignancies^[23][24]

• CNS drains and catheters represent disease^[25]

• In premature infants and neonates^[26]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

If left untreated, neurological complications may occur. Fungal meningitis may be complicated by abscesses, bone invasion, fluid collections, neurological deficits, ocular invasion, papilledema, neurodevelopmental delays in children, and seizures^{[1][2][3][4][5]} The mortality associated with fungal meningitis is high. Better prognosis is associated with early diagnosis, early initiation of the treatment and compliance of patients with medications.

If left untreated, neurological complications may occur.

The following are some complications that may follow fungal meningitis:^[2][3][4][5]

• Abscesses
• Bone invasion
• Fluid collections
• Neurological deficits
• Ocular invasion
• Papilledema
• Seizures^[1]
• Neurodevelopmental delays in children

Treatment of fungal meningitis in HIV-infected patients receiving HAART, organ transplantation, and pregnancy may result in immune reconstitution syndrome.^[6][7][8][9]

This may result in worsening of the pre-existing condition. Despite this, the duration of starting antifungal therapy when HAART has been initiated still remains unclear.^[10]

The mortality associated with fungal meningitis is high. Better prognosis is associated with early diagnosis, early initiation of the treatment and compliance of patients with medications.

Prior to the introduction of amphotericin B therapy, cryptococcal meningitis was almost always fatal. Now, although most of these patients can be cured with course of intravenous amphotericin B, the optimum duration of therapy is often unclear, and there is still a significant percentage of early deaths and late treatment failure.^[11][12][13]

The mortality of cryptococcal meningitis is high (10-30%).^[14]

Increasing levels of the following worsens the prognosis of HIV-negative cryptococcal meningitis patients with acute/subacute onset;

• Ratio of CSF glucose/blood glucose
• Impaired consciousness and
• Hospitalization length

Prognosis of coccidioidal meningitis

Prognosis is worst in patients with several sites of extrapulmonary dissemination compared to patients who have only meningeal involvement.^[15] Prior to the introduction of antifungal therapy, coccidioidal meningitis was almost always fatal.^[15]

Factors associated with a bad prognosis of coccidiodal meningitis are:^[16]

• Hydrocephalus

• Non-caucasian race

• Presence of an underlying disease

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