Fungal meningitis overview

# Overview
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. 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.

# Historical perspective
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. 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

# Classification
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.

# Pathophysiology
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.   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. 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-. 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.

# Causes
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. Other common causes of fungal meningitis include; Aspergillus spp., Blastomyces dermatitidis, Coccidioides immitis, Candida spp., Histoplasma capsulatum and Sporothrix schenckii. Rarely, fungal meningitis may be caused by Xylohypha (formerly Cladosporium) trichoides, Curvularia,  Mucor, Arthrographis kalrae, Pneumocystis jirovecii, Cryptococcus albidus,, Alternaria spp,, Rhodotorula spp,  Acremonium spp, Dreschlera spp, Malassezia spp, Scedosporium spp, Arthrographis spp,  Blastoschizomyces, Paecilomyces, Aureobasidium, Clavispora,  Ustilago, Exophiala (Wangiella) and Exserohilum

# Differentiating fungak meningitis from other Conditions
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.

# Epidemiology and Demographics
While cryptococcus and candida infections occur worldwide, other fungal infections tend to cluster in specific geographical regions. 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. Cryptococcal meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of HIV is high. The incidence of cryptococcal meningitis is almost the same as in meningococcal meningitis with an incidence of one case per 100,000 persons.
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  The incidence has decreased with the advent of HAART  although cases are still reported. 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 with approximately half of these resulting in death. The prevalence of fungal meningitis does not vary with gender. Non-Caucasian race have a higher prediclection to developing fungal meningitis especially coccidioidal meningitis The prevalence of fungal meningitis does not vary with age. 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 and in adults with neutropenia, often presenting with brain abscesses rather than meningitis. Children with certain conditions have higher incidence of fungal meningitis example myeloperoxidase deficiency, chronic granulomatous disease of childhood and chronic mucocutaneous candidiasis.

# Screening
It is recommended that patients with CD4 counts  100 cells/l, should have routine cryptococcal antigen screening. Patients with positive result are offered preemptive anti-fungal therapy.

# Risk Factors
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. 

# Natural History, Complications and Prognosis
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 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.

# Diagnosis

## History and Symptoms
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.On presentation patients may have the following symptoms, Headache, Neck stiffness, fever, Fatigue, Night sweats, cranial nerves involvement, Hydrocephalus, cranial neuropathy, Radiculopathy and cognitive and personality changes.

## Physical Examination
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.

## Laboratory Findings
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.

## CT
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.

## MRI
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).

# Treatment
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.