Cryptococcal meningitis

Cryptococcal neoformans etiological agent.

Approximately 1,000,000 cases annually and 300,000 deaths, worldwide.

Common cause of meningitis with HIV infection.

The second leading cause of HIV related death worldwide, with the majority of the deaths occurring in sub Saharan Africa.

The  increased use of immunomodulatory therapy and underlying natural susceptibility have changed the epidemiology such that deaths now are non-HIV infected patients account for approximately 1/3 of the deaths related to cryptococcal meningitis or meningoencephalitis.

One of the most common in serious HIV-related opportunistic infections among adults in sub Saharan Africa, leading to an estimate 135,900 deaths every year.

Infection occurs when a patient inhales the airborne spores of Cryptococcus neoformans.

Approximately 20% of cryptococcal, meningitis cases in the US occur in previously healthy persons without known immune deficits: 30 show however many of these patients have auto antibody disease.

A fungus found in soil around the world.

Cryptococcal polysaccharide capsule that is present causes a physical obstruction of the arachnoid villi, which leads to a failure to resorb CSF and in turn elevates intracranial pressure.

Poor outcomes with conventional anti-fungal treatment regimens are associated with the high mortality from cryptococcal meningitis.

The elevation in intracranial pressure is correlated with an increased number of organisms in the CSF.

Approximately half of HIV, infected patients with cryptococcal meningitis have pressures greater than 25 cm of water.

High cranial pressures are associated with headache, altered mental status, nausea, cranial nerve defects, cognitive sequelae, and increased short term mortality.

obstructive hydrocephalus can be readily diagnosed by MRI exam with the presence of increase ventricular size and transependymal flow or sulcral effacement.

Major risk factor is AIDS with CD4+ cell count of less than 100/µL.

Often considered in patients with HIV infection, but can occur in patients with impaired cell mediated immunity from other processes.

Healthy individuals immune system can easily fight the infection off.

The fungus often spreads from the lungs to other parts of the body, eventually making its way to the meninges.

In the meninges it can impair the brain’s ability to reabsorb CSF producing a build up within the skull often resulting in intractable headaches.

A complication of intracranial hypertension is cerebral edema with symptoms and signs that include headaches, vomiting, visual changes, papilledema, abducens nerve palsy, altered mental status, and ultimately coma.

When the disease is suspected lumbar puncture is the best first step in diagnosing the process.

Imaging with CT or MRI, the latter is more sensitive, is useful during the initial evaluation for identifying structural lesions, including hydrocephalus.

Typically, CSF studies reveal high opening pressure, lymphocytic pleocytosis, low glucose concentration, and high protein level.

CM Should be considered in all cases of lymphocytic meningitis.

CSF cryptococcal antigen testing has a rapid turnaround and can establish the diagnosis with high specificity and sensitivity.

Serum cryptococcal antigen testing can also be helpful in assessment of the disease.

Common process in patients with immunosuppressive states such as those treated with corticosteroids, organ transplantation, diabetes, cirrhosis of the liver and hematologic malignancies.

Fungal cultures of blood and CSF specimens can be helpful in the diagnosis.

The neurotropism of C neoformans caused by lack of complement mediation of opsonic activity in the CNS.

CSF dopamine is a precursor of cryptococcal melanin, which is associated with increased pathogenicity.

Patients usually present with subacute or chronic meningitis symptoms of a few weeks duration.

The symptoms such as headache, altered mental status, however, not specific.

Management of increased intracranial pressure is important to prevent cranial nerve palsies, visual impairment, impaired mentation, confusion and hallucinations.

Cryptococcal meningitis has not been reduced by the present treatment of cryptococcal infection due to the presence of  latent central nervous system reservoir.

Elevated white blood cell counts, with predominately, lymphocytes, and total protein levels and low glucose levels in CSF are suggestive of cryptococcal meningitis.

CSS fungal cultures are useful to establish the diagnosis into a differentiate from inflammatory sequelae.

Treatment of increased intracranial pressure include repeated lumbar punctures, placement of a ventriculostomy, and ventriculoperitoneal shunting.

Daily therapeutic lumbar punctures reduce cranial pressure and is associated with reduce mortality.

Other methods of managing intracranial pressure include lumbar drains, and ventricular peritoneal shunts.

Treatment in non-HIV infected patients includes amphotericin B and flucytosine.

Doses of amphotericin B are 0.7-1 mg per kilogram of body weight per day and flucytosine 100 mg per kilogram per day.

Combination of two agents results in more rapid results and with a decreased risk of relapse.

The combination of amphotericin B and flucytosine has not been shown to reduce mortality, as compared with amphotericin be

Fluconazole monotherapy can be used for mild cryptococcal disease not involving the CNS.

Preemptive fluconazole therapy administered over a period of 10 weeks has prevented progression to cryptococcal meningitis in 75% of patients who test positive for cryptococcal antigen.

Treatment for cryptococcal meningitis is lengthy and includes three stages: induction, consolidation, and maintenance.

Induction management consists of formulations of amphotericin B plus flucytosine is 4 to 6 weeks.

In a randomized open trial of induction therapy for cryptococcal meningitis in patients with HIV treated with amphotericin B, flucytosine and amphotericin B or fluconazole and amphotericin B: Amphotericin B and flucytosine for two weeks was associated with reduced mortality, as compared with four weeks of amphotericin B monotherapy, and the combination of fluconazole for two weeks was not a found to be of benefit (Day JN et al).

Single-dose liposomal amphotericin B combined with cytosine and fluconazole was not inferior to treatment with HIV associated cryptococcal meningitis with WHO recommended flucytosine, fluconazole and amphotericin B.

Increased intracranial pressure should be managed to decrease morbidity and mortality by using seral LPs.