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Cryptococcal meningitis

Disease name and synonyms

Cryptococcal meningitis

Fungi responsible 

Usually Cryptococcus neoformans. In non-immunocompromised people, C. gattii are proportionately more common. Very rarely other species of Cryptococcus.

Disease description

Subacute meningitis with increasing symptoms over 1-4 weeks. Headache, vomiting, intermittent fever and reduced mental acuity are the early clinical features. Later progressive decrease in conscious level, double vision then blindness, and stroke-like features occur, with raised intracranial pressure. Occasionally patients have focal neurological features. Focal central nervous system lesions are more common in non-immunocompromised people who may also develop communicating hydrocephalus and frequently also have focal lung lesions.

Frequency and global burden

Previously estimated at 1 million, the incidence  of AIDS-related CM is now falling due to antiretroviral therapy. A recent estimate is 278,250 cases each year. More common in sub-Saharan Africa and tropical countries (Brazil, Thailand, Malaysia, Papua New Guinea etc). In US, active population-based surveillance, conducted between 1992-1994, showed cryptococcosis developed in 2-5% of HIV-infected persons per annum.
Annual incidence has declined following widespread use of fluconazole and introduction of more effective combination antiretroviral treatment. Among HIV-negative persons in US, average annual incidence  has remained almost constant at about 1 case per 100,000 population.

Underlying problems and at risk patients

AIDS, transplantation and other immunocompromised patients. No underlying disease is present in some people, especially in the tropics.

Diagnostic testing

Cryptococcal antigen testing and culture. Cryptococcal antigen is detectable in cerebrospinal fluid (CSF) in >98% of patients. Occasionally antigen is positive and culture negative. Because raised intracranial pressure requires additional treatment, it should be measured when CSF is taken. Blood cultures (and rarely urine cultures) are also positive for C. neoformans in most patients. Cryptococcal antigen is positive in blood in >90% all patients with cryptococcal meningitis in AIDS, but less often in non-AIDS patients. Cryptococcal antigen may be detectable in urine too.

Treatments

Amphotericin (>0.7mg/Kg/d) plus flucytosine (75-100mg/Kg/d in split doses, if renal function normal) is the recommended treatment as induction therapy for at least two weeks followed by fluconazole (400mg/d) as maintenance therapy for at least 8 weeks. Lipids formulations of amphotericin B (3-6mg/Kg) can be used in place of conventional amphotericin B.

Alternative all oral therapies include fluconazole (>800mg/d) plus flucytosine 100mg/Kg/d in split doses).

Some amphotericin prior to an azole may significantly improve response rates. The use of flucytosine probably reduces relapse.

Raised intracranial pressure requires careful mechanical drainage with repeated lumbar punctures, a lumbar drain or intraventricular drain.

Detailed information about cryptococcosis treatment:

 IDSA clinical practise Guidelines 2010.

WHO management guidelines

Flucytosine on WHO essential medicines list

Outlook and prognosis

If diagnosed rapidly, treated with combined amphotericin B and flucytosine and raised intracranial pressure managed pro-actively, the 10 week mortality is probably under 20%. In patients treated late, and with only fluconazole therapy, the outcome is much poorer - >50% 10 week mortality in series from Africa. C. gattii infections probably respond less well. In those with underlying disease that cannot be controlled (ie lymphoma or untreated HIV infection), the outcome is poor.

Preventcrypto.org has much more information.

Images

Lumbar puncture being done in Uganda on a new HIV positive patient, to establish if he has cryptococcal meningitis. The patient is lying on his left side and the lumbar puncture needle is deep between his lumbar vertebra in the spinal canal, with clear cerebrospinal fluid (CSF) coming out slowly. Dr Henry is measuring his CSF lumbar pressure using a manometer (should be 12-19 cm H20). Over 65% of patients with cryptococcal meningitis have raised intracranial pressure, which needs repeat lumbar puncture in many patients to prevent death and visual loss. The CSF in the manometer (which is sterile) is used for analysis for protein, glucose, cell differential count, cryptococcal antigen detection, bacterial, fungal and mycobacterial culture and PCR for viruses, depending on the clinical circumstances.( Picture taken at Mulago National Referral Hospital, Kampala, Uganda and kindly supplied by David Boulware University of Minnesota).


Typical appearance of a skin lesion in a patient with disseminated cryptococcosis and meningitis. The raised edge, ulceration in the centre of the lesion is characteristic, although similar lesions are produced by Histoplasma and Penicillium marneffei.

Cryptococcus
Another example of a cryptococcal skin lesion


Microscopic appearance of C.neoformans


 Papilloedema of the retina indicating raised intracranial pressure, a major complication of cryptococcal meningitis. The earliest clinical sign of raised intracranial pressure is reduced pulsation of the retinal veins on direct ophthalmoscopy.

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