Cryptococcal Meningitis

A severe, life threatening fungal infection of the central nervous system caused predominantly by Cryptococcus neoformans. Cryptococcus gattii is also implicated, particularly in specific geographical regions and in some apparently immunocompetent hosts.

It is acquired through inhalation of environmental spores. Cryptococcus neoformans is particularly associated with bird droppings, especially pigeon excreta, as an environmental reservoir.

It occurs predominantly in significantly immunocompromised patients, most classically advanced HIV infection with a low CD4 count. It also occurs in solid organ transplant recipients and in other causes of significant cell mediated immune impairment.

It is a leading cause of adult meningitis in high HIV prevalence settings. Mortality is substantial without prompt recognition and treatment, including attention to raised intracranial pressure alongside antifungal therapy.

Pathophysiology and risk factors

• Following inhalation, the organism typically produces asymptomatic pulmonary infection with subsequent latency.
• Reactivation and haematogenous dissemination to the central nervous system occur with significant cell mediated immune impairment. This explains the strong association with advanced HIV infection (typically CD4 count below 100 cells per microlitre), the dominant global risk factor.
• The polysaccharide capsule is a key virulence factor. It contributes to immune evasion and to the characteristic, often severe raised intracranial pressure.
• The raised pressure is believed to reflect impaired cerebrospinal fluid drainage from capsular polysaccharide accumulation within the arachnoid villi. This has direct and critical management implications.

• Subacute onset of headache, fever, and, in a proportion, altered mental status, developing over days to a few weeks, is typical.
• The presentation is often more insidious than classical bacterial meningitis. Neck stiffness and photophobia are frequently less prominent or absent. Absence of classical meningism risks underestimating severity or delaying investigation.
• Raised intracranial pressure is a hallmark and clinically critical feature. It presents with severe headache and papilloedema, and, if inadequately managed, progressive visual loss and risk of herniation.
• The degree of raised pressure is often disproportionate to the apparent severity of the infection. It needs specific, active, ongoing management distinct from antifungal treatment alone.
• Cranial nerve palsies, seizures and focal neurological deficit can occur. They reflect either direct parenchymal involvement (cryptococcoma formation) or the effects of raised intracranial pressure.
• Disseminated disease can also involve the lungs (cough and breathlessness), skin and other organs. Skin lesions are characteristic umbilicated papules resembling molluscum contagiosum, particularly in advanced HIV infection.
• A previously undiagnosed HIV infection may first present with cryptococcal meningitis. HIV testing should be performed in every patient with this diagnosis where status is not already established.

• Lumbar puncture with measurement of opening pressure is essential for diagnosis and for initial and ongoing management of raised intracranial pressure.
• A markedly elevated opening pressure (frequently well above 25 cm of cerebrospinal fluid) is characteristic and needs specific active management.
• Cerebrospinal fluid cryptococcal antigen testing using a lateral flow assay offers rapid, highly sensitive and specific point of care diagnosis. It has transformed diagnostic capability.
• Serum cryptococcal antigen testing is also useful as a screening tool in asymptomatic, severely immunocompromised patients. Some high burden settings use it to identify subclinical infection before overt meningitis develops, allowing pre-emptive treatment.
• India ink staining of cerebrospinal fluid demonstrates the characteristic encapsulated yeast against a dark background. It is a rapid but less sensitive alternative where antigen testing is unavailable.
• Fungal culture of cerebrospinal fluid gives definitive confirmation. It also assesses organism viability, which is relevant to monitoring treatment response.
• Cerebrospinal fluid typically shows a lymphocytic pleocytosis, elevated protein and reduced glucose. The pleocytosis may be minimal or absent in advanced HIV infection because of profound immune impairment.
• Antigen or culture confirmation, rather than these non specific inflammatory parameters, establishes the diagnosis.
• Neuroimaging (computed tomography or, preferably, magnetic resonance imaging) should be obtained before lumbar puncture where there are focal neurological signs or significantly reduced consciousness, as for any suspected central nervous system infection.
• It should not unduly delay the essential diagnostic and therapeutic lumbar puncture in a patient without such concerning features.

• Induction treatment is liposomal amphotericin B 3 to 4 mg per kg intravenously once daily combined with flucytosine 25 mg per kg orally four times daily, continued for a minimum of two weeks.
• This is the current preferred first line regimen, with superior fungal clearance and mortality outcomes compared with amphotericin monotherapy or fluconazole based induction.
• Flucytosine has a narrow therapeutic index and a risk of myelosuppression. Adjust the dose and monitor according to renal function and flucytosine levels where available.
• Where flucytosine is unavailable, use amphotericin B monotherapy, or amphotericin combined with fluconazole 800 mg to 1200 mg once daily. These are generally less effective.
• Consolidation is fluconazole 400 to 800 mg once daily for a further eight weeks following successful induction.
• Maintenance (secondary prophylaxis) is fluconazole 200 mg once daily. It continues until adequate immune reconstitution has occurred. In HIV infection this is generally a CD4 count above 100 to 200 cells per microlitre sustained for at least twelve months on effective antiretroviral therapy.
• Management of raised intracranial pressure is a critical, distinct component of treatment alongside antifungal therapy.
• Perform therapeutic lumbar puncture at diagnosis, removing sufficient cerebrospinal fluid to reduce the opening pressure by approximately fifty percent, or to below 20 cm of cerebrospinal fluid. Repeat as clinically indicated, guided by persistent symptoms of raised pressure and repeat opening pressure measurement.
• Inadequately managed raised intracranial pressure is a major, independently modifiable contributor to mortality.
• Ventriculoperitoneal shunting or other neurosurgical intervention is considered for persistent, symptomatic raised intracranial pressure not adequately controlled with repeated therapeutic lumbar puncture, under specialist neurosurgical guidance.
• Timing of antiretroviral therapy in HIV associated cryptococcal meningitis needs careful consideration. Current guidance generally recommends a delay of at least four to six weeks after starting antifungal induction therapy.
• Earlier initiation carries a well established, significant risk of severe, potentially fatal immune reconstitution inflammatory syndrome affecting the central nervous system. This is an important exception to the generally favoured earlier antiretroviral therapy initiation in most other HIV associated opportunistic infections.
• Corticosteroids are not routinely recommended for HIV associated cryptococcal meningitis, in contrast to their established role in bacterial and tuberculous meningitis. Evidence shows no benefit and potential for harm.
• Monitor closely throughout treatment. Repeat lumbar puncture where indicated to assess ongoing pressure and, where relevant, fungal clearance. Monitor for antifungal toxicity: renal function with amphotericin, full blood count with flucytosine.
• The condition is severe but substantially treatable when managed on these principles.