Cryptococcal meningitis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Cryptococcus neoformans and C gattii are encapsulated environmental yeasts acquired by inhalation. Organisms disseminate from lung to CNS when cell-mediated immunity is impaired, especially in advanced HIV, but disease also occurs after transplantation, corticosteroids and in people without recognised immune deficiency.

The polysaccharide capsule impairs phagocytosis and obstructs CSF resorption, producing intracranial pressure that is partly independent of inflammatory cell count. Fungal clearance requires fungicidal induction with amphotericin plus flucytosine, followed by fluconazole consolidation and maintenance. Mechanical pressure control is a co-equal lifesaving treatment.

Key points

Cryptococcal meningitis usually evolves over days to weeks with headache, fever, malaise, cognitive change or visual symptoms; neck stiffness may be minimal.
Advanced HIV is the common context, but transplant, corticosteroids, malignancy and apparently immunocompetent disease occur.
Test serum and CSF cryptococcal antigen and culture; measure lumbar opening pressure every time it is clinically relevant.
Start induction with liposomal amphotericin B 4 mg/kg intravenously daily plus flucytosine 25 mg/kg orally four times daily for 2 weeks under specialist guidance.
Use serial therapeutic lumbar punctures for symptomatic or measured pressure elevation, removing sufficient CSF to reduce pressure safely.
Step to fluconazole consolidation only after clinical assessment and evidence of viable-organism clearance; antigen titre alone does not prove sterility.
Delay ART usually 4 to 6 weeks after effective antifungal treatment begins, individualised by HIV and infection teams.
Continue fluconazole consolidation and maintenance until the specified duration, viral suppression and immune-recovery criteria are met.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Cryptococcus neoformans

Environmental yeast associated with soil and bird-contaminated material causes most disease, especially in advanced cell-mediated immune deficiency.

Cryptococcus gattii

An environmental species can cause pulmonary and CNS disease in apparently immunocompetent hosts and may form cryptococcomas.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Pulmonary entry and dissemination
Inhaled yeast establishes lung infection and spreads haematogenously to meninges when macrophage and T-cell control fails.
2
Capsular immune evasion
The polysaccharide capsule inhibits phagocytosis and modulates inflammation, allowing a very high fungal burden despite scant CSF inflammatory cells.
3
CSF outflow obstruction
Yeast and capsular material impair arachnoid granulation resorption, raising pressure and threatening optic nerves and brain perfusion.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Subacute meningitisRed flag

Progressive headache, fever, nausea, cognitive slowing and weight loss over days to weeks suggests cryptococcal or tuberculous meningitis.

Raised pressureRed flag

Visual blurring, diplopia, vomiting, papilloedema or sixth-nerve palsy indicates pressure-related optic and cranial-nerve threat.

Advanced HIV contextRed flag

Oral thrush, wasting, previous opportunistic illness or unknown HIV status strengthens probability and prompts urgent HIV testing.

Pulmonary or disseminated diseaseRed flag

Cough, skin papules, bone pain or positive blood culture indicates disease beyond meninges and influences staging.

Red flags requiring action

Visual loss, cranial neuropathy or reduced consciousness requires urgent pressure measurement and repeated therapeutic lumbar puncture.
A normal brain scan does not exclude dangerous raised CSF pressure in cryptococcal meningitis.
Renal decline, hypokalaemia, hypomagnesaemia or cytopenia during induction can become fatal without daily monitoring and dose adjustment.
Starting ART immediately in cryptococcal meningitis increases dangerous CNS immune-reconstitution risk and requires planned delay.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
CSF opening pressure and analysisFirst step
Why
Diagnose meningitis and quantify a treatable mechanical threat.
Interpretation and limitations
Measure with the patient correctly positioned. High pressure prompts therapeutic drainage; low cells do not exclude disease in profound immune suppression.
02
CSF cryptococcal antigen and fungal culture
Why
Confirm capsular antigen and demonstrate viable yeast.
Interpretation and limitations
Antigen is highly sensitive but remains positive after killing. Culture sterility, symptoms and CSF findings guide phase transition.
03
Serum cryptococcal antigen and blood cultures
Why
Detect disseminated infection and screen advanced HIV before symptoms in indicated settings.
Interpretation and limitations
A high serum titre increases dissemination probability but does not replace lumbar puncture when CNS disease is possible.
04
HIV, CD4 and organ baseline
Why
Define immune context, ART timing and antifungal toxicity risk.
Interpretation and limitations
Obtain HIV RNA, CD4, FBC, renal, liver, potassium and magnesium urgently; treatment starts before every result returns.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Tuberculous meningitis

Subacute headache, low CSF glucose and cranial neuropathy overlap; mycobacterial culture, molecular testing and detailed neuroimaging remain essential.

Viral or bacterial meningitis

Acute tempo and CSF profile may differ, but coinfection and immune blunting require broad initial microbiology.

CNS lymphoma or toxoplasmosis

Focal lesions in advanced HIV can coexist with cryptococcal antigen and require imaging and tissue-directed evaluation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ASSESSDiagnose and measure pressureFirst stepSubacute meningitis or a positive cryptococcal antigen raises CNS cryptococcosis.

1Perform neurological and visual examination, HIV testing and urgent lumbar puncture with opening pressure when safe.
2Send CSF antigen, fungal culture and standard studies and obtain serum antigen, blood cultures and organ baselines.
3Remove CSF during the diagnostic puncture when pressure is symptomatic or substantially elevated and schedule repeat access.
4Start liposomal amphotericin B plus flucytosine promptly without waiting for fungal culture growth.

02TREATInduce fungal clearanceCSF supports cryptococcal meningitis and induction begins.

1Give dual induction for the specialist duration and monitor FBC, renal function, potassium, magnesium and liver tests at least daily initially.
2Repeat therapeutic lumbar puncture as often as symptoms or pressure require, targeting a meaningful reduction rather than a fixed volume.
3Do not use acetazolamide, mannitol or routine corticosteroid as a substitute for CSF removal; seek neurosurgical diversion when serial puncture fails.
4Re-culture CSF near the end of induction and extend or modify therapy when viable organisms or clinical instability remains.

03REVIEWConsolidate and restore immunityInduction is complete and clinical and culture evidence supports transition.

1Begin fluconazole consolidation at the specialist dose after successful induction, then maintenance until immune-recovery criteria are satisfied.
2Plan ART at about 4 to 6 weeks rather than immediately and monitor closely for paradoxical immune-reconstitution inflammation.
3Review visual function, headache, opening pressure, culture and adherence at every transition and investigate relapse before calling symptoms IRIS.
4Provide secondary prophylaxis, interaction monitoring and HIV retention support through a named specialist service.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provides fungicidal induction and faster CSF culture clearance than single-agent therapy.

Liposomal amphotericin B and flucytosine

Give liposomal amphotericin B 4 mg/kg intravenously once daily plus flucytosine 25 mg/kg orally every 6 hours for 2 weeks under current specialist guidance.

Use protocol weight, hydrate and monitor renal function, potassium, magnesium, FBC and flucytosine exposure; adjust both agents for organ dysfunction.

Suppresses residual yeast after fungicidal induction and bridges to maintenance.

Fluconazole consolidation

Give fluconazole 400 mg orally once daily for at least 8 weeks after successful induction under the current HIV or infection protocol.

Review liver function, QT, pregnancy and interactions and do not step down merely because antigen remains positive or symptoms briefly improve.

Prevents relapse while ART restores cryptococcus-specific immunity.

Fluconazole maintenance

Give fluconazole 200 mg orally once daily until minimum duration and immune-recovery criteria are met.

Check adherence, interactions and hepatic toxicity and never stop solely on calendar duration without viral suppression and CD4 criteria.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Blindness and cranial neuropathy

Sustained intracranial pressure damages optic nerves and stretches cranial nerves despite a microbiologically falling fungal burden.

IRIS

Immune recovery after ART can provoke severe inflammatory meningitis, pressure and mass lesions requiring exclusion of viable relapse.

Relapse and resistance

Inadequate induction, poor adherence, drug interaction or premature maintenance cessation permits recurrent viable fungal infection and clinical relapse.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure opening pressure and visual or neurological symptoms repeatedly until CSF pressure remains controlled without frequent drainage.
During induction check renal function, potassium, magnesium and FBC daily or more often when unstable and replace deficits proactively.
Use CSF culture, not antigen persistence alone, to assess viable clearance and investigate suspected relapse.
Coordinate ART start, HIV viral load, CD4 recovery, fluconazole interactions and maintenance stop through the specialist team.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Pressure is a treatment target

Antifungals do not immediately restore CSF outflow; repeated lumbar drainage prevents blindness and death while organisms clear.

Antigen outlives viable yeast

Persistent cryptococcal antigen after induction does not prove treatment failure; culture and clinical state answer viability.

Few CSF cells can be worse

Profound immune suppression may produce little pleocytosis despite a large organism burden and poor prognosis.

ART timing is disease specific

Immediate immune recovery is beneficial in most infections but increases mortality when started too early during cryptococcal CNS disease.

11Common pitfallsFrequent interpretation and management errors.

01
Failing to record opening pressure during diagnostic lumbar puncture and missing a reversible cause of visual loss.
02
Using antifungals alone while severe headache and cranial neuropathy from pressure continue.
03
Changing phases because antigen remains positive without checking CSF culture and clinical clearance.
04
Starting ART immediately or stopping maintenance before durable immune recovery.