TABLE 10.

Possible causes of recurrent symptoms and signs of meningitis in cryptococcal meningitis.

Symptoms	Causes
Attributable to CM
CM relapse†	Possible causes of CM relapse (positive fungal culture) Fungal: Inadequate induction therapy (e.g. suboptimal amphotericin B deoxycholate administration because of toxicity) Non-adherence to fluconazole consolidation or maintenance therapy Fluconazole resistance (uncommon if preferred induction regimens are used) CNS cryptococcomas or gelatinous pseudocysts (requiring prolonged induction therapy) Immunological: ART not initiated 4–6 weeks after CM induction therapy Immunological failure because of virological failure of ART
Paradoxical IRIS	Features of IRIS (most cases have negative CSF fungal culture) Occurs weeks to months after ART initiation Because of an inflammatory response directed at antigens of non-viable fungus Associated with higher CSF white cell counts, compared to the initial (culture positive) episode of CM Frequently accompanied by raised intracranial pressure and can be associated with focal brain inflammation and/or mass lesions
Persistently elevated ICP	Thought to be mediated by occlusion of arachnoid granulations by fungi and fungal capsule; this does not necessarily imply CM treatment failure.
Unrelated to CM
New diagnosis	Possible causes: Tuberculous meningitis Viral or bacterial meningitis Space-occupying lesion with cerebral oedema (e.g. tuberculoma, CNS malignancy) or hydrocephalus Non-infective (e.g. tension headache)

CM, cryptococcal meningitis; ART, antiretroviral treatment; IRIS, immune reconstitution inflammatory syndrome; CNS, central nervous system; ICP, intracranial pressure.

^†, Relapse is defined as recurring clinical features of CM because of recurrent or ongoing C. neoformans growth in the CNS, diagnosed on positive CSF fungal culture.