Background. HIV-positive people starting combined antiretroviral therapy may develop immune reconstitution to latent or treated opportunistic infections. Immune reconstitution to cerebral Cryptococcus is poorly understood and can be fatal. Case Presentation. A 33-year-old Zimbabwean female presented with cryptococcal meningitis and newly diagnosed HIV with a CD4 count of 51 cells/μL (4%). She was treated with amphotericin and flucytosine. Combined antiretroviral therapy was started four weeks later and she showed early improvement. However, over the ensuing 18 months, her clinical course was marked by periodic worsening with symptoms resembling cryptococcal meningitis despite having achieved CD4 counts ≥400 cells/μL. Although initially treated for relapsing cryptococcal immune reconstitution syndrome, a brain biopsy taken 17 months after initial presentation showed budding Cryptococci. Conclusion. This unusually protracted case highlights the difficulties in differentiating relapsing cryptococcal meningitis from immune reconstitution and raises questions concerning the optimum timing of initiation of combined antiretroviral therapy in such patients. 1. Introduction We describe a patient with cryptococcal meningitis and an atypical immune reconstitution syndrome (IRIS) with multiple relapses over 18 months. We explore the diagnostic and therapeutic challenges surrounding the recognition and management of such relapsing cryptococcal disease. We also elaborate on how this rare case provided further insight into the pathological progression of IRIS, a phenomenon still not fully understood. 2. Case In July 2005, a 33 year old Zimbabwean female, resident in the UK for 8 years, was admitted with a week history of fever, headache, and neck stiffness. She had no past medical history of note. Systemic examination showed fever and meningism but no focal neurological deficits. Blood tests revealed mild anaemia, lymphopenia, and raised C-reactive protein. An HIV test was positive with CD4 count of 51 cells/μL (4%). CT head without contrast showed marked meningeal inflammation but no focal lesions. A lumbar puncture (LP) revealed raised opening pressure (OP) of 27？cms？H20, lymphocyte count (30/cu？mm), protein (1.33？g/L), and CSF:？serum glucose ratio of 50%. Cerebral spinal fluid (CSF) microscopy showed multiple yeast with high cryptococcal antigen (CRAG) titre of >1？:？25,600. CSF Acid-alcohol fast bacilli (AAFB), toxoplasmosis, and viral screens were negative. The patient was started on standard amphotericin with flucytosine and prophylactic cotrimoxazole. On day
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