Brain biopsy was performed revealing numerous yeast-like organisms in the subarachnoid space and brain parenchyma surrounded by a fierce inflammatory reaction (Figure 1h, i). for 5 weeks with liposomal amphotericin B, 5-flucytosine and fluconazole. He recovered completely. Due to poor adherence he did not take fluconazole secondary prophylaxis and antiretroviral therapy (ART) regularly for the next 3 years. His CD4 count had fallen to 17 cells/l (Figure 1a). Beginning in December 2009, the patient became tagtail to his antiretroviral therapy consisting of tenofovir, emtricitabine, and efavirenz. By May 2010, his CD4 had risen to 123 cells/l (CD4% of 5%) with a viral load of <100 copies/ml. His CD4 count increased up to 272 cells/l by August 2013 with continuous HIV suppression (Figure 1a). == Determine 1 . == a. Time line of complete CD4 cells/l (blue line) and CD4 percentage of total lymphocyte population (red line) from 2006 through 2014. bg. Cerebral MRI imaging. b, d, f: Contrast enhanced T1 images. c, e, g: TIRM images. b, c. Imaging on admission showing prominent contrast meningeal enhancement (b) with underlying parenchymal edema (c). d, e. Follow-up imaging 4 weeks later, showing increased contrast enhancement (d) and cortical and subcortical edema and a new diecephalic- midbrain lesion (e) demonstrating the lag phenomenon in the radiologic appearances compared with clinical examination in CNS cryptococcosis. Two weeks later on completion of short steroid course there is a decrease of cortical contrast enhancement (f) and parenchymal edema (g). hi. Brain biopsy. h. Histological examination showing numerous yeast-like structures in the cortical tissue (Grocott stain, original magnification 400). Inset. High power magnification showing yeast budding suggesting that some yeasts are viable. i. Immunohistochemical examination showing strong CD8+ cellular reaction in VD2-D3 the parenchyma and subarachnoid space (mouse monoclonal antibody, Dako, Clon C8/144B, original VD2-D3 magnification 400). In January 2014, within a few days the patient experienced two focal sensory epileptic seizures affecting the left part of his body. On admission, left-sided distal leg paresis was detected. Cerebral MRI revealed multiple enhancing leptomeningeal and cortical lesions (Figure 1b, c). The CSF analysis showed 24 cells/l, 90% lymphocytes, protein of 1 025 mg/l (normal range: 150450) with normal lactate and normal glucose. The CSF opening pressure was 190 mmH2O. CSF India ink staining and CSF CRAG were negative on three consecutive LPs. Serum CRAG was 1: VD2-D3 4. The full microbiological work-up on CSF including fungal cultures was negative. A follow-up MRI one week later showed progression of the inflammatory lesions. Brain biopsy VD2-D3 was performed revealing numerous yeast-like organisms in the subarachnoid space and brain parenchyma surrounded by a fierce inflammatory reaction (Figure 1h, i). Budding was detected in a very small fraction of the yeast cells (Figure 1h). Brain tissue did not grow fungus, even after prolonged culture for 28 days. PCR on DNA extracted brain tissue revealed fungal DNA identified asCryptococcusspp., based on the ITS2 region of rDNA. The patient was started on liposomal amphotericin B (4 mg/kg/day) and 5-flucytosine (100 mg/kg/day) for 2 weeks followed by fluconazole 400 mg/day. After two weeks of antifungal treatment, there was a slight improvement in strength of the left lower limb, yet, a repeat MRI revealed further progression of the lesions (Figure 1d, e). Prednisolone (1 mg/kg/day) was added for 10 days with tapering over 7 days. Two weeks later the neurological examination revealed further improvement of muscle strength and MRI showed reduced edema and reduced contrast enhancement of the lesions (Figure 1f, g). On 3-month follow-up, neurological examination revealed normal muscle strength with mild spasticity. Brain MRI showed complete resolution of contrast enhancement and further reduction of lesion size. == Discussion == We describe a case of a patient with a symptomatic relapse eight years after the initial diagnosis of cryptococcal meningitis. The findings and clinical course had features of both paradoxical IRIS and microbiological relapse [13] with the brain biopsy demonstrating numerous cryptococcal organisms surrounded by intense CD3+CD8+T cell inflammation (Table 1). Both the brain tissue and CSF did not grow fungus. Lack of growth cannot fully exclude active microbial replication if the fungal CSF burden is low. In our case the lack of growth might also be due to technical issues because for the first 48 hours the tissue was cultured on SERPINF1 bacterial media. Alternatively, the immune response may have simultaneously resulted in containment of a slow growing cryptococcal infection resulting in few viable organisms and negative culture. And yet, the finding of budding yeast cells proves that viable organisms were present in the brain and the meninges. Of note, CSF CRAG was negative despite the high fungal burden on biopsy, again a sign of confinement of the infection to the brain with little antigen shedding into the.