A 32-year-old male who presented with headache, dizziness, nausea, and vomiting was admitted to  local hospital in October 2018. Two days later, he was diagnosed with HIV. He had a history of male sexual partners. His CD4 cell count and plasma HIV load were 15 cells/muL and 14,900 copies/mL, respectively. On physical examination, he had a body temperature (T) of 37.3 C, blood pressure (BP) of 113/50 mmHg, pulse (P) of 105 beats per minute (bpm), and respiration rate (R) of 20 breaths/min. Moreover, he had a stiff neck, positive meningeal irritation sign, and oral candidiasis. A lumbar puncture and cerebrospinal fluid (CSF) analysis was performed; he had an intracranial pressure (ICP) of >400 mmH2O, a CSF white blood cell (WBC) count of 50 cells/muL, neutrophils of 14%, glucose of 1.4 mmol/L, protein of 0.56 g/L, chlorine of 116 mmol/L, and CSF: serum glucose ratio of 0.33. India ink staining of the CSF revealed Cryptococcus, and CSF culture showed Cryptococcus neoformans. Brain imaging of computed tomography (CT) was unremarkable. Based on these findings, he was diagnosed with CM. Ventriculoperitoneal (VP) shunting to release the increased intracranial pressure was performed one week after his admission. He received antifungal therapy for 2 weeks (amphotericin B [0.7 mg/kg/day] and 5-flucytosine [100 mg/kg/day]), followed by consolidation with fluconazole (400 mg/day) for 8 weeks. After 14 days of antifungal therapy, the culture for Cryptococcus was negative. On day 28 of admission, highly active ART (HAART; lamivudine+ Tenofovir disoproxil fumarate +lopinavir/ritonavir) was initiated, and he was discharged from the hospital. After the discharge, the patient was followed up regularly and continued anti-Cryptococcus and ART treatment without obvious symptoms.
From August 2019 to March 2020, the patient was hospitalized in the local hospital due to repeated headaches, fever, and convulsions. His CD4 count gradually increased to 131 cells/muL, the HIV viral load decreased to undetectable level, ICP was between 150 and 220 mmH2O, CSF WBC count was 15-50 cells/muL, CSF glucose was between 2.2 and 2.3 mmol/L, and CSF: serum glucose ratio was between 0.43 and 0.53. The CSF protein increased up to 12.625 g/L at October 2019, no Cryptococcus was found in India ink staining, the CSF Cryptococcus antigen was positive, and Cryptococcus culture was negative. He was treated at local hospitals with dexamethasone of 5-10 mg QD for 10 days, and the dosage was then reduced gradually. The same anti-Cryptococcus and ART treatment were continued. The patient's headache improved, and he was discharged from the hospital with methylprednisolone (4 mg/day) for 2 weeks.
In May 2020, although an undetectable plasma viral load and CD4 count of 122 cells/muL, the patient's reactions were more sluggish at our hospital (the First Affiliated Hospital of Zhejiang University, China). On physical examination, he had a T of 36.9 C, BP of 111/79 mmHg, P of 108 bpm, and R of 18 breaths/min. He was well oriented, responded to questions slowly, and had a negative meningeal irritation sign. CSF analysis revealed an opening pressure of 150 mmH2O, WBC count of 120 cells/muL, glucose of 2.1 mmol/L, total protein level of 7.89 g/L, and CSF: serum glucose ratio was 0.41. Furthermore, no Cryptococcus was found in India ink staining, the CSF Cryptococcus antigen was positive, and Cryptococcus culture was negative. Culture and polymerase chain reaction testing for Epstein-Barr virus, cytomegalovirus, and herpes simplex virus-1 and -2 were negative. A T-SPOT test for Mycobacterium tuberculosis in blood was negative. Further, acid-fast staining of a sputum smear and the CSF culture for bacteria and fungi were negative. However, multiple intracranial lesions with meningeal enhancement were observed in brain magnetic resonance imaging (MRI) (Figure 1A).
On admission, the patient's Montreal Cognitive Assessment (MoCA; Beijing version; cut-off score, 26) and International HIV Dementia Scale (IHDS; cut-off score, 10) scores were 13 and 2.5, respectively. Although he was on standard anti-cryptococcal treatment and HAART, he had aseptic meningitis with cognitive impairment; he was diagnosed with paradoxical IRIS. After providing written informed consent, he received oral lenalidomide (one cycle: 25 mg/day for 21 days and no lenalidomide for 7 days according to the manufacturer's instructions) simultaneously with fluconazole and HAART. The patient was followed up at 0, 1, 2, 3, 6, and 12 cycles after lenalidomide treatment initiation. Blood tests (blood routine, liver function, kidney function, blood lipid, serum glucose, electrolyte, coagulation function, CD4 count, HIV viral load) and CSF examinations (CSF routine, biochemistry, culture, India ink staining, Cryptococcus antigen detection, Cryptococcus culture) were performed during each follow-up. Neuroimaging and cognitive evaluations were performed at baseline,1, 2, 6, and 12 cycles. Plasma and CSF samples were stored at -80 C for testing.
One cycle after this treatment, his headache was relieved, his cognitive function had recovered rapidly (MoCA and IHDS scores increased to 20 and 6.5, respectively), and he was able to communicate normally. CSF testing revealed a WBC count of 50 cells/muL, glucose of 1.9 mmol/L, CSF: serum glucose was 0.42 and total protein level of 1.64 g/L, which suggested an inflammation. Furthermore, CSF cultures were negative. After 6 cycles of lenalidomide therapy, his cognitive status returned to normal (MoCA and IHDS scores increased to 26 and 11, respectively). The CSF WBC count (14 cells/muL) and total protein levels (0.55 g/L) were reduced, and CSF cultures were negative. T2-weighted MRI revealed a significant reduction in the signal in the left frontal lobe lesion (Figure 1B). Lenalidomide treatment was terminated after 12 cycles, and the patient was followed up for 18 months. There were no abnormalities in the routine blood tests, liver and kidney function tests, and myocardial zymogram. As of the time of this report, he has remained asymptomatic and has resumed his normal duties.