Paradoxical central nervous system immune reconstitution syndrome in acquired immunodeficiency syndrome-related primary central nervous system lymphoma | Haematologica

摘要

Acquired immunodeficiency syndrome (AIDS)-related primary central nervous system lymphoma (AR-PCNSL) is an Epstein-Barr (EBV)-associated malignancy that occurs in severely immunocompromised human immunodeficiency virus (HIV)-infected patients. Lack of EBV-specific CD4+ T cells contributes to its pathogenesis.1 Although AR-PCNSL incidence in the United States (US) decreased with availability of combination antiretroviral therapy (cART), 26 PCNSL cases per 100,000 person-years continue to occur in persons with AIDS, making up over 10% of US HIV-associated lymphoma cases. Prognosis remains poor, with greater than 75% 2-year mortality.2 Neurological co-morbidities, difficulties distinguishing AR-PCNSL from other CNS pathology, undertreatment of AR-PCNSL and health care disparities may contribute to mortality.3Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) is characterized by neurological deterioration despite immune recovery from an immunodeficient state. In AIDS patients with CNS opportunistic infections (OIs) such as Cryptococcus, John Cunningham (JC) virus or cytomegalovirus (CMV),4 CNS-IRIS can complicate cART. CNS-IRIS is described as paradoxical when neurological deterioration occurs despite cART and treatment of a known underlying CNS infection. Risk factors include low CD4+ nadir at time of cART initiation and rate of peripheral HIV viral load (VL) decay. Diagnosis is supported by neuroradiological findings and in some cases, evidence of T-cell infiltration in pathological specimens.5 CNS-IRIS is associated with high morbidity and mortality, largely attributed to exacerbated neuroinflammation associated with antigen specific T cells.6 Changes in antigen-presenting cells, exaggerated innate immune responses, and dynamics of CSF HIV viremia may also contribute to CNS-IRIS pathogenesis.6,7 To our knowledge, paradoxical CNS-IRIS has not been previously described in the treatment of AR-PCNSL.We describe the case of a 54-year old man with HIV, not on cART, who presented with several months functional decline and more than two weeks progressively worsening altered mental status. Brain magnetic resonance imaging (MRI) showed a ring-enhancing left basal ganglia lesion with edema and mass effect. CSF examination was remarkable for 98 white blood cells (WBC)/mL and elevated protein. Microbiology studies were negative (Table 1).8,9 Peripheral CD4+ lymphocyte count was 2 cells/uL and HIV VL was 569,422 copies/mL. The patient started cART and was administered two weeks of empiric toxoplasmosis therapy. Despite antibiotics and decreasing HIV VL, he had no neurological improvement. Stereotactic needle brain biopsy was performed. Pathology revealed CD20+, EBV+ malignant lymphoid cells diagnostic of AR-PCNSL. He was referred to the National Cancer Institute (NCI) for treatment.View this table:View inlineView popupDownload powerpointTable 1. Results of repeated examinations of cerebrospinal fluid.At the NCI, his Eastern Cooperative Oncology Group (ECOG) performance status was 3 due to neurological compromise. Neurological exam demonstrated mixed aphasia, with limited speech production (anomia) and reception (difficulty with complex commands), but relatively preserved repetition. Right arm strength was decreased (4/5 deltoids, biceps and triceps, 2/5 finger extensors). CD4+ count was 52 cells/uL (CD4+/CD8+ ratio 0.02) and HIV VL 397 copies/mL. Anti-toxoplasmosis antibodies (IgG and IgM) were undetectable. Repeat CSF examination (Table 1, Protocol Baseline) showed 6 WBC/mL, elevated protein and EBV viral load of 850 copies/mL. Cytopathology and flow cytometry revealed no leptomeningeal lymphoma. Computerized tomography (CT) showed no systemic adenopathy. Brain 18fluorodeoxyglucose positron emission tomography (18FDG-PET) demonstrated pathological left basal ganglia uptake, ipsilateral diffuse cortical metabolic suppression and crossed cerebellar diaschisis. Ophthalmological exam revealed no intraorbital lymphom