A 55-year-old woman presented with a 2-week history of low-grade fever and holocephalic headache, which mostly resolved but were followed by a 2-week history of increasing dizziness, imbalance, and falls as well as gradual subtle mental confusion. Her medical history was significant for living related-donor renal transplantation 15 years earlier after end-stage hypertensive nephropathy.

Other medical history included hypertension, hyperthyroidism, osteoporosis, depression, and anxiety. Social history revealed no unusual travel or animal exposures and no history of tobacco, alcohol, or recreational drug use. Medications included cyclosporine, mycophenolate mofetil, prednisone, methimazole, aripiprazole, clonazepam, bupropion hydrochloride, and zolpidem tartrate. Examination revealed abnormal mental status, with reasonably good attention but some slowness, and decreased short-term and long-term memory. Findings on cranial nerve, motor, sensory, and reflex examinations were significant only for mild resting tremor of all extremities, minimal right arm weakness, and diffuse hyperreflexia. Magnetic resonance imaging showed multiple lesions on T2-weighted fluid attenuated inversion recovery (FLAIR) imaging involving white and gray matter (Figure 1). T1-weighted images after delivery of contrast showed multiple enhancing lesions, including 2 dominant enhancing masses in the right cerebellar hemisphere and in the corpus callosum (Figure 2). Lumbar puncture revealed opening pressure of 25 cm H₂O, a white blood cell count of 10/μL, a red blood cell count of 4/μL, a protein concentration of 160 mg/dL, a glucose level of 55 mg/dL (with a blood glucose level of 102 mg/dL; to convert to millimoles per liter, multiply by 0.0555), and negative cultures. The patient became increasingly lethargic and dysphagic, without systemic signs of fever or infection. Repeated computed tomographic imaging suggested increasing edema around the dominant lesions.

Posttransplant Lymphoproliferative Disorder.

ANSWER:

The history is of subacute symptoms mostly referable to the cerebellum but also consistent with a more central cerebral mass, as seen in the corpus callosum. Given the patient’s immunosuppression and the pronounced contrast enhancement, there was initial concern for an infectious mass or metastatic neoplasm. However, after lumbar puncture revealed only mild pleiocytosis and an elevated protein concentration as well as a normal glucose level and negative cultures, bacterial, fungal, and atypical bacterial causes seemed much less likely. There was no evidence for a primary malignant neoplasm, and the appearance of the lesions was not typical for metastatic disease. The involvement of gray matter in addition to white matter and the intense contrast enhancement made progressive multifocal leukoencephalopathy much less likely. Thus, the differential diagnosis was appropriately narrowed to posttransplant lymphoproliferative disorder vs central nervous system lymphoma. Further laboratory tests revealed active cytomegalovirus in the blood and high levels of Epstein-Barr virus genome in the cerebrospinal fluid. Bone marrow biopsy was uninformative and was negative for Epstein-Barr virus RNA. Because of her cognitive deterioration, a brain biopsy was performed. It revealed lymphohistiocytic infiltration with granuloma formation. However, in situ hybridization showed extensive presence of Epstein-Barr virus messenger RNA. All fungal and mycobacterial stains were negative. Immunophenotyping revealed a predominant T-cell population, with a subpopulation of B cells also present. There was no clear evidence for a clonal population indicative of lymphoma. A diagnosis of posttransplant lymphoproliferative disorder was made. This condition represents a polyclonal proliferative disorder related to Epstein-Barr virus infection of B cells. Typically, it occurs earlier in the course of immunosuppression but relates to the degree of immunosuppression and is typically reversible, although in some cases there may be subsequent development of frank lymphoma. Given her need for immunosuppression to retain her kidney transplant, she was given steroids and then high-dose methotrexate and rituximab. While she had some complications (including infections), she gradually improved, with mental status and gait returning to near baseline.

Source: JAMA