A 46-year-old right-handed woman was admitted to the hospital with pancytopenia. She had received chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil) 8 years previously for a left breast carcinoma. Bone-marrow aspiration and biopsy revealed hypercellular marrow with an increased number of blasts (15.2%). The patient was therefore diagnosed with therapy-related myelodysplastic syndrome (t-MDS). She subsequently progressed to t-AML (French-American-British classification M0) and received idarubicin (IDR) and cytarabine (Ara-C) to induce remission. At five months after the initial diagnosis, the patient underwent allogeneic PBSCT (allo-PBSCT) from a one-allele mismatched related donor after preparation with cyclosporine A (CyA) and total body irradiation (TBI). Full engraftment was confirmed on day 16. The initial post-transplant course was complicated by acute oral, gastrointestinal tract, and skin GVHD that resolved after treatment with prednisolone (PSL), CyA, and methotrexate (MTX). At five months after PBSCT, the patient developed chronic pulmonary GVHD in the form of bronchiolitis obliterans organizing pneumonia (BOOP). She was treated with oral PSL, which was tapered after achieving a good result.
At 19 months after PBSCT, the patient developed headache, night sweats, difficulty writing due to shaking hands, and memory loss. Her blood test results were normal. Cerebrospinal fluid (CSF) studies revealed pleocytosis (33.3x106/L), protein elevation (85 mg/dL), and low CSF glucose (45 mg/dL), while the patient was negative for oligoclonal IgG bands and malignant cells. Bacterial and fungal cultures, a CSF polymerase chain reaction (PCR) for the JC virus, and tests for Toxoplasma gondii, Cytomegalovirus, Herpes simplex, and Varicella zoster virus were all negative. Magnetic resonance imaging (MRI) revealed areas of confluent and asymmetrical hyperintensity on T2-weighted images (T2WI) and fluid-attenuated inversion recovery (FLAIR) in the bilateral cerebral white matter (Fig. 1A). Gadolinium-enhanced MRI of the brain revealed multiple punctate and curvilinear lesions spreading from the deep cerebral region to the subcortical white matter, the pons, and the cerebellar vermis (Fig. 1B and C). Furthermore, both diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps revealed diffuse areas of high-intensity (Fig. 1D and E). MR angiography (MRA) and susceptibility-weighted imaging (SWI) revealed normal findings.
Fourteen days after MRI, an open brain biopsy was performed to collect a piece of brain from the patient's left frontal lobe white matter. The biopsy revealed the perivascular infiltration of small, mature lymphocytes in the brain parenchyma, without any signs of inflammatory cell infiltration into the vessel walls. These infiltrates were mostly CD3- and CD8-positive on immunostaining. The formation of granulomas was observed in some portions of the examined brain tissue. In situ hybridization for Epstein-Barr Virus (EBV)-encoded small RNAs (EBERs) was negative (Fig. 2). Furthermore, no findings indicated the recurrence of the primary disease. In view of these facts, we diagnosed the patient as having CNS-cGVHD.
Treatment with three cycles of methylprednisolone pulse therapy (1,000 mg/day for 3 days) was initiated, which led to a dramatic improvement in the patient's cognitive and neuropsychiatric symptoms. Her brain MRI showed the shrinkage of the white matter lesions and the disappearance of the gadolinium-enhanced lesions (Fig. 1F). She was subsequently placed on maintenance therapy with oral PSL and tacrolimus. Three months after the onset of symptoms, we confirmed the disappearance of almost all of her neurological symptoms.