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Abstract Progressive multifocal leukoencephalopathy. (PML) is a rare demyelinating disease of the central nerv- ous system caused by the JC papovavirus, and ...

Neurol Sci (2008) 29:37–39 DOI 10.1007/s10072-008-0857-x


Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab Simona Bonavita • Renata Conforti • Antonio Russo • Rosaria Sacco • Alessandro Tessitore • Antonio Gallo • Marida Della Corte • Maria Rosaria Monsurrò • Gioacchino Tedeschi

Received: 12 November 2007 / Accepted: 21 December 2007 © Springer-Verlag 2008

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by the JC papovavirus, and is a well known complication in patients with lymphoproliferative diseases (LPDs) during chemotherapy. We report the case of a 59-year-old woman affected by B-cell LPD who underwent three cycles of chemotherapy with fludarabine and rituximab and developed atypical PML six months after the last cycle of chemotherapy. Our patient showed the following peculiarities: chemotherapy regimen was neither heavy nor prolonged; the onset of neurological symptoms was unexpectedly late; the MRI lesion was atypical for non-HIV-related PML, being monofocal and infratentorial with early gadolinium (Gd) enhancement and mass effect; survival was rather prolonged despite the lack of treatment. These data suggest that in patients with LPDs, the occurrence of progressive neurological deficits

S. Bonavita (쾷) · A. Russo · R. Sacco · A. Tessitore · A. Gallo · M. Della Corte · M.R. Monsurrò · G. Tedeschi Department of Neurological Sciences II University of Naples Piazza Miraglia 2 80138 Naples, Italy e-mail: [email protected] R. Conforti Neuroradiology Service II University of Naples Naples, Italy S. Bonavita · G. Tedeschi Institute “Hermitage Capodimonte” Naples, Italy e-mail: [email protected]

should induce the suspicion of PML even when clinical onset is late (with respect to chemotherapy) and in the presence of a single infratentorial lesion, with Gd enhancement and mass effect. Keywords Progressive multifocal leukoencephalopathy · Fludarabine · Rituximab · Lymphoproliferative disorders

Introduction Progressive multifocal leukoencephalopathy (PML) caused by the JC papovavirus (JCV) is a subacute encephalitis (seldom purely infratentorial) occurring in patients with severe cellular immune deficiency. PML was initially described after chemotherapy in patients with haematological malignancies [1]. Nowadays it is most frequently found in patients with human immunodeficiency virus (HIV) infection. Recently, three cases of PML have been reported in patients treated with natalizumab (a monoclonal antibody) for autoimmune diseases [2–4]. In April 2007, the Italian Drug Agency (AIFA) reported the occurrence of lethal PML in two patients with systemic lupus erythematosus and another case of PML in a patient with ANCA-negative vasculitis/cryoglobulinaemia previously treated with immunosuppressants and later with rituximab ( Changes in the natural history of PML in HIV-negative lymphoproliferative diseases (LPDs) have been attributed to novel therapies [5]. Rituximab is a chimeric anti-CD20 antibody with moderate single-agent activity in chronic lymphocytic leukaemia and indolent nonHodgkin lymphoma, whose effectiveness may be increased by fludarabine (a purine analogue) known to induce CD4 lymphopenia. Based on these data, and on the


Neurol Sci (2008) 29:37–39

non-overlapping toxicity profile of fludarabine and rituximab, combination therapy may be suggested in LPDs. On the other hand, a major concern with the concurrent use of purine analogues and rituximab is the potential risk of increased infections resulting from combined Tand B-cell depletion, reflecting, respectively, CD4 and CD20 lymphopenia. Due to the paucity of PML reports, the possible synergic effect of chemotherapeutical agents and rituximab in determining this lethal disease is still largely debated.

Case report In April 2004, a 59-year-old woman was diagnosed with B-cell LPD with deep abdomen lymphonodes and bone marrow involvement. On July 2004 she underwent treatment with R-FLUDA (rituximab 375 mg/m2 1 day+fludarabine 40mg/m2 for 5 days/28 days), which was then stopped after three cycles because of severe leukopenia and thrombocytopenia, while the LPD was in a remission state. In January 2006 she presented to us with progressive and fluctuating worsening of gait, which had begun in March 2005. Neurological examination showed: gait possible for a few steps with bilateral support, bilateral horizontal-rotatory nystagmus in the lateral gaze, left Babinski sign and intentional tremor on the right upper limb. MRI showed a single lesion, hyperintense in T2 and PD-weighted, and hypointense in T1-weighted images, with a faint peripheral gadolinium (Gd) enhancement in the right middle cerebellar peduncle and a slight mass effect on the IV ventricle (Fig. 1). An extensive work-up, including chest X-ray, HgB electrophoresis, total body CT scan with contrast medium, total body gallium scintigraphy and brain thallium scintigraphy, was negative. CSF analysis showed: total protein 27 mg/dl (normal value 20–50); albumin 19 mg/dl (15–30); IgG 0.6 mg/dl (

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