Fotemustine-related leukoencephalopathy

Abstract

Listen

Translate article

A 66-year-old woman with an 11-year history of melanoma initially treated by surgery, reaching stage IV at age 60 (with cervical and later also pancreatic lymph node metastases), received 9 cycles of 800 mg/m dacarbazine (given every 3 weeks, started at age 63) and 4 cycles of 3 mg/kg ipilimumab (a monoclonal antibody treatment, given every 3 weeks, started at age 64). Three months after the end of ipilimumab treatment, brain CT was normal (Fig. 1). Five months after the end of ipilimumab treatment, fotemustine (an alkylating antineoplastic agent) induction phase treatment was started, followed by 100 mg/m fotemustine every 3 weeks). Ten months after the start of fotemustine treatment, the patient developed mental slowing, cognitive deficit, and tetrapyramidal syndrome. CT and MRI showed dramatic, strictly supratentorial, symmetrical, leukoencephalopathy on FLAIR sequences in absence of gadolinium-enhancement on T1-weighted imaging, together with severe generalised subcortical brain atrophy (Fig. 1). At that time, fotemustine treatment was stopped. Lumbar puncture was performed, and repeated twice during the following 3 months. CSF analysis was strictly normal including PCR for JC virus. The patient refused brain biopsy. The patient worsened progressively, became bedridden, and died 6 months after onset of neurological deficit. The patient’s family refused autopsy. Differential diagnoses in our patient included brain lymphoma, progressive multifocal leukoencephalopathy, and toxic leukoencephalopathy. Symmetrical MRI abnormalities, the respect of deep grey nuclei, the absence of gadolinium-enhancement, and normal CSF analysis made lymphoma diagnosis in our patient unlikely. Absence of repeated PCR for JC virus and the very symmetrical MRI changes were against a diagnosis of progressive multifocal leukoencephalopathy. Toxic leukoencephalopathy has been reported in a large group of drugs including alkylating antineoplastic agents such as cyclophosphamide, carmustine, and busulfan, but not in fotemustine [1, 2]. Strictly toxic leukoencencephalopathy (i.e. non-JC-virus-related) has never been reported in dacarbazine, ipilimumab or other monoclonal antibody drugs. Although delayed toxic leukoencephalopathy due to dacarbazine or ipilimumab, lymphoma, and progressive multifocal leukoencephalopathy could not be ruled out completely (especially in the absence of histological examination), fotemustine-related toxic leukoencephalopathy seemed to be most probably the cause of leukoencephalopathy in our case, since fotemustine was the most recently administered drug preceding onset of neurological deficit and MRI abnormalities. D. Renard (&) C. Campello Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, Nimes Cedex 4 30029, France e-mail: dimitrirenard@hotmail.com