Unexpected subacute leucoencephalopathy following intrathecal methotrexate and cytarabine administration in a patient homozygous for MTHFR 677C→T polymorphism.

Background. Intrathecal administration (ITA) of chemotherapeutics, mainly Methotrexate (MTX) and Cytarabine (Ara-C), is a standard approach to central nervous system (CNS) prophylaxis of aggressive Non Hodgkin Lymphomas. MTX is known to cause diffuse symmetrical leucoencephalopathy in children. A genetic variant of Methylenetetrahydrofolate reductase (MTHFR) due to the 677C→T polymorphism determines a striking reduction in the enzyme activity and has been associated with increased toxicity during MTX administration in children. Reports of neurotoxic effects in adults are lacking, despite the increasing use of aggressive protocols in this age group. Aim. To report the case of an adult, carrying the MTHFR homozygous mutant 677TT genotype, who developed subacute leucoencephalopathy following intrathecal prophylaxis with MTX and Ara-C. Case report. A 32-year-old Caucasian male was diagnosed with aggressive B-cell lymphoma (stage IV B, bone marrow, liver and spleen involvement). Treatment was planned according to modified POG 8617 regimen (Todeschini G, Ann Oncol, 1997). Course A included CNS prophylaxis with intrathecal MTX (12 mg) and Ara-C (50 mg) at days 1 and 4. CSF biochemical examination was normal and cytospin was acellular. Six days after day 4 ITA, the patient became acutely confused and showed behavioural and speech disturbances. Motor impairment of the right leg was also recorded. Psy- chiatric assessment excluded a psychiatric origin for this disorder. Body temperature was normal and he had no signs of meningeal involvement. No signs of infection were found. Brain CT and MRI were unremarkable. EEG showed a pattern of diffuse cerebral dysfunction. Speech and behaviour disturbances improved starting from day +16, without com- plete recovery. Day +60 brain SPECT showed diffuse hypoperfusion, most evident at parieto-temporal regions bilaterally. At day +71 the patient had a seizure. EEG showed predominantly frontal disturbances. Brain MRI, performed 109 days after day 4 IT, showed bilateral hyperintense lesions in subcortical white matter in T2-weighted images. The molecular analysis detected a MTHFR 677TT homozygous mutant genotype. Discussion. The present case report indicates the possible event of severe CNS damage in adults undergoing ITA administration of MTX. The mechanisms underlying MTX toxicity remain uncertain. Review of possible mechanisms behind methotrexate neurotoxicity points towards several metabolic pathways affected by the drug. MTHFR is crucial to folate metabolism, essential for DNA synthesis and repair pathways as well as DNA methylation and its severe deficiency results in hyperhomocysteinemia, which can cause neurotoxicity. Although we cannot completely rule out the possible role of cytarabine in causing CNS toxicity in our patient, the clinical and radiological findings suggest the major role of methotrexate. Ara-C neurotoxicity is mainly reported in children and there is a preferential involvement of the spinal cord rather than the brain. The presence of the TT homozygosity in our case seems to confirm the predisposing role of this genotype for CNS damage in adults, extending the observations made in children. Given the high prevalence of the homozygous 677TT genotype in the Italian population, ITA MTX prophylaxis should be carefully followed-up and leucovorin rescue in adults should be considered.