Early CNS toxicity after intrathecal methotrexate

Central nervous system (CNS) being a sanctuary site, intrathecal methotrexate (IT MTX) has become a cornerstone for CNS prophylaxis for acute lymphoblastic leukemia. Recently we noticed eight pediatric patients developing transient neurological event following IT MTX. All of them were acute lymphoblastic leukemia (ALL) patients. Four were high risk patients and others were standard risk (based on total count and age). All of them received BFM 86 protocol. Seven were females. Their age ranged from 4–14 years and the median age was 11.5 years. All the patients had normal CSF studies. Five of them received IT MTX along with intravenous high dose MTX (HDMTX) 5 gm/m before the event. Two received cytosine arabinoside (AraC), (75 mg/m for 4 days) with IT MTX on day one. Only one received cranial irradiation before the event. All the patients developed the event between Day 11 to D14 of IT MTX. Seven patients had hemiparesis and one had quadriparesis. The neurological event recovered within 24 hours in seven of them and within 72 hours on the others. Cerebrospinal fl uid (CSF) study was normal in all patients. All of them were exposed to multiple doses of IT MTX prior to the event. Preservative free MTX recommended dosage (12 mg) was used for all patients and proper administration technique under sterile precautions was ensured. Imaging studies were conducted in all patients within 24 hours of the onset of the event and all had normal standard MR imaging study of the brain. The imaging studies were not repeated later. The incidence of various neurological events following IT-MTX is estimated around 4–15% [1]. Three distinct clinical patterns of neurotoxicity have been observed (a) an acute toxicity, occurring within hours of IT chemotherapy, probably resulting from chemical arachnoiditis; (b) sub acute toxicity occurring within days or weeks, and characterized by symptoms of seizures, transient paresis, or cerebellar abnormalities; and (c) a delayed leukoencephalopathy form that is more commonly observed when IT MTX is used with cranial irradiation [1]. The mechanism of methotrexate induced neurotoxicity is poorly understood. Both high-dose intravenous MTX and intrathecal MTX are proposed to have association with demyelination, white matter necrosis, loss of oligodendroglia, axonal swelling, microcystic encephalomalacia, and atrophy relatively selective for the deep cerebral white matter [2]. An altered myelin metabolism disturbance induced by S. Cyriac · T. G. Sagar · R. Rajendranath Department of Medical Oncology, Cancer Institute, 18 Sardar Patel Road, Guindy, Chennai 600 036, India