SUBACUTE LEUKOENCEPHALOPHATY (LE) FOLLOWING HIGH DOSE (HD) INTRAVENOUS (IV) AND INTRATHECAL (IT) METHOTREXATE (MTX) DURING TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) IN CHILDREN L.Fraquelli, M.Onoratelli, D.Barsotti, M.Posadas Martínez, C.Botana Rodriguez, L.Peralta, M.Rebollo, S.Evangelista, E.Alfaro, M.S.Felice Day Hospital, Hospital de Pediatría Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina We present a previously healthy 9 years old girl who presented bilateral lower limb pain since two months. Bone marrow showed blast cells and immunophenotyping was consistent with B precursor ALL. The cerebrospinal fluid (CSF) was negative for blast cells. She was treated with ALL-BFM therapy protocol that consisted of intravenous (IV) and IT MTX amongst other chemotherapeutic drugs. She achieved complete remission at 33th day. Ten days after the second cycle of high dose (HD) IV and IT MTX therapy, she developed sudden onset of rigth upper limb weakness, ipsilateral facial nerve palsy and aphasia. She was conscious with normal vital signs. The CSF study revealed no blast cells. Computed tomography and coagulation tests were normal. An electroencephalogram showed right spikes. She recovered within 2 days with no neurological deficits. T2 and FLAIR MRI showed symmetrical bilateral diffuse high intensity areas in corona radiata. The presumptive diagnostic was: MTX induced subacute leukoencephalopathy. She received Protocol II. Three months later RMN had not changed and she was asymptomatic. 4 months later, two cycles of IV and IT MTX therapy were given. Follow-up MRI revealed complete resolution. She had no recurrences of neurologic symptoms. MTX Neurotoxicity: May be associated with varying degrees of neurotoxicity, leukoencephalopathy is the most important Pathophysiological mechanisms are not well known. Probably multifactorial: ↑ accumulation of adenosine and homocysteine ​​↑ impaired excitatory amino acid metabolism and biopterin Usually reversible Acute Usually associated to IT MTX Symptoms: nausea, vomiting, aseptic meningitis, transverse myelopathy, acute encephalopathy. Occurs within 2-4 hours after administration and lasting 2-3 days. Subacute Symptoms: syndrome "stroke like“, confusion, disorientation, seizures, focal deficits (dysarthria, hemiparesis) aphasia. Usually occurs within 10 days of systemic therapy (usually not on the first dose). Generally reversed within 72 hours. Chronic Weeks or months after treatment. Changes in personality, impaired cognitive function, less often progressive demyelinating leukoencephalopathy, dementia. The pathophysiology is not well known METHOTREXATE: It is widely used in the treatment of ALL, NHL and other pediatric solid tumors (osteosarcoma). It has proven effective EV and IT administration in the prophylaxis and treatment of leukemia with CNS involvement. Inhibits dihydrofolate reductase enzyme, resulting in a decrease in the amount of reduced folate. This deficiency interferes with the metabolism of purines and pyrimidines Conclusion: Subacute MTX neurotoxicity occurs 2-14 days after IT or HD MTX. Changes in deep cerebral white matter not necessarily indicate an irreversible cytotoxic injury. MTX neurotoxicity in Hospital Garrahan (1599 ALL patients) Acute (0.3%): Seizures Subacute (1%): - Demyelination: 10 cases - Vasospasm: 6 cases Chronic (0.12%) demyelinating leukoencephalopathy 7 months later 14 months later

R1 R2 R1 H R 3’ H R 1’ H R 2’ TMO : 6-MP / MTX II RA II IA/IA’ d15d33 RS RM dg BFM/HPG MP / MTX IB Aum R1 H R 1’ H R 2’ H R 3’ II * M2 M5 LLA-T M5 LLA-BcpM2 IB Aum LLA-T -Bcp M5 6-MP / MTX **

From January-1995 to December-2012, 1159 new ALL cases were diagnosed. Neurotoxicity was detected in 43 patients (3.7%) in our Hospital and they were classified according to initial neurological symptoms.