Methotrexate Treatment Protocols and the Central Nervous System: Significant Cure With Significant Neurotoxicity

Shuper, Avinoam; Stark, Batya; Kornreich, Liora; Cohen, Ian J.; Aviner, Shraga; Steinmetz, A.; Stein, Joseph Allen; Goshen, Y.; Yaniv, Isaac

doi:10.1177/088307380001500902

Cited by 65 publications

(66 citation statements)

References 35 publications

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“…[21][22][23][24][25][26][27][28][29][30] Moreover, under description owing to insufficient means for monitoring is possible. When limited to grade 3-4 episodes, the neurological complications incidence in our series is 3.7%.…”

Section: Discussionmentioning

confidence: 99%

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

et al. 2006

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The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)7high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n ¼ 182) were randomized to weekly low-dose MTX at 25 mg/m 2 /week (LD MTX, n ¼ 81) or HD MTX at 1.5 g/m 2 /2 weeks Â 6 (n ¼ 77). Intermediate-risk group (IR, n ¼ 672) were randomized to LD MTX (n ¼ 290) or HD MTX at 8 g/m 2 /2 weeks Â 4 (n ¼ 316). Higherrisk group (HR, n ¼ 541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n ¼ 15 (1.1%), peripheral and spinal neuropathy: n ¼ 17 (1.2%) and encephalopathy: n ¼ 20 (1.4%). Age 410 years was significantly associated with neurotoxicity (P ¼ 0.01) and use of HD MTX is associated with encephalopathy (P ¼ 0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

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Section: Discussionmentioning

confidence: 99%

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

et al. 2006

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“…Lesnik et al (1998) demonstrated cerebellar-frontal subsystem changes on structural MRI in children with ALL treated before the age of 5 with chemotherapy only. Methotrexate is the cytostatic drug mostly implicated in central neurotoxicity in children with ALL (Shuper et al, 2000). Cerebral white matter changes (Chu et al, 2003;Dambska & Laure-Kamionowska, 1999;Surtees et al, 1998), neuronal damage (Chu et al, 2003;Quinn et al, 1998;Van Gool et al, 2000) and neurotransmitter abnormalities (Madhyastha et al, 2002) have been described in children treated with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Buizer

Sonneville

Heuvel‐Eibrink

et al. 2005

J. Inter. Neuropsych. Soc.

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Treatment for childhood acute lymphoblastic leukemia (ALL), which includes CNS prophylaxis, is associated with central and peripheral neurotoxicity. The purpose of the present study was to analyze the effects of chemotherapy on various levels of visuomotor control in survivors of childhood ALL treated without cranial irradiation, and to identify risk factors for possible deficits. Visuomotor function was compared between children after treatment for ALL (n 5 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n 5 38), and healthy controls (n 5 151). Three tasks were administered: a simple visual reaction time task and two tasks measuring visuomotor control with one requiring a higher level of cognitive control than the other. Visuomotor deficits were detected only in the ALL group, with poorer performance restricted to the condition requiring the highest level of control. Significant risk factors for poorer performance were female gender and a short time since end of treatment, and a trend was found for a young age at diagnosis. A high cumulative methotrexate dose was an adverse predictive factor in girls. The results indicate that chemotherapy-induced central neurotoxicity in childhood ALL treatment is associated with higher order visuomotor control deficits. Girls appear to be particularly vulnerable. (JINS, 2005, 11, 554-565.)

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“…Neurotoxicity can present in acute, subacute, or chronic forms. 6 Chronic MTX neurotoxicity develops slowly and may progress to permanent neurologic impairment, dementia, and gradual functional decline. 6 Acute toxicity may include headache, nausea, lethargy, altered mental status, blurred vision, seizure, or increased intracranial pressure developing within 1 day of administration.…”

Section: Sectionmentioning

confidence: 99%

“…6 Chronic MTX neurotoxicity develops slowly and may progress to permanent neurologic impairment, dementia, and gradual functional decline. 6 Acute toxicity may include headache, nausea, lethargy, altered mental status, blurred vision, seizure, or increased intracranial pressure developing within 1 day of administration. Stroke-like symptoms have a subacute presentation 5-15 days after IV or intrathecal administration, and have been estimated to occur in approximately 2% of patients receiving MTX.…”

Section: Sectionmentioning

confidence: 99%

Clinical Reasoning: A unique case of acute onset, progressive left hemiparesis

et al. 2012

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A 15-year-old, right-handed Hispanic boy with B-cell acute lymphoblastic leukemia (ALL) was transferred for acute onset of stroke-like symptoms. Appoximately 6.5 hours prior to arrival, the patient was in his normal state of health. At that time, he developed abrupt onset of headache and left arm tingling described as "ants crawling on my arm." He described associated dysarthria, dysphagia, and progression of symptoms over the first hour to include left lower extremity paresthesias. By the time of neurologic consultation, he reported some subjective improvement in left leg sensory deficits but was weak throughout his left hemibody. Past medical history was notable for B-cell ALL diagnosed 3 months earlier, for which the patient had undergone induction chemotherapy with vincristine, daunorubicin, pegylated asparaginase, and intrathecal methotrexate (IT-MTX) and cytarabine. He achieved remission and was being treated with consolidation chemotherapy consisting of systemic cyclophosphamide, cytarabine, mercaptopurine, vincristine, pegylated asparaginase, and IT-MTX. His most recent lumbar puncture with IT-MTX was 10 days prior to presentation, at which time CSF analysis had shown white blood cells 2/mm 3 , red blood cells 2/mm 3 , and unremarkable cytology (a few normal-appearing lymphocytes). Family history was negative for stroke. The patient denied current tobacco, alcohol, or drug use.Initial temperature was 98.9°F, blood pressure 112/52 mm Hg, heart rate 110, respirations 20, oxygen saturation 100% on room air. Examination demonstrated intact mental status. Cranial nerves were intact except for a left lower facial droop. Motor examination showed 5/5 strength throughout the right hemibody and 4/5 strength throughout the left. Deep tendon reflexes were 2ϩ throughout with flexor plantar responses. Sensation was decreased to pinprick over the left lower extremity from the thigh distally. Coordination was intact but gait was slightly wide-based.Initial laboratory assessment showed white blood cells 3,500/mm 3 , hemoglobin 7.4 g/dL, platelets 58,000/mm 3 , international normalized ratio 0.92, creatinine 0.4 mg/dL, all stable from prior values. Electrolytes were within normal limits. CT of the head was negative for acute abnormality.

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Methotrexate Treatment Protocols and the Central Nervous System: Significant Cure With Significant Neurotoxicity

Cited by 65 publications

References 35 publications

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Clinical Reasoning: A unique case of acute onset, progressive left hemiparesis

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