Severe Neurological Damage Associated With Methotrexate Therapy

Kay, H. E. M.; Knapton, P.J.; O’Sullivan, Jacintha; Wells, David G.; Harris, R.; Innes, ElizabethM.; Stuart, J.; Schwartz, F. C. M.; Thompson, E. N.

doi:10.1016/s0140-6736(71)90456-9

The Lancet

1971

DOI: 10.1016/s0140-6736(71)90456-9

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Severe Neurological Damage Associated With Methotrexate Therapy

H. E. M. Kay

P.J. Knapton

Jacintha O’Sullivan

et al.

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Cited by 19 publications

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“…Although rare, focal sensory motor signs, aphasia, dysarthria, ataxia, severe encephalopathy, acute cerebellar syndrome, seizure, and sudden death have been described. [1][2][3][4][5][6][7][8][9][10][11][12] Herein we report a patient who developed acute chorea after ITM administration and recovered completely within a week.…”

mentioning

confidence: 99%

Intrathecal Methotrexate-induced Acute Chorea

Örken

Yldrmak²,

Kenangıl

et al. 2009

Journal of Pediatric Hematology/Oncology

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mentioning

confidence: 99%

Intrathecal Methotrexate-induced Acute Chorea

Örken

Yldrmak²,

Kenangıl

et al. 2009

Journal of Pediatric Hematology/Oncology

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Parenchymatous degeneration of the central nervous system in childhood leukemia

Hendin¹,

DeVivo²,

Torack³

et al. 1974

Cancer

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A 7‐year‐old boy with acute lymphocytic leukemia suffered increasing dementia, seizures, ataxia, and spasticity. The neuropathologic findings appeared unique, and included extensive fibrillary gliosis, with lesser degrees of myelin loss and axonal dystrophy. Similar though less severe findings were observed on re‐examination of CNS tissues from 23 other children who died of leukemia. Subcortical fibrillary gliosis was particularly prominent in 22 of 23 cases, and occurred symmetrically in the subependymal and subpial regions, inferior olives, cerebellar roof nuclei, substantia nigra, internal and external capsules, subventricular nuclei, basis pontis, and ventral horns of the spinal cord. The subcortical fibrillary gliosis was out of proportion to the myelin pallor and was not associated with leukemic infiltration. Alzheimer Type II glia were also present diffusely in 22 of 24 cases. No clear etiologic association could be established between the severity of the neuropathologic alterations and the following actors: age at death, duration of illness, elevated intracranial pressure, or treatment regimens. However, the reported case demonstrated the most severe parenchymatous changes at autopsy and received the most intensive treatment of the CNS. This association suggests that the neurologic deterioration may be the consequence of antileukemic treatment. Additional studies to define the frequency of such CNS abnormalities and the factors leading to their development are needed.

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Intrathecal methotrexate overdose without neurotoxicity.Case report and literature review

Ettinger

Freeman

Creaven

1978

Cancer

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A 24-month-old female developed a central nervous system relapse, while in bone marrow remission, eight months after the diagnosis of acute lymphocytic leukemia was made. Inadvertently, she received 14 times the standard dose of intratheci.1 methotrexate (170 mg/m2 vs. 12 mg/m2). Treatment with intravenous leucovorin and oral dexamethasone was given. Her only symptomatology was mild headaches. No neurological abnormalities developed. Her cerebrospinal fluid methotrexate levels (5.2 X 10-% at 23 hours and 5.9 X ~O -' M at 47 hours) and half-life ( t "2 = 8 hours) were within the range previously A number of toxic reactions have been described following the use of I T M T X , but their etiology is not clear-cut and the upper dosing limit for I T M T X has not been clearly defined. Only one previous case report in the l i t e r a t~r e '~ describes a n I T overdose of M T X . This paper presents a second case of IT M T X overdose and a brief review of the neurotoxicity of I T M T X . 23,25,27,29From CASE REPORTA white female presented at the age of 15 months with a white count of 55,000/mm3 and was diagnosed as having acute lymphocytic leukemia. She was treated with vincristine, dexamethasone, L-asparaginase, three courses of high dose M T X and six doses of IT MTX.28 She went into complete remission and was maintained on pulses of vincristine and prednisone, daily 6-mercaptopurine, and weekly oral M T X for eight months when she presented with a several day history of irritability and vomiting. T h e cerebrospinal fluid (CSF) contained 2000 blasts/mm3. She was still in bone marrow remission. She was treated with three weekly doses of 12 mg/m2 I T M T X . O n the fourth week, she was admitted for intravenous and IT M T X . T h e CSF contained two white blood cells/ mm3, glucose of 40 mg% and protein of 23 mg%. Inadvertently, she was given 85 mg (170 mg/m20r 8.5 mg/kg) M T X I T instead of 6 mg (lE! mg/m2 or 0.6 mg/kg). T h e M T X was used undiluted from the vial, at a concentration of 25 mg/cc, or 3.4 cc total volume, with 0.00% w/v of benzyl alcohol as the preservative. This error was realized immediately. 'The iv M T X infusion was withheld and she was given leucovorin 85 mg iv STAT, followed by 6 mg iv every 6 hours for 24 hours and dexamethasone 4 mg/m2 orally in divided doses over 24 hours.Following the overdose, the CSF protein increased to 142 mg% at 47 hours, but no pleocytosis was seen. CSF M'TX levels, measured as previously described by inhibition of dihydrofolate reductase" were 5.2 X 10-% at 23 hours and 5.9 X ~O -' M at 47 hours, with a n estimated t % = 8 hours (Fig. 1). Serum M T X levels varied little between 5 hours (3.62 X ~O-'M)

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Severe Neurological Damage Associated With Methotrexate Therapy

Cited by 19 publications

References 1 publication

Intrathecal Methotrexate-induced Acute Chorea

Intrathecal Methotrexate-induced Acute Chorea

Parenchymatous degeneration of the central nervous system in childhood leukemia

Intrathecal methotrexate overdose without neurotoxicity.Case report and literature review

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