Neurotoxicity methotrexate

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

Ara-C—high doses can cause CNS toxicity (cerebellar dysfunction) neurotoxicity increases as infusion time increases dose reduced to 1 gm/M2 if age > 60, creatinine > 2, or if Methotrexate level at end of infusion is > 20 pmol/L... 

III. The answer is d, (Hardman, pp 1247, L135.) Leucovorin prevents methotrexate from inhibiting dihydrofolate reductase and reverses all of its adverse effects except neurotoxicity... 

In studies of the neurotoxic effects of low-dose methotrexate treatment, dizziness, headache, visual disturbances or hallucinations, lack of concentration, cognitive dysfunction, and depression-like symptoms were detected in 1-35% of patients (527,528). Advanced age and mild renal insufficiency were possible susceptibility factors (529). 

High-dose chemotherapy with cyclophosphamide, vincristine, prednisolone, and intrathecal methotrexate given for post-transplant lymphoproliferative disease was suggested to have favored the occurrence of acute ciclosporin neurotoxicity (headache, fever, seizures, and visual agnosia) in a 9-year-old cardiac transplant patient (239). Ciclosporin serum concentrations were normal and a further similar episode occurred on ciclosporin readministration. 

Aphn CG, Russell-Jones R. Acute dysarthria induced by low dose methotrexate therapy in a patient with erythrodermic cutaneous T cell lymphoma an unusual manifestation of neurotoxicity. Chn Exp Dermatol 1999 24(l) 23-4. 

Methotrexate causes a modest reduction in the theophylline clearance. Theophylline may reduce methotrexate-induced neurotoxicity, but there is the possibility that it may also reduce methotrexate efficacy. 

Four of 6 patients aged 3 to 16 years with acute lymphoblastic leukaemia and high-dose methotrexate-induced neurotoxicity had a complete resolution of their symptoms when they were given a 2.5-mg/kg aminophylline infusion over 1 hour. The other 2 had some improvement in symptoms. One patient also had symptom relief with rapid-release theophylline. Similar results were reported for another child who developed neurotoxicity after receiving high-dose methotrexate. In this case, aminophylline was reported not to alter methotrexate levels. A patient with methotrexate-induced leukoencephalopathy recovered after being given a combination of intravenous folinic acid with intravenous aminophylline 145 mg daily for 7 days. ... 

It is not known why theophylline clearance is altered. Methotrexate neurotoxicity may be linked witii increased levels of adenosine. Theophylline is a competitive antagonist for adenosine receptors at serum concentrations within the therapeutic range used in respiratory disease. ... 

The clinical importance of the small reduction in theophylline elearanee is uncertain, although it may be worth bearing this in mind in patients maintained at the higher end of the therapeutic levels for theophylline, as they may be more likely to develop toxicity. Aminophylline may reduce methotrexate-induced neurotoxicity, and, dthough there is some evidence that theophylline does not alter the cytotoxic effects of methotrexate, this requires confirmation. One UK manufacturer of methotrexate (licenced for... 

Bernini JC, Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA. Aminophylline for methotrexate-induced neurotoxicity. Lancet (1995) 345, 544-7. 

Acute neurotoxicity and myelotoxicity occurred in a boy with Hodgkin s lymphoma treated with vinblastine, doxorubicin and methotrexate when he was also given itraconazole. The toxicity did not occur when he was given the same chemotherapy without itraconazole. ... 

Cytotoxic edema has been described in a 17-year-old girl who was treated with intravenous methotrexate [71 ]. An MRI scan showed reduced diffusion in the left semi-ovale center in a non-vascular distribution, with predilection for the periventricular white matter. Patients with methotrexate-induced neurotoxicity generally have encephalopathy and stroke-Uke sjmiptoms and often recover despite white matter changes on MRI scans. 

The neurotoxicity of methotrexate has also been reviewed (95 ). In this review it was considered that neurotoxicity due to methotrexate has not been observed following systemic administration of methotrexate except in cases where intracarotid infusions were used. 

There has been considerable discussion on whether these effects have been due to the methotrexate or to contamination of preservaties in the solution available for intrathecal administration. The conclusion generally has been that preservative agents have been exonerated, and although it is suggested that Elliot s B solution does diminish the symptoms which follow immediately on intrathecal administration of methotrexate, it is probably unlikely that the severe forms of neurotoxicity are related to the ionic content of methotrexate solutions (21). 

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