Intrathecal Methotrexate and Acute Neurotoxicity: A Painful Experience
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Abstract:
Intrathecal treatment with methotrexate, an essential chemotherapeutic for both prophylaxis and treatment of central nervous system involvement of leukemia, may be associated with local neurotoxicity and/or systemic toxicity. Signs of acute neurotoxicity include confusion, disorientation, seizures, aphasia, ataxia, dysarthria, paresis and even paraly- sis. Presented here is a case of a 58 year old patient with acute lymphoblastic leukemia who developed acute neuro- toxicity after her 13th dose of intrathecal methotrexate. Available treatment options are also discussed.Keywords:
Neurotoxicity
Paresis
Dysarthria
Intrathecal
Acute lymphocytic leukemia
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Cyclosporine-A (CsA) and mycophenolate mofetil are immunosuppressive drugs used for the prevention of transplant rejection. Various clinical studies have been performed on different forms of CsA neurotoxicity, including tremor, paresthesia, confusion, ataxia, neuralgia, hemiplegia, occipital seizures, and transient cortical blindness. Mycophenolate is associated with several neurological side effects including headache, insomnia, dizziness, depression, confusion, hypertonia, and paresthesia. A 31-year-old male with a history of kidney transplantation was treated with CsA and mycophenolate mofetil, for 18 years. He had been referred to the emergency department with complaints of generalized tonic-clonic seizure for 1 minute and 15 minutes of the post-ictal phase. Almost all laboratory tests including cerebrospinal fluid analysis were within normal limits. Brain MRI findings were compatible with CsA-based neurotoxicity. The patient's symptoms and MRI findings improved on decreasing CsA to the minimum dose. CsA neurotoxicity is more common in intravenous therapy, early days of CsA administration, P450 inhibitors administration, and following liver transplantation. MRI findings in CsA neurotoxicity include signal changes in the cerebral cortex and juxtacortical white matter of the occipital lobes, temporal, parietal, and frontal lobes. Every year, many solid organ transplantations are performed. Many of these patients received CsA-based regimens for the prevention of rejection. Therefore, it is necessary to consider CsA neurotoxicity in suspected patients.
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A case of childhood acute lymphatic leukemia is presented; the patient manifested abdominal distention, loss of deep tendon reflexes, seizures and coma without laboratory evidence of CNS leukemia; the patient also demonstrated hyponatremia and serum hypotonicity with simultaneous urinary hypertonicity. It is felt that this syndrome was a manifestation of vincristine toxicity. The neurotoxicity of vincristine is reviewed and it is suggested that inappropriate ADH secretion (IADHS) may reflect a direct neurotoxic effect of vincristine on the central nervous system sites of ADH formation and/or storage.
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Coma (optics)
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Objective: To present a rare case of methotrexate induced cerebellar leukoencephalopathy with long term oral methotrexate use. Case presentation: A 59 year old female with rheumatoid arthritis treated with methotrexate and folate supplementation for greater than 10 years presented to the neurology clinic with signs of brain stem and cerebellar dysfunction. Symptoms included a slowly progressive ataxic gait, vertigo, nausea, vomiting, and bilateral tinnitus. Patient's physical exam revealed a left upper and lower limb ataxia with a wide base ataxic gait. MRI of her brain demonstrated symmetrical white matter lesions involving both cerebellar hemispheres, extending to the middle cerebellar peduncles without any post-gadolinium enhancement. An extensive investigation including infectious, vasculitic, autoimmune, paraneoplastic and cytologic studies in the serum and CSF were unremarkable. Vitamin B12 serum level was normal with an elevated homocysteine level. Methotrexate-induced encephalopathy was established. One month after discontinuation of methotrexate, the patient reported significant improvement in her gait and resolution of her nausea and vomiting. A repeat MRI of her brain five months after discontinuing her methotrexate demonstrated a significant decrease in the degree of T2 hyperintense signals within the white matter in the cerebellar hemispheres and middle cerebral peduncles. Discussion: Methotrexate-induced encephalopathy is a rare complication in MTX therapy. It ranges from mild reversible leukoencephalopathy to irreversible and even fatal disseminated necrotizing leukoencephalopathy. The involvement of the cerebellum is quite rare. Exact mechanism of this toxicity remains unclear. It has been proposed that homocysteine elevation and its excitatory effect on NMDA receptors is partially responsible. Early recognition of the condition and the withdrawal of methotrexate can improve outcomes. Genetic polymorphisms in methylenetetrahydrofolate reductase may influence the side effects of methotrexate. Pharmacogenetic screening needs to be considered for risk stratification of those at higher risk of toxicity before initiating therapy.
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Neurotoxicity is a well-documented adverse effect of methotrexate in the treatment of pediatric cancers. The spectrum of symptoms is broad, can include stroke-like episodes and seizures, and classically resolves within days. The majority of patients tolerate subsequent doses without recurrence of symptoms. The population of patients who experience persistent and irreversible neurologic symptoms is poorly described, with the existing literature suggestive of a relationship with radiation therapy. The authors present a case series of 2 patients with pre-B-cell acute lymphoblastic leukemia who developed severe and ultimately fatal methotrexate-related neurotoxicity in the absence of radiation.
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Figure 1a.MRI FLAIR images show bilateral multiple subcortical and cortical hyperintense lesions.Figure 1b.MRI images 3 weeks after developing PRES revealed significant improvement.
Intrathecal
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Three children with acute lymphocytic leukemia (ALL) developed delayed-onset transient hemiparesis and facial palsy after intrathecal (IT) administration of methotrexate (MTX) alone or as part of triple intrathecal chemotherapy for central nervous system (CNS) prophylaxis. The hemiparesis developed 10 to 14 days after IT therapy. Two of three children also experienced transient, profound expressive dysarthria. These episodes occurred during maintenance treatment after multiple IT administrations and without previous CNS toxicity. Two of three children received intermediate-dose MTX, 1 g/m2, not less than 5 weeks before events. These patients had not received cranial irradiation and had no evidence of CNS leukemia before or after these episodes. Ischemic changes on computerized tomographic scan or magnetic resonance imaging studies were documented in all three cases. Such changes are unusual manifestations of neurotoxicity in children after intrathecal therapy.
Hemiparesis
Acute lymphocytic leukemia
Dysarthria
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The case histories of two patients with acute lymphocytic leukemia, who developed central nervous system complication during combined chemotherapy are described. The neurological picture could be characterized by symptoms of headache, mental deterioration, hemiparesis and seizures. Following L-asparaginase administration one patient had intracranial thrombosis with focal seizures and hemiparesis associated with clotting abnormalities, including severe hypofibrinogenemia and decreased antithrombin III activity. In the other patient, it was after intrathecal administration of Methotrexate when mental deterioration associated with the symptoms of progressive leukoencephalopathy occurred. It arises the possibility that with increasing complexity of combined chemotherapy the occurrence rate of neurological complications will also increase.
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Hypofibrinogenemia
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An acute episode of encephalopathy after the infusion of 16 g methotrexate is reported in a 12-year-old girl with osteogenic sarcoma. The complication occurred during the 11th treatment course, when severe vomiting and diarrhea were followed by a low urine output with consecutive toxic concentrations of methotrexate in serum and cerebrospinal fluid leading to severe systemic and central nervous system toxicity. The onset of the central nervous system toxicity was acute with slurred speech, paresis of the external rectus eye muscles, ataxia, and hemiparesis, and symptoms resolved completely after 30 hours by treatment with calcium leucovorin and forced diuresis. After management of the cerebral and systemic toxicity, high-dose methotrexate treatment could be reinstituted, and was followed by no further complications. In contrast to the transient cerebral dysfunctions, probably caused by embolization of tumor tissue in the early course of high-dose methotrexate treatment, the acute neurologic syndrome observed in the current case after the prolonged use of methotrexate seemed to be related to direct central nervous system toxicity of the drug.
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