Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrathecal methotrexate

Asato, Reinin; Akiyama, Yuichi; Ito, Masako; Kubota, Masaru; Okumura, Ryota; Miki, Yukio; Konishi, Junji; Mikawa, Harukí

doi:10.1002/1097-0142(19921001)70:7<1997::aid-cncr2820700732>3.0.co;2-g

Cited by 116 publications

(67 citation statements)

References 19 publications

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“…A few days following administration, some patients have developed a toxic leukoencephalopathy with altered mental status and multifocal deficits. Within days to weeks, a transverse myelopathy with pain, sensory loss, paraplegia, and bladder dysfunction can [11][12][13] Treatment with low doses of purine analogs such as fludarabine (used in Case 1), cytarabine (used in Case 3), and 5-fluorouracil (used in Case 4) has also previously been known to result in at least rare white matter changes. These effects have generally been mild and reversible.…”

Section: Discussionmentioning

confidence: 99%

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Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies

2004

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We have observed an increasing number of autopsies on patients with chemotherapy-related complications. One complication is toxic leukoencephalopathy, which is due to a direct toxic effect of chemotherapeutic agents on the central nervous system white matter. Autopsies of four cases of toxic leukoencephalopathy were performed following standard protocols. The brain and spinal cord were examined routinely, and histological sections were taken for evaluation. We report here three patients with hematologic malignancies and one patient with metastatic carcinoma with chemotherapy-induced leukoencephalopathy. The first was a 56-yearold male treated with multiple chemotherapeutics for multiple myeloma. He presented with confusion and focal seizures with a rapid progression to coma and decerebrate posturing. The second was a 36-year-old male who developed mental status changes, ataxia and dysarthria following treatment for lymphoma. The third was a 16-year-old male who developed a profound peripheral and central neuropathy after chemotherapy treatment for Tcell acute lymphoblastic leukemia. The fourth was a 49-year-old female patient who was treated with multiple chemotherapeutics for Stage II breast carcinoma and subsequently developed visual acuity and field defects. The neuropathologic findings in these cases, although similar, varied in severity and distribution. The white matter was affected by severe myelin pallor, edema, and a prominent macrophage infiltrate in each of the cases. The location and extent of the central nervous system pathology correlated with the type and severity of clinical symptoms. These four cases, with their varied presenting symptoms, clinical courses, and degree of pathology, emphasize the importance of considering toxic leukoencephalopathy as an etiology of acute neurologic deterioration following high-dose chemotherapy.

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Section: Discussionmentioning

confidence: 99%

“…This effect is potentiated in the setting of coexisting chemotherapy, particularly intrathecal therapy. 12 Occupational exposures to organic solvents have been demonstrated to result in toxic leukoencephalopathy. [16][17][18][19][20][21][22] Environmental toxins such as carbon monoxide, arsenic, and CCl 4 have also been implicated.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies

2004

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“…Chronic neurotoxicity may occur after months to years and is usually associated with leukoencephalopathy, which can be transient and nonsymptomatic or severe, characterized by personality changes, progressive dementia, focal seizures, spastic quadriparesis, and stupor [2,10,11]. Severe leukoencephalopathy was associated with demyelination [2].…”

Section: Introductionmentioning

confidence: 99%

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Vezmar

Schüsseler

Becker

et al. 2008

Pediatric Blood & Cancer

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BackgroundSevere neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.ProcedureMTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m2) followed by calcium folinate rescue (3 × 15 mg/m2) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.ResultsIn non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.ConclusionIntrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.

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“…Studies have demonstrated that subacute MTX neurotoxicity occurs 2 to 14 days after high-dose or prolonged low-dose oral MTX. This neurotoxicity manifests with seizures, aphasia, encephalopathy and stroke-like symptoms (Asato et al, 1992;Rubnitz et al, 1998). Excessive production of reactive oxygen species (ROS) has been implicated in MTX hepatotoxicity, nephrotoxicity, intestinal toxicity and cardiotoxicity (Abd El-Twab et al, 2016;El-Sheikh et al, 2016;Mahmoud et al, 2017a,b).…”

Section: Introductionmentioning

confidence: 54%

Berberine mitigates methotrexate-induced oxidative stress and inflammation in the cerebrum of rats

Mahmoud¹,

Fadel²,

Ramadan³

et al. 2017

J App Pharm Sci

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Berberine is a natural isoquinoline alkaloid with multiple beneficial therapeutic effects. This study was designed to evaluate the protective effect of berberine against methotrexate (MTX)-induced oxidative stress and inflammation in the brain of rats. Rats received a single intraperitoneal injection of MTX (20 mg/kg) and orally administered 25 mg/kg and 50 mg/kg body weight berberine for 7 days. MTX-induced rats showed significantly increased lipid peroxidation and nitric oxide levels in the cerebrum. Treatment of the MTXinduced rats with berberine produced a significant decrease in cerebral levels of lipid peroxidation and nitric oxide. In addition, berberine induced a significant increase in reduced glutathione, superoxide dismutase, glutathione peroxidase and glutathione-S-transferase in the cerebrum of MTX-induced rats. Rats received MTX showed a significant up-regulation of nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β) expression in the cerebrum, an effect that was significantly reversed following treatment with berberine. In conclusion, berberine protects against MTXinduced neurotoxicity through attenuating oxidative stress and inflammation, and boosting the antioxidant defenses.

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Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrathecal methotrexate

Cited by 116 publications

References 19 publications

Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies

Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Berberine mitigates methotrexate-induced oxidative stress and inflammation in the cerebrum of rats

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