Oral route solution severe toxic reactions, including embryofetal toxicitymethotrexate can cause severe or fatal toxicities. Search in pubmed medline using the terms che motherapy and intrathecal, analysis of secondary and ter tiary information sources. Intrathecal methotrexate is an essential component of chemotherapy for acute lymphoblastic leukemia and is effective in preventing recurrences of central nervous. Most of the drug excreted into the bile passes through the intestine and is excreted focally, but the drug is also subject to partial intestinal reabsorption and to metabolism by enteric bacteria breithaupt and kuenzlen, 1982. The degree of the methotrexate neuro toxicity is multifactorial, dependent upon the. A painful experience article pdf available in uhod uluslararasi hematolojionkoloji dergisi 183. Methotrexate mtx can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. Methotrexateinduced neurotoxicity and leukoencephalopathy. Intrathecal it methotrexate mtx therapy is used widely for the prevention and treatment of central nervous system cns leukemia 1,2. A randomized controlled trial comparing intrathecal sustained.
Methotrexate injection, usp isotonic liquid, contains preservative is available in 25 mgml, 2 ml 50 mg vials. This drug is also used to treat leukaemia found in the csf. A toxic syndrome characterized by fever, headache, and vomiting, lasting 25 days, occurred in 61% of 39 children with acute leukemia in complete remission, receiving central nervous system prophylaxis with intrathecal methotrexate, and in 14% of 34 children receiving the same plus cranial radiation. In rheumatoid arthritis ra and other disorders, mtx is administered as longterm, lowdose therapy, usually 7.
Standard treatment for neoplastic meningitis requires frequent intrathecal it injections of chemotherapy and is only modestly effective. It has also been described in previous studies that there is an elevated level of homocysteine in. Articulo bilingue inglescastellano practical aspects of the. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. The necessarily vigorous treatment programs for leukemia, including central nervous. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. The neurotoxicity of methotrexate mtx is more severe when administered intrathecally it than by the oral and intravenous iv routes, and has been reported even with a single administration of therapeutic doses of 12 or 15 mg. In addition to systemic control of leukemia, it is crucial for prophylaxis and treatment of sanctuary sites, including the cns. Intrathecal it chemotherapy consisting of methotrexate, cytarabine, or the two in combination is frequently used for the prophylaxis and treatment of cns metastasis.
We defined refractory acute methotrexate neurotoxicity as. This inhibition interferes with dna synthesis and cell reproduction. A case of cauda equina syndrome in a leukemic patient due to intrathecal methotrexate volume 24 no 1 march 2007 29 introduction the leukemias may cause neurologic dysfunction through direct invasion of the nervous system. Intrathecal methotrexateinduced megaloblastic anemia in patients with acute leukemia sabah sallah, md, l. Methotrexate injection fda prescribing information, side. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities 5.
Aminophylline for methotrexateinduced neurotoxicity the lancet. Progressive motor polyradiculopathy and myelopathy associated. Although the hematologic and mucocutaneous toxicities are dose limiting, its neurotoxicity is especially worrisome because the ad. For meningeal leukemia and lymphomatous meningititis intrathecal methotrexate followed by high dose methotrexate infusion with other chemotherapeutic agents such hydrocortisone and arac is the standard of care throughout the world ruggiero et al. Intrathecal methotrexate nephrotoxicity shm abstracts. Cns toxicity may occur after hdmtx, and concurrent intrathecal treatment, cranial irradiation, infiltration of malignant cells, or concomitant cns toxins increase the risk, as well as confound the etiology. Recurrent intrathecal methotrexate induced neurotoxicity in. A case of cauda equina syndrome in a leukemic patient due. The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. As this case illustrates, even with intrathecal methotrexate toxicity, treatment with pharmacologically guided leucovorin rescue along with continuation of hydration and alkalinization will facilitate restoration of renal function and decrease the risk of impending systemic toxicity.
Dailymed methotrexate methotrexate sodium injection. Mtx inhibits dihydrofolate reductase, an enzyme that reduces folic acid to tetrahydrofolic acid. Three weeks later, diffusion abnormalities resolved, and t2weighted studies showed increased signal intensity of prolonged t2 changes in areas of. To elucidate mechanisms for methotrexate mtxinduced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0. Methotrexate concentrations were measured 7 days after the last doses of intrathecal and oral routes, using patients as their own controls. The absence of lumbosacral f waves motor responses without demyelinating findings may indicate early direct root toxicity. A 59yearold japanese man with diffuse bcell lymphoma who underwent systemic chemotherapy including methotrexate and 20gy of radiotherapy received intrathecal. Treatment of accidental intrathecal methotrexate overdose. Progressive motor polyradiculopathy and myelopathy. Methotrexate is the most commonly used agent for it administration. Although hdmtx is safely administered to most patients, it can cause significant toxicity, including acute kidney injury aki in 2%12% of patients.
Methotrexate injection, usp contains preservative rx only. Lymphoma, intrathecal chemotherapy, methotrexate, toxicity, paraneoplastic. Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Depocyt is a sustainedrelease formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid csf for more than 14 days after a single 50mg injection. Lymphoma, intrathecal chemotherapy, methotrexate, toxicity. Acute lymphocytic leukemia all is one of the most common malignancies of childhood with an incidence of four cases per 100,000 population. Nov 18, 2018 methotrexate mtx use can be associated with a variety of adverse effects over a wide range of severity. Neurologic complications associated with intrathecal. For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. Renal tubular transport is also diminished by probenecid. This page from great ormond street hospital gosh describes intrathecal methotrexate, how it is given and some of the possible side effects. Methotrexate myelopathy after intrathecal chemotherapy.
Methotrexate mtx was among the first drugs discovered to have significant activity against leukemia and remains an integral component of treatment for acute. Treatment of intrathecal methotrexate overdose with. Because of the high toxicity of these chemotherapeutic agents, however, their side effect profiles are potentially catastrophic. Methotrexate concentration monitoring is a standard component of highdose methotrexate treatment. Methotrexate toxicity develops due to increased patient susceptibility during treatment, excessive parenteral or intrathecal administration, therapeutic errors by patients e. Pdf link pdf citation elias jabbour, susan obrien, hagop kantarjian, guillermo garciamanero, alessandra ferrajoli, farhad ravandi, maria cabanillas, deborah a. Complications of intrathecal chemotherapy in adults. Histologic features of drug toxicity were restricted to the spinal cord. Successful treatment of intrathecal methotrexate overdose by using. Mtx is cleared from the body through both biliary and urinary routes. We describe here the case of an adolescent male with tcell all who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and. We conducted a randomized, controlled trial of depocyt versus.
This case illustrates the importance of considering the diagnosis of methotrexate toxicity in an adult patient with behavioural and speech disturbances, who received it by intrathecal route only and in whom the only indicator was an abnormal electroencephalographic study. Methotrexate is often administered intrathecally or into the cerebral ventricles, particularly in patients with central nervous system tumors. For treatment of a cns disease, it cytarabine may be given on the same schedule as it methotrexate twice weekly for 4 weeks, then weekly for 4 weeks, then once per month. Recurrent intrathecal methotrexate induced neurotoxicity in an. Pdf intrathecal methotrexate and acute neurotoxicity. Prompt recognition and treatment are essential to improve the outcome after massive itmtx overdose. The neurotoxicity of methotrexate mtx is more severe when administered intrathecally it than by the oral and intravenous iv routes, and has been reported also with administration of therapeutic doses of 12 or 15 mg. We sought to identify clinical, pharmacokinetic, and. Methotrexate mtx use can be associated with a variety of adverse effects over a wide range of severity. Methotrexate toxicitymethotrexate toxicity methotrexate mtx is a chemotherapeutic drug that is structurally similar to folic acid. A case of cauda equina syndrome in a leukemic patient due to. A change in therapy is absolutely indicated because continued methotrexate.
A toxic syndrome characterized by fever, headache, and vomiting, lasting 25 days, occurred in 61% of 39 children with acute leukemia in complete remission, receiving central nervous. The mechanism of methotrexate mtx neurotoxicity is not fully. The association between methotrexate therapy and idiosyncratic neurological complications is well recognised in children. Such patients require especially careful monitoring for toxicity, and require dose. Acute paraplegia after treatment with intrathecal methotrexate requires a complete spinal cord neuroimaging as well as electrodiagnostic examination. Each 25 mgml, 2 ml vial contains methotrexate sodium equivalent to 50 mg methotrexate, 0. For meningeal leukemia and lymphomatous meningititis intrathecal methotrexate followed by high dose methotrexate infusion with other chemotherapeutic agents such hydrocortisone and. Intrathecal methotrexateinduced necrotizing myelopathy. Diagnostic imaging showed restricted diffusion and fluidattenuated inversion recovery imaging findings were normal at presentation.
A change in therapy is absolutely indicated because continued methotrexate treatment may result in death. Methotrexate mtx is an essential drug in the treatment of childhood acute lymphoblastic leukemia all. Acute lumbar polyradiculoneuropathy as early sign of. Intrathecal use of mtx and clinical use of lowdose and intermediatedose mtx for both malignant and nonmalignant conditions are covered elsewhere. Review of dextromethorphan administration in 18 patients with. Systemic methotrexate exposure is greater after intrathecal. Methotrexate pharmacokinetic studies, performed on a patient with renal impairment who had toxic effects following 20 mgsq m of intrathecally administered. Intrathecal methotrexate is an essential component of chemotherapy for acute lymphoblastic leukemia and is effective in preventing recurrences of central nervous system leukemia. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. Data was normalized to the actual dose received per body surface area. Although hdmtx is safely administered to most patients, it can cause significant toxicity. Adverse effects of intrathecal methotrexate in children.
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Methotrexate pharmacokinetic studies, performed on a patient with renal impairment who had toxic effects following 20 mgsq m of intrathecally administered methotrexate, demonstrated prolonged serum concentrations of the drug, which accounted for the condition. Conversely, existing steatohepatitis may increase methotrexate toxicity. The brain weighed 1420 g and showed no gross abnormalities. Intrathecal methotrexate was given on an ageadjusted schedule. Major side effects of lowdose methotrexate uptodate.
Most individuals eliminate methotrexate predictably, but methotrexate elimination can be prolonged in some individuals, placing them at high risk for severe toxicity andor death if. A randomized controlled trial comparing intrathecal. Methotrexateinduced neurotoxicity and leukoencephalopathy in. Oct 01, 2019 methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. We report a case of intrathecal methotrexate neurotoxicity manifesting as left arm weakness and aphasia. Adverse effects of intrathecal methotrexate in children with. Subacute neurotoxicity is usually observed days to weeks following methotrexate infusion and manifests as seizures, hemiparesis, speech disturbances, and myelopathy, especially. Phillips, pharmd from the department of medicine, division of hematologyoncology dr sallah, department of pathology and laboratory medicine dr hanrahan, and leo jenkins cancer center dr. Systemic and intrathecal methotrexate mtx are integral components of acute lymphoblastic leukemia all therapy, but can be associated with neurotoxicity. Dosing is based on age in pediatric patients table 1 see pdf. Many risk factors for methotrexateinduced neurotoxicity are recorded in the literature include highdose treatment, intrathecal treatment, young age, and association with cranial radiation 3. Oct 20, 2004 intrathecal methotrexate at doses of 6 to 15 mg is widely used to treat and prevent leptomeningeal tumor spread.
Intrathecal methotrexate at doses of 6 to 15 mg is widely used to treat and prevent leptomeningeal tumor spread. Central nervous system cns being a sanctuary site, in trathecal methotrexate it mtx has become a cornerstone for cns prophylaxis for. Accidental intrathecal methotrexate overdoses, which result from medication preparation errors or when methotrexate prescribed for systemic administration is administered intrathecally, are rare but can cause severe or fatal toxicity 1 4. Clinical pearls volume issue 4 2016 hopa news membership.
However, administration at intervals of less than 1 week may result in increased subacute toxicity. However, mtx can cause acute, subacute, and longterm neurotoxicities. Whether the progressive motor neuropathy and progressive myelopathy are a toxicity of intrathecal methotrexate or a paraneoplastic phenomenon is a matter of debate. Recurrent intrathecal methotrexate induced neurotoxicity. Results the mean red cell methotrexate concentration 7 days after the last of four. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these mtxrelated toxicities during childhood acute lymphoblastic leukemia all therapy and provide data on safety of intrathecal and highdose mtx rechallenge in patients with neurotoxicity. Each 25 mgml, 2 ml vial contains methotrexate sodium equivalent to 50 mg.
Chemotherapeutic regimens include methotrexate mtx, as mtx crosses the bloodbrain barrier and can be administered intravenously and via an intrathecal. Prompt recognition and treatment are essential to improve the outcome after itmtx overdose. A case of cauda equina syndrome in a leukemic patient due to intrathecal methotrexate volume 24 no 1 march 2007 29 introduction the leukemias may cause neurologic dysfunction. The status of the lymphoma was improving on systemic chemotherapy. Both highdose intravenous mtx and intrathecal mtx are. Prompt recognition and treatment are essential to improve the outcome of accidental overdoses.
Acute toxicity manifests during or within hours following methotrexate infusions and is characterized by somnolence, confusion, headache, nausea, and dizziness. It consists of motor paralysis, cranial nerve palsies, and seizures or coma or both. Intrathecal methotrexateinduced megaloblastic anemia in. Most individuals eliminate methotrexate predictably, but methotrexate elimination can be prolonged in some individuals, placing them at high risk for severe toxicity andor death if leucovorin rescue therapy is prematurely discontinued. Serious toxic reactions and death have been reported with the use of methotrexate. Accidental intrathecal methotrexate overdoses, which result from medication preparation errors or when methotrexate prescribed for systemic administration is administered intrathecally, are rare but can cause severe or fatal toxicity. Intrathecal methotrexate great ormond street hospital. Rechallenging with intrathecal methotrexate after developing. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. The prevention of methotrexate toxicity by thymidine infusions in humans. Monitor closely and modify dose or discontinue for the following toxicities. The neurotoxicity of methotrexate mtx is more severe when administered intrathecally it than by the oral and intravenous iv routes, and has been reported even with a single administration. However, in addition to chemical arachnoiditis, methotrexate can induce severe myelopathy. Diagnostic imaging showed restricted diffusion and fluid.
1521 545 317 540 964 1519 828 1418 787 23 652 1454 1531 1144 359 880 1411 533 299 970 360 1130 504 162 958 432 1175 1115 567 325