Rechallenging with intrathecal methotrexate after developing. This drug is also used to treat leukaemia found in the csf. Nov 18, 2018 methotrexate mtx use can be associated with a variety of adverse effects over a wide range of severity. Adverse effects of intrathecal methotrexate in children with. Acute paraplegia after treatment with intrathecal methotrexate requires a complete spinal cord neuroimaging as well as electrodiagnostic examination. Search in pubmed medline using the terms che motherapy and intrathecal, analysis of secondary and ter tiary information sources. 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. A case of cauda equina syndrome in a leukemic patient due to. However, in addition to chemical arachnoiditis, methotrexate can induce severe myelopathy.
It consists of motor paralysis, cranial nerve palsies, and seizures or coma or both. 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. Oct 20, 2004 intrathecal methotrexate at doses of 6 to 15 mg is widely used to treat and prevent leptomeningeal tumor spread. Major side effects of lowdose methotrexate uptodate. 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. 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. Intrathecal it methotrexate mtx therapy is used widely for the prevention and treatment of central nervous system cns leukemia 1,2. 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. Prompt recognition and treatment are essential to improve the outcome after itmtx overdose. Central nervous system cns being a sanctuary site, in trathecal methotrexate it mtx has become a cornerstone for cns prophylaxis for. Recurrent intrathecal methotrexate induced neurotoxicity in an. Acute lumbar polyradiculoneuropathy as early sign of. Chemotherapeutic regimens include methotrexate mtx, as mtx crosses the bloodbrain barrier and can be administered intravenously and via an intrathecal.
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. In rheumatoid arthritis ra and other disorders, mtx is administered as longterm, lowdose therapy, usually 7. A 59yearold japanese man with diffuse bcell lymphoma who underwent systemic chemotherapy including methotrexate and 20gy of radiotherapy received intrathecal. Systemic methotrexate exposure is greater after intrathecal. A painful experience article pdf available in uhod uluslararasi hematolojionkoloji dergisi 183. Intrathecal methotrexate is a chemotherapy drug which is given to prevent leukaemia cells entering the cerebrospinal fluid csf around the spine and brain. 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. A change in therapy is absolutely indicated because continued methotrexate.
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. This inhibition interferes with dna synthesis and cell reproduction. The prevention of methotrexate toxicity by thymidine infusions in humans. Each 25 mgml, 2 ml vial contains methotrexate sodium equivalent to 50 mg methotrexate, 0. Pdf intrathecal methotrexate and acute neurotoxicity. Treatment of accidental intrathecal methotrexate overdose. For meningeal leukemia and lymphomatous meningititis intrathecal methotrexate followed by high dose methotrexate infusion with other chemotherapeutic agents such hydrocortisone and. 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. Results the mean red cell methotrexate concentration 7 days after the last of four. 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.
However, mtx can cause acute, subacute, and longterm neurotoxicities. Intrathecal methotrexateinduced megaloblastic anemia in patients with acute leukemia sabah sallah, md, l. Monitor closely and modify dose or discontinue for the following toxicities. Prompt recognition and treatment are essential to improve the outcome after massive itmtx overdose. Methotrexate toxicity develops due to increased patient susceptibility during treatment, excessive parenteral or intrathecal administration, therapeutic errors by patients e. It has also been described in previous studies that there is an elevated level of homocysteine in. Although the hematologic and mucocutaneous toxicities are dose limiting, its neurotoxicity is especially worrisome because the ad. 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. A change in therapy is absolutely indicated because continued methotrexate treatment may result in death.
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. 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. Complications of intrathecal chemotherapy in adults. Pdf link pdf citation elias jabbour, susan obrien, hagop kantarjian, guillermo garciamanero, alessandra ferrajoli, farhad ravandi, maria cabanillas, deborah a. Methotrexate concentrations were measured 7 days after the last doses of intrathecal and oral routes, using patients as their own controls. A case of cauda equina syndrome in a leukemic patient due. Three weeks later, diffusion abnormalities resolved, and t2weighted studies showed increased signal intensity of prolonged t2 changes in areas of. This page from great ormond street hospital gosh describes intrathecal methotrexate, how it is given and some of the possible side effects. Intrathecal methotrexate at doses of 6 to 15 mg is widely used to treat and prevent leptomeningeal tumor spread. Acute toxicity manifests during or within hours following methotrexate infusions and is characterized by somnolence, confusion, headache, nausea, and dizziness. Intrathecal methotrexate is an essential component of chemotherapy for acute lymphoblastic leukemia and is effective in preventing recurrences of central nervous system leukemia. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions.
Systemic and intrathecal methotrexate mtx are integral components of acute lymphoblastic leukemia all therapy, but can be associated with neurotoxicity. Progressive motor polyradiculopathy and myelopathy associated. Although hdmtx is safely administered to most patients, it can cause significant toxicity. Intrathecal methotrexate was given on an ageadjusted schedule. The degree of the methotrexate neuro toxicity is multifactorial, dependent upon the. 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. Articulo bilingue inglescastellano practical aspects of the.
Both highdose intravenous mtx and intrathecal mtx are. We sought to identify clinical, pharmacokinetic, and. Recurrent intrathecal methotrexate induced neurotoxicity in. Acute lymphocytic leukemia all is one of the most common malignancies of childhood with an incidence of four cases per 100,000 population. Methotrexate injection fda prescribing information, side. Neurologic complications associated with intrathecal.
Methotrexate mtx was among the first drugs discovered to have significant activity against leukemia and remains an integral component of treatment for acute. To elucidate mechanisms for methotrexate mtxinduced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0. 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. 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. Intrathecal methotrexate nephrotoxicity shm abstracts.
However, administration at intervals of less than 1 week may result in increased subacute toxicity. Lymphoma, intrathecal chemotherapy, methotrexate, toxicity, paraneoplastic. Many risk factors for methotrexateinduced neurotoxicity are recorded in the literature include highdose treatment, intrathecal treatment, young age, and association with cranial radiation 3. Whether the progressive motor neuropathy and progressive myelopathy are a toxicity of intrathecal methotrexate or a paraneoplastic phenomenon is a matter of debate. Review of dextromethorphan administration in 18 patients with. Mtx inhibits dihydrofolate reductase, an enzyme that reduces folic acid to tetrahydrofolic acid. Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Each 25 mgml, 2 ml vial contains methotrexate sodium equivalent to 50 mg. Methotrexate injection, usp contains preservative rx only. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.
Methotrexateinduced neurotoxicity and leukoencephalopathy in. 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. 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. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities 5. We report a case of intrathecal methotrexate neurotoxicity manifesting as left arm weakness and aphasia. Prompt recognition and treatment are essential to improve the outcome of accidental overdoses.
Dailymed methotrexate methotrexate sodium injection. Methotrexate concentration monitoring is a standard component of highdose methotrexate treatment. Recurrent intrathecal methotrexate induced neurotoxicity. The absence of lumbosacral f waves motor responses without demyelinating findings may indicate early direct root toxicity. Intrathecal methotrexateinduced megaloblastic anemia in. Treatment of intrathecal methotrexate overdose with. Clinical pearls volume issue 4 2016 hopa news membership.
Serious toxic reactions and death have been reported with the use of methotrexate. Methotrexate is often administered intrathecally or into the cerebral ventricles, particularly in patients with central nervous system tumors. Intrathecal methotrexate is an essential component of chemotherapy for acute lymphoblastic leukemia and is effective in preventing recurrences of central nervous. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Dosing is based on age in pediatric patients table 1 see pdf. Intrathecal methotrexateinduced necrotizing myelopathy. Progressive motor polyradiculopathy and myelopathy. Adverse effects of intrathecal methotrexate in children.
Aminophylline for methotrexateinduced neurotoxicity the lancet. Such patients require especially careful monitoring for toxicity, and require dose. Intrathecal it chemotherapy consisting of methotrexate, cytarabine, or the two in combination is frequently used for the prophylaxis and treatment of cns metastasis. In addition to systemic control of leukemia, it is crucial for prophylaxis and treatment of sanctuary sites, including the cns. Renal tubular transport is also diminished by probenecid. The mechanism of methotrexate mtx neurotoxicity is not fully. The status of the lymphoma was improving on systemic chemotherapy. Intrathecal methotrexate great ormond street hospital. We defined refractory acute methotrexate neurotoxicity as. Standard treatment for neoplastic meningitis requires frequent intrathecal it injections of chemotherapy and is only modestly effective.
Conversely, existing steatohepatitis may increase methotrexate toxicity. Methotrexate mtx is an essential drug in the treatment of childhood acute lymphoblastic leukemia all. 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. The necessarily vigorous treatment programs for leukemia, including central nervous. Methotrexate is the most commonly used agent for it administration. Histologic features of drug toxicity were restricted to the spinal cord. For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. Oct 01, 2019 methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.
This case illustrates the importance of considering the diagnosis of methotrexate toxicity. Intrathecal use of mtx and clinical use of lowdose and intermediatedose mtx for both malignant and nonmalignant conditions are covered elsewhere. Methotrexate pharmacokinetic studies, performed on a patient with renal impairment who had toxic effects following 20 mgsq m of intrathecally administered. Lymphoma, intrathecal chemotherapy, methotrexate, toxicity. A randomized controlled trial comparing intrathecal sustained. 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. 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. Methotrexate mtx can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. Methotrexate injection, usp isotonic liquid, contains preservative is available in 25 mgml, 2 ml 50 mg vials. Oral route solution severe toxic reactions, including embryofetal toxicitymethotrexate can cause severe or fatal toxicities.
Diagnostic imaging showed restricted diffusion and fluidattenuated inversion recovery imaging findings were normal at presentation. Methotrexateinduced neurotoxicity and leukoencephalopathy. We conducted a randomized, controlled trial of depocyt versus. 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. Mtx is cleared from the body through both biliary and urinary routes. 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. Subacute neurotoxicity is usually observed days to weeks following methotrexate infusion and manifests as seizures, hemiparesis, speech disturbances, and myelopathy, especially. Although hdmtx is safely administered to most patients, it can cause significant toxicity, including acute kidney injury aki in 2%12% of patients. Diagnostic imaging showed restricted diffusion and fluid. Methotrexate mtx use can be associated with a variety of adverse effects over a wide range of severity. Methotrexate myelopathy after intrathecal chemotherapy.
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