Methotrexate And Stroke: Is There A Link?

Methotrexate is a drug used in the treatment of acute lymphoblastic leukemia, which is the most common form of leukaemia in children. It is also used to treat rheumatoid arthritis. Methotrexate can cause neurotoxicity, which can manifest as stroke-like symptoms, including hemiparesis, seizures, and speech disorders. The stroke-like syndrome is a rare complication of intrathecal or high-dose methotrexate administration. It typically occurs within two weeks of methotrexate administration and resolves spontaneously within a few days. The pathophysiology of methotrexate-induced stroke-like syndrome is not well understood but may involve multiple mechanisms, including direct toxicity to the vascular endothelium and increased excitatory effects on N-methyl-D-aspartate receptors. The diagnosis of methotrexate-induced stroke-like syndrome is made based on clinical presentation and neuroimaging findings, particularly magnetic resonance imaging (MRI), which may show transient, multifocal, and reversible restricted diffusion in the subcortical and periventricular white matter. The treatment of methotrexate-induced stroke-like syndrome is primarily supportive, and most patients recover completely without sequelae. However, some drugs, such as dextromethorphan and aminophylline, have been used to manage neurological deficits caused by methotrexate neurotoxicity.

Methotrexate-induced stroke-like syndrome is a rare complication

Stroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose methotrexate administration. Its clinical features, which evoke acute cerebral ischemia with fluctuating course symptoms and a possible spontaneous resolution, have piqued the interest of the scientific community. The underlying pathogenesis, clinical and therapeutic management, and long-term outcomes are still not fully understood.

The incidence of subacute neurotoxicity is unclear. In one study, 369 children with diagnosed acute lymphoblastic leukemia (B-ALL) treated with both intravenous and/or intrathecal methotrexate, subacute encephalopathy occurred in 14 patients (3.8%). In other studies, the incidence was higher, ranging from 0.8% to 3.8%.

The clinical presentation of methotrexate-induced stroke-like syndrome typically includes hemiplegia and/or cranial nerve palsy, paresthesia, movement or speech disorders, and seizures. Symptoms usually develop within 2-14 days after drug administration and last from 15 minutes to 72 hours before resolving spontaneously without sequelae.

Neuroimaging studies are usually normal, but changes have been observed on MRI, such as areas of restricted diffusion on diffusion-weighted imaging and non-enhancing T2 hyper-intense lesions in the white matter. EEG might show diffuse slowing of the background activity.

Methotrexate-induced stroke-like syndrome is a rare but well-characterized complication of methotrexate administration. Its clinical features and correct treatment are still largely debated due to the worrisome clinical picture it presents. Further research is needed to better comprehend this syndrome.

Methotrexate-induced stroke-like encephalopathy

The pathophysiology of methotrexate-induced stroke-like encephalopathy is not fully understood but is likely multifactorial. It may involve direct damage to the vascular endothelium by homocysteine, increased excitatory effects on N-methyl-D-aspartate receptors, alterations in adenosine metabolism, chronic folate depletion, and direct neuronal damage by methotrexate.

The typical neuroimaging findings include hyperintensities on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) hypointensities in the subcortical white matter, sparing the cerebral cortex and not respecting vascular territories. These MRI findings support a non-vascular mechanism and help distinguish methotrexate-induced encephalopathy from acute cerebral infarction.

The management of methotrexate-induced stroke-like encephalopathy is primarily supportive, as most cases resolve spontaneously. However, additional treatments such as dextromethorphan, dexamethasone, aminophylline, and folic acid have been used in some patients. The decision to continue or discontinue methotrexate therapy must carefully weigh the potential risks of relapse against the anti-tumour benefits.

The main risk factors for methotrexate-induced stroke-like encephalopathy include high-dose or intrathecal methotrexate therapy, age above 10 years, and co-administration with other chemotherapeutic agents.

Methotrexate-induced stroke-like neurotoxicity

Methotrexate is an antimetabolite agent and antineoplastic drug used to treat cancers such as acute lymphoblastic leukaemia and osteosarcoma, as well as autoimmune diseases. It acts as a competitive inhibitor of the enzyme dihydrofolate reductase, blocking the synthesis of folate and tetrahydrofolate and inhibiting DNA synthesis.

Methotrexate-induced neurotoxicity may cause acute, subacute or chronic symptoms. The overall incidence of neurotoxicity ranges from 3 to 10%, and varies according to dose, route and frequency of administration. The weekly or biweekly administration of high-dose methotrexate, a prolonged low-dose oral treatment, and intrathecal administration may produce a subacute neurotoxicity called stroke-like syndrome (SLS). Symptoms of SLS include hemiplegia, hemisensory deficits, aphasia, dysarthria, dysphagia, diplopia and seizures. They develop 2-14 days after drug administration, last 15 minutes to 72 hours, and then resolve spontaneously without sequelae.

Neuroimaging studies are usually normal, but changes have been observed on MRI, such as areas of restricted diffusion on diffusion-weighted imaging and non-enhancing T2 hyper-intense lesions in the white matter. EEG might show diffuse slowing of the background activity. Treatment may consist of observation and supportive care alone, or drugs such as dextromethorphan, dexamethasone, aminophylline and folic acid.

The incidence of subacute neurotoxicity is unclear. In 369 children with acute lymphoblastic leukaemia treated with both intravenous and/or intrathecal methotrexate, subacute encephalopathy occurred in 14 patients (3.8%). In other studies, the incidence ranged from 0.8 to 3.8%, while in a recent paper it was much lower (0.2%).

Several hypotheses have been proposed for the mechanisms underlying SLS, including direct damage induced by methotrexate, and several methotrexate-related biochemical changes that could indirectly affect the central nervous system.

The main risk factors for methotrexate-induced neurotoxicity include high-dose or intrathecal therapy, association with cranial radiation, and age >10 years.

Methotrexate-induced stroke-like symptoms are benign and transient

Methotrexate is a folic acid antagonist commonly used to treat autoimmune diseases and malignancies. It is an essential drug in the treatment of acute lymphoblastic leukemia, which is the most common form of leukaemia in children. However, its usage is associated with some side effects, including neurotoxicity. Neurotoxicity associated with methotrexate is transient, and most patients continue to receive this therapy without intercurrences.

Methotrexate-induced neurotoxicity may present as acute, subacute, or chronic. Acute neurotoxicity occurs after a few hours of administration of the drug and includes drowsiness, disorientation, seizures, headache, and dizziness. Subacute neurotoxicity typically occurs between 2 and 14 days after exposure to prolonged low doses of oral methotrexate, intrathecal methotrexate, or high-dose methotrexate. It manifests with convulsions, changing in vision, motor deficits, behaviour alterations (lethargy), and stroke-like symptoms. These events are usually transient, and the majority of patients receive the new treatment without complications.

The stroke-like symptoms presentation is a benign rare neurological complication, mainly described after the administration of intrathecal methotrexate. It simulates a transitory cerebral vascular ischemic accident associated with a focal sensory-motor deficit and a language alteration. Moreover, it can occur an oculomotor nerve palsy and ataxia. The evolution is characterized by a fluctuation of the symptom's intensity, with complete resolution within hours or days. The diagnosis is confirmed with a cranial-cephalic MRI.

The benignity and transitory nature of these episodes don't establish a contraindication to continue the treatment, so the patient can carry on with the treatment.

Methotrexate-induced stroke-like symptoms can be treated with dextromethorphan

Methotrexate is an antimetabolite drug used in the treatment of cancers such as acute lymphoblastic leukemia (ALL) and malignancies. It can, however, cause central nervous system damage, particularly to the subcortical white matter, leading to stroke-like syndrome (SLS), a rare subacute neurological complication. SLS typically occurs within 21 days of methotrexate administration (intrathecal or high-dose intravenous treatment) and presents with neurological symptoms such as paresis, paralysis, aphasia, dysarthria, and altered mental status. The symptoms usually resolve spontaneously without any identifiable cause.

The treatment for SLS is primarily supportive care, and most cases resolve without any intervention. However, in some cases, additional medications such as dextromethorphan, dexamethasone, aminophylline, and folic acid have been used successfully. Dextromethorphan, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, is particularly useful in treating MTX neurotoxicity as it can inhibit the excitatory effects of homocysteine metabolites.

In summary, while MTX-induced SLS is a rare complication, it is important for healthcare professionals to be aware of its neurological side effects, which can be managed with dextromethorphan and other medications. Early recognition and appropriate treatment can lead to a swift and full neurological recovery in most patients.

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