Methotrexate (MTX) is a powerful antimetabolite drug used to suppress the immune system and slow cell growth. Physicians prescribe this medication for various conditions, including certain types of cancer and autoimmune diseases such as Rheumatoid Arthritis and psoriasis. Neuropathy describes damage to the nerves outside the brain and spinal cord, resulting in altered sensation, muscle weakness, or pain. While MTX is highly effective, nerve damage caused by the drug, known as methotrexate-induced neuropathy, is a recognized, though relatively uncommon, adverse effect. This specific form of neurotoxicity requires careful attention from both patients and healthcare providers.
The Biological Cause of Nerve Damage
Methotrexate harms nerve tissue primarily through its function as a folate antagonist. MTX works by inhibiting the enzyme dihydrofolate reductase (DHFR), which converts folic acid into its active form, tetrahydrofolate. This active folate is required for the synthesis of DNA, RNA, and proteins, which is why MTX selectively targets rapidly dividing cells. Although nerve cells do not divide rapidly, they still require consistent DNA synthesis and repair processes to maintain health and function.
Disruption of the folate pathway interferes with necessary cellular maintenance and repair cycles within the nervous system. This metabolic interference leads to direct neurotoxicity, affecting the structural integrity of peripheral nerves. MTX administration can result in impaired nerve conduction, reduced myelin thickness, and degeneration of the axon. Furthermore, the lack of proper folate metabolism contributes to elevated levels of homocysteine, a compound linked to nervous system toxicity.
The severity of neurotoxicity often relates to the dosage and route of administration. High-dose MTX, typically used in cancer treatment, carries a greater risk for acute central nervous system complications because it is more likely to cross the blood-brain barrier. Conversely, long-term, low-dose MTX, common for autoimmune conditions, is more frequently associated with peripheral nerve issues.
Identifying Neuropathy Symptoms
Methotrexate neuropathy most commonly involves the peripheral nervous system. Patients often report sensory symptoms that begin in the feet and hands, described as a “glove and stocking” distribution. These sensations include tingling, a pins-and-needles feeling, or persistent numbness that gradually spreads up the limbs. Pain is also a frequent complaint, often characterized as a burning, shooting, or electric-like discomfort.
Motor symptoms, involving muscle function, may also develop, leading to weakness, loss of dexterity, or difficulty with balance and walking. Peripheral symptoms can be chronic, developing slowly over months or years of low-dose therapy, or they can appear acutely following a higher dose.
Less commonly, MTX can cause central nervous system (CNS) toxicity, especially when administered intrathecally or at very high intravenous doses. CNS effects are distinct from peripheral neuropathy and may include fluctuating neurological deficits, confusion, seizures, or stroke-like symptoms. A rarer, delayed form of CNS toxicity, known as leukoencephalopathy, involves damage to the brain’s white matter, leading to difficulties with movement, coordination, and cognitive function. Any new or worsening nerve-related discomfort should be promptly reported to a healthcare provider.
Confirming the Diagnosis
Attributing nerve damage to methotrexate is often a diagnosis of exclusion. The first step involves a comprehensive medical review and physical examination to rule out other common causes of neuropathy. Physicians must test for conditions such as uncontrolled diabetes, vitamin B12 deficiency, thyroid disorders, or the possibility that the underlying autoimmune disease is causing the damage. Blood tests check B vitamin levels and assess markers of inflammation or other systemic issues affecting nerve health.
Specialized electrodiagnostic testing is used to confirm the presence and characteristics of the nerve damage. Nerve conduction studies (NCS) measure how quickly electrical signals move through motor and sensory nerves. Electromyography (EMG) assesses the electrical activity of muscle fibers and the nerves that supply them. These tests help determine if the neuropathy is primarily affecting the nerve’s covering (demyelinating) or the main body (axonal), and localize the site of damage.
Objective evidence of nerve injury, such as reduced nerve signal amplitude or slowed conduction velocity, is provided by NCS and EMG findings. The diagnosis is solidified by combining the pattern of nerve damage with a clear temporal relationship to the start of MTX therapy. For suspected central nervous system toxicity, magnetic resonance imaging (MRI) of the brain or spine may be necessary to visualize white matter changes or inflammation.
Treatment and Supportive Care
If methotrexate-induced neuropathy is confirmed, the drug dose may be reduced, or the medication may be discontinued entirely. In many cases, the nerve damage is reversible or at least stabilizes after the causative agent is removed.
A critical component of supportive care, particularly in high-dose settings, is the use of folinic acid, also known as leucovorin rescue. Folinic acid is an active folate form that bypasses the enzyme inhibited by MTX, protecting healthy cells, including nerve cells, from toxicity. This rescue therapy is administered on a strict schedule to mitigate systemic side effects without compromising the drug’s therapeutic effect.
Symptom relief is managed with supportive medications aimed at controlling neuropathic pain, such as specific nerve pain medications or anti-inflammatory drugs. Physical therapy can be beneficial for patients experiencing muscle weakness or difficulty with movement, helping to maintain strength and improve function. Addressing potential nutritional deficiencies is also important, and B vitamin supplementation may be recommended if blood tests indicate low levels. The goal of treatment is to alleviate symptoms and prevent further damage while ensuring the underlying condition remains well-managed.