Methotrexate (MTX) is a powerful chemotherapy agent and immune-system suppressant. It functions as an antimetabolite, specifically an antifolate, which prevents cells from utilizing folic acid to manufacture and repair DNA. This mechanism interferes with the rapid division of cancer cells, making it an effective therapy for various malignancies, including acute lymphoblastic leukemia and certain lymphomas. Understanding the specialized method of delivery is important for patient safety and education.
Why Intrathecal Delivery Is Necessary
The central nervous system (CNS), including the brain and spinal cord, is protected by the specialized blood-brain barrier (BBB). This barrier is highly selective, allowing essential nutrients to pass while blocking toxins and most foreign substances, including many systemic chemotherapy drugs. Standard delivery methods, such as oral or intravenous (IV) injection, are ineffective for treating cancer cells that have spread into the cerebrospinal fluid (CSF) or CNS tissues. The BBB prevents the drug from reaching therapeutic concentrations in this “sanctuary” site.
Intrathecal (IT) delivery bypasses the BBB by injecting the medication directly into the CSF. This allows the drug to bathe the brain and spinal cord, ensuring cancer cells receive an effective dose. IT delivery is used both to treat existing CNS involvement, such as leptomeningeal carcinomatosis, and as a prophylactic measure to prevent cancer cells from colonizing the CNS in high-risk hematological malignancies. Without this direct route, CNS relapse risk is significantly greater, as systemic therapies cannot adequately protect this area.
The Administration Procedure
The most common method for administering intrathecal methotrexate is a lumbar puncture, often called a spinal tap. The procedure is typically performed with the patient lying on their side or sitting and leaning forward, positions that expose the spinal interspaces. The practitioner identifies the injection site, usually between the L3-L4 or L4-L5 vertebrae in the lower back, to avoid the spinal cord.
A local anesthetic is injected to numb the skin and surrounding tissue. A sterile spinal needle is then inserted into the subarachnoid space, the area surrounding the spinal cord where the CSF flows. After confirming the needle is correctly positioned, often by aspirating a small amount of CSF, the preservative-free methotrexate solution is slowly injected over one to two minutes.
For patients requiring frequent or long-term IT treatments, the Ommaya reservoir is an alternative. This small, dome-shaped device is surgically implanted beneath the scalp and connected via a catheter to a ventricle in the brain. The reservoir allows the practitioner to inject the drug directly into the cerebral ventricles, ensuring better distribution throughout the upper CNS cavities compared to a lumbar injection.
Understanding Neurotoxicity
The primary risk associated with intrathecal methotrexate is neurotoxicity, which manifests in distinct ways depending on the time of onset.
Acute Neurotoxicity
Acute neurotoxicity typically occurs hours to a few days after injection, often presenting as chemical arachnoiditis, an inflammation of the membranes covering the brain and spinal cord. Symptoms include severe headache, nausea, vomiting, fever, and a stiff neck. These effects are usually self-limiting and resolve spontaneously.
Subacute Neurotoxicity
Subacute neurotoxicity generally appears between two and 14 days following treatment and involves more severe neurological symptoms. Patients may experience transient stroke-like symptoms, such as sudden onset of weakness (paresis), slurred speech (aphasia), or seizures. Imaging often reveals transient white matter changes (leukoencephalopathy), which usually resolve as clinical symptoms improve within a week or two.
Delayed or Chronic Neurotoxicity
The most concerning form is delayed or chronic neurotoxicity, occurring months or years after treatment completion. This complication is characterized by leukoencephalopathy, which involves damage to the brain’s white matter. Chronic leukoencephalopathy is associated with long-term cognitive impairment, memory loss, and a decline in executive functions. The risk is significantly higher when IT methotrexate is combined with cranial radiation or high cumulative drug exposure. The mechanisms behind this toxicity are complex, potentially involving disruption of the brain’s folate metabolism and direct damage to neuronal cells.
Safety Protocols and Monitoring
Given the potential for neurotoxicity, stringent safety protocols are implemented before, during, and after IT methotrexate administration. Pre-procedure requirements mandate a strict dosage verification process, meticulously checked by multiple authorized personnel to prevent fatal medication errors. Blood tests are required to confirm the patient has an adequate platelet count (typically over 40-50 x 10⁹/L) and normal coagulation times to minimize the risk of bleeding or spinal hematoma during the lumbar puncture.
During the procedure, practitioners must use sterile, preservative-free methotrexate, as many IV formulations contain preservatives that are toxic to the nervous system. The injection must be performed slowly, over a minute or two, to avoid a sudden increase in intrathecal pressure, which can contribute to drug maldistribution and neurotoxicity. After the injection, the patient is often instructed to lie flat for 30 to 60 minutes, which is thought to aid in the uniform distribution of the drug throughout the CSF and potentially reduce the incidence of post-puncture headaches.
Post-procedure monitoring includes observation for signs of neurotoxicity, such as new or persistent headaches, confusion, or focal weakness. If systemic absorption occurs (which can happen if the BBB is compromised), rescue medications like leucovorin (folinic acid) may be administered. Leucovorin counteracts the systemic effects of methotrexate by supplying the folic acid needed for healthy cell function.