Leukoencephalopathy can develop from long-term treatment of methotrexate even at low doses. In contrast to intravenous methotrexate for cancer patients, leukoencephalopathy induced by orally taken methotrexate may be associated with cognitive dysfunction and even death.Oxycodone is the main active ingredient in various oral pain relief medications. High doses of opiates such as oxycodone can lead to leukoencephalopathy. The activity of various opioid and nociceptive receptors appear to play a role in the disease; however, the exact mechanism remains unknown.Metronidazole, an antibiotic used to treat anaerobic and protozoal infections, has been known at high doses to produce neurologic symptoms associated with toxic leukoencephalopathy. Other
Toxic leukoencephalopathy may also result from carbon monoxide poisoning, ingestion of methanol, ingestion of ethylene, toluene toxicity, ethanol poisoning, ingestion of methylenedioxymethamphetamine (MDMA or "ecstasy"), or ingestion of paradichlorobenzene, which is a toxic agent in mothballs. Diagnosis
Due to advances in MRI, this neurological disorder has been characterized more successfully in more recent years. MRI can aid in the detection of injured brain tissue; however, the severity and extent of the damage demonstrated by imaging does not always reflect patient clinical status. Toxic leukoencephalopathy encompasses the degeneration of white matter tracts devoted to higher cerebral function; however, white matter can appear normal until the disease has progressed more intensely. Toxic leukoencephalopathy-related damage to central nervous system (CNS) white matter, typically of the periventricular nucleus, and other structures in the brain is often bilateral and symmetric.
Substance use
Leukoencephalopathy may result from the inhalation, intravenous injection, or ingestion of addictive substances. However, such occurrences are rare, sporadic, and often go undocumented. Leukoencephalopathy caused by inhalation of heroin, also known as "chasing the dragon" syndrome, is one of the most studied of these rare occurrences and has even been recognized for over twenty five years.It is believed by some researchers that heroin-induced leukoencephalopathy may be caused by a contaminant, or “cutting agent,” in the heroin. However, no such agent has been identified; and indeed, toxic leukoencephalopathy has been observed as a result of intoxication with contaminant-free opiates. Cases include a 65-year-old woman who had mistakenly been taking three times the dose of methadone that had been prescribed for pain management, and a young girl intoxicated with pure morphine sulfate tablets.Other drugs that have been associated with toxic leukoencephalopathy in much more rare occurrences include psychoactive drug 2C-E ("Europa"),  oxycodone, cocaine, and methadone. The dose–response relationship for these substances remains unclear. Chemotherapy
Various chemotherapy drugs have shown increased risk of cancer patients developing leukoencephalopathy. High doses of intravenous methotrexate, or intrathecal (injection into the spinal fluid) methotrexate are both necessary components of chemotherapy for acute lymphoblastic leukemia. However, these are known to cause asymptomatic leukoencephalopathy in children and young adults. Methotrexate-related leukoencephalopathy prevalence has been reported to decline with time and dosage. Other chemotherapeutic agents that have induced neurotoxicity include 5-fluorouracil and fludarabine. Medication neurotoxicity
Besides its role in chemotherapy, methotrexate is also used as an orally administered treatment for rheumatoid arthritis.