Toxic leukoencephalopathy is a rare condition that is characterized by progressive damage (-pathy) to

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

(-leuko-) in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

(-encephalo-), particularly

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

, due to causes such as exposure to substance use, environmental toxins, or chemotherapeutic drugs. The prevalence of this disease is infrequent and often goes unreported, especially in cases resulting from substance use. Magnetic resonance imaging (MRI) is a popular method to study and diagnose the disease. However, even with technological advances, the exact mechanism and underlying pathophysiology of toxic leukoencephalopathy remains unknown and is thought to vary between sources of toxicity. The clinical severity of toxic leukoencephalopathy also varies among patients, exposure time, concentration, and purity of the toxic agent. Some reversibility of the condition has been seen in many cases when the toxic agent is removed.

Signs and symptoms

Symptoms vary widely between sources of toxicity, dosage, length of time patient was exposed to the toxic substance, patient history, and patient genetics. Especially in the case of leukoencephalopathy developing due to substance use or environmental toxins, symptoms typically do not develop until several days to months after exposure to the pharmacological agent. Clinical features range from inattention, forgetfulness, and changes in personality to dementia, coma, and even death. Obvious signs of the condition are difficulty with cognitive function and

equilibrioception The sense of balance or equilibrioception is the perception of balance and spatial orientation. It helps prevent humans and nonhuman animals from falling over when standing or moving. Equilibrioception is the result of a number of sensory syste ...

. Common initial symptoms include confusion, somnolence, generalized seizures, headaches, and vision impairment. Young acute lymphoblastic leukemia patients with methotrexate-induced leukoencephalopathy appear asymptomatic. However, toxic leukoencephalopathy induced by substance use or environmental toxins have had more damaging side effects. Heroin-induced leukoencephalopathy has had three stages described. The first stage features soft (pseudobulbar) speech,

cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with symptom ...

, motor restlessness, and apathy/

bradyphrenia Bradyphrenia is the slowness of thought common to many disorders of the brain. Disorders characterized by bradyphrenia include Parkinson's disease and forms of schizophrenia consequently causing a delayed response and fatigue. Patients with bra ...

. The intermediate stage includes pyramidal tract and pseudobulbar signs, spastic paresis, myoclonic jerks, and choreoathetoid movements. The final or terminal stage is characterized by stretching spasms, akinetic mutism, hypotonic paresis, central pyrexia, and death. Similarly, leukoencephalopathy induced by orally administered methotrexate for arthritis patients presents similar symptoms including

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...

, and seizures; however, long-term cognitive effects remain unknown. Symptoms of leukoencephalopathy caused by overdose of metronidazole medication include dysarthria, gait disturbance, weakness of extremities, and mental confusion. Despite the pharmacological agent or source of toxicity, some patients completely recover from toxic leukoencephalopathy.

Related disorders

Posterior reversible encephalopathy syndrome Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a rare condition in which parts of the brain are affected by swelling, usually as a result of an underlying cause. Some ...

(PRES) can also result from medication toxicity. Symptoms similar to those of leukoencephalopathy patients have been seen in PRES patients. However, the prognosis of toxic leukoencephalopathy is typically slightly worse than that of PRES because toxic leukoencephalopathy is more likely to lead to ataxia, dementia, or coma. Hypoglycemic encephalopathy is often seen in diabetics as a result to accidental overdose with the long-acting sulfonylurea drug group. Brain regions affected by toxic leukoencephalopathy have been seen to be affected by this disease as well; however, hypoglycaemic encephalopathy has been known to involve both white and

grey matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingu ...

abnormalities.

Causes

Various pharmacological agents have been known to cause toxic leukoencephalopathy. The most common causes are substance use and chemotherapy; however, the disease has also occurred on the rare occasion as a side effect of certain medications and environmental toxins.

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 "Chasing the dragon" (CTD) (), or "foily" in Australian English, refers to inhaling the vapor from a heated solution of a powdered psychoactive drug on a sheet of aluminum foil. The moving vapor is chased after with a tube (often rolled foil) ...

" 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 A cutting agent is a chemical used to "cut" ( dilute or adulterate) recreational drugs with something less expensive than the drug itself. Overview The classical model of drug cutting, according to Preble and Casey (1969), refers to the way ...

,” 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 Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroi ...

that had been prescribed for pain management, and a young girl intoxicated with pure

morphine sulfate Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Th ...

tablets. Other drugs that have been associated with toxic leukoencephalopathy in much more rare occurrences include psychoactive drug

2C-E 2C-E is a psychedelic phenethylamine of the 2C family. It was first synthesized by Alexander Shulgin and documented in his book '' PiHKAL''. Like the other substances in its family, it produces sensory and cognitive effects in its physical reactio ...

("Europa"),

oxycodone Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

, and

. The

dose–response relationship The dose–response relationship, or exposure–response relationship, describes the magnitude of the response of an organism, as a function of exposure (or doses) to a stimulus or stressor (usually a chemical) after a certain exposure tim ...

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 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

. 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 Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...

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 Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

and nociceptive receptors appear to play a role in the disease; however, the exact mechanism remains unknown.

Metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It i ...

, 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 Carbon monoxide poisoning typically occurs from breathing in carbon monoxide (CO) at excessive levels. Symptoms are often described as " flu-like" and commonly include headache, dizziness, weakness, vomiting, chest pain, and confusion. Large ...

, ingestion of methanol, ingestion of ethylene,

toluene toxicity Toluene toxicity refers to the harmful effects caused by toluene on the body. Metabolism in humans While a significant amount of toluene, 25%–40%, is exhaled unchanged via the lungs, a greater proportion is metabolised and excreted via other pat ...

, ethanol poisoning, ingestion of

methylenedioxymethamphetamine 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...

(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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(CNS) white matter, typically of the periventricular nucleus, and other structures in the brain is often bilateral and symmetric. Heroin-induced leukoencephalopathy often involves damage to

cerebellar The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cereb ...

white matter, posterior cerebral white matter, posterior limb of internal capsule, and cerebellar peduncles. The

occipital lobe The occipital lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The name derives from its position at the back of the head, from the Latin ''ob'', "behind", and ''caput'', "head". The occipital lobe is the vi ...

is typically most affected though the

frontal Front may refer to: Arts, entertainment, and media Films * ''The Front'' (1943 film), a 1943 Soviet drama film * ''The Front'', 1976 film Music * The Front (band), an American rock band signed to Columbia Records and active in the 1980s and e ...

, parietal, and

temporal lobe The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in pro ...

s have shown involvement as well. Other toxins have been shown to extend damage to other structures of the brain, including the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

, dorsal

medulla Medulla or Medullary may refer to: Science * Medulla oblongata, a part of the brain stem * Renal medulla, a part of the kidney * Adrenal medulla, a part of the adrenal gland * Medulla of ovary, a stroma in the center of the ovary * Medulla of t ...

, and brainstem.

Treatment

With such a wide array of causes and unclear understanding of the pathophysiology, there is no known cure or treatment for the disease. In some cases of leukoencephalopathy induced by medications, such as methotrexate and metronidazole, the disease will reduce gradually once the medication is no longer distributed to the patient. Depending on the source of toxicity or pharmacological substance and severity of the white matter damage, many patients can have complete clinical recovery. Coenzyme Q and vitamin supplements, typically

vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

and

vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vi ...

, and other antioxidant therapies have been suggested to treat heroin-induced leukoencephalopathy patients. However, such treatments have rarely been trialed.