Toxic leukoencephalopathy

Toxic leukoencephalopathy
Toxic leukoencephalopathy
Other names	Toxic spongiform leukoencephalopathy

Last updated January 17, 2024

Toxic leukoencephalopathy is a rare condition that is characterized by progressive damage (-pathy) to white matter (-leuko-) in the brain (-encephalo-), particularly myelin, 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.^[1] Clinical features range from inattention, forgetfulness, and changes in personality to dementia, coma, and even death.^[2] Obvious signs of the condition are difficulty with cognitive function^[3] and equilibrioception.^{[ citation needed ]} Common initial symptoms include confusion, somnolence, generalized seizures, headaches, and vision impairment.^[4]

Young acute lymphoblastic leukemia patients with methotrexate-induced leukoencephalopathy appear asymptomatic.^[5] However, toxic leukoencephalopathy induced by substance use or environmental toxins have had more damaging side effects. Heroin-induced leukoencephalopathy has had three stages described.^[6] The first stage features soft (pseudobulbar) speech, cerebellar ataxia, motor restlessness, and apathy/bradyphrenia.^[1] 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, dysarthria, and seizures;^[4] however, long-term cognitive effects remain unknown.^[7] Symptoms of leukoencephalopathy caused by overdose of metronidazole medication include dysarthria, gait disturbance, weakness of extremities, and mental confusion.^[8] Despite the pharmacological agent or source of toxicity, some patients completely recover from toxic leukoencephalopathy.^[9]^[5]^[10]^[11]^[1]

Related disorders

Posterior reversible encephalopathy syndrome (PRES) can also result from medication toxicity.^[4]^[8]^[12] 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.^[4]

Hypoglycemic encephalopathy is often seen in diabetics as a result to accidental overdose with the long-acting sulfonylurea drug group.^[12] 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 abnormalities.^{[ citation needed ]}

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.^{[ citation needed ]}

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,^[13] also known as "chasing the dragon" syndrome,^[6] is one of the most studied of these rare occurrences and has even been recognized for over twenty five years.^[3]

It is believed by some researchers that heroin-induced leukoencephalopathy may be caused by a contaminant, or “cutting agent,” in the heroin.^[14] 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.^[14]

Other drugs that have been associated with toxic leukoencephalopathy in much more rare occurrences include psychoactive drug 2C-E ("Europa"),^[15] oxycodone,^[16] cocaine,^[8] and methadone.^[9] The dose–response relationship for these substances remains unclear.^{[ citation needed ]}

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.^[5] Methotrexate-related leukoencephalopathy prevalence has been reported to decline with time and dosage. Other chemotherapeutic agents that have induced neurotoxicity include 5-fluorouracil^[10] and fludarabine.^[17]

Medication neurotoxicity

Besides its role in chemotherapy, methotrexate is also used as an orally administered treatment for rheumatoid arthritis.^[11] 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.^{[ citation needed ]}

Oxycodone is the main active ingredient in various oral pain relief medications.^[16] 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.^{[ citation needed ]}

Metronidazole, an antibiotic used to treat anaerobic and protozoal infections, has been known at high doses to produce neurologic symptoms associated with toxic leukoencephalopathy.^{[ citation needed ]}

Other

Toxic leukoencephalopathy may also result from carbon monoxide poisoning, ingestion of methanol, ingestion of ethylene,^[8] toluene toxicity,^[3] ethanol poisoning, ingestion of methylenedioxymethamphetamine (MDMA or "ecstasy"), or ingestion of paradichlorobenzene,^[18] 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.^[8] Toxic leukoencephalopathy encompasses the degeneration of white matter tracts devoted to higher cerebral function;^[2] however, white matter can appear normal until the disease has progressed more intensely.^[1] 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. Heroin-induced leukoencephalopathy often involves damage to cerebellar white matter, posterior cerebral white matter, posterior limb of internal capsule, and cerebellar peduncles.^[1] The occipital lobe is typically most affected though the frontal, parietal, and temporal lobes have shown involvement as well. Other toxins have been shown to extend damage to other structures of the brain, including the hippocampus, dorsal medulla, and brainstem.^[8]

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.^[4]^[5]^[8] Depending on the source of toxicity or pharmacological substance and severity of the white matter damage, many patients can have complete clinical recovery.^{[ citation needed ]}

Coenzyme Q and vitamin supplements, typically vitamin C and vitamin E, and other antioxidant therapies have been suggested to treat heroin-induced leukoencephalopathy patients. However, such treatments have rarely been trialed.^[6]

Related Research Articles

<span class="mw-page-title-main">Methadone</span> Opioid medication

Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

<span class="mw-page-title-main">Poison</span> Substance that causes death, injury or harm to organs

A poison is any chemical substance that is harmful or lethal to living organisms. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broad sense.

Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

Wernicke-Korsakoff syndrome (WKS) is the combined presence of Wernicke encephalopathy (WE) and Korsakoff syndrome. Due to the close relationship between these two disorders, people with either are usually diagnosed with WKS as a single syndrome. It mainly causes vision changes, ataxia and impaired memory.

<span class="mw-page-title-main">Colchicine</span> Medication mainly used to treat gout

Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred than NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken by mouth.

Encephalopathy means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome has many possible organic and inorganic causes.

Hepatotoxicity implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.

Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.

Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease, and indicates that the liver has sustained severe damage. The complications are hepatic encephalopathy and impaired protein synthesis. The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days, and subacute as 4–12 weeks; both the speed with which the disease develops and the underlying cause strongly affect outcomes.

Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.

<span class="mw-page-title-main">Abrin</span> Chemical compound

Abrin is an extremely toxic toxalbumin found in the seeds of the rosary pea, Abrus precatorius. It has a median lethal dose of 0.7 micrograms per kilogram of body mass when given to mice intravenously. The median toxic dose for humans ranges from 10 to 1000 micrograms per kilogram when ingested and is 3.3 micrograms per kilogram when inhaled.

<span class="mw-page-title-main">Pneumonitis</span> General inflammation of lung tissue

Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris, aspiration, herbicides or fluorocarbons and some systemic diseases. If unresolved, continued inflammation can result in irreparable damage such as pulmonary fibrosis.

Toxic encephalopathy is a neurologic disorder caused by exposure to neurotoxic organic solvents such as toluene, following exposure to heavy metals such as manganese, as a side effect of melarsoprol treatment for African trypanosomiasis, adverse effects to prescription drugs, or exposure to extreme concentrations of any natural toxin such as cyanotoxins found in shellfish or freshwater cyanobacteria crusts. Toxic encephalopathy can occur following acute or chronic exposure to neurotoxicants, which includes all natural toxins. Exposure to toxic substances can lead to a variety of symptoms, characterized by an altered mental status, memory loss, and visual problems. Toxic encephalopathy can be caused by various chemicals, some of which are commonly used in everyday life, or cyanotoxins which are bio-accumulated from harmful algal blooms (HABs) which have settled on the benthic layer of a waterbody. Toxic encephalopathy can permanently damage the brain and currently treatment is mainly just for the symptoms.

<span class="mw-page-title-main">Chasing the dragon</span> Cantonese drug slang phrase

"Chasing the dragon" (CTD), or "foily" in Australian English, refers to inhaling the vapor of a powdered psychoactive drug off a heated sheet of aluminum foil. The moving vapor is chased after with a tube through which the user inhales. The "chasing" occurs as the user gingerly keeps the liquid moving in order to keep it from overheating and burning up too quickly, on a heat conducting material such as aluminium foil.

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. Someone with PRES may experience headaches, changes in vision, and seizures, with some developing other neurological symptoms such as confusion or weakness of one or more limbs. The name of the condition includes the word "posterior" because it predominantly though not exclusively affects the back of the brain. Common underlying causes are severely elevated blood pressure, kidney failure, severe infections, certain medications, some autoimmune diseases, and pre-eclampsia. The diagnosis is usually made by a brain scan (MRI) on which areas of swelling can be identified.

<span class="mw-page-title-main">Paracetamol poisoning</span> Toxicity due to paracetamol overdose

Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These symptoms include feeling tired, abdominal pain, or nausea. This is typically followed by absence of symptoms for a couple of days, after which yellowish skin, blood clotting problems, and confusion occurs as a result of liver failure. Additional complications may include kidney failure, pancreatitis, low blood sugar, and lactic acidosis. If death does not occur, people tend to recover fully over a couple of weeks. Without treatment, death from toxicity occurs 4 to 18 days later.

An equianalgesic chart is a conversion chart that lists equivalent doses of analgesics. Equianalgesic charts are used for calculation of an equivalent dose between different analgesics. Tables of this general type are also available for NSAIDs, benzodiazepines, depressants, stimulants, anticholinergics and others.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium It has a different meaning from the similar term opioid, used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

Grinker's myelinopathy, also known as anoxic leukoencephalopathy, is a rare disease of the central nervous system. The disease is characterized by a delayed leukoencephalopathy after a hypoxic episode. It is typically, though not necessarily, related to carbon monoxide poisoning or heroin overdose. It occurs in roughly 2.8% of those who experience an acute hypoxic/anoxic episode. Because of the wide range of symptoms and the delay in onset, it is often misdiagnosed as other neuropathologies. Grinker's myelinopathy was originally characterized by Roy R. Grinker in 1925 or 1926, depending on the source.

Alimentary toxic aleukia is a mycotoxin-induced condition characterized by nausea, vomiting, diarrhea, leukopenia (aleukia), hemorrhaging, skin inflammation, and sometimes death. Alimentary toxic aleukia almost always refers to the human condition associated with presence of T-2 Toxin.

References

1 2 3 4 5 Hagel J, Andrews G, Vertinsky T, Heran MK, Keogh C (October 2005). ""Chasing the dragon" - Imaging of heroin inhalation leukoencephalopathy". Canadian Association of Radiologists Journal. 56 (4): 199–203. PMID 16419370.
1 2 Filley CM, Kleinschmidt-DeMasters BK (August 2001). "Toxic leukoencephalopathy". N. Engl. J. Med. 345 (6): 425–32. doi:10.1056/NEJM200108093450606. PMID 11496854.
1 2 3 Buxton JA, Sebastian R, Clearsky L, Angus N, Shah L, Lem M, Spacey SD (2011). "Chasing the dragon - characterizing cases of leukoencephalopathy associated with heroin inhalation in British Columbia". Harm Reduction Journal. 8 (1): 3. doi: 10.1186/1477-7517-8-3 . PMC 3035193 . PMID 21255414.
1 2 3 4 5 Iyer, Ramesh; Apeksha Chaturvedi; Sumit Pruthi; Paritosh C. Khanna; Gisele E. Ishak (November 2011). "Medication neurotoxicity in children". Pediatric Radiology. 41 (11): 1455–1464. doi:10.1007/s00247-011-2191-3. PMID 21785849. S2CID 20277034.
1 2 3 4 Reddick WE, Glass JO, Helton KJ, Langston JW, Xiong X, Wu S, Pui CH (May 2005). "Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate". American Journal of Neuroradiology. 26 (5): 1263–1269. PMC 2396789 . PMID 15891195.
1 2 3 Offiah, C; E Hall (2008). "Heroin-induced leukoencephalopathy: characterization using MRI, diffusion-weighted imaging, and MR spectroscopy". Clinical Radiology. 63 (2): 146–152. doi:10.1016/j.crad.2007.07.021. PMID 18194689.
↑ Salkade, Pareg; Teh Aun Lim (Apr–Jun 2012). "Methotrexate-induced acute toxic leukoencephalopathy". Journal of Cancer Research and Therapeutics. 8 (2): 292–296. doi: 10.4103/0973-1482.98993 . PMID 22842379.
1 2 3 4 5 6 7 Sharma P, Eesa M, Scott JN (September 2009). "Toxic and acquired metabolic encephalopathies: MRI appearance". AJR Am J Roentgenol. 193 (3): 879–86. doi:10.2214/AJR.08.2257. PMID 19696305.
1 2 Cerase A, Leonini S, Bellini M, Chianese G, Venturi C (July 2011). "Methadone-Induced Toxic Leukoencephalopathy: Diagnosis and Follow-up by Magnetic Resonance Imaging Including Diffusion-Weighted Imaging and Apparent Diffusion Coefficient Maps". Journal of Neuroimaging. 21 (3): 283–286. doi:10.1111/j.1552-6569.2010.00530.x. PMID 20977538. S2CID 1012350.
1 2 McKinney, Alexander; Stephen A. Kieffer; Rogerich T. Paylor; Karen S. SantaCruz; Ayse Kendi; Leandro Lucato (July 2009). "Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging". American Journal of Roentgenology. 193 (1): 192–206. doi:10.2214/Ajr.08.1176. PMID 19542414.
1 2 González-Suárez I, Aguilar-Amat MJ, Trigueros M, Borobia AM, Cruz A, Arpa J (September 2013). "Leukoencephalopathy due to Oral Methotrexate". Cerebellum. 13 (1): 178–83. doi:10.1007/s12311-013-0528-1. PMID 24068485. S2CID 6854034.
1 2 Bathla, G; A.N. Hegde (May 2012). "MRI and CT appearances in metabolic encephalopathies due to systemic diseases in adults". Clinical Radiology. 22. 68 (6): 545–554. doi:10.1016/j.crad.2012.05.021. PMID 23142023.
↑ "Heroin-induced toxic leukoencephalopathy". appliedradiology.com. Retrieved 2018-03-07.
1 2 Salgado, Rodrigo (November 5, 2009). "Methadone-Induced Toxic Leukoencephalopathy: MR Imaging and MR Proton Spectroscopy Findings". American Journal of Neuroradiology. 31 (3): 565–566. doi: 10.3174/ajnr.A1889 . PMC 7963967 . PMID 19892815.
↑ Sacks J, Ray MJ, Williams S, Opatowsky MJ (October 2012). "Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E ("Europa")". Proc (Bayl Univ Med Cent). 25 (4): 374–6. doi:10.1080/08998280.2012.11928883. PMC 3448584 . PMID 23077393.
1 2 Odia, Yazmin Morales; Madhavi Jinka; Wendy C. Ziai (May 2010). "Severe Leukoencephalopathy Following Acute Oxycodone Intoxication". Neurocritical Care Society. 13 (4): 93–97. doi: 10.1007/s12028-010-9373-y . PMID 20440598. S2CID 5995875.
↑ Beitinjaneh, Amer; Alexander M. McKinney; Qing Cao; Daniel Weisdorf (March 2011). "Toxic Leukoencephalopathy following Fludarabine-Associated Hematopoietic Cell Transplantation". Biology of Blood and Marrow Transplantation. 17 (3): 300–308. doi: 10.1016/j.bbmt.2010.04.003 . PMID 20399878.
↑ Avila, Edward; Paul Schraeder; Ajit Belliappa; Scott Faro (January 2006). "Pica with paradichlorobenzene mothball ingestion associated with toxic leukoencephalopathy". Journal of Neuroimaging. 78-81. 16 (1): 78–81. doi:10.1177/1051228405280171. PMID 16483281. S2CID 10630614.