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Cocaine Levamisole Associated Vasculitis

Case Introduction

A 49 year old male with asthma presented to the emergency department (ED) with bilateral leg pain and sores. He states they started 2 weeks prior to presentation as a “biting sensation” and have been increasingly painful. He has been seen at multiple urgent cares without relief. He reports fever but denies any other symptoms or dermatological history. He states he is sleeping in his car and reports recent cocaine and tobacco use.
On physical exam, his blood pressure is 142/91 and his other vital signs are stable. He is laying in the stretcher writhing in pain and tearful. His bilateral lower extremities are covered with stellate ulcerated lesions with hyperpigmented borders. There are some surrounding palpable violaceous papules and plaques.
cocaine levamisole vasculitis 2
Ulcerated lesions seen on the right leg
cocaine levamisole vasculitis 1
Ulcerated lesions seen on the left leg
The patient’s labs are generally within normal distribution except he has a leukocytosis of 16,200, sedimentation rate 29, C-reactive protein 2.53. His toxicology screen is positive for cocaine and cannabis. Radiographs are normal, CT imaging shows subcutaneous edema within the distal calf and proximal ankle. Venous doppler negative for deep vein thrombosis. The patient is given IV analgesia and antibiotics and admitted to the hospital to be seen by dermatology and infectious disease.

Differential Diagnosis
– Leukocytolclastic Vasculitis
– Cocaine Levamisole toxicity or Levamisole induced necrosis syndrome (LINES)
– Arthroprod Hypersensivitiy
– Impetigo
– Livedoid vasculopathy (atrophie blanche)
– Bullous Pemphigoid

Discussion

Cocaine is the second most consumed drug (after cannabis) in Europe and North America, used by 3.9 million and 5.5 million people respectively.1López-Pelayo, Hugo, et al. “Emerging Trends in Drugs, Addictions, and Health.” Cocaine is a potent sympathomimetic with local anesthetic properties and euphorigenic effects via strong modulation of the brain’s reward system. Cocaine is also a potent vasoconstrictor which can lead to heart attacks and strokes.2Schwartz, Bryan G., Shereif Rezkalla, and Robert A. Kloner. “Cardiovascular effects of cocaine.” Circulation 122.24 (2010): 2558-2569. With more sustained use, cocaine users develop neuropsychiatric symptoms and neurocognitive sequelae.3Cadet, Jean Lud, and Veronica Bisagno. “Neuropsychological consequences of chronic drug use: relevance to treatment approaches.” Frontiers in psychiatry 6 (2016): 148484.
cocaine levamisole toxicity with hemorrhage bullae to the ear
Hemorrhage bullae to the ear1Buchanan JA, et al. J Med Toxicol 2011; 29:299 – 303
Cocaine is often laced with levamisole, an antihelminthic medication used to treat parasitic worms in animals. Previously approved for human use, levamisole was prohibited in the US around 2000 due to increased risk of rheumatic disease and vasculitis.4Brunt, Tibor Markus, et al. “Adverse effects of levamisole in cocaine users: a review and risk assessment.” Archives of Toxicology 91 (2017): 2303-2313 (Note: levamisole is still on the WHO critical medication list and used in most countries) Levamisole acts as an immunomodulator and immuno-enhancer by increasing macrophage chemotaxis and T-cell lymphocyte function. It has also been shown to stimulate neutrophils, up-regulate toll-like receptors and dendritic cell maturation.5Anderson, Ronald, et al. “In vitro stimulation of neutrophil motility by levamisole: maintenance of cGMP levels in chemotactically stimulated levamisole-treated neutrophils.” The Journal of Immunology 117.2 (1976): 428-432.
The reason levamisole is used to cut cocaine is that it is believed to have stimulant properties that can amplify or prolong the effects of cocaine. The theory is that it potentiates the nicotinic acetylcholinergic effects in the CNS, prolonging cocaine-induced euphoria. One study by the US Drug Enforcement Agency estimated that 87% of seized cocaine contained levamisole.6Drug Enforcement Administration. “National drug threat assessment (2018).” US Department of Justice DEA: Washington, DC (2017). Levamisole is also physically similar to cocaine which allows it to easily act as a cutting or bulking agent.
cocaine levamisole toxicity with hemorrhagie bullae to legs
Retiform purpuric skin lesions with eschar on lower extremities2James, Kellee T., et al. "Levamisole contaminated cocaine induced cutaneous vasculitis syndrome." Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health 14.5 (2013).
Levamisole adulterated cocaine has been associated with increased risk of neutropenia, agranulocytosis, vasculitis, retiform purpura, arthralgias and other forms of skin necrosis. In animal models, toxic effects of the central nervous system have been demonstrated. Many of these adverse effects are documented in patients receiving levamisole to treat malignancy (melanoma, adenocarcinoma of the colon) but also in case reports of cocaine users using levamisole adulterated cocaine. The concentration of levamisole has been increasing from less than 1% in 2001 to 10% of each cocaine sample in 2009.7US Department of Justice, National Drug Intelligence Center National Drug Threat Assessment 2010: Impact of Drugs on Society: US Department of Justice, National Drug Intelligence Center Web site. http://www.justice.gov/ndic/pubs38/38661/drugImpact.htm
Patients typically present with cutaneous manifestations consisting of large painful hemorrhagic bullae and/or necrosis. The face is commonly affected but can present anywhere on the body. The pathologic mechanism of these presentations is unclear, some patients present with true vasculitis while others have pseudovasculitis. Patients may also complain of arthralgias, typically affecting large joints, ear nose and throat complaints as well as malaise and fatigue. Laboratory findings include leukopenia, neutropenia, agranulocytosis, positive antinuclear antibody titers, positive anti-proteinase 3 titers, and positive perinuclear or cytoplasmic staining patterns for antineutrophil cytoplasmic antibodies.
The natural progression of the condition is generally benign and most cases will resolve without intervention. Treatment is primarily supportive as most cases will resolve with discontinuation of the levamisole-laced cocaine. Complete cessation of cocaine use is necessary as recurrence is common with re-exposure8Larocque, L. Hoffman, R. Clinical Toxicology: Levamisole in cocaine: Unexpected news from an old acquaintance. (2012), 50, 231-234. Patients presenting to the emergency department (ED) with undifferentiated symptoms will require admission and a workup as the differential diagnosis is often broad on initial presentation.

Case Conclusion

The patient was seen by multiple specialties while in the hospital. Infectious disease workup did not identify any organisms and antibiotics were de-escalated. Skin biopsy did not show any evidence of vasculitis or other primary dermatologic condition. The patient was seen by nephrology for proteinuria and pedal edema. Their working diagnosis was IgA nephropathy however much of the workup was pending at the time of discharge from the hospital. The patient was sent home on an unknown anti-hypertensive and subsequently did not follow back up.

3 Key Points

  1. Cocaine is almost always laced with the anti-helminthic drug Levamisole
  2. When symptomatic, most patients present with hemorrhagic bullae or necrosis
  3. Treatment is supportive and users must discontinue cocaine as recurrence is common

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