Authors: Jonathan Schneider, DO; Timothy Ekpo, DO
Affiliation: Mountain View Regional Medical Center Orthopedic Surgery Residency Program, Las Cruces, New Mexico (Dr. Schneider),
Henry Ford Allegiance Health Hospital, Division of Orthopedic Surgery (Dr. Ekpo)
We report on a rare case of levamisole-induced vasculitis with multiple areas of skin necrosis presenting acutely following right total knee arthroplasty. Cocaine usage prior to total knee arthroplasty can potentially lead to a catastrophic adverse effect of vasculitis with severe wound necrosis over the incisional site that can ultimately result in major reconstructive or limb salvage surgery. Levamisole, a previously approved anti-helminthic for parasitic infections was withdrawn from the U.S. market in early 2000 because of adverse health events such as neutropenia and vasculitis. 1,2,3 However, levamisole is now a common additive to illicit cocaine. It is thought to intensify the “high” by releasing dopamine in the brain and is a difficult adulterant to recognize. Potential risks of levamisole-laced cocaine include neutropenia, agranulocytosis, and vasculitis with ulcerated skin necrosis.4 Cases of severe agranulocytosis and skin necrosis associated with cocaine use have been reported since early 2002, with the face and ears commonly affected.5 However, to our knowledge, there have been no reports of this severe effect presenting in the acute post-operative period following total joint arthroplasty.
We report on a 55 year-old female with medical history of primary breast cancer status post-mastectomy with adjuvant treatment in 2014, chronic obstructive pulmonary disease, hypertension, depression, and degenerative joint disease who underwent a routine right primary total knee arthroplasty on April 26, 2017. Surgery was performed for right knee painful tri-compartmental osteoarthritis that failed symptomatic improvement with conservative treatment. The surgery was performed by a fellowship-trained joint reconstruction orthopedic surgeon specializing in primary total joint arthroplasty and revision arthroplasty at Henry Ford Allegiance Health in Jackson, Michigan. No complications were noted prior, during, or after surgery while in the hospital or in the PACU. The patient remained inpatient overnight one night and was discharged home the following day with no complications with a benign hospital course.
The patient was next seen at the orthopedic surgery clinic on post-operative day 7 on May 4, 2017 after she called the clinic with complaints of “new-onset painful scab-like black and purple lesions” over her right knee incisional site. The patient stated that she first noticed her incisional site “turning black” with worsening right knee pain on post-operative day 3, but thought it would go away on it’s own. Her knee pain progressively worsened over the follow days and new lesions appeared on her nose, hands, and breast.
Below are several clinical photos taken on May 4, 2017 at the orthopedic surgery clinic demonstrating multiple sites of skin maceration and necrotic ulceration over the right knee, breast, nose, earlobe and hands.
Clinical photos taken post-op day 7 demonstrating multiple sites of skin maceration and necrotic ulceration over the right knee, breast, nose, earlobe and hands.
At this point, the orthopedic surgeon was suspecting an autoimmune response, but was unsure of the clinical diagnosis and referred the patient the same day to a local hematologist/oncologist who examined the patient in their outpatient clinic. During the clinical visit with the hematologist/oncologist, the patient revealed a two-year history of cocaine abuse. The patient stated her last episode with cocaine was earlier that week just after arriving back home from surgery on post-operative day two. At this point, the hematologist/oncologist now had a high clinical suspision for levamisole-induced vasculitis with skin necrosis, and blood tests such as P-ANCA & C-ANCA (perinuclear and cytoplasmic anti-neutrophil cytoplasmic antibodies) both typically positive with this condition, were sent to the lab with both coming back positive two days later.
The patient was then referred to a local dermatologist who agreed to the diagnosis of levimisole-induced thrombophlebitis and vasculitis with skin necrosis. During the history portion of the encounter, the patient also revealed to the dermatologist a two-year history of cocaine abuse with several previous small ulcerative skin lesions on her hands and face that would come and go, but the previous lesions were never this large or painful. The patient was counseled on the direct relationship of her cocaine abuse to her skin lesions and was recommended that day to follow up with a local drug addiction and counseling agency and sent to a local infectious disease specialist the next day, however, she was non-compliant and did not follow up in the infectious disease outpatient clinic until a week later on May 11, 2017. The patient was immediately started on IV antibiotics, daily IV daptomycin for deep tissue infection. She followed up daily for her IV antibiotics and subjectively stated improved right knee since starting the antibiotics, however, on exam her right knee skin ulceration continued to progressively worsen. Below are clinical photos from the patient’s right knee on May 19, 2017 demonstrating a large black necrotic eschar over the entire incisional site.
Right knee clinical photo on May 19, 2017, just over three weeks post-op TKA demonstrating large black necrotic eschar measuring 18 x 12 cm over the entire incisional site.
Recorded blood labs values were drawn and read as following: CRP 3.3, WBC 2.3, Hgb 7.3, Hct 24.3, absolute segmented neutrophils 1.23, and a urine drug screen test positive for cocaine and oxycodone. It was decided by the orthopedic surgeon and infectious disease physician to admit the patient to the hospital for surgical intervention. The surgical plan was right knee irrigation and debridement with polyethylene exchange and right knee eschar debridement with a gastrocnemius flap by plastic surgery.
In the operating room, the patient underwent irrigation and debridement of the right knee with sharp excisional debridement of the necrotic dermis and subcutaneous tissue measuring approximately 18 x 12 cm. Minimal serous fluid was encountered with no purulence. The right knee polyethylene liner and prosthesis was not exposed after debridement and the right knee was irrigated with 3 L of normal saline. A medial gastrocnemius musculofascial cutaneous flap 19 x 5 cm was performed along with a split-thickness skin flap 36 x 12 cm. A wound vac was then placed at the time of surgery and adequate palpable dopplar pulses of the medial sural artery were assessed and maintained throughout the surgical course. 9
Clinical photos, right knee post-operative debridement, washout and gastrocnemius wound flap with wound vacuum application.
The patient remained in the hospital for two days after surgery and the patient was discharged on post-operative day two to a long-term care facility with daily wound care management and antibiotics.
On an outpatient basis, the patient routinely followed up with orthopedic surgery, plastic surgery, and a wound care specialist. However, on a follow-up visit with the outpatient plastic surgery clinic on August 2, 2017, local knee drainage residing from a new wound tunnel with subsequent exposure of the hardware was observed. During that visit, wound cultures were sent to the lab and came back positive for Pseudomonas aeruginosa colonization. Due to the infected hardware, orthopedic surgery recommended a two-stage revision knee arthroplasty with stage one consisting of irrigation and washout with radical debridement and placement of a static antibiotic spacer, this was performed after repeat urine drug screen test was negative. Surgery was performed for stage one right knee radicle debridement with placement of a static antibiotic spacer after repeat urine drug screen test was negative.
AP and Lateral R knee, post-operative radial knee debridement with static antibiotic spacer.
The patient tolerated the surgery well with no complications and the overall hospital course was benign. The patient was discharged from the hospital on post-operative day three.
On subsequent outpatient orthopedic surgery follow-up visits to the date of publication, the patient has continued to refuse replant of her total knee arthroplasty.
Levamisole, a previously approved anti-helminthic and immunomodulater utilized for human parasitic infections, rheumatoid arthritis, and some colon carcinoma was withdrawn from the United States market by the FDA in 2000 due to its extensive side effects. Adverse effects included, but were not limited to neutropenia, agranulocytosis, vasculitis, ulcerated skin necrosis, purpura, and arthralgia. 1 Levamisole is still approved and prescribed today by vetinary medicine practitioners for canines.
Levamisole had a resurgence in popularity in the United States on the black market as a common additive to illicit cocaine with it being a difficult adulterant to recognize. This was in large part due to the effect of intensifying the euphoric “high” by releasing more dopamine in the brain2,3 It quickly grew to become the most common adulterant to illicit cocaine estimated between 31.8-70% by some authors. 3,4 Several cases of severe agranulocytosis and skin necrosis associated with cocaine abuse were reported in 2006 with estimated levamisole-tainted cocaine spreading throughout the United States as early as 2002. An emergency medicine mass warning report was even issued in 2009 to bring awareness to health care providers, however, many physicians are still unaware of this unique and rare pathology.5 Diagnosis and reported clinical cases are increasing throughout the country, and to our knowledge there have been no published cases presenting in the acute post-operative period following total joint arthroplasty.
The combination of vague systemic symptoms with cutaneous involvement can make accurate diagnosis of this rare syndrome a challenge. In the medical setting, patients are frequently initially misdiagnosed with autoimmune vasculitis. Furthermore, infection (meningococcemia), drugs (warfarin-induced skin necrosis, unadulterated cocaine), and autoimmune diseases (cryoglobulinemia) can also present with similar findings such as retiform purpuric lesions.8
Due to the extensive differential, Lee et al8 provided a comprehensive diagnostic algorithm that first starts with urine toxicology screening for cocaine. This should occur within 48 hours by gas chromatography due to the short 5.6-hour half-life of levamisole.8 If urine is positive for cocaine, a complete blood count with differential will assess for agranulocytosis. If the patient is neutropenic, testing for ANCA, cryoglobulins, and antiphospholipid antibodies is also recommended.6,8 However, due to the combination of the extremely short half-life of the drug and the difficulty of obtaining gas chromatography, a high clinical suspicion is key with any history of cocaine abuse to obtain accurate diagnosis.
In general, supportive measures are the primary treatment modality recommended for levamisole-induced skin necrosis and its associated side effects. Some treatment options are wound care with medical immunosuppression, surgical excision alone, and early excision and grafting for skin necrosis.6 Following cessation of cocaine, medical immunosuppression and even plasmapheresis have been suggested as treatment options, but are currently unproven for levamisole-induced vasculitis. 6,7 Treating the adverse complications such as skin necrosis and ulceration should follow standard wound care management and surgical debridement principles similar observed in burn surgery management such as debridement back to healthy tissue. Miner et al 7 do suggest a benefit to early excision and grafting similar to full-thickness burns.7
Cocaine abuse prior to total knee arthroplasty can potentially result a detrimental adverse effect of vasculitis with severe wound necrosis over the incisional site that can ultimately result in major reconstructive or limb salvage surgery. Prior to elective total joint arthroplasty surgery, we recommend a thorough history and physical exam with a very low threshold for urine drug screening. Ultimately, some patients will still fall through the cracks, but this is a good reminder of a severe complication that can result by operating electively on a cocaine abuser with or without knowledge of their past medical history.
- Formeister, Eric, MS, Facial Cutaneous Necrosis Associated with Suspected Levamisole Toxicity From Tainted Cocaine Abuse, Annals of Otology & Rhinology & Laryngology, 2015 Vol 124 (30-34)
- Martello, S, Levamisole in Illicit Trafficking Cocaine Seized: One-Year Study. Journal of Psychoactive Drugs, 2017 Nov-Dec, 49(5).
- Muirhead, Trevor MD & Eide, Melody MD, MPH, Toxic Effects of Levamisole in a Cocaine User, N Engl J Med 2011; 364: e52
- Marx, John, MD, Rosens Emergency Medicine Text, 8th ed.
- Erik Kinzie, MD, 2009 by the American College of Emergency Physicians. Department of Psychiatry Louisiana State University School of Medicine New Orleans, LA
- Fredereicks, Charles, MD, Levamisole-induced Necrosis Syndrome: Presentation & Management, Wounds, 2017: 29(3):71-76
- Miner J, Gruber P, Perry TL. Early excision and grafting, an alternative approach to the surgical management of large body surface area levamisole-adulterated cocaine induced skin necrosis [published online ahead of print December 17, 2014]. Burns. 2015;41(3):e34–e40
- Lee KC, Ladizinski B, Federman DG. Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge. Mayo Clin Proc. 2012;87(6):581–586
- Henry Ford Allegiance Health Hospital Jackson, Michigan, Division of Orthopedic Surgery patient medical records