Periorbital Pyoderma Gangrenosum Associated With a Cocaine-Induced Midline Destructive Lesion: Case Report and Review of the Literature.

A 72-year-old woman with a history of chronic cocaine use presented 9 months after a dog bite with a large facial ulceration and absent sinonasal structures. Biopsies were negative for infectious, vasculitic, or neoplastic pathologies. The patient was lost to follow up for 15 months and returned with a significantly larger lesion despite abstinence from cocaine. Additional inflammatory and infectious workup was negative. Intravenous steroids were administered with clinical improvement. Therefore, she was diagnosed with pyoderma gangrenosum and cocaine-induced midline destructive lesion due to cocaine/levamisole. Pyoderma gangrenosum is a rare dermatologic condition that uncommonly involves the eye and ocular adnexa. Diagnosis involves clinical examination, response to steroids, exclusion of infectious or autoimmune conditions, and identifying potential triggers including cocaine/levamisole. This report highlights a rare presentation of periorbital pyoderma gangrenosum causing cicatricial ectropion associated with concomitant cocaine-induced midline destructive lesion and reviews important aspects of clinical manifestations, diagnosis, and management of pyoderma gangrenosum and cocaine/levamisole autoimmune phenomenon.

Levamisole-associated multifocal inflammatory encephalopathy: clinical and MRI characteristics, and diagnostic algorithm.

Levamisole-associated multifocal inflammatory encephalopathy (LAMIE) is a devastating adverse effect of levamisole (LEV) treatment. In Russia, people often use LEV without a doctor's prescription for anthelmintic prophylaxis. LAMIE often misdiagnosed as the first episode of MS or acute disseminated encephalomyelitis (ADEM). The aim of our study was to describe clinical, laboratory and morphological characteristics of LAMIE, magnetic resonance imaging (MRI) patterns and create an algorithm for the differential diagnosis. This study was a prospective observational study with retrospective analysis of cases. It was performed at two hospitals with ambulatory service for MS. We included 43 patients with LAMIE with follow-up was from 1 year to 5 years. Age was 19-68 y.o. with female predominance. The most typical manifestations of LAMIE were cerebellar, pyramidal and cognitive symptoms, and majority of patients had biphasic course of the disease. Three main types of MRI patterns were described: ADEM-like, MS-like, atypical demyelination. About 40% of patients had CSF specific oligoclonal bands synthesis, but only 20 % of them converted to MS during the period from 1 month until 2 years. The CSF albumin levels and immunoglobulin G index were elevated in LAMIE patients compared to reference values. We described results of brain biopsy in two cases. Therefore LAMIE should be considered in patients with demyelinating or inflammatory conditions with biphasic onset of the disease and variable MRI presentation.

[Cocaine-induced vasculitis and mimics of vasculitis]. / Kokain-induzierte Vaskulitiden und Vaskulitis-Mimics.

Cocaine is a psychotropic tropane alkaloid and stimulant drug. Nasal insufflation of cocaine powder is a common route of administration. In Germany, cocaine is frequently adulterated with levamisole, an anthelminthic drug with immunomodulatory effects. Both substances are linked to various autoimmune conditions. Cocaine-induced midline destructive lesions cause a progressive destruction of osteocartilaginous structures within the upper respiratory tract and can mimic localized granulomatosis with polyangiitis. In addition, systemic vasculitis due to cocaine and levamisole has been reported. Differentiation of these conditions from primary vasculitis can be challenging because antineutrophil cytoplasmic antibodies (ANCA) are commonly detected. Early diagnosis of these conditions is crucial as clinical improvement is closely related to drug cessation.

Late Onset of ANCA Vasculitis as a Side Effect of Levamisole Treatment in Nephrotic Syndrome.

Levamisole is effectively used in steroid-dependent nephrotic syndrome and the more frequent side effects reported are cytopenia and liver enzymes alterations. Several studies have demonstrated that this drug can induce high titers of circulating perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) and vasculitis, most of them occurring in the case of prolonged use. A four-year-old boy that was affected with steroid-dependent nephrotic syndrome was treated with Levamisole as a steroid-sparing agent at a dose of 2 mg/kg/48 h. After initiation of the treatment, the number of relapses drastically decreased, enabling a significant reduction in the cumulative steroid dose. Levamisole was well tolerated, and was therefore administered for several years. At the age of 15, he was also diagnosed with celiac disease. After nine years of continuous Levamisole treatment, he presented with a high fever, hand and foot joint arthritis, and increased levels of total and direct bilirubin. Since the symptoms started two days after the injection of the second dose of the COVID-19 vaccine, it was initially concluded that these manifestations were rare vaccination side effects. Therefore, he did not receive any specific treatments, and Levamisole was continued at the same dose. After an initial improvement, two months later, the patient presented with the same symptoms. Suspecting Levamisole-induced vasculitis, an ANCA titer was measured and this returned positive. Clinical manifestations and double positivity for both myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies argued against the fact that that these findings were secondary to vaccination, cocaine abuse, or celiac disease. Assuming that we were facing a rare drug reaction, Levamisole was promptly interrupted. This resulted in a rapid remission of fever and arthritis improvement, and a decrease in ANCA titers. By reporting this case, we want to raise awareness among clinicians regarding a rare complication of treatment with Levamisole that is often misdiagnosed due to the fact that the current literature lacks univocal guidelines regarding the precise timing of ANCA titrations and the duration of the treatment.

Levamisole causes a transient increase in plasma creatinine levels but does not affect kidney function based on cystatin C.

BACKGROUND: In pediatric patients treated with levamisole to prevent relapses of idiopathic nephrotic syndrome (INS), a transient and non-progressive rise in creatinine levels has been observed. It has been suggested that levamisole affects tubular secretion of creatinine. However, other potential mechanisms - nephrotoxicity and interference with the analytical assay for creatinine - have never been thoroughly investigated. METHODS: In three steroid-sensitive nephrotic syndrome (SSNS) patients with elevated plasma creatinine levels, treated with levamisole 2.5 mg/kg every other day, serum cystatin C was determined. The glomerular filtration rate (GFR) was estimated using the full age spectrum for creatinine and the full age spectrum for cystatin C equations. Interference of levamisole with the enzymatic creatinine assay was tested using spare human plasma of different creatinine concentrations spiked with levamisole (4, 20, and 100 µM). RESULTS: Three patients who received levamisole with elevated plasma creatinine levels had normal serum cystatin C levels and corresponding estimated GFR. There was no assay interference. CONCLUSION: Levamisole increases plasma creatinine levels, which is most probably due to impaired tubular secretion of creatinine since there was no assay interference and patients had normal eGFR based on serum cystatin C. However, interference of metabolites of levamisole could not be excluded. To monitor GFR, cystatin C in addition to creatinine should be used and be measured before and during levamisole use.

Adverse reactions with levamisole vary according to its indications and misuse: A systematic pharmacovigilance study.

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use. METHODS: All levamisole-related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use. RESULTS: Among the 1763 levamisole-related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2-2.6]), hepatobiliary disorders (2.4 [1.9-4.3]), vasculitis (6.5 [4.1-10.6]), encephalopathy (22.5 [17.4-39.9]), neuropathy (4.3 [2.9-7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole-related ADRs occurred when the drug was administrated for a non-anti-infectious indication. CONCLUSION: The great majority of the levamisole-related ADRs concerned its immunomodulatory indication and multiple-dose regimen. Our results suggest that single-dose treatments for anthelmintic action have a good safety profile.

Levamisole-Induced Leukoencephalopathy in Russia: Analysis of 30 Cases.

AIMS: The study aims to raise medical specialists' awareness regarding the severity of possible complications of levamisole administration, and demonstrate the role of accurate medical history collection in a differential diagnosis. BACKGROUND: Levamisole, an anthelmintic drug with immunomodulatory effects, has long been used worldwide till the early 2000s, when its association with demyelinating leukoencephalopathy was established. However, in the developing countries, it is still widely used for the prevention and treatment of helminthic invasion in humans. The actual prevalence of levamisole-induced multiple inflammatory leukoencephalopathy (LEV-induced MIL) in Russia remains unknown, and therefore, the study of its frequency and characteristics is indisputably important. OBJECTIVES: The objective of this study is to determine the clinical features and MRI findings of levamisole- induced MIL in the Russian population, and to analyse the frequency of diagnostic errors at the initial assessment. METHODS: A single-center retrospective analysis of total 30 patients who were diagnosed with LEV- induced MIL and attended the Research Center of Neurology was conducted. Inclusion criteria were 1) clinically: acute or subacute polysymptomatic onset of neurological disturbances, 2) MRI: multifocal demyelinating lesion with no evidence of dissemination in time, 3) anamnestic data: levamisole exposure from 2 to 8 weeks before symptoms onset as well as monophasic disease course (absence of relapses according to follow up assessments up to 3 years). RESULTS: Clinically, presentation with constitutional symptoms including headache, fever, fatigue and myalgia, focal motor disturbances and dysarthria prevailed in our cohort. On the brain MRI, multiple foci of demyelination with simultaneous gadolinium enhancement were observed. The link between neurological symptoms and levamisole intake has often been detected only during follow- up assessments. Patients were most often misdiagnosed with acute disseminated encephalomyelitis, stroke and multiple sclerosis. In most cases, LEV-induced MIL was successfully treated with intravenous corticosteroids and/or plasma exchange (PLEX), however, residual neurologic symptoms were preserved in some patients. Additionally, two detailed clinical cases of patients being initially misdiagnosed are presented in the article. CONCLUSION: The differential diagnosis remains difficult for suspected cases of LEV-induced MIL that could lead to delayed therapy initiation, and consequently incomplete recovery. Growing evidence suggests that a single administration of levamisole even in low doses might potentially lead to severe neurological deficit or death. Therefore, changes in medication management policies are required in order to prevent the uncontrolled use of levamisole.

Rare presentation of levamisole-induced leukoencephalopathy in a pediatric patient: seizure.

BACKGROUND: Levamisole is an imidazole derivative used in the treatment of various cancers, dermatological diseases, and parasitosis. Illegal use of levamisole by mixing it with cocaine in order to increase the psychotropic effects has also increased in recent years. Leukoencephalopathy is one of levamisole`s most prominent neurological side effects. CASE: Here we present the clinical, laboratory, imaging findings, treatment, and follow-up information of a 12-year-old girl who presented with seizures due to levamisole, which was prescribed to treat vitiligo. CONCLUSION: Levamisole-induced leukoencephalopathy should be considered in the differential diagnosis of demyelinating diseases, the neurotoxic effects of the drug should be well understood, and treatment should be initiated as soon as possible.

Pyoderma gangrenosum associated with levamisole-adulterated cocaine in a c-ANCA positive patient.

Pyoderma gangrenosum (PG) is an inflammatory, ulcerative condition that is characterized by painful ulcers that commonly present on the lower extremities. Up to half of PG cases are associated with underlying systemic disease, including inflammatory bowel disease, various autoimmune conditions, and malignancy. Another well-known association is the manifestation of PG with recreational cocaine use, especially cocaine contaminated with the adulterant agent levamisole. Once utilized for its immunomodulatory capabilities, levamisole was withdrawn from the market in 2002. It has since been repurposed to potentiate the amphetamine-like effects and duration of cocaine and has reduced preparation cost. We present a 52-year-old woman with chronic maxillary sinusitis and cocaine use disorder presenting with a two-week history of painful ulcers on bilateral lower extremities, each with a purulent base and undermined, violaceous borders. Urine toxicology was positive for cocaine and serologic studies were positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and lupus anticoagulant. Underlying conditions, especially that of granulomatosis with polyangiitis, were considered and ultimately ruled out. The patient's lesions exhibited a marked response with a short course of oral corticosteroids, typical of PG associated with levamisole. This case highlights the crucial role that drug abstinence plays in the prevention of recurrence.

Levamisole induced toxic epidermal necrolysis: A case report.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening immune-mediated hypersensitivity reactions. Various drugs, such as Non Steroidal Anti-inflammatory drugs (NSAIDS), allopurinol, anticonvulsants and antibiotics, have been implicated as triggering agent of SJS/TEN. Levamisole is frequently used as an antihelminthic and as an immunomodulator in cases of nephrotic syndrome. However, levamisole has not been reported as a trigger for SJS/TEN. The current case describes levamisole-induced TEN in a 15-year-old male who presented to emergency with erythematous lesions, blistering and denudation of skin involving up to 30% of body surface area. Algorithm of drug causality for epidermal necrolysis scoring was applied for causality assessment and a relationship was found to be "possible". Immediate withdrawal of levamisole along with a short course of corticosteroids and cyclosporine led to improvement in signs and symptoms. Clinicians should be aware of the possible association of levamisole and SJS/TEN.

Cocaine Consumption and Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis: A Case Report.

ABSTRACT: Cocaine is often sold in a mixture with levamisole to increase the profit margin and potentiate the euphoric effect. Apart from an overdose, cocaine can induce a wide range of clinical symptoms. We present a case of cocaine/levamisole-induced pauci-immune glomerulonephritis. A 22-year-old patient was sent to the hospital after a laboratory result showed an unexpected acute kidney injury, with an estimated glomerular filtration rate of 34 mL/min/1.73 m2. The medical history included cocaine abuse. Renal biopsy showed a pauci-immune necrotizing glomerulonephritis. Antineutrophil cytoplasmic antibodies were positive with a perinuclear staining pattern and target specificity for leucocyte myeloperoxidase (antimyeloperoxidase). Despite treatment, the kidney function did not show significant improvement. The forensic implication of this case is that even if the toxicological values are not high enough to suggest a lethal intoxication, an idiosyncratic reaction on cocaine and/or levamisole has to be taken into account.

Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occusion - Part II: Coagulation Disorders, Emboli, and Other. / Dermatopatología de la oclusión intraluminal vascular: parteII (coagulopatías, émbolos y miscelánea).

Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. It also has a wide variety of causes, including thrombi, which we recently addressed in partI of this review. In this second part, we look at additional causes of vascular occlusion.

Agranulocitosis febril y artropatía reactiva asociada a consumo de cocaína en un paciente HLA B27 positivo / Febrile agranulocytosis and reactive arthropathy associated with cocaine consumption in an HLA B27 positive patient

Resumen La agranulocitosis asociada al consumo de cocaína es un fenómeno vinculado a la presencia de levamisol, un agente antihelmíntico e inmunomodulador, usado como adulterante de la cocaína. Esta reacción puede presentarse con mayor frecuencia en personas con HLA B27. Además de la agranulocitosis, las personas que consumen cocaína adulterada con levamisol pueden desarrollar fiebre, lesiones en piel, artralgias y, menos frecuentemente, artritis y entesitis inflamatoria. Presentamos el caso de un paciente consumidor de cocaína, con genotipo HLA B27, que desarrolló agranulocitosis febril y artropatía reactiva. En sangre se detectó la presencia de ANCA p, ANCA atípico y MPO, y fueron excluidas otras causas de agranulocitosis. Fue tratado con corticoides y posteriormente metotrexato, terapia de deshabituación, con buena evolución.

Abstract Agranulocytosis associated with cocaine use is a phenomenon linked to the presence of levamisole, an anthelminthic and immunomodulating agent, used as an adulterant to cocaine. This reaction has been associated with the presence of HLA B27. In addition to agranulocytosis, people who use levamisole-adulterated cocaine may develop fever, skin lesions, arthralgias, and less frequently, inflammatory enthesitis and arthritis. We present the case of a cocaine-consuming patient with HLA B27 genotype, who developed febrile agranulocytosis and inflammatory arthropathy. The presence of p ANCA, atypical ANCA and MPO was detected in blood, and other causes of agranulocytosis were excluded. He was treated with corticosteroids and later methotrexate, therapy for addiction, with good evolution.

Cocaine Use and Levamisole-Induced Vasculitis: A Multiple Case Study.

BACKGROUND: Levamisole is an immunomodulatory medication previously used to treat rheumatoid arthritis and some types of cancers; it was banned for use in humans in 2000 owing to its harmful side effects. Use of levamisole-laced cocaine is associated with a life-threatening syndrome characterized by a necrotizing purpuric rash leading to tissue destruction and necrotic wounds. This Clinical Challenges article summarizes our experience with the care of 2 adult women diagnosed with levamisole-related vasculitis. CASE: Case 1 is a 46-year-old woman who presented with joint pain in her hands and legs, along with bilateral ear pain, swelling, and bleeding. She was initially diagnosed with vasculitis and possible systemic lupus erythematosus. She experienced multiple recurrences and exacerbation of her condition over a period of months. She was ultimately diagnosed with levamisole-related vasculitis from recurrent cocaine use resulting in bilateral above the knee amputations. The second case is a 50-year-old woman who presented to our emergency department with redness and swelling of her bilateral lower extremities. She developed blisters and pustules that rapidly evolved into abscesses and red lesions over the course of several months. Her wounds also deteriorated despite topical therapy that occurred in a context of recurring use of cocaine. CONCLUSIONS: Our experience with these cases suggests that WOC nurses should consider levamisole-induced vasculitis in all patients presenting with unexplained vasculitis-type lesions, and particularly when these lesions occur in the context of known or suspected use of illicit substances such as cocaine. Given the absence of clinical guidelines for this increasingly prevalent condition, we recommend wound care based on principles of moist wound healing, combined with judicious use of therapies with antimicrobial activity and nonadherent dressings to reduce pain. Finally, we strongly recommend that care of these patients occurs as one part of a multidisciplinary care approach that focuses on cessation of the use of cocaine and all other illicit substances.

A Unique Presentation of Levamisole-Induced Antineutrophil- Cytoplasmic-Antibody-Positive Vasculitis Presenting as Inflammatory Orbitopathy.

A 35-year-old woman with a history of cocaine abuse presented with progressively worsening OS pain. Neuroimaging revealed a 3-cm ill-defined left orbital lesion involving the intraconal and extraconal spaces. The orbital mass was biopsied via an anterior orbitotomy approach. Pathology demonstrated prominent angiocentric granulomatous and lymphoplasmacytic inflammation consistent with vasculitis. Laboratory tests were significant for neutropenia, positive perinuclear antineutrophil cytoplasmic antibodies with high titer, and positive myeloperoxidase antibodies, consistent with levamisole-induced vasculitis. To the authors' knowledge, this is the first reported case of cocaine-levamisole-induced vasculitis presenting as orbitopathy.

A fatal case of levamisole induced bone marrow failure.

A 20-year-old college student presented with high grade, intermittent fever for 10 days associated with blood stained loose stools after taking tablet levamisole for 17 days for vitiligo vulgaris. He was febrile, had a toxic appearance and appeared pale. Investigations showed neutropaenia with thrombocytopaenia. Blood cultures were sterile and stool cultures did not grow any enteric pathogens. His bone marrow examination was suggestive of an aplastic anaemia. He was administered empirical antibiotics, granulocyte colony stimulating factor and platelet transfusions. However, his fever and blood stained stools persisted. A repeat bone marrow examination after 2 weeks still revealed a hypoplastic marrow. Hence, a diagnosis of a levamisole induced bone marrow failure was made. While being worked up for an allogeneic stem cell transplantation, he developed neutropaenic enterocolitis and refractory septic shock with carbapenem resistant Klebsiella pneumoniae and succumbed to his illness.

Optimal duration of adjuvant therapy for stage III colon cancer.

Colon cancer remains a major cause of mortality worldwide. Following adequate surgical resection of lymph node-positive colon cancer, the standard of care since 2004 has been to administer an oxaliplatin-containing regimen (eg, FOLFOX or CAPOX) for 6 months. These regimens have consistently improved oncologic outcomes compared with non-oxaliplatin therapies in multiple adjuvant randomized controlled trials. However, oxaliplatin-induced cumulative dose-dependent neurotoxicity is a major cause of morbidity that can persist years after treatment. The IDEA collaboration is a study that pooled data from 6 concurrent phase 3 trials comparing 3 vs 6 months of adjuvant FOLFOX or CAPOX to evaluate whether a shorter duration of therapy could maintain efficacy while reducing neurotoxicity. In this article, we review the history of adjuvant therapy in stage III colon cancer and comprehensively detail the results of the IDEA collaboration. A risk-based approach focusing on efficacy, toxicity, and patient selection is emphasized to guide discussions regarding the optimal duration of adjuvant therapy in stage III colon cancer.

Levamisole-Induced Vasculitis in the Lower Extremities: A Case Report.

BACKGROUND: Since 2006 there have been increased reports of severe agranulocytosis and vasculitis associated with levamisole use. Historically, levamisole was an immunomodulatory agent used in various cancer treatments in the United States. Currently the drug is used as an antihelminthic veterinary medication, but it is also used as an additive in freebase cocaine. There are multiple reports of levamisole-induced vasculitis in the head and neck but limited reported cases in the lower extremities. This article describes a 60-year-old woman who presented to the emergency department with multiple painful lower-extremity ulcerations. RESULTS: Radiographs, laboratory studies, and punch biopsy were performed. Physical examination findings and laboratory results were negative for signs of infection. Treatment included local wound care and education on cocaine cessation, and the patient was transferred to a skilled nursing facility. Her continued use of cocaine, however, prevented her ulcers from healing. CONCLUSIONS: Local wound care and cocaine cessation is the optimal treatment for levamisole-induced lesions. With the increase in the number of patients with levamisole-induced vasculitis, podiatric physicians and surgeons would benefit from the immediate identification of these ulcerations, as their appearance alone can be distinct and pathognomonic. Early identification of levamisole-induced ulcers is important for favorable treatment outcomes. A complete medical and social history is necessary for physicians to treat these lesions with local wound care and provide therapy for patients with addictions.

[Clinical case of levamisole-induced multifocal inflammatory leukoencephalopathy]. / Levamizol-indutsirovannaia vospalitel'naia leikoéntsefalopatiia.

Levamisole is an immunomodulatory drug which can trigger development of levamisole-induced multifocal inflammatory leukoencephalopathy (LIMIL) in patients treated for helminthic invasion, aphthous stomatitis, cancer, or cocaine users. LIMIL clinical case in patient 45 years old after single dose of levamisole (taken without any medical prescription) was described. We presented clinical history and clinical picture, MRI and laboratory data and treatment results during 1-year observation. According to similarity of LIMIL with acute disseminating encephalomyelitis or debut of multiple sclerosis and high frequency of levamisole usage in Russia (usually without medical prescription) LIMIL should be included in differential diagnosis in demyelinating disorders and treated according to current clinical recommendation.