Levamisole

Chemistry
Tetramisole was first introduced in the mid 1960s as an antihelminthic agent. Tetramisole is a racemic mixture, and it was subsequently shown that the levo isomer held the antihelminthic properties, so levamisole was isolated. In the 1970s it was found to have immunomodulatory properties.

Cocaine
In 2016, the Drug Enforcement Agency (DEA) reported that 87% of cocaine samples tested contained levamisole, but this was lower in 2017 with 40% of samples tested containing levamisole. In 2010 a study showed that 78% of urine toxicology specimens that were positive for cocaine were also positive for levamisole.

Systemic Side effects

 * Agranulocytosis: thought related to autoantibodies and associated with HLA-B27 status but also occurred in patients with other HLA types. Typically reversed spontaneously after discontinuation of levamisole.
 * Thrombocytopenia: typically resolved after discontinuation of levamisole and recurred frequently if it was restarted.
 * Vasculitis: first reported in two case reports in 1978, with both leukocytoclastic vasculitis and cutaneous vasculitis.
 * Nephropathy/glomerulonephritis: rare but has been reported
 * Arthritis
 * Rash: diffuse erythema with urticaria, maculopapular rash that is scaly, exfoliative bullous dermatitis, lichen planus-like lesions, and fixed drug eruption
 * GI upset: anorexia, nausea/vomiting, diarrhea
 * SIADH: rare

Multifocal inflammatory leukoencephalopathy

 * History:
 * In 1976 levasimole was studied as a potential treatment for multiple sclerosis (MS), but when given to seven patients, five of them developed worsened MS symptoms. Despite this, it was pursued further -- subsequent studies were not suggestive of harm but failed to show benefit, and this approach for MS treatment was abandoned.  Subsequent animal studies showed evidence of perivascular macrophage infiltration in dogs given levamisole.
 * In 1992 there were initial reports of patients with neurological symptoms while taking 5-FU and levamisole for colon adenocarcinoma, after 3-5 months of treatment. Two patients presented with a 2-3 week decline in mental status with memory disturbance, unsteady gait, and slurred speech.  A third patient presented with transient episodes of loss of consciousness and had an increase in unilateral deep tendon reflexes.  MRI showed globular T2/FLAIR periventricular hyperintensities, more supratentorial than infratentorial, nearly all contrast-enhancing. Biopsies were done in two patients and were consistent with demyelination.  Overall syndrome appeared consistent with multiple sclerosis, but no patients had a history of multiple sclerosis, and two of the patients were over age 65. A 4th case was reported in 1993, beginning with diplopia, then confusion, ataxia, dysarthria, and limb paresthesias, progressing for two weeks.  This was followed by a 5th report in 1995.  Although all of these cases included treatment with 5-FU as well (a common regimen for colon cancer), but in 1995 a subsequent report described a similar syndrome in a patient with malignant melanoma treated with levamisole alone, and in 1996 a similar report was published with levamisole alone used to treated colon cancer. Reports later began to emerge from China about a high correlation of prior treatment with levamisole or tetramisole and symptoms of "encephalitis."  The Food and Drug Administration removed levamisole from the US market in 1999 due to its systemic side effects of vasculitis and agranulocytosis.
 * Epidemiology: In 1994 an abstract from China reported on 202 patients with "antihelminthic imidazoles-induced delayed encephalopathy," describing that the disease affected sexes equally, both middle-aged and youth, delayed occurrence after 2-5 weeks with subacute or acute onset.
 * Pathophysiology: Biopsies have shown demyelination wiith perivascular cuffing by lymphocytes and abundant macrophages, axons generally well-preserved. Levamisole stimulates T-cell activity and enhances B-lymphocyte function and IL-2, and also inhibits function of the blood-brain barrier. No dose-dependency is seen.
 * Time course
 * Usually delayed by two weeks but can be up to several months after initial exposure to the medication
 * Symptoms:
 * Encephalopathy
 * Ataxia: the initial and most common symptom in one case review, affecting over 60% of cases
 * Memory disturbance
 * Aphasia
 * Dysarthria
 * Vertigo
 * Paresthesias in legs
 * Diplopia
 * Facial weakness
 * Limb weakness: common, affecting 42-75% of cases
 * Visual disturbance
 * Seizures
 * Diagnostic Studies:
 * CSF
 * Lymphocytic pleocytosis
 * Oligoclonal bands (positive)
 * Normal protein and glucose
 * Imaging
 * MRI: Multiple enhancing T2/FLAIR white matter hyperintensities, hypointense on T1. Mostly supratentorial but nearly 50% of patients had infratentorial lesions as well. Minimal (if any) surrounding edema. In contrast to MS, corpus callosum is often spared. Usually does not involve basal ganglia, thalamus, or brainstem but it can involve cortex. There are rare reports of it mimicking Balo's concentric sclerosis.
 * Treatment and Prognosis:
 * Discontinuation of levamisole. This condition has been reported to have a high recurrence rate with further treatment, which was 8.8% in a series of 202 cases of "imidazole-induced encephalopathy" (not specifically levamisole).
 * Corticosteroids: The two patients initially treated in 1992 were treated with dexamethasone 16 mg/day for one month with subsequent taper. One patient had radiographic and clinical progression over two weeks without steroids, but had subsequent improvement with dexamethasone therapy. In one series of 202 cases of "imidazole-induced encephalopathy" (not specifically levamisole), of those treated with steroids, 47% of patients had cure, 45% had improvement, 4% died, and 62% had lifelong disability. In a 2006 case review of 31 cases of levasimole-induced multifocal inflammatory encephalopathy previously published in the literature, 29 of 31 patients (94%) of patients had improvement.  Seven patients (23%) had complete recovery within two months after steroids.
 * Plasmapheresis: tried in some cases
 * Observation: In one case report the patient improved on his own without treatment.
 * Plasmapheresis: tried in some cases
 * Observation: In one case report the patient improved on his own without treatment.

Muscle spasms
This is unproven, but there are two case reports of limb cramping in pediatric patients after one dose of the medication.

Stimulation and insomnia
Described in one series of patients given levamisole.