Levamisole-induced leukoencephalopathy, also known as levamisole-associated multifocal inflammatory leukoencephalopathy, is a rare but likely under-diagnosed demyelinating toxic leukoencephalopathy.
Levamisole is a medication which was previously used to treat parasitic infections, aphthous ulcers, rheumatological conditions, and colorectal cancer 1-4. However, its usage was largely discontinued due to the serious adverse effect of agranulocytosis 1-3. In addition to being a prescription medication, levamisole is also a common adulterant with the illicit drug cocaine, present in up to 86% of cocaine samples 2.
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Epidemiology
Levamisole-induced leukoencephalopathy typically affects young adults, but can affect patients from any age demographic 1. It is widely suspected that this condition is under-recognized and thus under-diagnosed 1,5.
Clinical presentation
There is a median latency of approximately 30 days between exposure to levamisole and development of this clinical syndrome, however there is a wide range between 1 day and time periods exceeding 4 months 1. The severity of the clinical syndrome does not seem to correlate with the exposed dose of levamisole 1.
The potential clinical features are diverse and manifest in an acute or subacute fashion 1-4. These clinical features may include 1-3,5,9:
encephalopathy
focal neurological deficits (e.g. weakness, ataxia, dysphasia, dysphagia)
seizures
constitutional symptoms (e.g. fever, headache, myalgias)
In addition to levamisole-induced leukoencephalopathy, levamisole may also be associated with an ANCA vasculitis, which typically presents with cutaneous vasculitis (e.g. purpuric rash), and rarely has other organ (e.g. renal, pulmonary) involvement 6.
Pathology
The pathogenesis of levamisole-induced leukoencephalopathy has not been fully elucidated. It is thought that levamisole can induce autoinflammation and/or autoimmunity which can lead to demyelination 1-4.
Markers
Levamisole detection in the urine is the ideal marker to detect its presence 2. However, urine levels may be undetectable in patients presenting with levamisole-induced leukoencephalopathy if the sample is not taken promptly, as levamisole has a short half-life of approximately 5.6 hours 2.
In examination of CSF, levamisole-induced leukoencephalopathy can demonstrate pleocytosis and positive intrathecal-origin oligoclonal bands 1,3,5,7.
Microscopic appearance
Brain biopsy is generally not necessary to diagnose levamisole-induced leukoencephalopathy, but when performed, demonstrates demyelination with perivascular lymphocytes and macrophage infiltration 8.
Radiographic features
CT
CT can initially be normal 8. As the condition progresses, there are hypoattenuating regions corresponding to regions of high T2/FLAIR signal changes on MRI (see below) 8.
MRI
Generally, patients have multiple, bilateral, asymmetric, and initially patchy and ovoid T2/FLAIR hyperintensities affecting the centrum semiovale, often with a periventricular predominance, and sparing subcortical U-fibers 1-8. In approximately one-half of cases the basal nuclei can be similarly involved, and in approximately one-third of cases the posterior fossa can be similarly involved 1.
Affected regions may additionally have high signal on DWI and may have a variable enhancement pattern on T1 C+ (Gd), with described patterns including patchy and ring enhancement 1-7. The optic nerves and spinal cord are notably spared 1.
Treatment and prognosis
The mainstay of treatment is withdrawal of levamisole, including cessation of use of levamisole-adulterated cocaine 1. Corticosteroids, such as pulsed intravenous methylprednisolone, are often used initially 1,4. Depending on clinical severity and response to corticosteroids, other immunosuppressive techniques may be utilized, such as plasma exchange or intravenous immunoglobulin 1,4. Symptomatic therapy is also recommended, such as antiseizure agents in patients with seizures.
With prompt treatment, nearly all patients have a favorable recovery 1. Aforementioned abnormal MRI features can improve significantly following treatment 5.
Differential diagnosis
other toxic leukoencephalopathies, including direct effects from cocaine (which tend to be vascular in etiology 1)