Levamisole-induced leukoencephalopathy

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.

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-recognised 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-fibres ^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 utilised, 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 favourable 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 aetiology ¹)

• multiple sclerosis ^1,6

• acute disseminated encephalomyelitis (ADEM) ¹

• posterior reversible encephalopathy syndrome (PRES) ²