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1 Section of Neuroradiology, Department of Radiology. 2 Servei de Neurologia-Neuroimmunologia. Centre d'Esclerosi Múltiple de Catalunya (Cemcat). 3 Surgical Intensive Care Unit and Anesthesiology Department. 4 Neurology Department. 5 Service d'Anatomo-Pathologie.
MIL is a potential complication of the use of levamisole-adulterated cocaine samples.
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Tumefactive demyelinating lesions are an unusual finding in levamisole-induced MIL.
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The Balo's concentric sclerosis pattern we describe in two of our patients is exceptional.
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Hair-samples are worth being tested for both cocaine and levamisole.
Abstract
Background:
Cocaine is the most common illicit stimulant drug used in Europe, and it can potentially affect the central nervous system due to a direct effect, or by means of additive drugs. Levamisole has been increasingly used as an additive drug since it extends the stimulating effects of cocaine. This has led to an increase in the detection of levamisole adverse reactions, including levamisole-induced multifocal inflammatory leukoencephalopathy (MIL), a potentially lethal monophasic cerebral demyelinating disease.
Methods:
We present three adult patients who developed a MIL with tumefactive demyelinating lesions, leading to encephalopathy and motor manifestations. All these patients had in common a history of chronic or acute use of cocaine. Imaging findings revealed a tumefactive MIL, following a Balo's Concentric Sclerosis (BCS) pattern in two cases.
Results:
The pathophysiology of levamisole-induced MIL may depend on an immunological mechanism, producing multiple demyelinating lesions affecting the subcortical and periventricular white matter, basal ganglia and/or brainstem. Atypical demyelinating lesions are an unusual finding in levamisole-induced MIL. Specifically, the BCS pattern is a rare finding in these patients: to our knowledge, only two more cases mimicking BCS have been reported in the literature, which have also occurred in chronic cocaine users.
Conclusions:
Based on the history and images of our patients and other two similar case reports, we suggest a probable pathophysiological relationship between levamisole-adulterated cocaine use and the occurrence of MIL with atypical demyelinating lesions, even when they present following a BCS imaging pattern.
Cocaine is the most common illicit stimulant drug used in Europe. It can potentially affect the central nervous system due to its direct effect, or by means of additive drugs in adulterated cocaine samples, such as levamisole. Levamisole, the L-isomer of tetramisole, is an anthelmintic agent with significant immunomodulatory properties (
), which has started to be used as an additive to cocaine as it enhances and extends the stimulating effects of cocaine when they start fading out, and reduces the cost of the adulterated sample. Nowadays, it is one of the main adulterants of cocaine in Europe.
Chronic exposure to levamisole may lead to severe adverse reactions, including neutropenia, agranulocytosis or cutaneous vasculitis, and levamisole-induced multifocal inflammatory leukoencephalopathy (MIL), a potentially lethal cerebral demyelinating disease.
In this report, we present three young patients with a history of cocaine abuse without previous neurological symptoms, who developed MIL with tumefactive demyelinating lesions, two of them following a Balo's Concentric Sclerosis (BCS) imaging pattern.
2. Case 1
A 39-year-old man presented a 10-day history of progressive confusion, disorientation, behavioral changes and speech impairment. He had a history of chronic cocaine inhalation. Examination revealed a mild right hemiparesis, global hyperreflexia and predominant motor aphasia. Cerebrospinal fluid (CSF) analysis showed a slightly raised proteins and urine tests were positive for cocaine. On admission, a head computed tomography (CT) scan showed multiple hypodense white matter lesions affecting both brain hemispheres, with a subtle post-contrast ring enhancement (not shown). Brain magnetic resonance imaging (MRI) showed multiple large lesions in the subcortical white matter of both brain hemispheres (Fig. 1A–C). The lesions showed a concentric ring pattern on T2-weighted fluid-attenuated inversion recovery (FLAIR) images, with peripheral diffusion restriction (Fig. 1B), consistent with tumefactive demyelinating lesions following a BCS pattern.
Fig. 1Imaging findings in patients 1 (A–D) and 2 (E–H). Patient 1 at the time of admission showed several lesions affecting the subcortical frontoparietal white matter of both cerebral hesmispheres, better depicted on T2-weighted FLAIR sequences (A), with peripheral diffusion restriction on ADC maps (B) and ring-enhancement after contrast administration on T1-weighted sequences. Both T2-FLAIR (A) and post-gadolinium (C) images showed an alternating concentric ring pattern. A follow-up MRI performed one year after admission (D) showed radiological improvement of the lesions. Patient 2 at the time of admission showed two white matter lesions in the right and left frontal lobes, which showed high signal intensity on axial T2-weighted (F) and FLAIR (E) sequences. The left-side lesion had a heterogeneous enhancement with a concentric ring pattern on post-gadolinium T1-weighted images (G). This pattern was also seen on T2-weighted images (F). The ADC maps (H) depicted a peripheral laminar restriction.
A 33-year-old woman was admitted with a 4-day history of progressive weakness in her right upper limb. She had a history of chronic cocaine inhalation. Examination revealed distal weakness in her right upper and lower limbs and a paretic gait. Oligoclonal bands were positive on CSF analysis, and urine tests were positive for cocaine. Head CT (not shown) revealed two demyelinating lesions, affecting the right periventricular and left subcortical white matter of both frontal lobes, better depicted on MRI (Fig. 1E–H). After contrast administration, they had opened-ring (not shown) and concentric enhancement patterns (Fig. 1G), respectively. Diffusion was restricted in the periphery (Fig. 1H).
4. Case 3
A 32-year-old man presented a 2-week history of progressive confusion, behavioral disorders, visual hallucinations and fever (38.1 °C). He had a history of daily cocaine abuse for the last two months. A brain MRI showed multiple confluent white matter lesions with minimal mass effect affecting mainly both frontal lobes, with peripheral diffusion restriction and mild peripheral contrast enhancement (Fig. 2A–F). Clinical status worsened abruptly during admission. Stereotaxic biopsy was performed, revealing intense necrotizing encephalitis associated with perivascular lymphocytic (CD3+ and CD4+) infiltration (Fig. 2G). Eight days after admission, the patient passed away. Postmortem hair samples showed significant concentrations of both cocaine and levamisole.
Fig. 2Imaging findings in patient 3. Axial pre (A) and post-gadolinium (B) T1-weighted, and T2-weighted FLAIR (C, D) images show multiple confluent white matter lesions with minimal mass effect and heterogeneous contrast enhancement affecting the frontal lobes and the genu of the corpus callosum, and also the parietal white matter bilaterally. No signs of hemorrhage or calcifications were seen on T2*-weighted images (E). The ADC maps showed peripheral restriction (F). Brain biopsy specimen (G) showed perivascular lymphocytic infiltration and vasculitis and macrophages infiltration with necrosis (hematoxylin-eosin, original magnification X10).
Multifocal inflammatory leukoencephalopathy is a well-established stand-alone complication of therapeutic levamisole administration, but it should also be considered as a potential adverse effect of levamisole-adulterated cocaine samples. It is probable that the physiopathology of levamisole-induced MIL depends to a large extent on an immunological mechanism, since biopsy materials show lymphocytic infiltrates, it responds to immunosuppressive therapy and it usually has a latent period of at least two weeks (
Imaging findings in MIL include multiple demyelinating lesions, affecting the subcortical and periventricular white matter (most frequently frontal and parietal lobes), basal ganglia and/or brainstem with variable surrounding vasogenic edema but no significant mass effect. After contrast administration, up to one third can show ring enhancement (
). Tumefactive demyelinating lesions are an unusual finding in levamisole-induced MIL. Specifically, the BCS pattern seen in two of our patients (cases 1 and 2) is exceptional: to our knowledge, there are only two other cases reported in the literature (
), also in chronic cocaine users who had the typical concentric rings on T2-weighted MRI sequences representing alternating layers of demyelinated, remyelinated, and normal myelinated white matter. Peripheral diffusion restriction and contrast enhancement represents the advancing front of demyelination.
One of our patients had been tested for levamisole levels. In that case, only post-mortem hair samples were positive. This would imply that hair-samples are worth being tested, especially if there has been a long time since the last cocaine administration.
Our three patients were treated with intravenous methylprednisolone, 1000 mg daily for five days, and one of them (case 3) also with plasma exchange. During admission, one patient had a lethal outcome and the other two had a slow gradual recovery (Fig. 1D). Despite this improvement, a cognitive and speech disorder persisted in one of them (case 1). On a 5-year clinical and radiological follow-up, no relapses were found in the two surviving patients.
6. Conclusion
Based on the history and images of our patients and other two similar case reports, we suggest a probable pathophysiological relationship between levamisole-adulterated cocaine use and the occurrence of MIL with tumefactive demyelinating lesions, even when they present following a BCS imaging pattern.
Declaration of Competing Interest
The authors declare that they have no conflict of interest regarding this manuscript.
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