Cocaine-induced toxic leucoencephalopathy with complete clinical recovery

Abstract

A 45-year-old man, a regular cocaine user, presented with confusion and unusual behaviour to the emergency room. On examination he was unable to perform simple tasks or follow commands. He was treated for possible central nervous system infection. MRI of the brain showed multiple bilateral T2 hyperintense periventricular and deep white matter foci, best appreciated on FLAIR with contrast enhancement. He continued deteriorating, eventually becoming catatonic with extensor posturing and increased tone, requiring intensive therapy unit management. Repeat MRIs were also noted to show worsening changes. He was treated for a presumed inflammatory leucoencephalopathy with intravenous methylprednisolone, immunoglobulins, as well as plasmapheresis. After 2 weeks, the patient started to show clinical improvement with eventual transfer to a rehabilitation hospital. A year after his first presentation, the patient scored 30 out of 30 on the MMSE and his neurological examination was normal.

Background

Cocaine-induced toxic leucoencephalopathy is a rare disorder which can cause significant disability. This case study is intended to increase awareness of this condition. Drug users presenting with altered mental function with an MRI showing diffuse bilateral symmetrical cerebral white matter involvement with sparing of the subcortical U fibres, brainstem and cerebellar white matter should have trials of pulsed steroid therapy, intravenous immunoglobulins and plasmapheresis. The prognosis is generally poor and can be rapidly fatal; however, some rare cases recover fully, as is seen in this case report.

Case presentation

A 45-year-old man, with a known case of anxiety on Stilnox and a regular cocaine abuser, was brought to the emergency department by his parents with a 2-day history of confusion and unusual behaviour. The patient could not provide a history. He had bumped his head against a cupboard the previous day and had suffered a fall with mild head injury 2 weeks prior to his presentation. According to his parents, the patient had last taken cocaine 2–3 days before coming to the emergency room.

On examination, his pupils were dilated and briskly reactive to light. Over the left occipital area, a small, infected superficial wound was noted with a purulent exudate. There was no neck stiffness and his gait was normal. The patient was not cooperative, unable to perform simple tasks and was not following commands. He was moving all four limbs in purposeful movement. Plantars were downgoing, but his reflexes could not be elicited. His temperature was 37.4°C and parameters were stable.

The patient was treated with intravenous ceftriaxone, aciclovir and co-amoxiclav for broad cover of central nervous system (CNS) sepsis. Brain MRI showed multiple bilateral T2 hyperintense periventricular and deep white matter foci, best appreciated on fluid-attenuated inversion recovery (FLAIR), showing extensive symmetrical enhancement with contrast (figure 1A,B). Following MRI, he was also started on a 5-day course of intravenous methylprednisolone 500 mg daily for a presumed inflammatory leucoencephalopathy.

Figure 1.

Progressive MRI. (A) MRI of the head on admission, (B) after 5 days, (C) 2 weeks after admission, (D) 1 month after admission, (E) 3 months after admission and (F) 10 months after admission.

The patient remained confused but obeyed commands inconsistently, with episodes of agitation treated with haloperidol. He was also treated with regular lorazepam after a detailed history revealed benzodiazepine abuse. The patient was also reviewed by the psychiatric team in the hospital.

The patient kept deteriorating, becoming more withdrawn and uncommunicative, progressing to catatonia. On examination he had extensor posturing, a generalised increased tone, worse on the left, with upgoing plantars. Creatine kinase (CK) was elevated. Baclofen was initiated. He was regularly spiking temperatures, and was treated with ciprofloxacin for the scalp wound infection which had cultured Staphylococcus aureus. He was transferred to the intensive care unit.

A second 5-day course of intravenous methylprednisolone was administered. A third MRI of the head (figure 1C) showed further worsening changes, in keeping with leucoencephalopathy. At this point, our patient was noted to be withdrawing to pain, with no eye opening or vocal response. A 5-day course of intravenous IgG 30 g daily was given. Following this, he was noted to have become slightly better; he was no longer in extensor posture and was opening his eyes spontaneously.

At this point it was decided to attempt plasmapheresis with 5% albumin replacement fluid. Unfortunately plasma exchange was complicated by a hydropneumothorax which required a chest drain. The plasma exchange course was therefore interrupted but was restarted 2 days later. In total, three sessions of plasma exchange were performed.

After approximately 1 month from admission, around 2 weeks after plasma exchange, our patient was noted to visually track the examiner. Continued improvement was noted, and he slowly started moving his limbs spontaneously and obeying commands. He continued with regular physiotherapy while in the hospital. Botox injections were administered to the upper limbs with good response.

His mini-mental state examination (MMSE) 2 months after admission was 14 out of 30. Eventually the patient was transferred to a rehabilitation hospital after nearly 3 months from admission. On discharge from hospital 2 months after admission, his MMSE was 14 out of 30.

Investigations

Blood investigations on admission revealed a white cell count of 4.32x10⁹/L and a C reactive protein (CRP) of 4.5. Serum ethanol was <10, but urine was positive for cocaine and negative for amphetamine, methamphetamines, opiates, cannabinoids and 3,4-Methyl​enedioxy​methamphetamine (MDMA). HIV, syphilis and hepatitis screen was negative. No bacteria were cultivated from the blood, and other routine blood investigations were normal. CT of the brain was normal.

MRI showed the previously described changes compatible with bilateral leucoencephalopathy (figure 1A).

In view of the degree of enhancement, a progressive multifocal leucoencephalopathy (PML) could not be excluded at the time. Magnetic resonance (MR) venogram and MR angiography of the brain were normal. Serial MRI scans showed increasingly worsening white matter changes, despite clinical improvement (figure 1D,E).

A CT of the thorax, abdomen and pelvis did not reveal any significant abnormality.

Cerebrospinal fluid (CSF) examination was normal, and no bacteria were cultivated. CSF PCR was negative for enterovirus, herpes simplex virus, parechovirus, mumps and varicella virus. Serology and CSF PCR for John Cunningham (JC) virus were also negative.

Electroencephalography (EEG) showed a slow background in the theta range over both hemispheres. There were no focal abnormalities or epileptiform.

An autoantibody screen was negative, including antithyroid peroxidase antibody, rheumatoid factor, antimitochondrial antibody, antismooth muscle antibody, total extractable nuclear antigen, antineutrophil cytoplasmic antibody, antimyeloperoxidase and antiproteinase 3 antibody. Vasculitis screen and serum protein electrophoresis were also negative. Testing for autoimmune encephalitis, including antivoltage-gated potassium channel antibodies, AMPAR (anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) antibody and anti-N-methyl-D-aspartate receptor antibodies (NMDA), was negative. Serum C3 was normal and C4 was slightly raised at 404 mg/L. Serum IgM was slightly raised at 2.78 g/L, with normal IgG, IgA and flow cytometry. Borrelia IgM was found to be positive, but western blot was negative. ACE and onconeural antibodies (anti-Hu, anti-Ri and anti-Yo) were negative. Testing for BK virus and JC virus was negative.

Differential diagnosis

On admission, this man was treated with a possible CNS infection in view of the new onset of symptoms of confusion and fever. He was therefore pre-emptively treated with ceftriaxone and dexamethasone (to cover for possible bacterial infection) and acyclovir (to cover for possible viral encephalitis). A lumbar puncture did not show any abnormality however, and the possibility of CNS infection was deemed to be less likely. CSF virology PCR was also negative.

The MRI showed bilateral periventricular hyperintensities which enhanced with contrast administration.

Our differential diagnosis at this stage included possible PML, and JCV testing was performed on CSF which returned as negative. In the context of his cocaine abuse, the possibility of cocaine vasculitis or cocaine leucoencephalopathy was considered.

Intravenous steroids were administered and plasma exchange was performed to treat these possibilities, and improvement was in fact noted after the third cycle of plasma exchange. The MRI findings are less consistent with cocaine-related vasculitis and more in keeping with previous MRI findings reported in toxic leucoencephalopathy. However, a brain biopsy was not performed in this case. Another possible differential considered, in view of his MRI findings (namely, symmetrical white matter hyperintensities), was an inherited leucodystrophy. This was however not considered to be very likely in view of his acute deterioration, cocaine use and rapidly deteriorating MRI changes.

Treatment

• Intravenous ceftriaxone, aciclovir and co-amoxiclav.

• Intravenous methylprednisolone.

• Intravenous immunoglobulins.

• Plasmapheresis.

Outcome and follow-up

After transfer to the rehabilitation hospital, the patient continued to improve. Within 4 months from presentation, he was walking independently and coping with most activities of daily living. He was being followed up by psychiatry and psychology to help with anxiety and abstinence from drugs of abuse. After a month the patient was discharged home.

He was reviewed at the neurology outpatient clinic 1 year from first presentation. An MMSE performed at this time showed a score of 30 out of 30. Neurological examination was normal. Repeat MRI of the head showed some improvement but with persistent white matter changes, especially in the basal ganglia (figure 1F). He had not used drugs for 1 year. Apart from some complaints of low mood, he was fully independent and had returned to his previous functional status.

Discussion

Toxic leucoencephalopathy secondary to cocaine use has been documented in previous case reports. Cocaine-related brain damage can be classified into primary neurotoxic effects of cocaine on the brain, resulting in toxic leucoencephalopathy; the secondary effects caused by compromised cerebral blood flow, leading to ischaemic or haemorrhagic stroke, vasospasm, or cerebral vasculitis; and the tertiary effects of cocaine related to hypoxia caused by cardiopulmonary collapse.^{1 2}

Cocaine-induced leucoencephalopathy may present in several different ways. These include an altered level of consciousness, confusion, impaired language, altered vision, fever or spasticity. Prognosis is poor—the condition progresses rapidly and often leads to death. Rarely it has been reported to result in complete recovery, as in our case.^2–4 In the reported case, the history, clinical and imaging findings led to the diagnosis of cocaine-induced leucoencephalopathy.

Various investigations are necessary to rule out other possible causes of similar presentations. The typical imaging in toxic leucoencephalopathy shows diffuse bilateral symmetrical cerebral white matter involvement with sparing of the subcortical U fibres. These findings are best appreciated on FLAIR MRI with no contrast enhancement after administering a paramagnetic agent. Unlike what is typically found in heroin vapour inhalation, in cocaine-induced leucoencephalopathy the brainstem and cerebellar white matter are not involved.^{2 5 6}

The typical histological findings of cocaine-induced leucoencephalopathy include a widespread profound vacuolar degeneration of the white matter in both hemispheres, with sparing of the subcortical U fibres.² Axonal injury is another characteristic finding with accumulation of amyloid precursor protein. Electron microscopy may show splitting and unravelling of myelin sheaths, axonal swelling and severe axonal loss.⁵ A brain biopsy was not performed on our patient.

The aetiology of this condition is not fully understood. It has been previously suggested that it could be due to a defect in mitochondrial function similar to the leucoencephalopathy related to heroin vapour inhalation, resulting in high levels of lactate in white matter and a good response to antioxidants.^{1 5 7} Besides the direct toxic effect on mitochondrial function and myelin, hypoxic injury may also play a part in axonal damage and the formation of spongiform white matter.² An important contributor in cocaine-induced leucoencephalopathy seems to be levamisole, an adulterant found in up to 69% of cocaine samples, which has been clearly linked to cutaneous vasculitis and agranulocytosis.^{3 8 9} The pathology behind this has been postulated to be similar to other spongiform encephalopathies, where fluid becomes entrapped in small vacuoles inside the myelin lamellae. Expansion of these vacuoles may explain the apparent progression of the MRIs despite clinical improvement, as in our case.^{2 3}

There is no official consensus on the ideal treatment of toxic leucoencephalopathy. It was suggested that supplements containing vitamins E and C and coenzyme Q10 may be beneficial in heroin vapour inhalation leucoencephalopathy.^{6 7} The primary treatment of cocaine-induced leucoencephalopathy seems to be supportive.² Other modalities of treatment have targeted suppression of immune-mediated demyelination within the CNS, such as steroid pulse therapy, which was shown to be an effective treatment; however, the response is inconsistent.^{3 10 11}

Intravenous immunoglobulins and plasma exchange were shown to result in good outcomes in some patients. The hypothesis behind the use of plasma exchange is that of removing the antibodies and cytokines involved in the inflammatory process of levamisole-induced leucoencephalopathy.^{11 12} It has been shown that the most important step in management is discontinuing exposure to levamisole, thus reducing the risk of levamisole-induced complications, such as cutaneous vasculopathy, unexplained neutropaenia and leucoencephalopathy, as was seen in our case.⁸

There are no international consensus guidelines as to the recommended mode of treatment in cases of toxic leucoencephalopathy. Our patient seems to have improved following the use of plasma exchange, showing continued improvement following the completion of three plasmapheresis sessions. This is in contrast to many reported cases where progression to death was rapid.^{1 5} In spite of this, we cannot advocate the use of immunosuppression as opposed to supportive treatment alone, and further studies in this area would be useful.

Such cases with non-specific presentation require an extensive work-up to exclude other possible disorders that may mimic cocaine-induced leucoencephalopathy. These include ischaemia, multiple sclerosis, adrenoleucodystrophy and PML.² Our patient was also treated empirically with acyclovir and ceftriaxone to cover for possible CNS infections until CSF results excluded an infectious cause.

Diagnosing cocaine-induced leucoencephalopathy entails a high level of suspicion. Since the rate of recurrence is significant, making the right diagnosis helps in providing appropriate counselling to the patient about the risk of potentially life-threatening complications and also discuss professional help to stop cocaine use. So far, except for the human leukocyte antigen (HLA) B27 status, the frequency of recurrence suggests that susceptibility to the effects of levamisole occurs on an individual basis.¹¹ Neurological toxicity is dose-independent and can occur in an idiosyncratic manner, even being triggered with a low dose of levamisole for a short duration.¹¹

Learning points.

• Cocaine leucoencephalopathy is an uncommon condition that can present with altered mental function in drug users.

• MRI shows diffuse bilateral symmetrical cerebral white matter involvement with sparing of the subcortical U fibres, brainstem and cerebellar white matter.

• Treatments attempted include pulsed steroid therapy, intravenous immunoglobulins and plasma exchange.

• The prognosis is generally poor and the condition can be rapidly fatal, although some cases may rarely recover fully.