Mefloquine, an antimalarial medication with efficacy against JC virus, was used to treat progressive multifocal leukoencephalopathy. A 54-year-old woman with sarcoidosis presented with a progressive cerebellar syndrome. MRI showed lesions affecting the right cerebellum that progressed over time to the brainstem. JC virus was found in the cerebrospinal fluid (CSF), and brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy. Mefloquine 1000 mg/week was initiated 6 months after symptom onset. Clinical progression stopped immediately, and JC virus became undetectable in the CSF. No clinical or imaging evidence of disease progression has occurred over 20 months of follow-up. This is the first report of successful treatment of progressive multifocal leukoencephalopathy with mefloquine.
- Progressive multifocal leukoencephalopathy
- JC virus
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Progressive multifocal leukoencephalopathy (PML) is an incurable white matter disease associated with JC virus. We describe a case of PML in a woman with pulmonary sarcoidosis and demonstrate disease stabilisation using mefloquine, an antimalarial medication.
A 54-year-old woman with a 6-year history of pulmonary sarcoidosis was given 50 mg prednisone once daily for progressive pulmonary symptoms. Over the following month, a planned taper in steroid dose was under way when the patient developed dysarthria, dysmetria and ataxia. The patient was not taking other medications and had no significant medical history before the diagnosis of pulmonary sarcoidosis. Mental status and systemic examination were normal with no evidence of fever or lymphadenopathy. Neurological examination confirmed scanning dysarthria, right-sided dysmetria on finger–nose and heel–shin testing and wide-based ataxic gait with falls to the right.
Investigations showed a normal complete blood count, electrolytes, liver and renal function tests. Magnetic resonance imaging (MRI) of the brain with gadolinium demonstrated an area of T2 hyperintensity within the white matter of the right cerebellum without gadolinium enhancement (figure 1A, post gadolinium images not shown). There were 15 white cells in the cerebrospinal fluid (95% lymphocytes), normal glucose and 469 mg/l of protein. Hepatitis C viral PCR was negative. The working diagnosis was neurosarcoidosis, and the patient was treated with a 3-day pulse of intravenous methylprednisolone; 50 mg of oral prednisone daily was restarted, and a brain biopsy was arranged. A CT of the chest, abdomen and pelvis was normal.
Within 2 weeks, the patient returned with worsening gait imbalance, right-sided facial numbness and significant nausea and vomiting. Physical examination showed sharp-touch sensory impairment of the right side of the face. There was worsening of the dysmetria and gait ataxia. Repeat MRI demonstrated progression of the T2 signal abnormality with extension into the right brachium pontis and left cerebral peduncle (figure 1B). Lumbar puncture demonstrated positive JC viral PCR with 33 700 copies/ml of cerebrospinal fluid (CSF).1 A subsequent biopsy of the cerebellar lesion was consistent with PML without evidence of sarcoidosis (figure 2). In light of a diagnosis of PML, additional predisposing conditions were investigated. Testing for HIV-1 and HIV-2 was negative. The patient had a decrease in absolute CD4 count (0.42×109/l) with a normal CD8 count (0.667×109/l) and, therefore, an inverted CD4/CD8 ratio (0.6) and a decrease in the natural killer cell count (0.06×109/l). No additional abnormalities were found.
Prednisone was stopped. Risperidone, a 5-HT2A receptor antagonist thought to competitively inhibit viral binding to susceptible cells in the central nervous system,2 was started. This was discontinued when liver enzyme elevation occurred. In a similar manner to risperidone, mirtazapine may also inhibit JC viral interaction with cells,3 and thus a trial of therapy was started. Ondansetron and pantoprazole were used for intractable nausea and vomiting.
The disease continued to progress over 4 months with worsening dysarthria, dysphagia, gait ataxia, immobility and emotional lability. There was bilateral horizontal nystagmus, right sided pyramidal weakness and bilateral dysmetria. Repeat MRI showed extensive white matter T2 hyperintensities extending into the right cerebral peduncle, further into the right cerebellar white matter and into the left cerebellar peduncle. Intravenous cidofovir was started at a dose of 5 mg/kg once every 2 weeks for six cycles,4 but her condition continued to worsen (figure 1C). Six months after disease onset, mefloquine, an antimalarial agent, was started at 500 mg twice weekly. A high dose of mefloquine was prescribed based on the dosing for active therapy in drug-resistant malaria (25 mg/kg/week).
No further progression occurred, and within 4 weeks, there were signs of clinical improvement with stabilisation of nausea and vomiting and improvements in speech and right-sided dysmetria. An elevation in liver enzymes occurred, requiring a reduction in the dose of mefloquine to 250 mg once weekly. Serial CSF viral titres while taking mefloquine were 429 copies/ml after 1 month treatment and undetectable after 5 months. Mefloquine was discontinued after the JC viral DNA was no longer detectable in the CSF. There was no evidence base in the literature to guide this decision. However, since the medication had caused some hepatic enzyme elevation during its use, the systemic effects of mefloquine were considered when making the decision to discontinue mefloquine. Repeat MRIs showed continued stabilisation of the white matter lesions without further progression 16 months after disease onset. At 20 months, the patient's condition is stable with normal cognition but residual ataxia (requires assistance for ambulation) and pseudobulbar palsy requiring ongoing rehabilitation therapy. The nausea has improved, and the patient is able to eat and drink with feeding assistance and to move her hands. There has been no recurrence of sarcoidosis and no progression of neurological symptoms.
This case illustrates the difficulty encountered in managing patients with PML. In the face of ongoing disease progression and failed therapeutic trials, there is scant literature to support decision making. PML is currently not curable. Many case reports exist describing potential therapies including cytosine arabinoside,5 interferon,6 cyclosporin A,7 cidifovir,4 mirtazapine4 8 alone or in various combinations. Few case series or well-controlled clinical trials exist, and therefore, it is difficult to assess the safety and efficacy of each agent.
Recent research has suggested that mefloquine is effective against JC virus, the causative agent in PML. Brickelmaier et al reported that, in vitro, mefloquine can inhibit the viral infection rate in cultured human glial cells and astrocytes at micromolar concentrations.9 In addition, mefloquine is known to penetrate the blood–brain barrier.9 A second set of experiments by the same group suggested that mefloquine is effective against two different JC virus strains in cell culture even after the onset of infection. JC viral DNA replication also appears to be inhibited by mefloquine.9 Furthermore, mefloquine is known to accumulate in brain tissue at levels much higher than its effective concentration.10 The main mechanism thought to be responsible for the reported anti-JC viral activity is inhibition of viral replication rather than inhibition of virus entry into the cell. A randomised, rater-blinded study designed to assess the effectiveness of mefloquine in patients with PML is currently under way (sponsored by Biogen Idec, NCT00746941). The primary end point for this study is JC viral DNA quantitation in the CSF, and the secondary end point is neurological status and brain MRI.
Few data exist regarding recovery in non-AIDS-associated PML. Cessation of immune suppression or immune reconstitution, as seen with initiation of highly active antiretroviral therapy in AIDS patients, may improve survival in patients already manifesting symptoms of PML. In patients having PML as an AIDS-defining illness, the mean survival time after diagnosis was 7.5 months.11 In patients with a known diagnosis of AIDS, the mean survival time was only 3.2 months.11 Longer survival time was associated with increased CD4 cell counts.11 Whether there is spontaneous recovery of biopsy-proven PML within the non-AIDS population is not well reported in the literature.
In non-AIDS patients, PML is seen in the context of systemic sarcoidosis treated with steroids. More rarely, sarcoidosis has been associated with PML before the onset of steroid therapy. A recent case report and review of the literature presents only three cases in which PML developed in patients with symptoms of sarcoidosis in the absence of immune modulation with steroids or other agents.12 It may be that characteristics of the sarcoid itself predispose patients with systemic sarcoidosis to the development of PML. In this case, the short course of steroids is unlikely to have triggered the onset of infection by JC virus, especially since disease progression continued long after the discontinuation of prednisone. The ongoing neurological deterioration until the introduction of mefloquine could suggest either coincidental recovery or a role for mefloquine in the recovery.
The dosing and efficacy of mefloquine in the setting of PML remains to be determined. The patient reported had an increase in liver enzymes (aspartate transaminase and alanine transaminase) while on 500 mg mefloquine twice weekly. A reduction in the dose to 250 mg once weekly resulted in a decrease in liver enzymes and continued disease stabilisation. No other side effects were noted while taking mefloquine. Twenty months after the onset of symptoms, the patient remains clinically stable without further neurological decline. Improvements have been made in voice projection, nausea and vomiting. No JC viral DNA is detectable in the CSF, and mefloquine has been discontinued. Although the clinical response of our patient clearly followed the initiation of mefloquine, the efficacy and safety of this drug in the treatment of PML can only be determined by additional studies preferably in the form of randomised and controlled trials.
The authors would like to thank Dr J. Berger and Dr C. Power for their advice and expertise regarding progressive multifocal leukoencephalopathy and the administration of mefloquine in this setting.
Study Sponsorship No external funding was provided for this project.
Disclosures The authors have no financial interest in the products discussed within this case report.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of The University of Western Ontario Research Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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