- Case report
- Open Access
- Open Peer Review
Asymptomatic progressive multifocal leukoencephalopathy: a case report and review of the literature
© The Author(s). 2018
- Received: 17 January 2018
- Accepted: 28 May 2018
- Published: 1 July 2018
We report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with debilitating neurologic symptoms. Very few cases have documented a completely asymptomatic course of the disease.
A 26-year-old white woman with multiple sclerosis was treated with natalizumab. She was diagnosed as having progressive multifocal leukoencephalopathy based on characteristic magnetic resonance imaging lesions after 27 infusions of natalizumab. She had no neurologic deficits at the time of diagnosis and John Cunningham virus in cerebrospinal fluid was detected at 15 copies/ml. She was initially treated with mefloquine and mirtazapine and remained asymptomatic for 3 months. She later developed worsening magnetic resonance imaging lesions related to immune reconstitution inflammatory syndrome. At that time, she received intravenously administered immunoglobulin and high-dose intravenously administered methylprednisolone with radiologic improvement of the lesions.
Our case report illustrates that early detection of asymptomatic progressive multifocal leukoencephalopathy and its subsequent treatment resulted in a benign clinical course. In consideration of the additional small number of cases of asymptomatic progressive multifocal leukoencephalopathy that have been reported, we conclude that routine magnetic resonance imaging surveillance is important for patients with multiple sclerosis who are at high risk for developing natalizumab-associated progressive multifocal leukoencephalopathy.
- Multiple sclerosis
- Progressive multifocal leukoencephalopathy
- Magnetic resonance imaging
Progressive multifocal leukoencephalopathy (PML) is the leading adverse effect from using natalizumab in the treatment of multiple sclerosis (MS). PML is a progressive multifocal disease involving the white matter and typically presents with subacute onset of symptoms including altered mental status, visual and motor deficits, and ataxia . Natalizumab-associated PML carries an average mortality of 23% and survivors often develop debilitating neurologic deficits from the disease and its treatment sequelae, such as immune reconstitution inflammatory syndrome (IRIS), in which there is a paradoxical worsening of the infection due to overwhelming inflammatory reaction by the recovering immune system after discontinuing the immunosuppressing agent . PML is caused by John Cunningham virus (JCV), and patients on natalizumab therapy receive serum JCV antibody index testing and surveillance with interval magnetic resonance imagings (MRIs) to assess PML risk and detect early stages of the disease. PML is seen on MRI as multifocal, asymmetric periventricular and subcortical lesions with minimal mass effect or enhancement . Despite measures of clinical vigilance, PML often presents with new neurologic deficits prior to its diagnosis.
We report the case of a patient diagnosed as having PML based on characteristic MRI lesions from a routine surveillance scan who was clinically asymptomatic at the time of diagnosis and continued to have minimal disability throughout the course of the disease.
Repeat MRI at 2 months following diagnosis showed no changes in her brain lesions. She remained asymptomatic until 3 months after diagnosis when she noticed mild dysmetria of her left hand that progressed to a tremor. The following month a repeat brain MRI revealed a few small enhancing lesions in her left frontal lobe suggestive of IRIS (Fig. 1c, d). The hyperintensities in the bilateral precentral gyri remained stable. Imaging of her cervical spine revealed a new non-enhancing cord lesion. She was then treated for 5 days with intravenously administered immunoglobulin and restarted on glatiramer acetate for MS treatment. A repeat CSF examination in February 2017 showed JCV PCR of 31 copies/ml.
Five months following her diagnosis, a repeat brain MRI showed interval development of T2 signal abnormality with mild enhancement in multiple areas including the brainstem, cerebellum, and bilateral cerebral hemispheres (Fig. 1e, f). A repeat lumbar puncture was performed. JCV PCR in the CSF was undetectable. Mefloquine and mirtazapine were discontinued. Given the MRI findings, she was treated for ongoing inflammation associated with IRIS versus a possible exacerbation of her underlying MS with high-dose intravenously administered methylprednisolone (IVMP) 1500 mg daily for 3 days. She was then transitioned from glatiramer acetate to ocrelizumab for treatment of MS. Six months following her diagnosis she reported changes in left hand dexterity and right upper extremity phasic spasms. A repeat lumbar puncture was performed and JCV PCR remained undetectable. She continued MRI surveillance followed by treatment with high-dose IVMP for a total of six courses until there was significant resolution of enhancement on her brain MRI (Fig. 1g, h). Following treatment, she has residual left hand dysmetria and tremor as well as right upper extremity phasic spasms. At 1-year follow-up, her EDSS is 2.0.
The patient described in this case report underwent an asymptomatic course of PML treated with mefloquine and mirtazapine. Due to the early discovery of PML in our patient and her intact neurologic examination at the time of diagnosis, we chose not to treat with plasma exchange (PLEX) in order to decrease the speed of immune reconstitution, which has been associated with stronger inflammation in patients with HIV-PML . Further studies showed PLEX conferred no additional benefit of reduced mortality or improved outcome in patients who received PLEX (n = 184) versus those who did not (n = 35) for treatment of natalizumab-associated PML . The neurologic deficits sustained toward the end of this patient’s treatment were thought to be from IRIS rather than the progression of PML lesions. While there is no definitive method of distinguishing PML lesions from those caused by IRIS , the presence of gadolinium enhancement on brain MRI along with undetectable JCV favored the diagnosis of IRIS rather than development of new PML lesions.
Case reports of natalizumab-associated progressive multifocal leukoencephalopathy with asymptomatic disease course
Authors and Reference number
EDSS at diagnosis
Development of IRIS
CSF JCV (copies/ml)
Risk factors 
This case report
Bilateral asymmetric confluent non-enhancing hyperintensities in the bilateral subcortical precentral gyri
Mefloquine and mirtazapine
27 natalizumab infusions, JCV-positive, JCV index 3.58
Blinkenberg et al. 
Right cerebellar peduncle hyperintense lesions
None, PML undiagnosed until presentation of PML-IRIS following natalizumab cessation
47 natalizumab infusions, JCV-positive
Fabis-Pedrini et al. 
Mildly enhancing small patchy lesions in left brainstem, cerebral peduncle, pontine tegmentum, and left brachium points
PLEX, mefloquine, mirtazapine, prednisone
Treatment with natalizumab for 54 months, JCV-positive
Mc Govern and Hennessay 
Left posterior parietal non-enhancing hyperintensity
Treatment with natalizumab for 3 years
When diagnosed early and treated, PML can present with a mild or even asymptomatic disease course. Clinical vigilance and routine MRI surveillance is important for patients with MS who are at high risk for developing natalizumab-associated PML.
We wish to thank the patient for consenting to the publication of this case report.
CW and YZ wrote the case presentation section of the manuscript. YZ also wrote all other sections of the manuscript. AF revised the first draft of the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This case report was approved by the internal research ethics committee of University of Texas Southwestern Medical Center in accordance with the code of ethics of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Yinan Zhang has no conflict of interests to declare. Crystal Wright is a speaker for Genzyme and Novartis and is involved in a clinical trial with MED Day. Angela Flores is a speaker and consultant for Biogen and Genentech. The authors declare that they have no competing interests.
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