Dr Mills is is a Postdoctoral Fellow, Department of Neurology, Dr Mao-Draayer is Associate Professor and Duirector, Neuroscience Research Autoimmunity Center of Excellence, Multiple Sclerosis Center, Department of Neurology, Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI.
relapsing-remitting multiple sclerosis (RRMS)
cerebrospinal fluid (CSF)
immune reconstitution inflammatory syndrome (IRIS)
progressive multifocal leukoencephalopathy (PML)
A 45-year-old man with a 12-year history of relapsing-remitting multiple sclerosis (RRMS) presented with a loss of balance and weakness on the left side of his body. His symptoms had worsened over the past 2 weeks. He had been stably treated with natalizumab for the past 4 years with no relapses during this period. MRI using the T2 FLAIR sequence was performed to look for white matter hyperintensities associated with demyelinating lesions. The MRI showed evidence of a large area of hyperintense signal within the right superior frontal cortical and subcortical white matter regions, with no enhancement (Figure 1A).
The subcortical localization of the large confluent signal and lack of enhancement was more consistent with lesions associated with progressive multifocal leukoencephalopathy (PML) than with RRMS. Natalizumab treatment was suspended and a cerebrospinal fluid (CSF) sample was taken to test for the JC virus via polymerase chain reaction. JC virus was detected in the CSF sample, with a viral copy number > 500. To completely clear natalizumab from his system, in an effort try to restore immunocompetence into the CNS, the patient received plasmapheresis and intravenous immunoglobulin therapy, followed by 2 weeks of corticosteroid treatment.
The patient was readmitted 1 month later, once again with worsening weakness on the left side of his body. This worsening of clinical condition is consistent with the development of immune reconstitution inflammatory syndrome (IRIS). MRI revealed worsening of the T2 hyperintensity in the right frontal cortical region as well as patchy enhancement in the left hemisphere, indicative of PML-IRIS (Figure 1B). He received another round of plasmapheresis, intravenous immunoglobulin, and corticosteroid treatment. He also began treatment with the CCR5 inhibitor maraviroc, and continued outpatient treatment with maraviroc. Within 6 months his clinical symptoms had stabilized coupled with resolution of the T2 right frontal cortical hyperintensity signal (Figure 1C).
The diagnosis of PML in MS patients is particularly challenging, since they are both demyelinating diseases. Consequently, the presentation of PML can overlap with RRMS, and symptoms can be mistaken for flares of MS disease activity, which makes patient history is an important aspect of the diagnosis. Natalizumab is typically very effective in reducing relapses in RRMS patients, but has the highest incidence of PML of currently available MS therapies, with an incidence of 4.2 per 1000 patients.1 Therefore, the sudden onset of new relapse-like symptoms in a patient stably treated with natalizumab for an extended period should be treated as a possible case of PML. Assays used to determine JC virus sero-status have had a high false-negative rate, and natalizumab treatment has been shown to increase the rate of JCV seroconversion.2,3 Thus, PML remains a possibility even in patients that have previously tested negative for JC virus.
MRI should be performed to examine new lesions; however, it can be difficult to distinguish MRI activity related to MS or PML. Recent advances have been made in the effort to create more conclusive MRI based diagnostic criteria that distinguish MS and PML. The presence of punctate T2/FLAIR hyperintense lesions with a “milky way appearance” near the primary PML lesion has been strongly associated with natalizumab-associated PML, and generally absent in MS patients without PML.4,5
In addition to the appearance of T2 hyperintensities, the location of the lesions can also be used to guide the diagnosis. Large lesions in the cortical grey matter, juxtacortical white matter, and subcortical regions that involve U fibers are more often associated with PML, whereas focal lesions in the periventricular white matter are more consistent with MS.5,6 However, despite these advances, because of the significant overlap on clinical measures between RRMS and PML the only currently available method to confirm the diagnosis of PML is to perform a spinal tap to have CSF tested for JC virus via polymerase chain reaction and/or brain biopsy, but the latter is more invasive and thus less commonly done.
Once the diagnosis of PML has been confirmed, it is necessary to restore immunocompetence to the CNS as soon as possible, which in the case of natalizumab-associated PML involves clearance of the drug, typically through plasmapheresis. However, natalizumab cessation often leads to the development of IRIS, which can exacerbate neurological damage. Findings suggest that when detected early, it may be possible to manage PML without plasmapheresis, which allows for a slower rate of CNS immune reconstitution and thus lowers the risk of IRIS.7 Ideally, treatment would restore the CNS immune system without leading to systemic overreaction. Unfortunately, aside from plasmapheresis, treatment options for aggressive PML are limited. While IRIS can lead to worsening disability, the rapid and effective reconstitution of CNS immunocompetence likely underlies the increased rates of survival for patients with natalizumab-associated PML, relative to other cohorts of PML patients.8
Until better treatment options are available, the focus should remain on efforts to minimize and manage IRIS. Corticosteroids have most commonly been used to manage IRIS, with variable success.9 The CCR5 inhibitor maraviroc has been used successfully without plasma exchange in some natalizumab-associated PML patients to avoid IRIS.10,11 However, not all patients respond to maraviroc, and it is still unclear what patient or treatment regimen characteristics are most relevant for a positive response. Going forward, testing of peripheral immune response to JC virus could be useful in identifying patients likely to have an IRIS response and tailoring treatments accordingly.
• PML can present with similar clinical symptoms as relapse in RRMS patients
• MRI features are similar for MS and PML demyelinating lesions, but can often be distinguished by lesion location, particularly when present in cortical and subcortical regions
• CSF JC virus polymerase chain reaction and/or brain biopsy are necessary to confirm diagnosis of PML
• Patients with natalizumab-associated PML are prone to developing IRIS following plasma exchange
• New diagnostic tests and treatments are needed to better manage PML and PML-IRIS
Dr Mills is currently supported by a grant from Kirschstein-NRSA 4T32HD007505-20. Dr Mao-Draayer has served as a consultant and/or had received grant support from Acorda, Bayer Pharmaceutical, Biogen, Chugai Pharma EMD Serono, Novartis, Questor, Teva Neuroscience, Genentech, and Sanofi-Genzyme. She is also currently supported by grants from NIH NIAID Autoimmune Center of Excellence: UM1-AI110557; NIH NINDS R01-NS080821, Novartis, and Chugai.
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1. Steiner I, Benninger F. Maraviroc in PML-IRIS: a separate ball game under HIV infection and natalizumab? Neurol Neuroimm Neuroinflam. 2017;4:e331.
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