Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS
Abstract
Objective:
Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons.
Case Report and Results:
The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus–specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy (1H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures.
Conclusions:
New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. 1H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.
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Copyright © 2012 by AAN Enterprises, Inc.
Publication History
Received: September 9, 2011
Accepted: November 28, 2011
Published online: April 18, 2012
Published in print: May 1, 2012
Disclosure
Dr. Gheuens is funded by NIH grant T32 AI07387-21 and is a fellow of the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center–Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer Inc. and Merck & Co. Dr. Smith has received consulting/advisory fees and speaking honoraria but not grant support or standing committee income from all of the manufacturers of FDA-approved products for multiple sclerosis treatment. Dr. Wang is supported in part by NIH grant R01 NS047029. Dr. Alsop is an inventor on several patents related to perfusion MRI (US Patent Nos. 7,545,142, 7,369,888, 6,980,845, 6,717,405), for which he has received royalties from GE Healthcare and Siemens Medical; receives research support from GE Healthcare and is also supported by grants from the NIH, CA115745, EB004582, MH80729, MH077073, DC008796, NS047029, CA101942, AG031720, AG028076, DK084463, and the Congressionally Directed Military Research Program of the Department of Defense, SC090251; and serves as Associate Editor of Magnetic Resonance in Medicine. Dr. Lenkinski is supported in part by NIH grant R01 NS047029 and receives research support from GE Healthcare. Dr. Koralnik is funded by NIH grants R56 NS 041198, R01 NS 047029 and K24 NS 060950; has received a research grant from Biogen Idec and the National Multiple Sclerosis Society; served on scientific advisory boards for Hoffmann La Roche, GlaxoSmithKline and Merck Serono; received consulting fees from Bristol Myers Squibb, Ono Pharmaceuticals, Merck Serono, Hoffmann La Roche, GlaxoSmithKline, Perseid Therapeutics, Vertex Pharmaceutical, Johnson & Johnson; and is an editorial board member for the Journal of NeuroVirology and receives royalties from UpToDate for topics on the management of HIV and CNS mass lesions and on PML. Go to Neurology.org for full disclosures.
Authors
Author Contributions
Dr. Gheuens was involved in patient care, imaging and immunologic studies, writing the first draft of the manuscript, and preparing the figures. Dr. Smith was involved in patient care and revising the manuscript. Dr. Wang was involved in performing the imaging and collecting the MRS data and revising the manuscript. Dr. Alsop was involved in performing the imaging and collecting the MRS data and revising the manuscript. Dr. Lenkinski was involved in performing the imaging and collecting the MRS data and revising the manuscript. Dr. Koralnik was involved in patient care, imaging and immunologic studies, and supervising, editing and revising the manuscript, and preparing the figures.
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- Epilepsia partialis continua revealing idelalisib-associated PML-IRIS: clinical and pathological features, Journal of NeuroVirology, 26, 3, (437-441), (2019).https://doi.org/10.1007/s13365-019-00821-3
- Host-Immune Interactions in JC Virus Reactivation and Development of Progressive Multifocal Leukoencephalopathy (PML), Journal of Neuroimmune Pharmacology, 14, 4, (649-660), (2019).https://doi.org/10.1007/s11481-019-09877-8
- Treatment of natalizumab‐associated PML with filgrastim , Annals of Clinical and Translational Neurology, 6, 5, (923-931), (2019).https://doi.org/10.1002/acn3.776
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- Metabolic profiles by 1H-magnetic resonance spectroscopy in natalizumab-associated post-PML lesions of multiple sclerosis patients who survived progressive multifocal leukoencephalopathy (PML), PLOS ONE, 12, 4, (e0176415), (2017).https://doi.org/10.1371/journal.pone.0176415
- Multiple sclerosis update: use of MRI for early diagnosis, disease monitoring and assessment of treatment related complications, The British Journal of Radiology, 90, 1074, (20160721), (2017).https://doi.org/10.1259/bjr.20160721
- Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS, Journal of Neurology, Neurosurgery & Psychiatry, 89, 5, (535-541), (2017).https://doi.org/10.1136/jnnp-2017-316886
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We thank Marousi et al. for their comments on our paper. We agree that PML may also occur in the setting of occult of minimal immunosuppression, as seen in 5 cases at our center and in 33 previously reported patients. [1] As they mention, clinicians should be aware that either PML-IRIS or a relapse of MS may occur after discontinuation of natalizumab.
1. Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 2010;81:247-254.
For disclosures, contact the editorial office at [email protected].
Gheuens et al. presented a case of PML-IRIS 2 months after natalizumab discontinuation. [1] Their patient had an active history of ethanol abuse, which can be considered a 'functional' equivalent to immunosuppression. Interestingly, prior use of immunosuppressants has been included to the recently developed risk-stratification algorithm for PML. [2] This case underscores the need for clinicians to adopt a wider concept of immunosuppression, rather than restricting it solely to the use of pharmacologic agents. We and others published 3 cases of definitive severe MS rebound about 2 months following natalizumab discontinuation [3-5], and further implied that younger patients are more prone to such relapses. [5] However, Gheuens et al. concluded that new enhancing MRI lesions after natalizumab withdrawal may also be the manifestation of PML-IRIS. [1]. As experience from patients discontinuing natalizumab and switching to other therapies mounts, a high degree of clinical vigilance for both incidences (i.e. MS rebound and PML) should follow the immediate post- natalizumab period. However, until official guidelines are issued, it is unclear exactly how patients should be treated in the interval between natalizumab and the next therapeutic choice.
1. Gheuens S, Smith DR, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ. Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. Neurology;78:1390-1393.
2. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab- associated progressive multifocal leukoencephalopathy. N Engl J Med;366:1870-1880.
3. Lenhard T, Biller A, Mueller W, Metz I, Schonberger J, Wildemann B. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology;75:831-833.
4. Hellwig K, Gold R. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology;76:1362-1363; author reply 1363.
5. Marousi S, Giannouli E, Karkanis I, Tagaris GA, Karageorgiou CE. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology;76:1362-1363; author reply 1363. For disclosures, contact the editorial office at [email protected].