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November 9, 2011

Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS

J. Kuhle, MD, R. Gosert, PhD, R. Bühler, MD, T. Derfuss, MD, R. Sutter, MD, Ö. Yaldizli, MD, E.-W. Radue, MD, C. Ryschkewitsch, MT, E.O. Major, PhD, L. Kappos, MD, S. Frank, MD, and H.H. Hirsch, MD, MSAuthors Info & Affiliations
December 6, 2011 issue
77 (23) 2010-2016
https://doi.org/10.1212/WNL.0b013e31823b9b27
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Abstract

Objective:

To describe the diagnosis and management of a 49-year-old woman with multiple sclerosis (MS) developing a progressive hemiparesis and expanding MRI lesion suspicious of progressive multifocal leukoencephalopathy (PML) 19 months after starting natalizumab.

Results:

Polyomavirus JC (JCV)–specific qPCR in CSF was repeatedly negative, but JCV-specific antibodies indicated intrathecal production. Brain biopsy tissue taken 17 weeks after natalizumab discontinuation and plasmapheresis was positive for JCV DNA with characteristic rearrangements of the noncoding control region, but histology and immunohistochemistry were not informative except for pathologic features compatible with immune reconstitution inflammatory syndrome. A total of 22 months later, the clinical status had returned close to baseline level paralleled by marked improvement of neuroradiologic abnormalities.

Conclusions:

This case illustrates diagnostic challenges in the context of incomplete suppression of immune surveillance and the potential of recovery of PML associated with efficient immune function restitution.

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Supplementary Material

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Information & Authors

Information

Published In

Neurology®
Volume 77 • Number 23 • December 6, 2011
Pages: 2010-2016
PubMed: 22076540

Copyright

Copyright © 2011 by AAN Enterprises, Inc.

Publication History

Received: March 31, 2011
Accepted: June 7, 2011
Published online: November 9, 2011
Published in print: December 6, 2011

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Disclosure

Dr. Kuhle receives research support from the Swiss Multiple Sclerosis Society. Dr. Gosert reports no disclosures. Dr. Bühler has served on a scientific advisory board for Biogen-Dompé AG and has received funding for travel from Merck Serono, sanofi-aventis, UCB, Biogen-Dompé AG, and Janssen. Dr. Derfuss serves on scientific advisory boards for and has received funding for travel and speaker honoraria from Merck Serono, Bayer Schering Pharma, Novartis, and Biogen Idec; his spouse is an employee of Novartis; and he receives research support from Merck Serono, Novartis, Biogen Idec, the German Research Foundation, and the Swiss MS Society. Dr. Sutter has received research support from the Swiss Scientific Society and the Gottfried and Julia Bangerter-Rhyner Foundation and holds stock options from Novartis and Roche. Dr. Yaldizli serves on a scientific advisory board for Merck Serono and has received funding for travel or speaker honoraria from Bayer Schering Pharma and Teva Pharmaceutical Industries Ltd. Dr. Radue has served as a consultant for and received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Novartis, and Merck Serono; and receives research support from Novartis, Biogen Idec, Merck Serono, Actelion Pharmaceuticals Ltd, and Basilea Pharmaceutica Ltd. C. Ryschkewitsch reports no disclosures. Dr. Major receives research support from the NIH/NINDS, Division of Intramural Research. Dr. Kappos has received research support through the University Hospital Basel from Acorda Therapeutics Inc., Actelion Pharmaceuticals Ltd, Advancell, Allozyne, Barofold, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera Pharmaceuticals, Shire Plc, Roche, Teva, UCB, and Wyeth, and also from the Swiss MS Society, the Swiss National Research Foundation, European Union, Gianni Rubato, and Roche and Novartis Foundations; and serves on the editorial board of Multiple Sclerosis Journal, International Journal of Multiple Sclerosis, and Swiss Archives of Neurology and Psychiatry. Dr. Frank and Dr. Hirsch report no disclosures.

Authors

Affiliations & Disclosures

J. Kuhle, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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R. Gosert, PhD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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R. Bühler, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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T. Derfuss, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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R. Sutter, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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Ö. Yaldizli, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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E.-W. Radue, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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C. Ryschkewitsch, MT
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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E.O. Major, PhD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
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L. Kappos, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
View all articles by this author
S. Frank, MD
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
View all articles by this author
H.H. Hirsch, MD, MS
From the Department of Neurology (J.K., T.D., R.S., Ö.Y., L.K.), Clinical Neuroimmunology, Department of Biomedicine (J.K., T.D., L.K.), Intensive Care Unit (R.S.), Medical Image Analysis Center (E.-W.R.), Division of Neuropathology, Institute of Pathology (S.F.), and Division of Infectious Diseases & Hospital Epidemiology (H.H.H.), University Hospital Basel, Basel; Clinical & Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine (R.G., H.H.H,), University of Basel, Basel, Switzerland; Department of Neurology (R.B.), Bürgerspital, Solothurn, Switzerland; and Laboratory of Molecular Medicine and Neuroscience (C.R., E.O.M.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
View all articles by this author

Notes

Address correspondence and reprint requests to Dr. Ludwig Kappos, Clinical Neuroimmunology, Departments of Biomedicine and Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland [email protected]
Study funding: Assays performed at the NINDS/NIH are funded through the Division of Intramural Research to the Laboratory of Molecular Medicine and Neuroscience.

Author Contributions

Dr. Kuhle, Dr. Bühler, Dr. Sutter, Dr. Yaldizli, Dr. Kappos: patient counseling. Dr. Kuhle, Dr. Gosert, C. Ryschkewitsch, Dr. Major, Dr. Kappos, Dr. Frank, Dr. Hirsch: analysis of patient samples, interpretation of results and writing of the manuscript. Dr. Bühler, Dr. Derfuss, Dr. Sutter, Dr. Yaldizli, Dr. Radue: interpretation of results and revising the manuscript.

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