Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

User menu

  • Subscribe
  • My Alerts
  • Log in
  • Log out

Search

  • Advanced search
Neurology
Home
The most widely read and highly cited peer-reviewed neurology journal
  • Subscribe
  • My Alerts
  • Log in
  • Log out
Site Logo
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

Share

February 08, 2011; 76 (6) Clinical/Scientific Notes

Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

A. Vennegoor, M.P. Wattjes, E.T.L. van Munster, R.L. Kriekaart, B.W. van Oosten, F. Barkhof, J. Killestein, C.H. Polman
First published February 7, 2011, DOI: https://doi.org/10.1212/WNL.0b013e31820b7644
A. Vennegoor
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M.P. Wattjes
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E.T.L. van Munster
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R.L. Kriekaart
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B.W. van Oosten
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Barkhof
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Killestein
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C.H. Polman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS
A. Vennegoor, M.P. Wattjes, E.T.L. van Munster, R.L. Kriekaart, B.W. van Oosten, F. Barkhof, J. Killestein, C.H. Polman
Neurology Feb 2011, 76 (6) 574-576; DOI: 10.1212/WNL.0b013e31820b7644

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
382

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Progressive multifocal leukoencephalopathy (PML) has developed in more than 40 patients with multiple sclerosis (MS) treated with natalizumab.1 Clifford et al.2 recently described the first 28 confirmed cases in which, in almost all, PML presented as an aggressive disease with a short interval between first symptoms and diagnosis.

Case report.

In September 2002, a 30-year-old previously healthy woman presented with walking difficulties. Neurologic examination showed a bi-pyramidal syndrome, ataxia, and sensory disturbance in all extremities. After MRI of the brain and cervical spinal cord, which showed multiple typical T2-weighted white matter lesions, diagnosis of a clinically isolated syndrome suggestive of a first episode of MS was established.

In January 2003, the patient started interferon-β-1a, which she discontinued in October 2003 because of depressive symptoms. From March 2004 until December 2006, she used glatiramer acetate. Still, several clinical relapses occurred.

In March 2007, the patient started natalizumab infusions. She had no clinical exacerbations since. Routine MRI of the brain 1 year later showed no active lesions.

A second MRI in February 2009 was initially interpreted as showing no new lesions. In retrospect, subtle and diffuse abnormalities were visible in cortical and subcortical areas (figure). Since June 2009, she had mild progressive cognitive problems. For example, she made repetitive phone calls up to 6 times a day and was forgetting appointments. For that reason, in October 2009, a new MRI was performed, showing a new pontine lesion and progression of the diffuse abnormalities in both hemispheres (figure).

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure MRI

(A) Evolution of MRI manifestations during treatment with natalizumab. Transverse T2-weighted MRI of the supratentorial and infratentorial brain. The MRI in January 2007 (A.a) was performed prior to the initiation of natalizumab therapy; it shows multiple focal demyelinating lesions. The MRI scan performed in February 2009 (A.b) shows subtle, rather diffuse gray and white matter changes in the cortex and the adjacent white matter of the left middle and inferior frontal gyrus. These changes were not interpreted as representing important pathology. The MRI scan performed in October 2009 (A.c) presents multifocal new and progressive areas of diffuse demyelination in the cortex and white matter of both hemispheres suggestive of progressive multifocal leukoencephalopathy (white arrows). Also note the rapid development of focal (left superior frontal gyrus) as well as diffuse cortical atrophy between February and October 2009. The MRI scan performed on January 18, 2010 (A.d), shows remarkable diffuse lesions. (B) Course of MRI manifestations after cessation of natalizumab treatment. Transverse gadolinium-enhanced T1-weighted MRI of the supratentorial brain. The MRI scan of January 18, 2010 (B.a), performed 2 months after cessation of natalizumab treatment, shows, next to the new lesion in the mesencephalon, diffuse enhancement, especially right temporal and frontal on both sides. This enhancement pattern was interpreted as consistent with immune inflammatory reconstitution syndrome. The MRI scan of January 25, 2010 (B.b), shows progression of the bilateral areas of pathologic enhancement in the white matter. About 10 days after completion of a course of IV immunoglobulins (scan date February 8, 2010; B.c), MRI changes in terms of pathologic enhancement were more pronounced. Immediately after the IV corticosteroid treatment (scan date February 12, 2010; B.d), the pathologic enhancement pattern had almost completely disappeared.

In November 2009, after 36 natalizumab infusions, the patient developed an acute delirium. Because of the suspicion of PML, natalizumab infusions were discontinued. CSF JC virus viral load was positive both in the Laboratory of the University Center of Utrecht (<250 copies/mL) and in the Laboratory of Molecule Medicine and Neuroscience (57 copies/mL), confirming the diagnosis of PML. At the time all CSF results became available, the patient's condition had spontaneously improved. Because of this and the last natalizumab infusion more than 2 months ago, it was decided not to treat the patient with plasma exchange (PLEX) or immunoabsorption.

MRI on January 18, 2010 (figure), showed remarkable diffuse lesions and new focal lesions bilateral in the mesencephalon. Some patchy gadolinium enhancement was seen in both hemispheres. These findings were suggestive of immune reconstitution inflammatory syndrome (IRIS).

As the patient was recovering clinically, 1 week of further observation was considered appropriate. Because the preplanned follow-up MRI of January 25 (figure) showed obvious progression of gadolinium enhancement, IV immunoglobulin (IVIg), 4 days, 0.5 mg/kg, was administered. Two weeks after IVIg, the patient's clinical condition worsened: mental slowness, disorientation, and headaches developed. MRI showed progression of gadolinium enhancement (figure). We decided to start IV methylprednisolone (5 days, 1,000 mg). Her clinical condition improved within days and the MRI performed after this treatment showed a remarkable decrease in gadolinium enhancement (figure). Final clinical assessment at our hospital was on July 15, 2010. At that point the patient was clinically stable.

Discussion.

This case of PML presents a number of uncommon features. Most remarkable is the extremely protracted and indolent course of PML. Whereas clinical symptoms existed at least 3 to 6 months before diagnosis, we could see subtle MRI abnormalities already 9 months before diagnosis. These early MRI abnormalities were very similar to those described in the case reports by Linda et al.3 and Langer-Gould et al.4 Lesions in frontal regions might contribute to an even longer delay.

Another remarkable feature is the relatively mild disease severity although another 9 natalizumab infusions were given after the initial MRI manifestations.

In our patient, IRIS could be clearly distinguished from PML as a separate clinical episode, with secondary worsening after initial improvement, during which gadolinium enhancement on MRI was a prominent feature.

Whereas, in general, it is recommended to aggressively treat IRIS with IV methylprednisolone, some experts in Europe advise treatment with IVIg, as was also administered to some patients described by Clifford et al.2 Because IRIS was clinically mild, maybe because PML was mild, or because this patient was not treated with PLEX or immunoabsorption, we treated her with IVIg. This case reaffirms the recommendation that progressive symptoms and worsening MRI evidence of PML should be treated aggressively with steroids.

This case shows that in a patient with MS treated with natalizumab clinical and radiologic vigilance is extremely important, because PML can present as an indolent disease with a protracted course which remains relatively benign for many months despite continued treatment with natalizumab.

Footnotes

  • Disclosure: Dr. Vennegoor has received research support through his institution from Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd. Dr. Wattjes has received speaker honoraria from Janssen, Bayer Schering Pharma, and Biogen Idec; and has received research support through his institution from UCB, Merck Serono, and Novartis. Dr. van Munster has received research support through his institution from Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, and GlaxoSmithKline; and has served on a scientific advisory board or consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, and Novartis. Dr. Kriekaart has received research support through his institution from Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, and GlaxoSmithKline; and has served as a consultant for Biogen Idec. Dr. van Oosten has received research support through his institution from Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd. Dr. Barkhof serves on scientific advisory boards for Lundbeck Inc., Bayer Schering Pharma, sanofi-aventis, UCB, Novartis, Biogen Idec, BioMS Medical, Merck Serono, and GE Healthcare; serves on the editorial boards of Brain , the Journal of Neurology, Neurosurgery, and Psychiatry, European Radiology, the Journal of Neurology, and Neuroradiology ; has received speaker honoraria from Novartis and Merck Serono; serves as a consultant for sanofi-aventis, UCB, Novartis, Biogen Idec, BioMS Medical, and Medicinova, Inc.; and receives research support from the Dutch MS Research Foundation. Dr. Killestein serves on scientific advisory boards for Novartis and Merck Serono; serves on the editorial board of Multiple Sclerosis International; serves as a consultant for Merck Serono; has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme Corporation, and Novartis. Dr. Polman serves on scientific advisory boards for Actelion Pharmaceuticals Ltd, Biogen Idec, Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., Merck Serono, GlaxoSmithKline, UCB, Roche, and Antisense Therapeutics Limited; serves on the editorial boards of Lancet Neurology and Multiple Sclerosis; has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, Novartis, and Teva Pharmaceutical Industries Ltd.; and receives research support from Biogen Idec, Bayer Schering Pharma, GlaxoSmithKline, Novartis, UCB, Merck Serono, Teva Pharmaceutical Industries Ltd., the European Community (EEC), and from the Dutch Multiple Sclerosis Society.

  • Received May 27, 2010.
  • Accepted August 27, 2010.
  • Copyright © 2011 by AAN Enterprises, Inc.

References

  1. 1.↵
    1. Clifford DB,
    2. DeLuca A,
    3. Simpson DM,
    4. et al
    . Progressive multifocal leukoencephalopathy with natalizumab treatment of multiple sclerosis. Neurology 2010;74(suppl 2):PL01.003.
  2. 2.↵
    1. Clifford DB,
    2. DeLuca A,
    3. Simpson DM,
    4. et al
    . Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438–446.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Linda H,
    2. von Heijne A,
    3. Major EO,
    4. et al
    . Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009;361:1081–1087.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Langer-Gould A,
    2. Atlas SW,
    3. Green AJ,
    4. et al
    . Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381.
    OpenUrlCrossRefPubMed
View Abstract

Letters: Rapid online correspondence

  • Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS
    • Michael Y. Ko, Assistant Professor, 1653 Rush University Medical Ctr, W. Congress Parkway, Chicago, Illinois 60612michael_ko@rush.edu
    • Dusan Stefoski, Roumen Balabanov
    Submitted May 25, 2011
  • Reply from the authors
    • A. Vennegoor, MS Center Amsterdam, MS Center Amsterdam, the NetherlandsA.Vennegoor@vumc.nl
    • M.P. Wattjes, E.T.L. van Munster, J. Killestein, and C.H.
    Submitted May 25, 2011
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis

Dr. Robert Pitceathly and Dr. William Macken

► Watch

Related Articles

  • No related articles found.

Topics Discussed

  • All Clinical Neurology
  • Multiple sclerosis
  • MRI

Alert Me

  • Alert me when eletters are published

Recommended articles

  • Article
    Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab
    Alyssa A. Toorop, Zoë Y.G. van Lierop, Eva E.M. Strijbis et al.
    Neurology: Neuroimmunology & Neuroinflammation, October 13, 2020
  • Articles
    Immune reconstitution inflammatory syndrome in natalizumab-associated PML
    I.L. Tan, J.C. McArthur, D.B. Clifford et al.
    Neurology, August 10, 2011
  • Articles
    Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy
    P. Vermersch, L. Kappos, R. Gold et al.
    Neurology, May 16, 2011
  • Article
    Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy
    Evelyn Dubois, Christoph Ruschil, Felix Bischof et al.
    Neurology - Neuroimmunology Neuroinflammation, October 29, 2015
Neurology: 100 (12)

Articles

  • Ahead of Print
  • Current Issue
  • Past Issues
  • Popular Articles
  • Translations

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Activate a Subscription
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise