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 01, 1997; 48 (2) Article

A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis

A. E. Miller, L. A. Morgante, L. Y. Buchwald, S. M. Nutile, P. K. Coyle, L. B. Krupp, C. A. Doscher, F. D. Lublin, R. L. Knobler, F. Trantas, L. Kelley, C. R. Smith, N. La Rocca, S. Lopez
First published February 1, 1997, DOI: https://doi.org/10.1212/WNL.48.2.312
A. E. Miller
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. A. Morgante
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. Y. Buchwald
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. M. Nutile
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. K. Coyle
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. B. Krupp
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. A. Doscher
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. D. Lublin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. L. Knobler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Trantas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. Kelley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. R. Smith
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. La Rocca
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Lopez
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis
A. E. Miller, L. A. Morgante, L. Y. Buchwald, S. M. Nutile, P. K. Coyle, L. B. Krupp, C. A. Doscher, F. D. Lublin, R. L. Knobler, F. Trantas, L. Kelley, C. R. Smith, N. La Rocca, S. Lopez
Neurology Feb 1997, 48 (2) 312-314; DOI: 10.1212/WNL.48.2.312

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
255

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Abstract

Article abstract-We determined the effect of influenza vaccine in patients with relapsing/remitting MS. Considerable controversy surrounds the question of whether to administer influenza vaccines to MS patients. Prevention of a febrile viral illness is clearly desirable in MS, and previous studies suggest that immunization is safe. Despite this, many clinicians avoid vaccination because they fear precipitating an MS exacerbation. We conducted a multicenter, prospective, randomized, double-blind trial of influenza immunization in patients with relapsing/remitting MS. In the autumn of 1993, 104 patients at five MS centers received either standard influenza vaccine or placebo. Patients were followed for 6 months for evaluation of neurologic status and the occurrence of influenza. Influenza was operationally defined as fever >or=to 38 degrees C in the presence of coryza, cough, or sore throat at a time when the disease was present in the community. Attacks were defined in the standard manner, requiring objective change in the examination. Patients were examined at 4 weeks and 6 months after inoculation and were contacted by telephone at 1 week and 3 months. They were also examined at times of possible attacks but not when they were sick with flu-like illness. Three vaccine patients and two placebo patients experienced attacks within 28 days of vaccine (no significant difference). Exacerbation rates in the first month for both groups were equal to or less than expected from published series. The two groups showed no difference in attack rate or disease progression over 6 months. Influenza immunization in MS patients is neither associated with an increased exacerbation rate in the postvaccination period nor a change in disease course over the subsequent 6 months.

NEUROLOGY 1997;48: 312-314

The Advisory Committee on Immunization Practices currently recommends annual influenza immunization for persons at increased risk for complications of the disease. [1] It further encourages consideration of vaccination for anyone wishing to avoid illness. However, the decision whether to recommend influenza immunization to patients with MS remains highly controversial. Neurologic dysfunction has been anecdotally associated with a variety of vaccines. [2,3] Thus, many practitioners advise against influenza immunization because of fear that it will precipitate an exacerbation of MS, despite previous studies that suggest no increased risk. [4-6] We postulated that patients could safely receive influenza immunization and might benefit from a reduction in additional neurologic dysfunction as a result of decreases in pseudoexacerbations, associated with the fever of influenza, as well as true attacks precipitated by the viral illness. We report here the results of a multicenter, double-blind, randomized, placebo-controlled trial of influenza immunization versus placebo vaccination that we conducted during the influenza season of 1993.

Methods.

In the autumn of 1993, 104 patients at five MS centers were randomized to receive either standard influenza immunization (Wyeth-Ayerst, Philadelphia, PA) or placebo injection, consisting of the vaccine diluent. Randomization sequence was assigned separately for each center. Patients were eligible for inclusion if they had clinically definite relapsing-remitting MS with a Kurtzke expanded disability status score [7] of less than 6.5 (i.e., ambulatory with no more than a unilateral aid). Patients were excluded if they had experienced an acute exacerbation or treatment with corticosteroids in the previous 4 weeks. Eligible patients had not been treated with immunosuppressive medications, interferon-beta, or copolymer 1 within the preceding 6 months. Patients were also excluded if they had a history of a prior adverse reaction to influenza vaccine or were allergic to egg products.

Patients were then followed for 6 months for evaluation of neurologic status and the occurrence of influenza. Influenza was operationally defined as fever >or=to38 degrees C in the presence of coryza, cough, or sore throat at a time when the disease was known to be present in the community. Exacerbations of MS were operationally defined as an objective change on the neurologic examination resulting in an increase of at least 0.5 on the expanded disability status scale (EDSS) or an increase of at least one grade on the scores of two or more of the Kurtzke functional system scores (FSS) or two grades on one of the FSS. Symptoms must have persisted for more than 24 hours, and the neurologic changes must have occurred in the absence of fever or lasted for more than 48 hours beyond the existence of fever of >or=to38 degrees C. Symptoms were scored by the blinded neurologist as pseudoexacerbations on the basis of telephone assessment if subjective deterioration of neurologic status occurred in the context of fever >or=to38 degrees C lasting >or=to24 hours.

Patients were examined by the blinded neurologist at 4 weeks and 6 months after inoculation and were contacted by telephone at 1 week and 3 months by the blinded study nurse. They were also examined at times of possible attacks but were not seen when they were sick with flu-like illness.

Sample size calculation, assuming an alpha of 0.05 with a two-tailed test and a power of 80%, was determined assuming a moderate effect size (i.e., equivalent to one half of an SD) with a frequency of attacks similar to published figures. A moderate effect size was chosen because it was believed to be the smallest effect size having clinical significance in the context of the goals of the study. Sample size calculations were performed using a computer program for statistical power analysis. [8]

Comparison of attacks in the first 28 days after vaccine was performed using Fisher's exact test. Attack incidence of 6 months was compared using chi square analysis. Comparison of the incidence of influenza was performed using Fisher's exact test. The number of patients worsening over 6 months was compared using chi square. The comparison of mean change in EDSS was performed using the t test for independent samples.

Results.

Forty-nine patients received influenza vaccine and 54 patients received placebo. The groups did not differ significantly in age, gender, or disability. During the 28 days after inoculation, three vaccine patients and two placebo patients experienced MS exacerbations (no significant difference). Over the 6-month follow-up period, vaccine patients experienced 11 attacks (annual rate 0.45) and placebo patients, 6 attacks (annual rate 0.22). The difference in attack rates was not statistically significant. The mean time of onset of relapse after flu vaccine (91.5 days) exceeded that for placebo patients (55.3 days), further substantiating the lack of association between flu vaccine and MS exacerbations (Table 1). Using the operational definition of influenza, surprisingly, seven immunized patients were scored as experiencing the illness, compared with three in the placebo group, but this difference was not significant. There was no significant difference in the numbers of patients who worsened in the 6-month study period (8, vaccine; 10, placebo), nor in the mean change in EDSS (0.02, vaccine; 0.09, placebo). Pseudoexacerbations occurred in three patients (27%) who were scored as experiencing influenza.

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 1. Relationship of MS exacerbations to date of immunization

Discussion.

This is the largest prospective study examining the effect of influenza immunization of MS patients and the first to follow patients through an entire influenza season. The results confirm previous studies and indicate that influenza vaccination is safe for MS patients because it is not associated with an increased risk of exacerbation. After a previous retrospective review of influenza vaccination had suggested it was well-tolerated with no increase in relapse rate, Bamford et al. [5] conducted a prospective, but uncontrolled and unblinded, study in which MS patients receiving vaccine had no increase in relapse rate compared with the unimmunized control subjects during 4 weeks of study. Myers et al. [6] reported a prospective, double-blind, placebo-controlled study in which 33 patients receiving swine influenza vaccine experienced two relapses, compared with four attacks in 33 placebo-treated patients and two attacks in 22 untreated control subjects during the 3 weeks after immunization. Over a 3-month follow-up period, four relapses occurred in each group. There were no significant differences among these results.

Recent clinical trials of interferon-beta 1b, [9] beta 1a, [10] and copolymer 1 [11] in patients with active relapsing-remitting disease reported exacerbation rates among placebo-treated patients ranging from 0.82 to 1.31 annually. A previous natural history study by Goodkin et al, [12] noted an attack rate of 0.6 annually. Based on a comparison with these data, our immunized patients experienced an attack rate lower than expected at both 4 weeks and 6 months after inoculation.

The apparent occurrence of more influenza cases in the vaccine group than in the placebo group, although not statistically significant, was surprising. Most cases probably reflect either noninfluenza respiratory illnesses or significantly attenuated influenza infections. This is supported by many cases scored as influenza being minor illnesses in which fever was low or brief, and the usual myalgias that accompany influenza were absent.

In conclusion, influenza immunization appears to be safe in patients with relapsing-remitting MS. It is not associated with a significantly increased attack rate in the postimmunization period nor with an increased rate of MS progression. In view of the demonstrated safety of influenza immunization, we believe vaccination can be recommended to MS patients.

  • Copyright 1997 by Advanstar Communications Inc.

REFERENCES

  1. 1.↵
    Prevention and control of influenza: vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1994;43(RR-9):1-13.
  2. 2.↵
    Miller H, Cendrowski W, Schapira K. Multiple sclerosis and vaccination. BMJ 1967;2:210-213.
    OpenUrlFREE Full Text
  3. 3.
    Rabin J. Hazard of influenza vaccine in neurologic patients. JAMA 1973;225:63-64.
    OpenUrlCrossRef
  4. 4.↵
    Sibley WA, Bamford CR, Laguna JF. Influenza vaccination in patients with multiple sclerosis. JAMA 1978;236:1965-1966.
    OpenUrl
  5. 5.↵
    Bamford CR, Sibley WA, Laguna JF. Swine influenza vaccination in patients with multiple sclerosis. Arch Neurol 1978;35:242-243.
    OpenUrl
  6. 6.↵
    Myers LW, Ellison GW, Lucia M, et al. Swine influenza virus vaccination in multiple sclerosis. J Infect Dis 1977;136:S546-554.
    OpenUrl
  7. 7.↵
    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-1452.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    Borenstein M, Cohen J. Statistical power analysis: a computer program. Hillsdale, NJ: Lawrence Earlbaum Associates, 1988.
  9. 9.↵
    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind placebo-controlled trial. Neurology 1993;43:655-661.
    OpenUrl
  10. 10.↵
    Jacobs L, Cookfair D, Rudick R, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-294.
    OpenUrl
  11. 11.↵
    Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276.
    OpenUrlFREE Full Text
  12. 12.↵
    Goodkin DE, Hertsgaard D, Rudick RA. Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis: implications for clinical trials. Arch Neurol 1989;46:1107-1112.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
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
    • Abstract
    • Methods.
    • Results.
    • Discussion.
    • REFERENCES
  • Figures & Data
  • Info & Disclosures
Advertisement

SARS-CoV-2 Vaccination Safety in Guillain-Barré Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy, and Multifocal Motor Neuropathy

Dr. Jeffrey Allen and Dr. Nicholas Purcell

► Watch

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published

Recommended articles

  • Article
    Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis
    Ludwig Kappos, Matthias Mehling, Rafael Arroyo et al.
    Neurology, January 30, 2015
  • Article
    Disability Outcomes in the N-MOmentum Trial of Inebilizumab in Neuromyelitis Optica Spectrum Disorder
    Romain Marignier, Jeffrey L. Bennett, Ho Jin Kim et al.
    Neurology: Neuroimmunology & Neuroinflammation, March 26, 2021
  • Articles
    Neurologic complications of influenza A(H1N1)pdm09
    Surveillance in 6 pediatric hospitals
    Gulam Khandaker, Yvonne Zurynski, Jim Buttery et al.
    Neurology, September 19, 2012
  • Articles
    Influenza vaccination in MS
    Absence of T-cell response against white matter proteins
    N.F. Moriabadi, S. Niewiesk, N. Kruse et al.
    Neurology, April 10, 2001
Neurology: 100 (13)

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