A New Perspective On Survival Outcomes In Multiple Sclerosis

A New Perspective on
Survival Outcomes in
Multiple Sclerosis
3 Editorial Introduction: Life Expectancy in MS: Implications for Clinicians
Stuart D. Cook, MD, Guest Editor
5 Survival in MS: Current Insights from International Registries and
Databases
Kjell-Morten Myhr, MD; Nina Grytten Torkildsen, PhD
11 Impact of Treatment on Long-Term Survival in MS: Summary of Results
from Interferon Beta-1b 21-Year Long-Term Follow-up Study
Anthony T. Reder, MD; Sven Schippling, MD
17 Life Expectancy in MS: Communication Strategies for Clinicians and
Advocacy Organizations
David Bates, MA, MB, BChir, FRCP; Dawn Langdon, MA, MPhil, PhD
22 Continuing Medical Education Posttest
23 CME Answer Sheet/Evaluation
The Official Publication of the Consortium of Multiple Sclerosis Centers
September 2012 Volume 14, Supplement 4
Special Supplement
Jointly sponsored by the Consortium of Multiple Sclerosis Centers and Delaware Media Group
This continuing education supplement is supported by an educational grant from
Bayer HealthCare Pharmaceuticals, Inc.
ijmsc.org

Supplement to the International Journal of MS Care
2
FACULTY
GUEST EDITOR
Stuart D. Cook, MD
Professor, Department of Neurology
and Neurosciences
University of Medicine and Dentistry
of New Jersey
Newark, NJ, USA
DISCLOSURES
Stuart D. Cook has disclosed the following
financial relationships:
Sources of Funding for Research: Bayer
HealthCare (no personal compensation)
David Bates has disclosed the following
financial relationships: Contracted Research:
Biogen, Novartis, Sanofi; Consulting Agree-
ments: Bayer HealthCare, Biogen, Serono.
Nina Grytten Torkildsen has disclosed no
relevant financial relationships.
Dawn Langdon has disclosed the following
financial relationship(s): Consulting Fees
(e.g., advisory boards): Bayer Healthcare;
Fees for Non-CME services received directly
from commercial interest or their agents (e.g.,
speakers’ bureaus): Bayer HealthCare, Merck
Serono, Serono Symposia, Teva; Contracted
Research: Bayer HealthCare.
Kjell-Morten Myhr has disclosed no relevant
financial relationships.
Anthony T. Reder has disclosed the follow-
ing financial relationships:
Consulting Agreements: Bayer, Biogen,
Novartis, Questcor, Sanofi-Aventis, Serono,
Teva Neuroscience. Fees for Non-CE Services
(e.g. Speaker’s Bureaus): Bayer, Novartis,
Serono, Teva Neuroscience.
Sven Schippling has disclosed the following
financial relationships:
Consulting Agreements: Bayer, Biogen Idec,
Novartis, Teva Neuroscience
Reviewer
Laurie Scudder has disclosed no relevant
financial relationships.
Planners and Managers
June Halper has disclosed the following finan-
cial relationships:
Consulting Agreements: Acorda Therapeutics
The following planners and managers have
disclosed no relevant financial relationships:
Joseph J. D’Onofrio, Frank Marino,
Katherine Wandersee
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A New Perspective on Survival
Outcomes in Multiple Sclerosis
Continuing Education Information
Target Audience
This publication is targeted to physicians and other practitioners who have an interest in treat-
ing multiple sclerosis (MS).
Educational Objectives
Upon completion of this educational activity, the participant should be able to:
•฀Discuss฀new฀indings฀from฀the฀recent฀retrospective฀controlled฀study฀and฀registry฀data฀per-
taining to survival in MS to enhance treatment decisions based on these data related to
patient outcomes.
•฀Analyze฀current฀data฀about฀long-term฀effects฀of฀disease-modifying฀treatment฀in฀MS฀on฀out-
comes including disability and life expectancy.
•฀Apply฀strategies฀for฀discussing฀long-term฀prognosis฀and฀survival฀with฀patients฀and฀families,฀
taking into account disease-specific, personal, regional, and cultural factors.
Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and poli-
cies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint
sponsorship of the Consortium of Multiple Sclerosis Centers (CMSC) and the Delaware Media
Group. The CMSC is accredited by the ACCME to provide continuing medical education for
physicians.
The CMSC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Cred-
its™. Physicians should claim only the credit commensurate with the extent of their participation
in the activity.
Release Date: September 30, 2012
Credit for this program expires on September 30, 2013.
Method of Participation
Follow these steps to earn CME credit:
1. Read the target audience, learning objectives, and author disclosures.
2. Study the educational content online or printed out.
3. Choose the best answer to each test question. To receive a certificate, you must receive a passing
score as designated at the top of the test. The CMSC encourages you to complete the Activity
Evaluation to provide feedback for future programming.
Code: CMSC-2012/14-4
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Approval does not imply endorsement by the CMSC or ACCME of any commercial products dis-
cussed in conjunction with an educational activity.
Disclosure of Unlabeled Use
This CME activity may contain discussion of published and/or investigational uses of agents that
are not approved by the FDA. CMSC, Bayer HealthCare Pharmaceuticals, Inc., and Delaware
Media Group do not recommend the use of any agent outside of the labeled indications. The opin-
ions expressed in the educational activity are those of the faculty and do not necessarily represent
the views of the CMSC, Bayer HealthCare Pharmaceuticals, Inc., or Delaware Media Group.
Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance
patient outcomes and their own professional development. The information presented in this activ-
ity is not meant to serve as a guideline for patient management. Any medications, diagnostic pro-
cedures, or treatments discussed in this publication should not be used by clinicians or other health
care professionals without first evaluating their patients’ conditions, considering possible contraindi-
cations or risks, reviewing any applicable manufacturer’s product information, and comparing any
therapeutic approach with the recommendations of other authorities.
This continuing education program is supported by an educational grant from Bayer HealthCare
Pharmaceuticals, Inc.

3
Life Expectancy in Multiple Sclerosis
Implications for Clinicians
Stuart D. Cook, MD
Guest Editor
T
he influence of multiple sclerosis (MS) on sur-
vival has been known for many years, affecting
particularly those patients who are severely
disabled.1
However, the topic of survival in MS has his-
torically been considered to be of only minor relevance
in MS management. The majority of studies in MS
have explored short-term outcomes, and many stan-
dard MS texts have depicted the disease as having little
or no impact on life expectancy.2-4
Since 1983, a growing number of population-
based registries have shown that MS patients have a
mean decrease in survival time of 6 to 12 years com-
pared to age- and sex-matched population controls.5-9
More recently, mega databases with thousands of MS
patients and matched controls (including insurance
company–derived vital status reports, national death
certificates, and large-scale patient registries) have con-
firmed the results of these smaller population-based
registries in showing a disadvantage for people with
MS in terms of survival.10
In this issue, Norwegian
MS specialist Kjell-Morten Myhr describes the current
status of European and North American databases and
registries฀and฀summarizes฀their฀indings.
Together with long-term follow-up data from a
pivotal interferon treatment trial, these findings have
led to a compelling picture of the impact of the disease
on survival that has been previously missing from our
knowledge base.11
In their review in this issue, Anthony
Reder and Sven Schippling report the interferon
beta-1b (IFNβ-1b) 21-year follow-up data within the
context of a hopeful message of improving long-term
prognosis with treatment. The study showed that MS
patients who were initially treated with placebo had
significantly higher mortality rates than patients treated
initially with IFNβ-1b, suggesting that even a 5-year
delay in starting interferon therapy may affect mortal-
ity outcomes.11
Since the details of post-study therapy
were not precisely known, one cannot definitively
conclude that early treatment with IFNβ-1b was solely
responsible for the difference in death rates, and not
early treatment followed by subsequent treatment with
other disease-modifying therapies (DMTs). Only addi-
tional, robust long-term studies of DMTs with simi-
larly high case ascertainment can determine the answer.
Regardless, it is likely that early treatment played an
important role. It is also of interest that baseline T2
lesion load on magnetic resonance imaging was found
to be a predictor of mortality in the study.
We have reason to believe that the beneficial effect
of early treatment on survival is likely to be applicable
to other DMTs. Some placebo-controlled trials of
relapsing-remitting MS (RRMS) and clinically iso-
lated syndrome (CIS) have shown that subjects who
receive therapy initially may have improved long-term
outcomes, compared with those started on placebo
and later moved to active therapy.12-14
This has con-
tributed to the widespread recommendation that
patients with CIS or RRMS be treated with DMTs as
early as possible.
It is common for prognostic outcomes to be a part
of the medical decision-making process, as we see in
cancer, cardiovascular disease, and many other condi-
tions.15,16
Yet many MS care practitioners have hesitat-
ed to discuss survival information with patients. With
the large body of new data emerging, however, this
topic has very likely become unavoidable. In conveying
survival information to patients, healthcare practitio-
ners must bear in mind that patients want and expect
better quality of life along with extended length of
INTRODUCTION
A
From: Department of Neurology and Neurosciences, University of
Medicine and Dentistry of New Jersey, Newark, NJ, USA. Corre-
spondence: Stuart D. Cook; email: cooksd@umdnj.edu.

4
life.17-19
How to approach this discussion in a truthful
yet balanced and patient-specific manner is the subject
of the article here by David Bates and Dawn Langdon
based on insights from a group of 20 distinguished
thought leaders and representatives of MS patient
advocacy groups from around the world.
The articles in this special supplement to the
International Journal of MS Care are compiled from
a gathering of these international MS experts and
advocacy leaders in Oslo, Norway, held in June 2012.
The฀goal฀of฀the฀meeting฀was฀to฀assess฀and฀analyze฀the฀
latest survival information in MS, discuss how this
new information affects MS patients and their families,
and determine the best way for clinicians and advocacy
groups to convey the message in an honest yet positive
manner. Although knowledge of premature mortality
in MS will obviously be of concern to our patients, the
good news is that disability may be prevented and out-
comes leading to premature mortality may be dimin-
ished with early and probably continued therapy. o
References
1. Cook SD. Handbook of Multiple Sclerosis. 4th ed. New York: Taylor &
Francis; 2006.
2. Burks JS, Johnson KP. Multiple Sclerosis: Diagnosis, Medical Manage-
ment, and Rehabilitation. New York: Demos; 2000.
3. Lucchinetti CF, Hohlfeld R. Multiple Sclerosis 3. 1st ed. Philadelphia:
Saunders Elsevier; 2010.
4. McDonald WI, Noseworthy JH. Multiple Sclerosis 2. Boston: Butter-
worth-Heinemann; 2003.
5. Kingwell E, van der Kop M, Zhao Y, et al. Relative mortality and sur-
vival in multiple sclerosis: findings from British Columbia, Canada. J
Neurol Neurosurg Psychiatry. 2012;83(1):61-66.
6. Bronnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival
and cause of death in Danish patients with multiple sclerosis. Brain.
2004;127(Pt 4):844-850.
7. Leray E, Morrissey SP, Yaouanq J, et al. Long-term survival of patients
with multiple sclerosis in West France. Mult Scler. 2007;13(7):
865-874.
8. Smestad C, Sandvik L, Celius EG. Excess mortality and cause of
death in a cohort of Norwegian multiple sclerosis patients. Mult Scler.
2009;15(11):1263-1270.
9. Sumelahti ML, Hakama M, Elovaara I, et al. Causes of death among
patients with multiple sclerosis. Mult Scler. 2010;16(12):1437-1442.
10. Reshef S, Cutter G, Golub HI, et al. Mortality in multiple sclerosis in the
United States (MIM-US): a retrospective, cohort study of survival and
mortality trends. Program and abstracts from the 64th Annual Meeting
of the American Academy of Neurology, April 21-28, 2012, New
Orleans, LA. Poster P06.195.
11. Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: a randomized
cohort study 21 years after the start of the pivotal IFNbeta-1b trial.
Neurology. 2012;78(17):1315-1322.
12. Randomised double-blind placebo-controlled study of interferon beta-
1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of
Relapses and Disability by Interferon beta-1a Subcutaneously in Mul-
tiple Sclerosis) Study Group. Lancet. 1998;352(9139):1498-1504.
13. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early
treatment with interferon beta-1b after a first clinical event suggestive
of multiple sclerosis: 5-year active treatment extension of the phase 3
BENEFIT trial. Lancet Neurol. 2009;8(11):987-997.
14. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate
on conversion to clinically definite multiple sclerosis in patients with
clinically isolated syndrome (PreCISe study): a randomised, double-
blind, placebo-controlled trial. Lancet. 2009;374(9700):1503-1511.
15. Liu Y, Yang YM, Zhu J, et al. Prognostic significance of hemoglobin
A1c level in patients hospitalized with coronary artery disease: a sys-
tematic review and meta-analysis. Cardiovasc Diabetol. 2011;10:98.
16. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused
update incorporated into the ACC/AHA 2007 Guidelines for the
Management of Patients with Unstable Angina/Non-ST-Elevation
Myocardial Infarction: a report of the American College of Cardiol-
ogy Foundation/American Heart Association Task Force on Practice
Guidelines developed in collaboration with the American Academy
of Family Physicians, Society for Cardiovascular Angiography and
Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol.
2011;57(19):e215-367.
17. Crayton HJ, Rossman HS. Managing the symptoms of multiple sclero-
sis: a multimodal approach. Clin Ther. 2006;28(4):445-460.
18. Janssens AC, van Doorn PA, de Boer JB, et al. Impact of recently
diagnosed multiple sclerosis on quality of life, anxiety, depression and
distress of patients and partners. Acta Neurol Scand. 2003;108(6):
389-395.
19. Kargiotis O, Paschali A, Messinis L, et al. Quality of life in mul-
tiple sclerosis: effects of current treatment options. Int Rev Psychiatry.
2010;22(1):67-82.

5
5
From: Norwegian Multiple Sclerosis Competence Centre, Depart-
ment of Neurology, Haukeland University Hospital, University of
Bergen, Norway (KM); Department of Clinical Medicine, University
of Bergen, Norway (NGT). Correspondence: Kjell-Morten Myhr;
email: kjell-morten.myhr@helse-bergen.no.
Survival in MS: Current Insights from
International Registries and Databases
Kjell-Morten Myhr, MD
Nina Grytten Torkildsen, PhD
M
ortality in multiple sclerosis (MS) is a diffi-
cult subject to discuss, given the high degree
of disability this disease can cause over a life-
time and the wide variability in long-term outcomes.
A considerable body of international data on mortality
in MS has recently emerged from multiple large-scale
studies based on registry and large database analyses.
These data derive largely from MS population-based
mortality studies in Norway, Denmark, Finland,
South Wales, France, the United States, and Canada
encompassing more than 11,000 subjects (Table 1).1-8
Findings from most of these studies show a remarkably
consistent pattern of reduced life expectancy of 8–12
years in a largely untreated population with MS. By
addressing this fact and examining the causes of death
related to MS, providers of MS care might better assist
patients with long-term planning and treatment deci-
sions. In addition, these data serve as a baseline for
future studies that may demonstrate how longevity is
affected by improvements in diagnosis and treatment
of MS.
Registry-Based Survival Studies in MS
This article reviews MS survival findings from two
different types of studies: registries and databases. The
World฀Health฀Organization฀(WHO)฀deines฀a฀registry฀
as: “a file of documents containing uniform informa-
tion about individual persons, collected in a systematic
and comprehensive way.”9
Population-based registries
refer to a geographically defined population and aim to
register all cases of the disease in that population. Thus
they are comprehensive but can be difficult to accrue.10
Examples of registries in MS include the North Ameri-
can Research Committee on Multiple Sclerosis (NAR-
COMS) and several European registries discussed in
this article.
Databases are less comprehensive in terms of the
range and type of information collected for any indi-
vidual, but allow for much larger numbers of cases to
be represented.10
Because MS is a relatively rare dis-
ease, large cohorts are useful for identifying a sufficient
number of subjects for meaningful survival informa-
tion.11
Some MS patient databases are derived from
managed health systems, such as the OptumInsight
Research database derived from United Healthcare
records.11
Hordaland Study, Western Norway
The Western Norway study of MS survival was
derived from data gathered in Hordaland County, an
area with an MS prevalence of 151 per 100,000 per-
sons. In this registry, we followed 878 people with MS
over a period of up to 50 years (mean follow-up time
20.4 years) (Table 2).2
The population with MS in this
study survived a median of 41 years from disease onset,
compared with 49 years in the age- and sex-matched
population.฀This฀resulted฀in฀a฀standardized฀mortality฀
ratio (SMR) of 2.7, representing a 2.7-fold higher risk
of dying during the observation period (Figure 1).
As shown in Table 1, this SMR overlaps closely with
that observed in most of the other recent international
registry studies of survival in MS.1,3,4,6,7
When the data
were broken down by gender, women with MS had a
longer median survival time of 43 years from disease
onset (vs. 51 years in the general population) than
men, with a time of 36 years (vs. 46 years in the gen-
eral population).2
However, examining the SMR or
risk relative to the general population, women with MS
actually had a significantly higher risk of dying than
men with MS (SMR 3.11 vs. 2.23 for men; P = 0.02).

6
Although many studies have suggested that men with
MS have a poorer prognosis with respect to disability,
the Western Norway data and those of other recent
MS registry studies (Eastern Norway, Denmark, Fin-
land, France, and Canada) show that the poorer prog-
nosis for males does not carry through to survival.1,4-7
When we examined MS survival rates according to
disease classification, those patients with primary pro-
gressive MS (PPMS) had a higher risk of death from
MS (43 years for relapsing-remitting disease vs. 26
years for PPMS; P = 0.02).2
฀We฀also฀analyzed฀whether฀
survival rates had improved over the 50-year period,
Table 2. Survival analysis from Hordaland Registry, Western Norway2
• Prevalence of MS 151 per 100,000
• Analysis based on 878 patients with MS onset between 1953 and 2003
• Mean follow-up period 20.4 years
• 198 patients had died by 2005 data analysis
• MS survival rates were measured according to:
– Median survival from onset of MS
– Standardized mortality ratio (SMR): mortality risk compared with age- and sex-matched general population
– Relative mortality ratio (RMR): comparison of SMR within MS patient subsets, adjusting for age at onset using
extended Cox regression model
Table 1. Population-based survival studies in MS
First author Population/time period Cohort size SMR
Reduced life
expectancy
Grytten Torkildsen2
Mult Scler. 2008
Western Norway
1953–2003
878 2.66
(95% CI: 2.31–3.06)
8 years
Smestad6
Mult Scler. 2009
Oslo, Eastern Norway
1940–1980
368 2.47
(95% CI: 2.09–2.90)
Female: 11.2 years
Male: 7.4 years
Bronnum-Hansen1
Brain. 2004
Danish MS Registry
1949–1996
9881 2.89
(95% CI: 2.81±2.98)
~10 years
Sumelahti7
Mult Scler. 2010
Finland
1964–1993
1595 2.8
(95% CI: 2.6–3.1)
Hirst3
JNNP. 2008
South Wales
1985–2006
373 2.79
(95% CI: 2.44–3.18)
7.5 years
Leray5
Mult Scler. 2007
West France
1976–2004
1879 1.3
(95% CI: 1.01–1.7)
Wallin8
Brain. 2000
USA
1956–1996
2489 2.18
(Not specified)
Kingwell4
JNNP. 2012
Canada
1980–2004
6917 2.88
(95% CI: 2.71–3.07)
~6 years
SMR=standardized mortality ratio

7
with time breakdowns of 1953–1967, 1968–1982, and
1983–2003. This analysis showed a trend toward bet-
ter survival in later years (Table 3), but greater reduc-
tions are anticipated in the future as more patients are
studied who have received disease-modifying therapies
(DMTs).
The Western Norway data also suggested that
patients with MS who had a younger age of disease
onset had a significantly higher risk of dying during
the study observation period (RMR 0.65, P < 0.001).
This was probably related to the impact of competing
risks of death associated with advanced age. Cause of
death among the 198 deceased MS patients was also
analyzed,฀ with฀MS฀attributed฀as฀the฀cause฀in฀more฀
than half (112; 56.5%).
Cardiovascular disease
(13.1%), cancer (10.6%),
and infectious/respiratory
diseases (5.1%) were the
other top causes in this
population.2
When cause
of death in this study was
compared with that of
the Danish and Finnish
registry studies, similar
rates for MS and cancers
are seen across studies
(Table 4).1,2,7
European MS Registry
Study
The European MS
Platform is an umbrel-
la฀ organization฀ of฀ 38฀
national MS societies from 34 European countries rep-
resenting approximately a half million people with MS,
as well as their families and caregivers and MS care
providers. At present, 15 of the participating countries
have MS registries available at the national or regional
levels, but there remains a lack of reliable, accurate
data on MS, its treatment, and its effect on quality of
life. The European Register for MS (EUReMS)—co-
funded by the European Union in the framework of
the Health Program—is a planned project for collec-
tion and aggregation of a large amount of data on MS
disease progression, patient quality of life, and survival
across Europe.12
฀Within฀a฀few฀years,฀organizers฀of฀this฀
program will have determined a set of core data to be
collected, drawing from approximately 10 existing
national registries from European countries (Table 5).
Among the goals of the EUReMS project is to
learn more about the long-term consequences of
MS, including neurophysical and neuropsycho-
logical disability, quality of life, and life expectancy.
European MS Platform representatives and member
physicians have observed that, until recently, the
effect of the disease on life expectancy has seldom
been discussed with patients or officially within the
member฀organizations.12
Canadian Registry Study
Kingwell and colleagues recently reported findings
of a survival study based on a large Canadian cohort
Figure 1. Hordaland study, median survival from onset of MS2
Reproduced with permission from Grytten Torkildsen et al. Mult Scler. 2008.2
41 yrs 49 yrs
Reproduced with permission from Grytten Torkildsen et al. Mult Scler. 2008;14(9):1191-1198. 2
Reduced life expectancy of 8 years
Standardized mortality ratio = 2.66 (2.31 – 3.06)
Table 3. Decline in relative mortality ratio
by time period2
Overall RMR for the total observation period was 0.90
(95% CI: 0.71–1.15)
Compared to the reference period 1953–1967
(RMR = 1.0):
• RMR during 1968–1982 declined to 0.94 (95% CI:
0.67–1.32)
• RMR during 1983–2003 declined to 0.79 (95% CI:
0.47–1.33)
RMR=relative mortality ratio

8
of 6917 people with MS from British Columbia con-
ducted from 1980 to 2004.4
These authors exam-
ined the effects on survival of gender, type of disease
course at onset, and age at MS onset. Survival rates
were compared with the general population using
SMR analysis. This study showed longer survival
times among people with MS compared with other
recent reports, with median survival ages of 78.6
years (95% confidence interval [CI] 77.5–79.7) for
women and 74.3 years (95% CI 73.1–75.4) for men.
However, life expectancy was reduced by 6 years rela-
tive to the general population (median 84.5 years for
women and 80.4 years for men). As expected, PPMS
was associated with a higher relative mortality ratio
(RMR) compared with relapsing disease (RMR 1.52;
95% CI 1.30–1.80). Survival from onset of MS was
41.3 years for men and 49.8 years for women. Most
of the people with MS in this cohort had not been
exposed to DMTs during their lifetimes. Relative to
the improved survival rates observed in the general
population, this study did not show a correspond-
ing improvement in survival over time among people
with MS.4
MS Survival Findings from Large Databases
Survival in Multiple Sclerosis in the United States
(SIMS-US) Study
Unlike registries, the information available from
large or “mega” databases is often more limited in
scope, but allows for analysis among much larger popu-
lations. OptumInsight is a large healthcare database
managed by a division of United Healthcare, covering
the period between 1993 and the present and contain-
ing documentation on more than 39 million people.
The Survival in Multiple Sclerosis in the United States
(SIMS-US) study is an ongoing retrospective study
comparing survival and mortality trends in patients
with MS against a matched cohort using the OptumIn-
sight database.11
In a recent report from the SIMS-US
study, 31,501 subjects with MS and 92,511 age- and
gender-matched controls without MS (3 control sub-
jects per MS subject) were followed from 1993 to
2009. Information on all participants was checked
against the United States National Death Index (NDI)
to confirm vital status and date and cause of death
when applicable.11
The report, presented by Reshef and
colleagues at the 2012 annual meeting of the American
Table 4. Causes of death among people with MS, Nordic countries2
Cause of death from death
certificate
Danish MS Registry
1949–19961
N = 9881 (%)
Norway, 1953–20032
N = 878 (%)
Finland, 1946–19937
N = 1595 (%)
Multiple sclerosis 56.4 56.5 58
Cardiovascular diseases 15.5 13.1 8
Cancer 10.1 10.6 11
Infectious and respiratory diseases 4.7 5.1 12
Other diseases 8.8 5.6 5
Accidents and suicide 4.5 2.5 5 accidents; 1 suicide
Unknown (NA) 6.6 (NA)
Table 5. Goals for European Register for MS (EUReMS) by 201412
• Determine core medical and clinical data on people with MS to be fed into EUReMS from 10 national registries
• Determine core socioeconomic data on MS being fed into EUReMS from 10 national registries
• Create the basis for a irst scientiic research project using EUReMS data coming from 10 national registries
• Undertake Directorate-General (DG) Research-funded MS research project on European level, using European Union
funds to allow for the expansion of the EUReMS network

9
Academy of Neurology, compared the SIMS-US find-
ings with survival data from North American Research
Committee on Multiple Sclerosis (NARCOMS) using
data collected between 1996 and 2008.11
NARCOMS
is a voluntary MS registry involving more than 36,000
participants.
The goals of the SIMS-US study were to:
•฀Estimate฀rates฀of฀all-cause฀and฀cause-speciic฀mortal-
ity in MS compared with the general population
•฀Compare฀survival฀since฀birth฀(life฀span)฀in฀MS฀ver-
sus the general population
•฀Estimate฀survival฀since฀MS฀diagnosis฀in฀the฀NAR-
COMS population
A relatively small difference in age at death between
those with MS (59.9) and control subjects (61.3) was
attributed to the fact that this report was generated
within the first decade of data collection. However, the
overall mortality rate (deaths per 100,000 person-years)
was higher for people with MS (901.6) than for those
in the control population (439.8; SMR=1.7). Plotted
on a survival curve, these findings appear similar to
those derived from the NARCOMS registry (Figure
2). NARCOMS recorded a total of 3161 deaths (1324
per 100,000 person-years; 95% CI 1278–1371) and
SMR of 1.9 for MS vs. non-MS cohort (95% CI 1.8–
2.0).11
The OptumInsight cohort differs from some of
the other MS survival studies reported because greater
than 60% of the patients with MS received DMTs at
some point in their disease course. Results from both
analyses show a gap in survival rates between MS and
non-MS populations that closely replicates the find-
ings from other registry studies in North America and
Europe discussed here.
Population-Based Cohort Study of British Patients
with MS
A population-based cohort study using data from
Great Britain was also reported recently in a paper
by Lalmohamed and colleagues.13
These investigators
sought to determine the influence of lifestyle param-
eters, including body weight and smoking habits, on
mortality rates and cause of death among people with
MS. Data were derived from the General Practice
Research Database, Hospital Episode Statistics, and
national death certificates from January 2001 through
March 2008. This included 1270 subjects with MS,
matched by age, gender, and lifestyle practices with up
to฀6฀control฀subjects฀per฀MS฀patient.฀Mortality฀hazard฀
rate ratios (HRs) were estimated using Cox propor-
tional฀hazard฀models.13
The results showed that people with MS have a 3.5-
fold increased rate of all-
cause mortality relative to
controls (Table 6). This
hazard฀ratio฀was฀increased฀
further among current
smokers (but not former
smokers) and in subjects
with low body mass index
(BMI). In terms of cause
of death, the highest
hazard฀ ratios฀ were฀ asso-
ciated with death from
infectious and respiratory
causes (HR 7.69, 95%
CI 4.92–12.02) and were
significantly increased
for deaths related to
cardiovascular diseases
(2.4-fold) and cancer
(1.9-fold) (Table 7).13
The investigators con-
cluded that smoking and
respiratory diseases are
Figure 2. Survival curves since birth: MS vs. matched controls11
OIR=OptumInsight; NARCOMS=North American Research Committee on Multiple Sclerosis.
Reprinted with permission from Reshef et al. AAN 2012.11

10
important and potentially preventable factors related
to increased mortality among people with MS in Great
Britain.
Conclusions: Registry and Database
Findings on Survival
Overall, registry studies specific to MS and large
population-based cohort studies show that survival
among people with MS is reduced relative to the gen-
eral population by approximately 8–12 years. Kaplan-
Meier survival curves indicate that the divergence
between MS and non-MS groups manifests during the
first 10 years of follow-up and persists in later years.
Based on data collected thus far—albeit from a largely
untreated population identified using older diagnostic
criteria—median survival in people with MS is 30 to
40 years from disease onset. People with MS have a
higher risk of death from all causes, and available data
suggest that more than 50% die of causes related to
MS, although most studies lack consistent terminol-
ogy and methods for defining primary and secondary
causes of death.
The year 2012 has brought the emergence of more
hard data about survival in MS than has ever been
available, but many unanswered questions remain,
including how survival trends may change with the
current population of MS patients who are usu-
ally diagnosed and treated earlier, how better overall
healthcare and symptom management may affect MS
survival, and how to best apply information about MS
life expectancy in treatment decisions, patient educa-
tion, and public health policy. Although patients with
MS should be counseled about how MS survival find-
ings apply to their particular medical condition, care
providers must bear in mind that the overall goal of
care is usually to maintain the highest possible quality
of life for the longest time possible. This sentiment was
summed up by a former president of a European MS
society, who stated: “I want to add life to my years, not
necessarily years to my life.” o
References
2004;127(Pt 4):844-850.
2. Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of
death in multiple sclerosis: results from a 50-year follow-up in Western
Norway. Mult Scler. 2008;14(9):1191-1198.
3. Hirst C, Swingler R, Compston DA, et al. Survival and cause of death
in multiple sclerosis: a prospective population-based study. J Neurol
Neurosurg Psychiatry. 2008;79(9):1016-1021.
865-874.
6. Smestad C, Sandvik L, Celius EG. Excess mortality and cause of
death in a cohort of Norwegian multiple sclerosis patients. Mult Scler.
2009;15(11):1263-1270.
7. Sumelahti ML, Hakama M, Elovaara I, et al. Causes of death among
patients with multiple sclerosis. Mult Scler. 2010;16(12):1437-1442.
8. Wallin MT, Page WF, Kurtzke JF. Epidemiology of multiple sclerosis
in US veterans. VIII. Long-term survival after onset of multiple sclerosis.
Brain. 2000;123( Pt 8):1677-1687.
9. Brooke EM. The current and future use of registers in health information
systems. Geneva World Health Organization Publication No. 8. Avail-
able at: http://whqlibdoc.who.int/offset/WHO_OFFSET_8.pdf.
10. European Commission Rare Diseases Task Force. Patient Registries in
the Field of Rare Diseases. Updated June 2011. Available at: http://
ec.europa.eu/health/rare_diseases/docs/patient_registries_rev2011.
pdf.
12. Making EUReMS count for people with multiple sclerosis. Lancet Neu-
rol. 2011;10(10):865.
13. Lalmohamed A, Bazelier MT, Van Staa TP, et al. Causes of death in
patients with multiple sclerosis and matched referent subjects: a popula-
tion-based cohort study. Eur J Neurol. 2012;19(7):1007-1014.
Table 6. British cohort study: Effect of
lifestyle factors on mortality13
Lifestyle factor Hazard ratio
All-cause mortality HR 3.51, 95% CI 2.63–4.69
Current smokers HR 6.72, 95% CI 4.16–10.87
BMI < 20 kg/m2
HR 6.67, 95% CI 3.50–12.73
HR=hazard ratio; BMI=body mass index
Adapted from: Lalmohamed et al. Eur J Neurol. 2012.13
Table 7. Causes of death in MS from
British cohort study13
Cause of death
MS
(N=69)
Control
subjects
(N=141)
Multiple sclerosis 30.4% 0
Cardiovascular disease 30.4% 45.4%
Cancer 20.3% 36.9%
Infectious respiratory diseases 58.0% 27.0%
Acute respiratory infections 27.5% 14.9%
Pneumonia only 24.6% 14.9%
Non-infectious respiratory diseases 21.7% 12.1%
Adapted from: Lalmohamed et al. Eur J Neurol. 2012.13

11
11
Impact of Treatment on Long-Term Survival
in MS: Summary of Results from Interferon
Beta-1b 21-Year Long-Term Follow-up Study
Anthony T. Reder, MD
Sven Schippling, MD
T
raditional descriptions of multiple sclerosis
(MS)฀characterize฀the฀disease฀as฀causing฀dis-
ability and health complications, but having
little effect on life expectancy.1-5
MS practitioners
sometimes observe a detrimental effect on patients’ life
span, particularly in progressive or severe disease, and
natural history studies of untreated MS patients show a
7- to 10-year decline in longevity.6
However, few hard
facts have permeated into the MS world. The topic of
“Expanded Disability Status Scale (EDSS) 10” is rarely
discussed with patients or family members.7,8
The
long-term effects of MS disease-modifying therapies
(DMTs) have been studied mostly in noncontrolled,
retrospective designs and primarily in terms of sur-
rogate outcomes or “soft” endpoints such as disability
and magnetic resonance imaging (MRI) of demyelinat-
ing effects.9-12
Few studies have investigated how MS
influences mortality and whether long-term DMT can
affect the odds of survival.13,14
Long-Term Follow-up of Pivotal Interferon
Trial
The original placebo-controlled studies of MS
therapies were initiated 20 or more years ago. These
trials generated baseline data about a group of people
with relapsing-remitting MS (RRMS) that can provide
information about survival time and cause of death.12
Long-term follow-up of the pivotal study of interferon
beta-1b (IFNβ-1b; Betaseron®
/Betaferon®
) had a high
ascertainment rate of 98.4%.13,15,16
After approximately
21 years, 366 of the 372 RRMS patients enrolled in
the pivotal study were located for assessment of the
primary endpoint of vital status and, if deceased, the
secondary endpoint of cause of death. The 6 patients
lost to follow-up were distributed equally among the 3
treatment arms of the pivotal study.15
In the original pivotal trial, beginning in 1988, 372
patients฀were฀randomized฀to฀one฀of฀3฀treatment฀arms:฀
placebo, 50 mcg IFNβ-1b, or 250 mcg IFNβ-1b (Fig-
ure 1).12,17
฀Patients฀remained฀on฀the฀randomized฀treat-
ment during the trial for a median of 3.8 years (maxi-
mum 5.1 years) before IFNβ-1b was licensed for use
in 1993 and every patient was offered active treatment
with IFNβ-1b. After the placebo-controlled phase
ended, all patients received “regular medical care”
going forward. Many of them switched to or remained
on the approved drug at 250 mcg.18
In a retrospec-
tive analysis, no significant differences were identified
among the groups in the level or type of medical care
received.16,19
No significant differences in baseline char-
acteristics were identified between the 3 groups in the
21-year long-term follow-up study (Table 1).15
These
baseline values differed from those seen in the current
trials of newer MS drugs, due to changes in the pat-
terns of MS diagnosis and treatment over the years.20
Patients enrolled in the pivotal interferon trials had a
7- to 8-year history of MS, were older at the time of
MS diagnosis (mean 30–32 years), had symptoms lon-
ger before their diagnosis (range 3–5 years), and were
older at study enrollment (mean 35–36 years). The
median EDSS score at baseline in each of the groups
was 3.0 (0–5.5), which is a higher degree of disability
From: Department of Neurology, Neurology and Inflammatory Dis-
ease Infusion Center, The University of Chicago, Chicago, IL (AR);
Department of Neuroimmunology and MS Research, Neurology
Clinic, University Medical Center Zurich, Zurich, Switzerland (SS).
Correspondence: Sven Schippling; email: sven.schippling@usz.ch.

12
than in treatment-naïve patients studied in more recent
clinical trials.21-23
Reduction in Mortality Among Patients
Started on Active Treatment vs. Placebo
At the 21-year follow-up, 285 of the 366 original
study participants available for follow-up were still
alive (78%) and 81 patients were deceased.15
The
primary endpoint of the IFNβ-1b 21-year follow-up
study฀was฀time฀from฀study฀randomization฀based฀on฀an฀
intent-to-treat analysis. The secondary endpoint was
cause of death, obtained through a variety of sources
including death certificates, and verified by an inde-
pendent adjudication
committee blinded to
the treatment group.24
There was a significant
reduction (P = 0.0173)
in all-cause mortality
among patients who were
originally assigned to
the 250 mcg interferon
arm vs. patients random-
ized฀to฀the฀placebo฀arm฀
(Figure 2).15
Those
treated with interferon
earlier had a reduced risk
of฀ dying฀ (hazard฀ ratio)฀
over the time span of 21
years of 46.8%. The 50
mcg interferon arm had a
similar฀46%฀hazard฀ratio฀
for mortality compared
to placebo.15
These findings suggest that initiating effective MS
therapy earlier in the course of the disease has an
important long-term effect on mortality, even if the
groups ultimately receive the same quality of treat-
ment approximately 5 years later. It is important to
note that what was considered “earlier treatment” in
the late 1980s does not reflect our current definition
of “early treatment” in MS. Today, early treatment is
better described as treatment with a DMT soon after
an initial demyelinating event, or in clinically iso-
lated syndrome (CIS). The effects of early treatment
on relapses are greater than in the pivotal trial. In the
BENEFIT study of patients with CIS, treatment with
IFNβ-1b significantly delayed conversion to clini-
cally definite MS (CDMS). At the end of the 2-year
study, 28% of patients in the treatment group had
developed CDMS compared to 45% of those receiv-
ing placebo (44% reduction).19
In the PreCISe Study
of CIS, treatment with glatiramer acetate significantly
delayed the onset of CDMS (time for 25% of patients
to convert to CDMS was prolonged by 115% over 2
years).25
Natural history data show that patients who
experience fewer MS relapses in the first 2 years after
diagnosis have significantly delayed onset of disability
from MS, as defined by time to reach EDSS 6 (Table
2).26
Together these findings suggest that delaying
Table 1. Baseline characteristics evaluated
in pivotal trial
• Sex (% female sex)
• Mean number of relapses in previous 2 years
• Median EDSS score
• Age at disease onset, diagnosis, and start of pivotal trial
• Duration of disease since onset; since diagnosis
• T2 burden of disease, cm2
• 3rd ventricular width, mm
Data adapted from Goodin et al. Neurology. 2012.15
Figure 1. 21-year long-term follow-up study design
LTF=long-term follow-up
IFNβ MS Study Group, et al. Neurology. 199517
; Ebers et al. J Neurol Neurosurg Psychiatry. 201018
; Reder et
al. Neurology. 201013
; Goodin et al. Neurology. 2012.15
Figure 1. 21‐Year long‐term follow‐up study design
Regular medical care*
Primary endpoint: All-cause mortality-free survival comparison between IFNB-1b 250
mcg vs. placebo per intent-to-treat
*No systematic differences in care observed
Betaseron approved
N=372
250 mcg
50 mcg
Placebo
1988 1993 2005 2006 2009 2010
98.4% ascertainment
Pivotal trial 16-year LTF 21-year LTF
LTF=long-term follow-up;
Primary endpoint: All-cause mortality-free survival comparison between IFNβ-1b 250
mcg vs. placebo per intent-to-treat

13
CDMS and limiting the number of early relapses may
have an important influence on long-term outcomes.
By today’s standard of MS care and early treatment,
patients could be expected to have improved long-term
outcomes, potentially including longer survival rates.
When the Kaplan-Meier survival curve from the
placebo arm of the 21-year long-term study is overlaid
with the survival curve from the Norwegian registry
study described in this issue,15,27
there is marked over-
lap. The parallel curves indicate that the outcomes of
MS patients in the placebo group, whose treatment was
delayed by approximately 3 years, are consistent with
those seen in other large studies (Figure 3). Similari-
ties in the course of MS
between multiple large-
scale studies further vali-
date our knowledge base
about the “natural his-
tory” of long-term out-
comes. The natural histo-
ry data are a comparator
for potential effects of
DMT on longevity.27
Baseline Predictors
of Poorer Outcome
The baseline disease
and demographic char-
acteristics of patients in
the pivotal IFNβ-1b trial
were well matched for all
known relevant variables
across the three treat-
ment arms. In the long-
term follow-up study,
these baseline data were
examined for any particular disease characteristics that
might predict poorer prognosis on the hard endpoint
of mortality (Table 3).14
This analysis showed that males with MS had a
slightly higher risk of mortality than females. Higher
disability measured with EDSS also predicted poorer
long-term prognosis. Among those who died, a higher
percentage had EDSS ≥ 3 at baseline (51.2% for living,
64.2% for deceased; P = 0.044). In addition, patients
with a higher baseline MRI T2 burden of disease had
a worse prognosis over 21 years (19.2 ± 20.0 cm2
for
living, 26 ± 25.4 cm2
for deceased; P < 0.002).7,28
Brain
atrophy,฀as฀quantitated฀by฀size฀of฀the฀third฀ventricle,฀
also appeared to be a baseline predictor of mortal-
ity. Patients with a higher rate of atrophy (>4.6 mm
vs. ≤4.6 mm) had a poorer prognosis. A bivariate
analysis was used to compare effects of these baseline
characteristics with the effect of treatment with IFNβ-
1b.฀Despite฀any฀of฀these฀predictors,฀the฀hazard฀ratio฀
(reduction of risk of dying over 21 years) in the IFNβ-
1b 250 mcg group vs. the placebo group remained
relatively consistent at approximately 0.5 across all the
baseline variables.28
This suggests that treating patients
with MS within 8 years of disease onset improved sur-
Figure 2. Time from study randomization to death15
HR=hazard ratio; CI=confidence interval; IFNβ-1b=interferon beta-1b
Reprinted with permission from Goodin et al. Neurology. 2012.15
Figure 2. Time from study randomiza;on to death
Earlier treatment with IFNB-1b was associated with a 46.8% reduction in the
hazard of dying for all-cause mortality over 21 years compared with initial
placebo treatment
At risk:
IFNB-1b 250 µg
Placebo
124
123
124
120
121
117
118
109
104
88
HR=0.532 (95% CI: 0.314–0.902)
46.8% reduction in hazard ratio
Log rank, P=0.0173
IFNB-1b 250 µg
Placebo
65%
70%
75%
80%
85%
90%
95%
100%
0 2 4 6 8 10 12 14 16 18 20 22
Proportion
of
patients
who
are
still
alive
Time (Years)
HR=0.532 (95% CI: 0.314–0.902)
46.8% reduction in hazard of dying
Log rank, P = 0.0173
HR=hazard ratio; CI=confidence interval; IFNB-1b=interferon beta-1b;
Table 2. Association between early
relapses and disability progression26
# Relapses in Years 1 and 2 Time to EDSS 6
1 22.7 years
2 18.7 years
> 3 15.1 years
Natural history of MS progression in untreated patient population
of 1023 in London, Ontario, followed yearly between 1972 and
1984. Data adapted from Scalfari et al. Brain. 2010.26
Earlier treatment with IFNβ-1b was associated with a 46.8% reduction in the
hazard of dying for all-cause mortality over 21 years compared with initial
placebo treatment
IFNβ-1b 250 µg
Placebo
At risk:
IFNβ-1b 250 µg
Placebo

14
vival regardless of whether the patient had other indica-
tors of poor prognosis.
Causes of Death: MS-Related?
The specific cause of death in a person with a chron-
ic, longstanding illness such as MS is often attributed
to factors other than the disease process. Attributing
a death to another disease such as pneumonia skews
the data away from MS-related mortality. In addition,
quality of healthcare can have a dramatic impact in the
later stages of MS, with careful maintenance of cardio-
pulmonary, urinary/renal,
and skin health directly
related to reduction of
life-threatening compli-
cations.29-31
Finally, the
added risks of lifestyle
factors such as smoking,
and comorbidities such as
diabetes mellitus, must be
taken into consideration
when calculating mortal-
ity risk.32,33
The 21-year follow-up
study had a dedicated
adjudication committee
to determine causes of
death in a blinded man-
ner.24
This committee
consisted of one member of the study steering com-
mittee, an independent neurologist (not involved with
the study), and an independent pulmonary/critical
care specialist. Of the 81 deaths occurring in the group
of 366 re-identified patients from the pivotal study,
causes of death were grouped into eight categories
(Table 4).7
Cause of death was considered always MS-related if
one or more of the following criteria were met: EDSS
score ≥ 7 at any time before death, suicide, or when
Figure 3. Natural history data vs. 21-year long-term follow-up
LTF=long-term follow-up; RRMS=relapsing-remitting multiple sclerosis; CI=confidence interval
Grytten Torkildsen et al. Mult Scler. 200827
; Goodin et al. Neurology. 2012.15
Proportion
of
patients
who
are
still
alive
RRMS
General
popula;on
95% CI
Figure 3. Natural history data vs. 21‐year LTF (placebo arm):
Time from disease onset to death
Data from
Norway
21-Year LTF
Placebo
RRMS=relapsing-remitting multiple sclerosis
Table 3. Baseline characteristics: deceased vs. alive
Characteristic
Alive
(n=285)
Deceased
(n=81) P value
Female sex, no. (%) 204 (71.6) 50 (61.7) 0.102
No. relapses in previous 2 yr (mean±SD) 1.7 ± 0.8 1.6 ± 0.8 0.606
EDSS score, median (range) 3.0 (0–5.5) 3.0 (0–5.5) 0.077
Proportion of EDSS ≥ 3 51.2% 64.2% 0.044
Age at disease onset, yr (mean±SD) 27.3 ± 6.7 27.8 ± 7.8 0.853
Age at diagnosis, yr (mean±SD) 30.8 ± 6.6 31.9 ± 7.5 0.309
Age at start of pivotal trial, yr (mean±SD) 35.2 ± 7.1 36.2 ± 7.5 0.347
Duration of disease since onset, yr (mean±SD) 7.9 ± 6.0 8.4 ± 6.7 0.714
Duration of disease since diagnosis, yr (mean±SD) 4.4 ± 4.1 4.4 ± 4.6 0.730
T2 burden of disease, cm2
(mean±SD) 19.2 ± 20.0 26.0 ± 25.4 0.002
EDSS=Expanded Disability Status Scale; SD=standard deviation; yr=years
Baseline characteristics of patients identiied at 21-year long-term follow-up at the start of the pivotal trial by vital status at 21-year long-
term follow-up.
Bayer HealthCare, data on ile

15
MS was listed on the death certificate as the only or
primary cause. Cause of death was considered “prob-
ably MS-related” when there was significant brain stem
pathology, pulmonary infection, aspiration pneumo-
nia, respiratory insufficiency, pulmonary embolism,
sepsis (especially urosepsis), or death due to trauma or
an accident. Cause of death was determined likely “not
to be related to MS” in cases of cancer, cardiovascular
disease, or other infections.7
Cause of death adjudication was possible for 69 of
the 81 deceased patients. The mean age at death was
51.7 with a significant standard deviation of ±8.7 years.
Of the 69 for whom cause of death could be assessed,
78.3% of deaths were determined by the committee
to be MS-related. Among the non-MS-related deaths,
there appeared to be no over-representation in any one
category or any unusual cause of death. Relatively early
deaths included 6 cancers and 10 vascular deaths.7
Among the 69 cases in which cause of death was
determined, the non-MS-related deaths were distribut-
ed roughly equally among the three arms of the trial.28
Among those who died of MS, however, a greater
proportion (26) were in the group assigned to receive
placebo at study onset compared with the IFNβ-1b
50 mcg and 250 mcg groups (12 and 16, respectively
(Table 5). Death from pulmonary infection was more
frequent in the placebo arm compared with the active
treatment arm.
Discussion
Although databases have provided survival informa-
tion on untreated patients with MS, the implications of
these survival findings have been largely overlooked by
MS societies and in patient literature.2,3
MS is indeed a
disease that can shorten life span. This information can
be applied as part of an overall approach to treatment
that฀emphasizes฀both฀quality฀of฀life฀and฀length฀of฀life.
With near-complete patient ascertainment (98.4%),
an฀initial฀randomized,฀placebo-controlled฀trial฀design,฀
and the longest period of follow-up for a treatment-
exposed MS population, the data from the 21-year
IFNβ-1b long-term follow-up study show benefit of
therapy on survival in patients with RRMS. The data
strongly suggest that mortality differences between
initial-placebo and active-treatment groups are MS-
related.
Because this study began in the 1980s, the data do
not show us what survival in MS might look like 20
years from now, considering the dramatic improve-
ments in the standards of MS diagnosis, treatment, and
overall disease management in the past 3 decades. Will
these advances in care close the gap between people
with MS and those without MS? A placebo group is no
longer a viable option for anything other than short-
term trials, so it is likely that a controlled study of this
nature will not be possible again. Future studies will
need฀to฀use฀different฀methods฀to฀analyze฀survival฀and฀
other long-term outcomes in MS.
Improvement in mortality risk is a powerful end-
point relevant to clinical trials in cancer, cardiovascular
disease, diabetes, and many other disease states, and is
often considered in the risk-benefit analysis for using
certain therapies. Patients and families are often aware
of new data regarding MS, and can now gain access to
the information on survival in this long-term follow-up
and in the accumulated registry data on survival in MS.
When discussing the data with patients and families,
the message should be a positive one because of the evi-
dence of improved survival in those who receive effec-
tive DMTs earlier in the disease process. o
Table 4. Cause of death categorization
used by adjudication committee
• Cardiovascular disease and stroke
• All cancers
• Pulmonary infectious disease
• Septicemia or sepsis
• Accidental death
• Suicide
• Other cause, multiple sclerosis
• Other cause, not listed
Table 5. Distribution of deaths in intent-to-
treat population
Of 81 total deaths, cause was determined for 69. Of these,
78.3% were determined to be MS-related.
Death
MS-related Placebo
IFNβ-1b 50
mcg
IFNβ-1b 250
mcg
No 6 5 4
Yes 26 12 16
NA* 5 5 2
*Not available. Cause of death not determined.
IFNβ-1b=interferon beta-1b
Data adapted from Reder et al. AAN 2012.7

16
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Engl J Med. 2000;343(13):938-952.
11. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon
beta-1a for disease progression in relapsing multiple sclerosis. The Mul-
tiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol.
1996;39(3):285-294.
12. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis.
I. Clinical results of a multicenter, randomized, double-blind, place-
bo-controlled trial. The IFNβ Multiple Sclerosis Study Group. Neurolo-
gy. 1993;43(4):655-661.
13. Reder AT, Ebers GC, Traboulsee A, et al. Cross-sectional study asses-
sing long-term safety of interferon-beta-1b for relapsing-remitting MS.
Neurology. 2010;74(23):1877-1885.
14. Goodin DS, Traboulsee A, Knappertz V, et al. Relationship between
early clinical characteristics and long term disability outcomes: 16 year
cohort study (follow-up) of the pivotal interferon beta-1b trial in multiple
sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(3):282-287.
Neurology. 2012;78(17):1315-1322.
16. Ebers GC, Reder AT, Traboulsee A, et al. Long-term follow-up of
the original interferon-beta1b trial in multiple sclerosis: design and
lessons from a 16-year observational study. Clin Ther. 2009;31(8):
1724-1736.
17. Interferon beta-1b in the treatment of multiple sclerosis: final outcome
of the randomized controlled trial. The IFNβ Multiple Sclerosis Study
Group and The University of British Columbia MS/MRI Analysis
Group. Neurology. 1995;45(7):1277-1285.
18. Ebers GC, Traboulsee A, Li D, et al. Analysis of clinical outcomes
according to original treatment groups 16 years after the pivotal IFNβ-
1b trial. J Neurol Neurosurg Psychiatry. 2010;81(8):907-912.
19. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early
treatment with interferon beta-1b after a first clinical event suggestive
of multiple sclerosis: 5-year active treatment extension of the phase 3
BENEFIT trial. Lancet Neurol. 2009;8(11):987-997.
20. Klawiter EC, Cross AH, Naismith RT. The present efficacy of multiple
sclerosis therapeutics: Is the new 66% just the old 33%? Neurology.
2009;73(12):984-990.
21. Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate
in patients with relapsing-remitting multiple sclerosis: a multicentre,
randomised, double-blind, placebo-controlled phase IIb study. Lancet.
2008;372(9648):1463-1472.
22. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial
of oral fingolimod in relapsing multiple sclerosis. N Engl J Med.
2010;362(5):387-401.
23. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral
laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):
1000-1009.
24. Ebers GC, Goodin DS, Reder AT, et al. Cause of death in patients with
multiple sclerosis: the 21-year long-term follow-up study. Program and
abstracts from the 21st Meeting of the European Neurological Society,
May 28-31, 2011, Lisbon, Portugal. Poster P429.
25. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate
on conversion to clinically definite multiple sclerosis in patients with
clinically isolated syndrome (PreCISe study): a randomised, double-
blind, placebo-controlled trial. Lancet. 2009;374(9700):1503-1511.
26. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of
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term disability. Brain. 2010;133(Pt 7):1914-1929.
28. Data on file. Bayer Healthcare, July 6, 2011.
29. Ben-Zacharia AB. Therapeutics for multiple sclerosis symptoms. Mt
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30. Bergamaschi R. Prognosis of multiple sclerosis: clinical factors predict-
ing the late evolution for an early treatment decision. Expert Rev Neu-
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32. Marrie RA, Horwitz R, Cutter G, et al. Comorbidity delays diag-
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17
17
From: Department of Neurology, The Institute of Neuroscience,
Newcastle University, Newcastle upon Tyne, England (DB); Depart-
ment of Psychology, Royal Holloway University of London, London,
England (DL). Correspondence: Dawn Langdon; email: d.langdon@
rhul.ac.uk.
Life Expectancy in MS: Communication
Strategies for Clinicians and Advocacy
Organizations
David Bates, MA, MB, BChir, FRCP
Dawn Langdon, MA, MPhil, PhD
O
nly a few decades ago, healthcare practitio-
ners debated whether to convey a diagnosis
of multiple sclerosis (MS) immediately to a
patient, or whether to delay this news. When delayed,
it was presumably for the sake of preserving the per-
son’s emotional well-being until a clearer diagnostic
determination could be made.1
Likewise, cognition,
sexuality, and other seemingly “difficult” topics related
to MS and once considered taboos have gradually
become more open avenues for communication with
patients.
With new data emerging from multiple studies on
survival in MS,2-4
a similar debate has evolved about
how to communicate these findings to people with
this disease. This question is particularly relevant given
that the new data challenge the previous understanding
about long-term prognosis in this disease, demonstrat-
ing consistently that MS reduces overall life expec-
tancy.4-6
Should MS practitioners and MS advocacy
organizations฀steer฀clear฀of฀the฀topic฀of฀survival฀alto-
gether? Play it down to avoid increasing patients’ anxi-
ety about the unknown? Or promote it as part of a call
to improve awareness and care of the disease?
In June 2012 a distinguished group composed of 20
representatives from MS medical and patient advocacy
organizations฀worldwide฀(Table 1) convened in Oslo,
Norway, to review the current survival data and discuss
the most appropriate strategies for communicating this
information.฀The฀overall฀consensus฀emphasized฀mes-
sages of hope, about the potential to improve longevity
in MS with early and effective treatment, and acknowl-
edged patients’ goals for improved quality of life along
with increased life expectancy.
Table 1. MS Patient Advisory Board
meeting participants
Communicating life expectancy in MS: Is it time for reas-
sessment?
Oslo, Norway, June 22, 2012
Vanja Bašic Kes, Croatia
David Bates, United Kingdom
Karl Baum, Germany
Ulf Baumhackl, Austria
Jack Burks, USA
Eleonora Cocco, Italy
Stuart Cook, USA
Douglas Franklin, USA
Andras Guseo, Hungary
Judith Haas, Germany
June Halper, Consortium of MS Centers, USA
Beatrika Koncan Vracko, Slovenia
Jerzy Kotowicz, Poland
Dawn Langdon, UK
Elizabeth McDonald, Australia
Lea-Anne Morgan, New Zealand
Kjell-Morten Myhr, Norway
Juhani Ruutiainen, Finland
Sven Schippling, Switzerland
Christoph Thalheim, European MS Platform, Belgium

18
Patient Preferences for Communication of
MS Prognostic Information
It is not uncommon for MS texts, websites, and
even current literature to state that MS does not affect
survival.7-10
This trend has persisted despite contradic-
tory research findings and clinical experience, and may
reflect an outdated or even somewhat “paternalistic”
view—that patients are better off not dwelling on a
negative concept that may or may not affect them.11
This avoidance mirrors that of other “difficult”
topics in MS that were formerly delayed or avoided—
such as cognition or sexual dysfunction—but are now
integral topics in MS education.12-16
Even the timing
of delivering an MS diagnosis has been the subject of
debate. Overall, studies show that patients prefer ear-
lier disclosure of an MS diagnosis, but not all patients
report having been satisfied with this experience.17-20
In
a 2004 survey of Greek patients with MS, 91% favored
learning the diagnosis immediately, but only 44%
reported having this experience.21
When these authors
surveyed Greek neurologists 4 years later, 95% of the
217 physicians responding said they favor informing a
patient of a definite MS diagnosis and 74% said they
do so immediately.22
Yet only 42% said they use the
term “multiple sclerosis” in this discussion (instead
using terms such as “demyelinating disorder”). The
neurologists surveyed noted that patients’ personali-
ties and mental status were factors in their timing and
approach to communication of the diagnosis.22
In
contrast, Janssens and colleagues from the Netherlands
determined that patients prefer an earlier diagnosis and
found that 75% of patients surveyed were satisfied with
the timing of diagnosis disclosure.23
A paper by Chalfant and colleagues from Australia
suggested that the news of an MS diagnosis could trig-
ger symptoms of posttraumatic stress disorder (PTSD)
in some individuals.19
According to these authors, the
current Diagnostic and Statistical Manual of Mental
Disorders฀recognizes฀life-threatening฀illness฀as฀a฀poten-
tial stressor that can precipitate PTSD.24
Of 58 MS
patients evaluated for PTSD, 9 (16%) met symptom
criteria. “These findings suggest that a significant pro-
portion of MS patients experience PTSD-type reac-
tions,” they concluded.19
What do we know about patients’ preferences
regarding discussion of prognosis and life expectancy
in MS? One might think that patients would prefer to
avoid “depressing” topics such as end-of-life consider-
ations, but current research by Buecken and colleagues
from Germany contradicts this notion.25
In a survey to
which 573 people with MS responded, 62% (n=358)
said they wanted the subject of disease progression and
death and dying to be addressed by their physicians.
Breaking this question down, 76% of those surveyed
said they thought discussion of disease progression was
important, while 44% said they thought discussion of
death and dying was unimportant. A significant portion
of surveyed patients who felt their doctors were avoid-
ing the discussion of uncomfortable topics perceived
these doctors as “less empathetic” (P < 0.001).
These authors and others recommend that MS care
practitioners use empathy and individual judgment
in discussing critical aspects of patients’ illness. The
ultimate goal is to provide balanced, accurate informa-
tion and support to the individual, rather than creating
or exacerbating emotional distress. Janssens and col-
leagues investigated how the perception of prognostic
risk affected the potential for anxiety, depression,
and disease-related distress in 101 people with MS.26
Patients were asked how they perceived their risk of
2-year, 10-year, and lifetime prognosis for wheelchair
dependence, disability status, anxiety, depression, and
disease-related distress. Patients who had higher per-
ceptions of these risks were bothered by more intrusion
of MS-related thoughts and feelings. Those who felt
they had a high 2-year risk of wheelchair dependence
had significantly higher levels of anxiety and depres-
sion. The authors noted that the findings “underscore
the importance of informing patients with chronic
disorders about the short-term prognosis of important
long-term consequences of disease.”26
Many experts caution that the manner of commu-
nication is often as important as the content of the
message. Solari and colleagues studied how people in
Italy respond to the news of their MS diagnosis, based
on focus group meetings involving neurologists, nurses,
psychologists, and people with MS.17
All 23 people
with MS reported the discovery of their diagnosis as a
powerfully evocative and unforgettable moment. Many
noted poor levels of support and information sur-
rounding the moment. The authors suggested that fur-
ther improvements be made in communication of dif-
ficult subjects, including appropriate setting (privacy,
no interruptions, sufficient time), information tailored
to the individual, and continuity of care.17

19
Rationale for Communicating Life
Expectancy Data to MS Patients
At the meeting in Oslo in June 2012, international
representatives฀of฀MS฀advocacy฀and฀medical฀organiza-
tions split into groups to share their views and experi-
ences regarding communication of life expectancy and
prognosis to patients with MS. The groups generally
agreed that survival information should be included
as part of the educational message for most patients,
based on the following rationale:
•฀Many฀people฀with฀MS฀today฀are฀well฀informed฀and฀
use online sources to maintain a high level of current
knowledge about their disease. New survival data are
widely available via Internet sources. However, while
population-based studies are useful for predicting
outcomes in large groups, they are not useful for
predicting the outcome or expected course for any
given individual. Thus, the information must be put
into context for each individual by health profession-
als who are familiar with the patient.
•฀Data฀emerging฀from฀the฀21-year฀long-term฀follow-
up study2
and the MS international registries4-6,27,28
are considered by thought leaders and advocates to
be robust, convincing, and important as part of an
overall message about early treatment.
•฀The฀21-year฀data฀show฀a฀46.8%฀decrease฀in฀all-cause฀
mortality for patients whose treatment is initiated
early in the course of their disease.2
The message of
hope is that people with MS should be encouraged
to start treatment early and maintain therapy with
effective agents. Although long-term survival data
are currently available for only interferon beta-1b,
this finding is believed likely to be applicable to
other MS disease-modifying agents.
•฀The฀recent฀revisions฀to฀the฀McDonald฀MS฀diagnos-
tic criteria by Polman and colleagues should result
in earlier diagnosis of milder disease and may render
the historical survival data obsolete.29
•฀The฀group฀acknowledged฀that฀discussion฀of฀life฀
expectancy and long-term prognosis is common in
the management of many disease states (e.g., car-
diovascular disease, diabetes, many cancers).30-35
In
these conditions therapeutic decisions may be partly
based on whether a treatment increases the odds of
survival (for example, in secondary stroke preven-
tion).36,37
As consideration of survival outcomes
becomes part of the standard of care in an increasing
number of chronic disease states, it is reasonable to
expect that this component will be incorporated into
the decision-making process in MS.
Barriers to discussing survival in MS were also
assessed by the group, as listed in Table 2. Among
them were cultural and patient-specific differences in
attitudes about disease prognosis, time constraints for
counseling patients adequately, and concerns about
suicide among people with MS. However, the group
agreed that there is a greater potential for patients to
receive misleading information from other sources
(e.g., gossip about celebrities who have MS); thus the
opportunity to address the information in a profession-
al setting is usually in the best interest of the patient.
Communication Strategies for MS
Clinicians
For MS clinicians, the group concurred that mes-
sages about survival should be part of an overall posi-
tive message, which includes:
•฀The฀beneits฀of฀early฀and฀effective฀disease-modifying฀
treatment
•฀Focus฀on฀quality฀of฀life฀and extending length of life
when possible
•฀Managing฀MS฀in฀the฀whole฀person
•฀Emphasis฀on฀the฀positive฀strides฀made฀in฀MS฀thera-
py and management.
In their analysis of professional communication
strategies for patients with chronic diseases (including
MS, fibromyalgia, end-stage renal disease, and non-
insulin-dependent diabetes), Thorne and colleagues
observed that “courtesy, respect, and engagement”
are overall communication priorities expressed by
patients.38
These authors have identified several com-
Table 2. Barriers to discussing survival
information with MS patients
• Attitudes about this topic may differ among cultures
• In some areas, early treatment is not available or not
reimbursed
• A certain percentage of patients may have no interest in
discussing survival
• Clinicians may have a fear or hesitancy about conveying
“bad news”
• Concerns about risk of suicide among people with MS
• Lack of time for adequate counseling of patients (great-
er priorities on existing symptoms and disease control
rather than projecting into the future)

20
munication approaches that patients rated as helpful,
in contrast to unhelpful approaches that may be per-
ceived as a turn-off or condescending (Table 3).38,39
This might include introducing topics using open-
ended questions, to determine what the person/family
understand already and how the message might be best
tailored for them.
Clinicians and other MS educators should exercise
judgment in determining how to best communicate
survival and prognosis information about the disease,
taking into account educational and cultural differ-
ences among individuals.
Communication Strategies for MS
Advocacy Organizations
MS฀patient฀advocacy฀organizations฀have฀played฀an฀
enormously important role in improving patient care,
increasing education and public awareness, and sup-
porting research and advancement of knowledge in this
disease. Meetings such as the one held in Oslo are an
important way for advocacy group representatives from
around the globe to share ideas and gain an under-
standing of the challenges and changes encountered
by these groups and the people they represent. The
breakout groups at the Oslo meeting agreed that MS
advocacy฀organizations฀have฀a฀role฀in:
•฀Setting฀a฀positive฀tone฀for฀the฀messages฀about฀MS฀to฀
patients and the public at large
•฀Providing฀balanced,฀accurate฀information
•฀Providing฀support฀and฀education฀for฀clinicians
•฀Developing฀tools฀to฀help฀MS฀clinicians฀educate฀their฀
patients
•฀Advocating฀on฀behalf฀of฀patients฀with฀financial฀
decision-makers.
Regarding communication of the message about
MS฀survival,฀representatives฀of฀advocacy฀organizations฀
at the meeting generally felt that survival information
should be communicated to the public. The manner
and approach to communication are important, and
cultural differences and local practices should be taken
into account. As such, representatives of MS patient
advocacy groups should assess the communication and
educational needs within their constituent communi-
ties. MS advocacy groups serve as a valuable resource
to฀clinicians,฀healthcare฀organizations,฀and฀the฀public.฀
Because practicing MS clinicians often lack the time
and/or the counseling experience required to best
frame discussions involving prognosis and survival, MS
advocacy groups should work with MS care facilities in
the area to develop tools that can be used by clinicians
to educate patients.
Table 3. Helpful and unhelpful communication in MS
Coping focus Helpful Unhelpful
Managing fear Timely, relevant, accurate information Withholding information, using statistics,
sugarcoating
Validating patient experience Dismissing patient claims
Taking charge Assistance from healthcare professionals Feeling alone and isolated in managing MS
Providing as much information as possible—
more is better
Inaccurate or outdated information, false hope
Acknowledging the limits of medical science Belief that medical science has all the answers
Crafting a life MS is only one aspect of their life MS is their life
Validating symptoms Minimizing symptoms
Willingness to learn and explore therapeutic
alternatives
Inlexibility in thinking and researching
Respecting the patient as a competent and
knowledgeable partner
Condescension, platitudes, reprimanding
Adapted with permission from: Thorne et al. Patient Educ Couns. 2004.38

21
Conclusion
The available data on survival in MS provide a
strong rationale for decreasing disability and delay-
ing death by initiating early and probably continuous
therapy in MS patients with approved disease-modify-
ing agents. This information should be given to most
patients early, at the time of initial definitive diagno-
sis or shortly thereafter. An important caveat, which
should be conveyed to patients, is that many deaths
appear to be related to advanced or aggressive forms
of MS. Many of these cases may now be preventable
through early treatment with the currently available
and emerging MS disease-modifying agents. o
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22
1. Findings from multiple sclerosis (MS) population-based
registries in Europe and the United States show a pattern of
reduced life expectancy ranging from:
A. 3 to 5 years
B. 8 to 12 years
C. 12 to 15 years
D. no consistent patterns have emerged
2. The correct term for “a file of documents containing uni-
form information about individuals, collected in a system-
atic manner” is:
A. database
B. cohort
C. registry
D. archive
3. In the Western Norway MS study, factors found to increase
risk of mortality during the study period included all of the
following except:
A. female gender
B. primary progressive course
C. younger age at onset of MS
D. diagnosis between 1983 and 2003
4. In the Western Norway MS study and others described in
this issue, the cause of death for most people with MS is
attributed to a cause other than MS.
A. True
B. False
5. In the interferon beta-1b (IFNβ-1b) 21-year follow-up study,
the reduction in mortality risk among patients receiving ini-
tial active treatment (250 mcg) vs. those randomized initially
to placebo was:
A. 22.8%
B. 38.3%
C. 46.8%
D. 54.7%
6. In the IFNβ-1b 21-year follow-up study, baseline factors
associated with higher mortality risk included all of the fol-
lowing except:
A. female gender
B. higher baseline EDSS
C. higher brain atrophy measure
D. higher T2 disease burden
7. In the IFNβ-1b 21-year follow-up study, significant brain
stem pathology was classified by the adjudication committee
as a cause of death that was:
A. always MS-related
B. probably MS-related
C. likely unrelated to MS
D. indeterminate
8. Limitations to the IFNβ-1b long-term study data on mortal-
ity in MS include all of the following except:
A. data do not reflect a population on long-term disease-modi-
fying therapy (DMT)
B. similar data are not available for multiple DMTs
C.฀ data฀are฀not฀from฀a฀randomized,฀placebo-controlled฀study
D. data are not replicable with additional placebo-controlled
studies
9. Discussing survival information with people with MS has
been likened to the challenges of discussing what other
aspects of the disease?
A. diagnosis
B. cognitive dysfunction
C. sexual dysfunction
D. all of the above
10. Being informed of an MS diagnosis has been associated
with symptoms of posttraumatic stress disorder in some
individuals.
A. True
B. False
11. The group of MS advocates and clinicians that convened
in Norway in June 2012 agreed that survival should be
discussed with patients as part of a positive message that
includes:
A. clear evidence that survival rates will improve with the cur-
rently available treatments
B. clear evidence that all approved disease-modifying treat-
ments have a similar effect on survival
C. focus on quality of life and positive strides made in MS
therapy and management
D. all of the above
12. The barriers encountered by MS care providers in discuss-
ing survival information with patients include:
A. evidence that most patients do not want to discuss longevity
data
B. fear or hesitancy on the part of the clinician in conveying
bad news
C. lack of survival data representing a wide geographical region
D. lack of consistent survival findings among natural history
studies of MS
Posttest
A New Perspective on Survival Outcomes in Multiple Sclerosis
To receive contact hours, please read the program in its entirety, answer the following posttest questions, and complete the
program evaluation. A certificate will be awarded for a score of 75% (9 correct) or better. A certificate will be mailed within 4
to 6 weeks. There is no charge for CME credit.
By Mail: CMSC, Attn: CPE Dept., 359 Main Street, Suite A, Hackensack, NJ 07601
By Fax: 201-678-2290
Via the Web: Program can be accessed on the International Journal of MS Care (IJMSC) website, http://IJMSC.org. Click
on the appropriate supplement and follow the instructions to complete the online posttest and evaluation forms.

23
A New Perspective on Survival Outcomes in Multiple Sclerosis
Please answer the following questions by circling the appropriate rating:
5 = Outstanding 4 = Good 3 = Satisfactory 2 = Fair 1 = Poor
Extent to Which Program Activities Met the Identified Objectives: After completing this activity, participants should be better able to:
1) Discuss new findings from the recent retrospective controlled study and registry data pertaining to survival in MS to enhance treatment
decisions based on these data related to patient outcomes ............................................................................................................................ 5 4 3 2 1
2)฀Analyze฀current฀data฀about฀long-term฀effects฀of฀disease-modifying฀treatment฀in฀MS฀on฀outcomes฀including฀disability฀and฀life฀expectancy฀ 5 4 3 2 1
3) Apply strategies for discussing long-term prognosis and survival with patients and families, taking into account disease-specific, personal,
regional, and cultural factors ....................................................................................................................................................................... 5 4 3 2 1
To what extent was the content:
4)฀Well-organized฀and฀clearly฀presented .......................................................................................................................................................... 5 4 3 2 1
5) Current and relevant to your area of professional interest............................................................................................................................ 5 4 3 2 1
6) Free of commercial bias............................................................................................................................................................................... 5 4 3 2 1
7) Clear in providing disclosure information................................................................................................................................................... 5 4 3 2 1
General Comments
8) As a result of this continuing education activity (check only one):
r I will modify my practice. (If you checked this box, how do you plan to modify your practice?) _________________________________
__________________________________________________________________________________________________________
r I will wait for more information before modifying my practice.
r The program reinforces my current practice.
r No, I will not modify my practice.
Please indicate any barriers you perceive in implementing these changes:
r Cost r Cultural or language barriers
r Lack of time to assess/counsel patients r Reimbursement/insurance issues
r Lack of administrative support r Concerns about patient safety/well being
9) This activity will assist in the improvement of my (check all that apply):
r Competence r Performance r Patient outcomes
Suggestions for future topics/additional comments: _____________________________________________________________________
__________________________________________________________________________________________________________
Follow-up
As part of our continuous quality-improvement effort, we conduct postactivity follow-up surveys to assess the impact of our educational interven-
tions on professional practice. Please check one:
r Yes, I would be interested in participating in a follow-up survey.
r No, I would not be interested in participating in a follow-up survey.
There is no fee for this educational activity.
Request for Credit (Please print clearly)
Name_________________________________________________________________ Degree ____________________________________
Organization __________________________________________________________ Specialty ____________________________________
Address ____________________________________________________________________________________________________________
City _____________________________________________________________________________ State____________ ZIP_____________
Phone ___________________________________________________________________________ Fax________ E-mail _____________
Signature ________________________________________________________________ Date __________________________________
EVALUATION FORM
By Mail: CMSC, Attn: CPE Dept., 359 Main Street, Suite A, Hackensack, NJ 07601
By Fax: 201-678-2290
Via the Web: Program can be accessed on the International Journal of MS Care (IJMSC) website, http://IJMSC.org. Click on the appropriate
supplement and follow the instructions to complete the online posttest and evaluation forms.
Posttest Answer Key
1 2 3 4 5 6 7 8 9 10 11 12

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