777377

research-article2018
MSJ0010.1177/1352458518777377Multiple Sclerosis JournalM Riemenschneider, LG Hvid

MULTIPLE
SCLEROSIS MSJ
JOURNAL

Topical Review

Is there an overlooked “window of Multiple Sclerosis Journal

2018, Vol. 24(7) 886­–894

opportunity” in MS exercise therapy? DOI: 10.1177/

https://doi.org/10.1177/1352458518777377
1352458518777377
https://doi.org/10.1177/1352458518777377

Perspectives for early MS rehabilitation © The Author(s), 2018.

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Morten Riemenschneider , Lars G Hvid, Egon Stenager and Ulrik Dalgas

Abstract: While early medical treatment has proven effective in MS, early-phase MS rehabilitation has Correspondence to:
M Riemenschneider
not gained much attention in MS research and clinical practice. Exercise therapy is one of the most prom- Department of Public Health,
Section of Sport Science,
ising treatment strategies in MS rehabilitation. Here, we provide a topical review investigating when Aarhus University, Dalgas
exercise therapy is initiated in existing MS studies, showing that exercise is initiated at a rather late Avenue 4, 8000 Aarhus C,
Denmark.
disease stage, where it predominantly serves as a symptomatic treatment. Recent findings in MS sug- mori@ph.au.dk
gest that exercise may have neuroprotective and disease-modifying effects. Such findings along with the Morten Riemenschneider
Lars G Hvid
findings from medical trials that an early-stage “window of opportunity” exists leads to the proposal that Ulrik Dalgas
early exercise therapy should be an increased focus in research and clinical practice for persons with MS. Department of Public Health,
Section of Sport Science,
A further perspective relates to other rehabilitation interventions that are also initiated at a later disease Aarhus University, Aarhus C,
Denmark
stage, as these may also take advantage of an early-phase approach.
Egon Stenager
Institute of Regional Health
Research, University of
Keywords: Multiple sclerosis, rehabilitation, exercise therapy, early treatment, window of opportunity Southern Denmark, Odense,
Denmark/Department of
Neurology, MS-Clinic
Date received: 23 February 2018; revised: 10 April 2018; accepted: 24 April 2018 of Southern Jutland
(Sønderborg, Esbjerg,
Kolding), Sønderborg,
Denmark
Introduction initiation of rehabilitative interventions are currently
In multiple sclerosis (MS), great medical advances existing in MS research.
have been made, resulting in a substantial number of
disease-modifying therapies (DMTs). One recent find- Exercise therapy is one of the most promising and
ing is that initiation of medical treatment at an early well-researched rehabilitative interventions in MS,
disease stage affects the progression of MS more than and it has numerous beneficial effects on symptoms
at a later stage.1 Specifically, Comi et al.2 reported that in persons with MS.8 Of note, a recent study further-
early interferon-beta (IFN-β) treatment positively more provided the first data on the benefits of exer-
influenced the rate of conversion from clinically iso- cise on MRI outcomes, suggesting a potential
lated syndrome (CIS) to clinical definite MS as well as neuroprotective and disease-modifying effect in per-
magnetic resonance imaging (MRI) measures of dis- sons with MS,9 and such effects of exercise may add
ease activity and lesion burden. Furthermore, post hoc further importance to an “early treatment” approach
analyses from the TRANSFORMS and FREEDOMS in MS. To substantiate whether there is a lack of
phase 3 studies showed superior efficacy of fingoli- “early treatment” exercise studies in MS, the aim of
mod on relapse rate and lesion load in patients who this paper is to review the existing literature on treat-
had their first symptom less than 3 years ago.3 Despite ment initiation of exercise therapy. Based on this
the advances in DMT, MS is still a serious and detri- review, we will discuss if there may exist an over-
mental condition with significant disease activity, looked “window of opportunity” in exercise therapy
impaired neurological functions, and progression of of persons with MS.
disability that requires effective adjuvant rehabilitative
interventions.4 In a number of related neurological dis-
orders including stroke,5 diabetic neuropathy,6 and What do we do?
Parkinson’s disease,7 early initiation of rehabilitative Exercise therapy - defined as planned and systemati-
efforts are considered crucial in optimizing the effects cally structured repetitive physical activity - has
of the specific rehabilitation treatment. To our knowl- gained substantial attention over the last two decades
edge, no reviews or original studies focusing on early and is now widely recommended for patients with

886 journals.sagepub.com/home/msj

MS.8 But how and when do we tend to use exercise
therapy in the treatment of MS?
Exercise therapy covers a spectrum of exercise
modalities ranging from endurance training to resist-
ance training, all of which are safe and feasible in
patients with MS.10 Despite the variety of symptoms
displayed by patients with MS, a wide range of func-
tional and health-related parameters are generally
modifiable by exercise.11 In specific, original and
review studies have focused intensely on investigat-
ing the beneficial effects of exercise on fatigue, bal-
ance, walking, cognition, depressive symptoms, and
quality of life.12–15 Also, the effects of different exer-
cise modalities and a potential dose–response rela-
tionship has been evaluated.16 However, none of the
existing reviews have focused extensively on when in
the disease course exercise therapy has been applied,
and a knowledge gap seems to exist for this part. A
previous comprehensive literature review focusing on
the effects of exercise therapy included 54 studies
published until 2012, did summarize some informa-
tion on the respective study populations, but did not
make in-depth analyses of the timing of exercise
interventions.14 We therefore updated the review by
conducting a literature search in the electronic data-
bases MEDLINE and EMBASE. The search terms
included “exercise” OR “exercise therapy” AND
“multiple sclerosis,” and clinical trials published from
2012 and forward were included. Pilot studies, studies
reporting on the same exercise intervention as a previ-
ous article, and studies without sufficient information
on disease duration in the intervention group were
excluded. Figure 1 illustrates the timing of exercise
initiation in the existing exercise studies providing
sufficient information on disease duration. Data were
taken from the previous review by Latimer-Cheung et
al.14 as well as from the current review. The mean
(95% confidence interval) disease duration was calcu-
lated for each study. It is clearly shown that an unin-
vestigated “window of opportunity” exists both in the
early stages after diagnosis, but also in the diagnostic
delay from the debut symptom to the actual time of
diagnosis (illustrated by the hatched area in Figure
1).17
Specifically, the study with the lowest average disease
duration at baseline in the intervention group included
patients with a mean (standard deviation (SD)) of 4.9
(2.3) years since diagnosis.83 Consequently, initiation
of exercise therapy at an early disease stage has so far
not been investigated. This is probably due to the gen-
eral focus on the effects of exercise on symptoms and
physical function. Hence, patients with clearly evident
and manifested symptoms and functional disabilities
journals.sagepub.com/home/msj
M Riemenschneider, LG Hvid et al.
are generally included to evaluate the positive impact
of exercise. In support, 89% of the exercise therapy
studies in the current review have included patients
with a mean Expanded Disability Status Scale (EDSS)
score of ≥3, suggesting mild to moderate disability in
numerous functional systems. In some studies, certain
symptoms served as inclusion criteria, where patients
have to display severe levels of a particular
symptom.55,61,67,80,84
Specific guidelines on exercise therapy do exist for per-
sons with MS,14,16 but these only recommend exercise as
a tool to manage certain MS symptoms and improve gen-
eral health. This will likely contribute to a rather late
introduction of exercise in clinical practice, and exercise
therapy from an early time-point in the disease course is
thus not a fully integrated part of MS care.85 Consequently,
patients with MS are generally still less physically active
than advised when compared to healthy persons.86 This
invites an evaluation of what we know from early treat-
ment strategies in other areas and thus a rethinking of the
current use of exercise in clinical practice.
What do we know?
Currently, we have substantial knowledge about the
beneficial effects of different exercise modalities in
persons with MS.13 However, one aspect that seems to
have slipped the attention of researchers and clini-
cians in the field of exercise therapy and rehabilita-
tion in MS is the impact of “timing.”
From research on medical DMTs, it is well-known
that the timing of treatment initiation is crucial for the
long-term prognosis.4,87 The rationale underlying
early medical treatment in MS is to preserve the neu-
rological reserve of patients. Neurological reserve is
generally defined by two components: brain reserve
(the actual volume of the brain) and cognitive reserve
(the processing abilities of the brain).88 The neuro-
logical reserve is thus the capacity of the central nerv-
ous system (CNS) to compensate for MS-related
injuries. By preservation of the neurological reserve,
the critical point by which injuries to the CNS are
irreversible and manifests as clinical symptoms is
likely postponed. Therefore, the purpose of therapeu-
tic strategies should be to minimize relapse rate, num-
ber and volume of lesions, and general brain atrophy.
Importantly, trials have shown that different medical
DMTs that are initiated at an early disease stage are
capable of precisely that.89 In particular, several stud-
ies suggest that there are a “window of opportunity”
early in the disease course before irreversible neuro-
logical damage manifests, as DMTs have proven
more effective in terms of reducing relapse rate,3,87,90
887
Multiple Sclerosis Journal 24(7)
Figure 1. Overview of MS exercise studies and the overlooked “window of opportunity.”18–82
lesion load,3,90,91 brain atrophy,87 and disability pro-
gression,87,90–94 when initiated within this window.
This emphasizes that timing of treatment initiation is
of great clinical importance in MS.
Although there have been no studies examining the
impact of timing, recent investigations of the poten-
tial neuroprotective and disease-modifying effects of
exercise may pave the way for a new and somewhat
overlooked application of exercise in MS. Several
888
animal studies have shown that exercise can delay
disease-onset and attenuate disease severity in mice
with Experimental Autoimmune Encephalomyelitis
(EAE) - an animal model of MS - by protecting
against inflammatory infiltration, demyelination, and
axonal loss.95–97 In human subjects, a recent review of
exercise therapy studies reported a lower relapse rate
(27% reduction) in patients involved in exercise inter-
ventions, when compared to control groups, indicat-
ing a disease-modifying effect of exercise.10 In line
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 M Riemenschneider, LG Hvid et al.

Figure 2. (a) Conceptual figure showing the functional and neurological reserve in persons with MS throughout the
disease course, and the effects of different medical treatment strategies and the hypothetical effects of timing of exercise
therapy initiation. (b) The functional and neurological reserve in persons with MS and the effects of exercise based on
information from previous reviews regarding the effects of exercise on MS11,12.

with this, Tallner et al.98 observed a trend toward a
lower relapse rate in patients with MS with a high ver-
sus low Sport Index (participation in structured exer-
cise). Finally, and most recently, the first pilot data on
the benefits of exercise on MRI outcomes in persons
with MS were published. In the randomized con-
trolled cross-over study by Kjolhede et al.9 including
relapse–remitting MS patients all treated with IFN-β,
24 weeks of progressive resistance training showed a
trend toward reduced brain atrophy along with indica-
tions of lesion shrinkage. Furthermore, higher abso-
lute cortical thickness values were observed in 19 of
74 investigated cortical regions. Altogether, the
results from this study are the first to suggest direct
neuroprotective and disease-modifying effects fol-
lowing high-intense exercise on biomarkers of dis-
ease progression in MS.
Why don’t we?
With the new insights into the effects of exercise
therapy, along with the established consensus from
medical trials in MS, that there is an “window of
opportunity” early in the disease course for

journals.sagepub.com/home/msj 889
Multiple Sclerosis Journal 24(7)
disease-modifying treatments,1 why not initiate
exercise therapy early in the disease course as well?
Potentially already at the time of the first MS symp-
toms. It may be possible to postpone the conversion
to clinical definite MS and furthermore to preserve
the neurological reserve as well as the physical and
functional reserve of patients even better than by the
existing medical DMTs alone. Initiation of exercise
therapy before irreversible neuronal damage and
degeneration occurs may ultimately reduce the man-
ifestation and progression of disabilities further.
This novel concept is presented in Figure 2(a), and
Figure 2(b) details the elements and status of the
functional and neurological reserve in persons with
MS and the effects of exercise.
Early initiation of exercise therapy is a specific exam-
ple, but the concept may hold even greater perspec-
tives. Some symptoms and functional deficits are
present already in the early stages of MS (e.g.
fatigue,88 walking,99 cognition100), and early imple-
mentation of exercise therapy as well as other reha-
bilitative strategies may reduce or even postpone
these impairments. As such, this concept may apply to
a broader field of rehabilitative interventions in MS.
If early rehabilitation can postpone functional and
neurological impairments in addition to DMTs, this is
of great interest to the individual MS patient, yet also
to the health care system. A recent report on the costs
of MS in Europe revealed that medical DMTs repre-
sent the majority of health care costs for patients with
mild MS.101 Early implementation of exercise therapy
and other rehabilitory interventions may be a cost-
effective adjuvant strategy to reduce disability pro-
gression and the huge costs associated with this even
further. Also, early rehabilitory interventions may
improve the general health of the patients and thereby
reduce the increased risk of lifestyle-related comor-
bidities to a greater extent.102
Conclusion
Medical trials imply that there is a “window of oppor-
tunity” early in the disease course of MS, where dis-
ease-modifying treatment is particularly effective. A
review of exercise therapy studies reveal that exercise
predominantly serve as symptomatic treatment and
therefore is initiated at a rather late disease stage in
MS, leaving the early “window of opportunity”
largely uninvestigated. At the same time, recent stud-
ies have shown that exercise holds the potential to
protect against neurodegeneration and to modify the
disease course. On this basis, studies investigating
exercise therapy as an adjuvant treatment strategy in
the early stages of MS are highly warranted. This
890
novel concept, exemplified by exercise therapy, may
hold the potential to be applied in a broader MS reha-
bilitation context, and if proven effective, it would be
of significant value to the individual MS patients (i.e.
quality of life), as well as to the health care system
(i.e. cost-effective).
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
Funding
The author(s) declared receipt of the following finan-
cial support for the research, authorship, and/or pub-
lication of this article: This Topical Review is a part
of Morten Riemenschneiders PhD, which is sup-
ported by the following foundations: Tryg, the Danish
MS Society, Augustinus, Director Jacob Madsen and
wife Olga Madsen, and Knud and Edith Eriksens
memorial fund.
ORCID iD
Morten Riemenschneider https://orcid.org/0000-
0003-1903-0333
References
   1. Elovaara I. Early treatment in multiple sclerosis. J
Neurol Sci 2011; 311(Suppl. 1): S24–S28.
    2. Comi G, Filippi M, Barkhof F, et al. Effect of early
interferon treatment on conversion to definite
multiple sclerosis: A randomised study. Lancet 2001;
357(9268): 1576–1582.
    3. Agius M, Meng X, Chin P, et al. Fingolimod therapy
in early multiple sclerosis: An efficacy analysis of
the TRANSFORMS and FREEDOMS studies by
time since first symptom. CNS Neurosci Ther 2014;
20(5): 446–451.
   4. Ziemssen T, Derfuss T, De Stefano N, et al.
Optimizing treatment success in multiple sclerosis. J
Neurol 2016; 263(6): 1053–1065.
   5. Langhorne P, Bernhardt J and Kwakkel G. Stroke
rehabilitation. Lancet 2011; 377(9778):
1693–1702.
    6. Singleton JR, Smith AG and Marcus RL. Exercise as
therapy for diabetic and prediabetic neuropathy. Curr
Diab Rep 2015; 15(12): 120.
    7. Frazzitta G, Maestri R, Bertotti G, et al. Intensive
rehabilitation treatment in early Parkinson’s disease:
A randomized pilot study with a 2-year follow-up.
Neurorehabil Neural Repair 2015; 29(2): 123–131.
   8. Motl RW, Sandroff BM, Kwakkel G, et al. Exercise
in patients with multiple sclerosis. Lancet Neurol
2017; 16(10): 848–856.
journals.sagepub.com/home/msj

  9. Kjolhede T, Siemonsen S, Wenzel D, et al. Can
resistance training impact MRI outcomes in
relapsing-remitting multiple sclerosis? Mult Scler
2017. Epub ahead of print 1 July 2017. DOI:
10.1177/1352458517722645.
10. Pilutti LA, Platta ME, Motl RW, et al. The safety of
exercise training in multiple sclerosis: A systematic
review. J Neurol Sci 2014; 343(1–2): 3–7.
  11. Dalgas U. Exercise therapy in multiple sclerosis and
its effects on function and the brain. Neurodegener
Dis Manag 2017; 7(6s): 35–40.
  12. Motl RW and Sandroff BM. Benefits of exercise
training in multiple sclerosis. Curr Neurol Neurosci
Rep 2015; 15(9): 62.  
  13. Dalgas U, Stenager E and Ingemann-Hansen
T. Multiple sclerosis and physical exercise:
Recommendations for the application of resistance-,
endurance- and combined training. Mult Scler 2008;
14(1): 35–53.  
  14. Latimer-Cheung AE, Pilutti LA, Hicks AL, et al.
Effects of exercise training on fitness, mobility,
fatigue, and health-related quality of life among
adults with multiple sclerosis: A systematic review  
to inform guideline development. Arch Phys Med
Rehabil 2013; 94(9): 1800–1823.e3.
  15. Heine M, van de Port I, Rietberg MB, et al. Exercise
therapy for fatigue in multiple sclerosis. Cochrane
Database Syst Rev 2015(9): CD009956.  
  16. Latimer-Cheung AE, Martin Ginis KA, Hicks AL,
et al. Development of evidence-informed physical
activity guidelines for adults with multiple sclerosis.
Arch Phys Med Rehabil 2013; 94(9): 1829–136e7.  
  17. Bentzen JTL, Flachs EM, Stenager E, et al.
Diagnostic delay in multiple sclerosis 2010;
16(suppl. 10): 14.
  18. Petajan JH, Gappmaier E, White AT, et al. Impact  
of aerobic training on fitness and quality of life in
multiple sclerosis. Ann Neurol 1996; 39(4):
432–441.
  19. Sutherland G and Andersen MB. Exercise and
multiple sclerosis: Physiological, psychological,  
and quality of life issues. J Sports Med Phys Fitness
2001; 41(4): 421–432.
  20. Mostert S and Kesselring J. Effects of a short-term
exercise training program on aerobic fitness, fatigue,
health perception and activity level of subjects with  
multiple sclerosis. Mult Scler 2002; 8(2): 161–168.
  21. DeBolt LS and McCubbin JA. The effects of home-
based resistance exercise on balance, power, and
 
mobility in adults with multiple sclerosis. Arch Phys
Med Rehabil 2004; 85(2): 290–297.
22. Romberg A, Virtanen A, Ruutiainen J, et al. Effects
of a 6-month exercise program on patients with
journals.sagepub.com/home/msj
M Riemenschneider, LG Hvid et al.
multiple sclerosis: A randomized study. Neurology
2004; 63(11): 2034–2038.
23. Schulz KH, Gold SM, Witte J, et al. Impact of
aerobic training on immune-endocrine parameters,
neurotrophic factors, quality of life and coordinative
function in multiple sclerosis. J Neurol Sci 2004;
225(1–2): 11–8.
24. Freeman J and Allison R. Group exercise classes
in people with multiple sclerosis: A pilot study.
Physiother Res Int 2004; 9(2): 104–107.
25. Taylor NF, Dodd KJ, Prasad D, et al. Progressive
resistance exercise for people with multiple sclerosis.
Disabil Rehabil 2006; 28(18): 1119–1126.
26. Rampello A, Franceschini M, Piepoli M, et al. Effect
of aerobic training on walking capacity and maximal
exercise tolerance in patients with multiple sclerosis:
A randomized crossover controlled study. Phys Ther
2007; 87(5): 545–555.
27. McAuley E, Motl RW, Morris KS, et al. Enhancing
physical activity adherence and well-being in
multiple sclerosis: A randomised controlled trial.
Mult Scler 2007; 13(5): 652–659.
28. Perez LF, Prieto JM and Tutor JC. A thermodynamic
study of beta-N-acetylhexosaminidase enzyme
heterogeneity in cerebrospinal fluid from patients
with multiple sclerosis. Ups J Med Sci 2007; 112(3):
296–302.
29. Dalgas U, Stenager E, Jakobsen J, et al. Resistance
training improves muscle strength and functional
capacity in multiple sclerosis. Neurology 2009;
73(18): 1478–1484.
30. Dettmers C, Sulzmann M, Ruchay-Plossl A, et al.
Endurance exercise improves walking distance in
MS patients with fatigue. Acta Neurol Scand 2009;
120(4): 251–257.
31. Geddes EL, Costello E, Raivel K, et al. The effects
of a twelve-week home walking program on
cardiovascular parameters and fatigue perception of
individuals with multiple sclerosis: A pilot study.
Cardiopulm Phys Ther J 2009; 20(1): 5–12.
32. Szecsi J, Schlick C, Schiller M, et al. Functional
electrical stimulation-assisted cycling of patients
with multiple sclerosis: Biomechanical and
functional outcome—a pilot study. J Rehabil Med
2009; 41(8): 674–680.
33. Cakt BD, Nacir B, Genc H, et al. Cycling progressive
resistance training for people with multiple sclerosis:
A randomized controlled study. Am J Phys Med
Rehabil 2010; 89(6): 446–457.
34. Conklyn D, Stough D, Novak E, et al. A home-
based walking program using rhythmic auditory
stimulation improves gait performance in patients
with multiple sclerosis: A pilot study. Neurorehabil
Neural Repair 2010; 24(9): 835–842.
891
Multiple Sclerosis Journal 24(7)
  35. Fimland MS, Helgerud J, Gruber M, et al. Enhanced
neural drive after maximal strength training in
multiple sclerosis patients. Eur J Appl Physiol 2010;
110(2): 435–443.  
  36. Freeman JA, Gear M, Pauli A, et al. The effect of
core stability training on balance and mobility in
ambulant individuals with multiple sclerosis: A
multi-centre series of single case studies. Mult Scler  
2010; 16(11): 1377–1384.
  37. Konečný L, Pospíšil P, Vank P, et al. Combination of
aerobic and resistant training in multiple sclerosis.
Scr Med Fac Med Univ Brun Masarykianae 2010;
83(2): 98–106.  
  38. Salem Y, Scott A and Belobravka V. Effects of an
aquatic exercise program on functional mobility in
individuals with multiple sclerosis: A community-
based study. J Aquatic Phys Ther 2010;  
18: 22–32.
  39. Collett J, Dawes H, Meaney A, et al. Exercise for
multiple sclerosis: A single-blind randomized trial
comparing three exercise intensities. Mult Scler  
2011; 17(5): 594–603.
  40. Hayes HA, Gappmaier E and LaStayo PC. Effects
of high-intensity resistance training on strength,
mobility, balance, and fatigue in individuals with  
multiple sclerosis: A randomized controlled trial. J
Neurol Phys Ther 2011; 35(1): 2–10.
  41. Pilutti LA, Lelli DA, Paulseth JE, et al. Effects of 12
weeks of supported treadmill training on functional  
ability and quality of life in progressive multiple
sclerosis: A pilot study. Arch Phys Med Rehabil
2011; 92(1): 31–36.
  42. Sabapathy NM, Minahan CL, Turner GT, et al.
 
Comparing endurance- and resistance-exercise
training in people with multiple sclerosis: A
randomized pilot study. Clin Rehabil 2011; 25(1):
14–24.
  43. Salem Y, Scott AH, Karpatkin H, et al. Community-
 
based group aquatic programme for individuals with
multiple sclerosis: A pilot study. Disabil Rehabil
2011; 33(9): 720–728.
  44. Smith DC, Lanesskog D, Cleeland L, et al.
Motivational interviewing may improve exercise  
experience for people with multiple sclerosis: A
small randomized trial. Health Soc Work 2012;
37(2): 99–109.
  45. Kargarfard M, Etemadifar M, Baker P, et al. Effect
of aquatic exercise training on fatigue and health-  
related quality of life in patients with multiple
sclerosis. Arch Phys Med Rehabil 2012; 93(10):
1701–1708.
  46. Claerbout M, Gebara B, Ilsbroukx S, et al. Effects of
3 weeks’ whole body vibration training on muscle
strength and functional mobility in hospitalized
892
persons with multiple sclerosis. Mult Scler 2012;
18(4): 498–505.
47. Bombardier CH, Ehde DM, Gibbons LE, et al.
Telephone-based physical activity counseling for
major depression in people with multiple sclerosis. J
Consult Clin Psychol 2013; 81(1): 89–99.
48. Coote S, Hogan N and Franklin S. Falls in people
with multiple sclerosis who use a walking aid:
Prevalence, factors, and effect of strength and
balance interventions. Arch Phys Med Rehabil 2013;
94(4): 616–621.
49. Dalgas U, Stenager E, Lund C, et al. Neural drive
increases following resistance training in patients
with multiple sclerosis. J Neurol 2013; 260(7):
1822–1832.
50. Mark VW, Taub E, Uswatte G, et al. Constraint-
induced movement therapy for the lower extremities in
multiple sclerosis: Case series with 4-year follow-up.
Arch Phys Med Rehabil 2013; 94(4): 753–760.
51. Garrett M, Hogan N, Larkin A, et al. Exercise in the
community for people with minimal gait impairment
due to MS: An assessor-blind randomized controlled
trial. Mult Scler 2013; 19(6): 782–789.
52. Negahban H, Rezaie S and Goharpey S. Massage
therapy and exercise therapy in patients with
multiple sclerosis: A randomized controlled pilot
study. Clin Rehabil 2013; 27(12): 1126–1136.
53. Tarakci E, Yeldan I, Huseyinsinoglu BE, et al. Group
exercise training for balance, functional status,
spasticity, fatigue and quality of life in multiple
sclerosis: A randomized controlled trial. Clin Rehabil
2013; 27(9): 813–822.
54. Aydin T, Akif Sariyildiz M, Guler M, et al.
Evaluation of the effectiveness of home based or
hospital based calisthenic exercises in patients with
multiple sclerosis. Eur Rev Med Pharmacol Sci
2014; 18(8): 1189–1198.
55. Bisht B, Darling WG, Grossmann RE, et al. A
multimodal intervention for patients with secondary
progressive multiple sclerosis: Feasibility and effect
on fatigue. J Altern Complement Med 2014; 20(5):
347–355.
56. Medina-Perez C, De Souza-Teixeira F, Fernandez-
Gonzalo R, et al. Effects of a resistance training
program and subsequent detraining on muscle
strength and muscle power in multiple sclerosis
patients. Neurorehabilitation 2014; 34(3): 523–530.
57. Nilsagard YE, Von Koch LK, Nilsson M, et al. Balance
exercise program reduced falls in people with multiple
sclerosis: A single-group, pretest-posttest trial. Arch
Phys Med Rehabil 2014; 95(12): 2428–2434.
58. Pilutti LA, Dlugonski D, Sandroff BM, et al.
Randomized controlled trial of a behavioral
intervention targeting symptoms and physical
journals.sagepub.com/home/msj

activity in multiple sclerosis. Mult Scler 2014; 20(5):  
594–601.
59. Sandroff BM, Klaren RE, Pilutti LA, et al.
Randomized controlled trial of physical activity,
cognition, and walking in multiple sclerosis. J
Neurol 2014; 261(2): 363–372.  
60. Sosnoff JJ, Finlayson M, McAuley E, et al. Home-
based exercise program and fall-risk reduction
in older adults with multiple sclerosis: Phase 1
randomized controlled trial. Clin Rehabil 2014;
28(3): 254–263.  
61. Straudi S, Martinuzzi C, Pavarelli C, et al. A task-
oriented circuit training in multiple sclerosis: A
feasibility study. BMC Neurol 2014; 14: 124.
  62. Carter A, Daley A, Humphreys L, et al. Pragmatic
intervention for increasing self-directed exercise
behaviour and improving important health outcomes  
in people with multiple sclerosis: A randomised
controlled trial. Mult Scler 2014; 20(8): 1112–1122.
  63. Gandolfi M, Munari D, Geroin C, et al. Sensory
integration balance training in patients with multiple  
sclerosis: A randomized, controlled trial. Mult Scler
2015; 21(11): 1453–1462.
  64. Hansen D, Wens I, Keytsman C, et al. Ventilatory
function during exercise in multiple sclerosis and  
impact of training intervention: Cross-sectional and
randomized controlled trial. Eur J Phys Rehabil Med
2015; 51(5): 557–568.
  65. Kjolhede T, Vissing K, de Place L, et al.  
Neuromuscular adaptations to long-term progressive
resistance training translates to improved functional
capacity for people with multiple sclerosis and is
maintained at follow-up. Mult Scler 2015; 21(5):
599–611.
  66. Wonneberger M and Schmidt S. Changes of gait  
parameters following long-term aerobic endurance
exercise in mildly disabled multiple sclerosis
patients: An exploratory study. Eur J Phys Rehabil
Med 2015; 51(6): 755–762.
  67. Braendvik SM, Koret T, Helbostad JL, et al.
Treadmill training or progressive strength training to
improve walking in people with multiple sclerosis?  
A randomized parallel group trial. Physiother Res Int
2016; 21(4): 228–236.
  68. Briken S, Rosenkranz SC, Keminer O, et al. Effects
of exercise on Irisin, BDNF and IL-6 serum levels
in patients with progressive multiple sclerosis. J  
Neuroimmunol 2016; 299: 53–58.
  69. Davies BL, Arpin DJ, Liu M, et al. Two different
types of high-frequency physical therapy promote
improvements in the balance and mobility of persons  
with multiple sclerosis. Arch Phys Med Rehabil
2016; 97(12): 2095–101e3.
journals.sagepub.com/home/msj
M Riemenschneider, LG Hvid et al.
70. Fox EE, Hough AD, Creanor S, et al. Effects of
pilates-based core stability training in ambulant
people with multiple sclerosis: Multicenter, assessor-
blinded, randomized controlled trial. Phys Ther
2016; 96(8): 1170–1178.
71. Hoang P, Schoene D, Gandevia S, et al. Effects of
a home-based step training programme on balance,
stepping, cognition and functional performance
in people with multiple sclerosis—a randomized
controlled trial. Mult Scler 2016; 22(1): 94–103.
72. Kierkegaard M, Lundberg IE, Olsson T, et al. High-
intensity resistance training in multiple sclerosis—
An exploratory study of effects on immune markers
in blood and cerebrospinal fluid, and on mood,
fatigue, health-related quality of life, muscle
strength, walking and cognition. J Neurol Sci 2016;
362: 251–257.
73. Keller JL, Fritz N, Chiang CC, et al. Adapted
resistance training improves strength in eight weeks
in individuals with multiple sclerosis. J Vis Exp
2016(107): e53449.
74. Razazian N, Yavari Z, Farnia V, et al. Exercising
impacts on fatigue, depression, and paresthesia in
female patients with multiple sclerosis. Med Sci
Sports Exerc 2016; 48(5): 796–803.
75. Tallner A, Streber R, Hentschke C, et al. Internet-
supported physical exercise training for persons with
multiple sclerosis—a randomised, controlled study.
Int J Mol Sci 2016; 17(10): 1667.
76. Alvarenga-Filho H, Sacramento PM, Ferreira TB,
et al. Combined exercise training reduces fatigue
and modulates the cytokine profile of T-cells
from multiple sclerosis patients in response to
neuromediators. J Neuroimmunol 2016;
293: 91–99.
77. Feys P, Moumdjian L, Van Halewyck F, et al. Effects
of an individual 12-week community-located “start-
to-run” program on physical capacity, walking,
fatigue, cognitive function, brain volumes, and
structures in persons with multiple sclerosis. Mult
Scler 2017. Epub ahead of print 1 November 2017.
DOI: 10.1177/1352458517740211.
78. Kalron A, Rosenblum U, Frid L, et al. Pilates exercise
training vs physical therapy for improving walking
and balance in people with multiple sclerosis: A
randomized controlled trial. Clin Rehabil 2017;
31(3): 319–328.
79. Learmonth YC, Adamson BC, Kinnett-Hopkins D, et
al. Results of a feasibility randomised controlled study
of the guidelines for exercise in multiple sclerosis
project. Contemp Clin Trials 2017; 54: 84–97.
80. Manca A, Cabboi MP, Dragone D, et al. Resistance
training for muscle weakness in multiple sclerosis:
Direct versus contralateral approach in individuals
893
Multiple Sclerosis Journal 24(7)

with ankle Dorsiflexors’ disparity in strength. Arch
Phys Med Rehabil 2017; 98(7): 1348–156e1.
  81. Peruzzi A, Zarbo IR, Cereatti A, et al. An innovative  
training program based on virtual reality and
treadmill: Effects on gait of persons with multiple
sclerosis. Disabil Rehabil 2017; 39(15): 1557–1563.
  82. Ozkul C, Guclu-Gunduz A, Irkec C, et al. Effect
of combined exercise training on serum brain-
derived neurotrophic factor, suppressors of cytokine  
signaling 1 and 3 in patients with multiple sclerosis.
J Neuroimmunol 2018; 316: 121–129.
  83. McCullagh R, Fitzgerald AP, Murphy RP, et al.
Long-term benefits of exercising on quality of life  
and fatigue in multiple sclerosis patients with mild
disability: A pilot study. Clin Rehabil 2008; 22(3):
206–214.
  84. Heine M, Verschuren O, Hoogervorst EL, et al.  
Does aerobic training alleviate fatigue and improve
societal participation in patients with multiple
sclerosis? A randomized controlled trial. Mult Scler
2017; 23(11): 1517–1526.
  85. European Multiple Sclerosis Platform. MS Barometer  
2015: Raising the voice of people with MS,
vol. 4, 2015, http://www.emsp.org/wp-content/
uploads/2017/02/BAROMETER-2015-28.02.2017.
pdf
 
  86. Klaren RE, Motl RW, Dlugonski D, et al. Objectively
quantified physical activity in persons with multiple
sclerosis. Arch Phys Med Rehabil 2013; 94(12):
2342–2348.
published as an Erratum in Neurology 2001; 57(6):
1146.)
92. Rovaris M, Comi G, Rocca MA, et al. Long-term
follow-up of patients treated with glatiramer
acetate: A multicentre, multinational extension
of the European/Canadian double-blind, placebo-
controlled, MRI-monitored trial. Mult Scler 2007;
13(4): 502–508.
93. Johnson KP, Ford CC, Lisak RP, et al. Neurologic
consequence of delaying glatiramer acetate therapy
for multiple sclerosis: 8-year data. Acta Neurol
Scand 2005; 111(1): 42–47.
94. Trojano M, Pellegrini F, Paolicelli D, et al. Real-life
impact of early interferon beta therapy in relapsing
multiple sclerosis. Ann Neurol 2009; 66(4):
513–520.
95. Rossi S, Furlan R, De Chiara V, et al. Exercise
attenuates the clinical, synaptic and dendritic
abnormalities of experimental autoimmune
encephalomyelitis. Neurobiol Dis 2009; 36(1):
51–59.
96. Pryor WM, Freeman KG, Larson RD, et al. Chronic
exercise confers neuroprotection in experimental
autoimmune encephalomyelitis. J Neurosci Res
2015; 93(5): 697–706.
97. Benson C, Paylor JW, Tenorio G, et al. Voluntary
wheel running delays disease onset and reduces pain
hypersensitivity in early experimental autoimmune
encephalomyelitis (EAE). Exp Neurol 2015; 271:
279–290.

Visit SAGE journals online
journals.sagepub.com/
home/msj
SAGE journals
87. Kappos L, O’Connor P, Radue EW, et al. Long-term
effects of fingolimod in multiple sclerosis: The
randomized FREEDOMS extension trial. Neurology
2015; 84(15): 1582–1591.
88. Giovannoni G, Butzkueven H, Dhib-Jalbut S, et al.
Brain health: Time matters in multiple sclerosis.
Mult Scler Relat Disord 2016; 9(Suppl.1): S5-S48.
89. Cross AH and Naismith RT. Established and novel
disease-modifying treatments in multiple sclerosis. J
Intern Med 2014; 275(4): 350–363.
90. Kappos L, Traboulsee A, Constantinescu C, et al.
Long-term subcutaneous interferon beta-1a therapy
in patients with relapsing-remitting MS. Neurology
2006; 67(6): 944–953.
91. PRISMS Study Group and the University of British
Columbia MS/MRI Analysis Group. PRISMS-4:
Long-term efficacy of interferon-beta-1a in relapsing
MS. Neurology 2001; 56(12): 1628–1636. (Also
  98. Tallner A, Waschbisch A, Wenny I, et al. Multiple
sclerosis relapses are not associated with exercise.
Mult Scler 2012; 18(2): 232–235.
  99. Langeskov-Christensen D, Feys P, Baert I, et al.
Performed and perceived walking ability in relation
to the Expanded Disability Status Scale in persons
with multiple sclerosis. J Neurol Sci 2017; 382:
131–136.
100. Amato MP, Portaccio E, Goretti B, et al. Cognitive
impairment in early stages of multiple sclerosis.
Neurol Sci 2010; 31(Suppl. 2): S211–S214.
101. Kobelt G, Thompson A, Berg J, et al. New insights
into the burden and costs of multiple sclerosis in
Europe. Mult Scler 2017; 23(8): 1123–1136.
102. Marck CH, Neate SL, Taylor KL, et al. Prevalence
of comorbidities, overweight and obesity in an
international sample of people with multiple sclerosis
and associations with modifiable lifestyle factors.
PLoS ONE 2016; 11(2): e0148573.

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