Early Phase Multiple Sclerosis Patients Present Substantial Deficits in Physical-,Cognitive-,and Patient-reported Outcomes Compared to Matched Healthy Controls

Abstract

Background

Early identification of potential deficits is of utmost importance as early diagnosis and early treatment has been shown to be crucial to reduce disease activity and disease impact—leading to the notion of “Time matters” in multiple sclerosis (MS).

Objective

The aim of the present study was to compare physical-, cognitive-, and patient-reported outcomes in early phase MS patients with matched healthy controls (HC).

Methods

This cross-sectional study included 84 patients early in the disease course of MS (≤2 years from diagnosis) and 84 age- and sex-matched HC. All participants underwent a comprehensive test battery including physical-, cognitive-, and patient-reported outcomes.

Results

Relative deficits for patients with MS compared to HC corresponded to 7% to 35% in walking capacity (Timed 25-Foot Walk Test, 6 Spot Step Test, 6 Minute Walk Test), 5% for upper limb function (9 Hole Peg Test), 27% for aerobic capacity (maximal oxygen uptake), 17% to 38% for physical activity level (Baecke Sport Index and accelerometer counts/minute), 68% for fatigability (Walking Fatigability Index), 150% for fatigue (Modified Fatigue Impact Scale), 4% to 20% for cognitive function (Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, and Selective Reminding Test), and lastly, 7% to 8% for quality of life (Short Form-36 health survey). Only the Symbol Digit Modalities Test and Selective Reminding Test Delayed did not differ between groups, statistically.

Conclusion

Early phase MS patients present substantial deficits in physical-, cognitive-, and patient-reported outcomes compared to HC. These early impairments highlight the importance of early initiatives aimed at preserving and/or building of reserve capacity.

Keywords

multiple sclerosis rehabilitation early diagnosis

Introduction

From the very start of the disease, multiple sclerosis (MS) damages various structures of the central nervous system including both the gray and white matter and their myelin, axons, and neurons.^1,2 Over time, the disease status will go from asymptomatic and prodromal to symptomatic—supposedly as the neurological reserve capacity (the inherent finite compensatory potential of the brain) becomes exhausted.^3,4 Symptoms often manifest as motor symptoms (eg, impaired walking ability and capacity, balance issues, increased fatigability, and reduced dexterity), cognitive symptoms (eg, impaired memory and processing speed), and/or excessive fatigue.⁵ The development of MS symptoms has been shown to be closely related to disability status as well as to a reduction in health-related quality of life (HRQoL).^5,6 However, most domains evolve (worsen) in a non-linear and displaced manner and little is known about the time-dependent trajectory of impairments across physical-, cognitive-, and patient-reported domains in patients with MS (pwMS)—particularly not in the early stages of the disease course.

In a review by Zakzanis,⁷ it was reported that patients with relapsing-remitting MS (RRMS), with a mean time since diagnosis of 4.8 years, exhibit impaired cognitive function on standard neuropsychological tests, especially in the area of memory function. Also, 1 recent study has shown reduced balance and walking abilities as well as a higher prevalence of fatigue in non-disabled pwMS diagnosed within 5 years.⁸ Furthermore, a recent topical review from our research group also found that other impairments seem to present themselves within the first 5 years after diagnosis.⁹ The review revealed deficits corresponding to 8% to 34% and small-to-large numerical effect sizes (0.35-2.85) across physical- and cognitive domains along with patient-reported outcomes in comparison to healthy controls (HC). The conclusion was, however, based on a summary of different study findings and thus different subject characteristics. The conclusion was also limited by the small number of studies across each domain, the small number of subjects in each study, the heterogeneity in MS subtypes (eg, inclusion of clinically isolated syndrome [CIS] patients in some studies), and the different outcomes being categorized to target the same domain. Furthermore, data on disease duration were based on mean values, thereby allowing large variations in disease duration (ie, potentially including patients that may not be considered to have early MS), complicating the interpretation of the results. In addition, basic physiological outcomes, such as aerobic capacity, have not yet been studied in early MS. This is likely of importance since aerobic capacity is a well-known health and performance marker in MS as well as associated with patient disability level.^10,11 A further limitation of the existing studies is that most studies have only evaluated single domains rather than performing a comprehensive profiling of a well-established patient cohort with early MS covering multiple domains.

Early identification of potential deficits is of utmost importance as early diagnosis and early treatment have been shown to be crucial to reducing disease activity and disease impact—leading to the notion that “Time matters” in MS.¹² However, the sparse literature and inconsistent classification of MS (and CIS) groups reviewed by Thrue et al⁹ makes it challenging to determine when and to what degree deficits present themselves, that is, before the clinical diagnosis of MS, around the time of diagnosis (very early MS), or within the first years after diagnosis (early MS). Moreover, no studies identified by the review of Thrue et al⁹ evaluated deficits in patients with early MS compared to matched HC using a comprehensive test battery covering multiple physical-, cognitive-, and patient-reported outcomes. To address the existing limitations in the sparse existing literature, a well-powered study comparing a newly diagnosed (<2 years since diagnosis) group of MS patients to matched HCs on multiple domains would, therefore, shed further light on (very) early deficits within the early “window of opportunity.”¹³ Furthermore, such a study holds the potential to guide clinicians in optimizing restorative/preventive clinical exercise and rehabilitation interventions.

Therefore, the aim of the present study was to compare physical function (walking ability and capacity, hand dexterity, aerobic capacity, and physical activity level), cognitive function (processing speed, attention, and memory), and patient-reported outcomes (HRQoL, fatigue, and physical activity level) in patients early in the disease course of MS (≤2 years from diagnosis) to age- (±5 years) and sex-matched HC. It was hypothesized that patients early in the disease course of MS would show deficits in line with those found by Thrue et al⁹ across physical-, cognitive-, and patient-reported outcomes.

Methods

Study Design and Participants

The present cross-sectional study is an addition to The Early Multiple Sclerosis Exercise Study (EMSES) by Riemenschneider et al^14,15 Details on recruitment and eligibility for pwMS along with a thorough description of methodologies of applied outcomes have been published previously in a separate study protocol¹⁴ as well as in the main paper,¹⁵ and will therefore only briefly be summarized here. Recruitment and eligibility of HC have not been described elsewhere, and data from matched HC are exclusive for this study. The study is approved by The Central Denmark Region Committees on Health Research Ethics (1-10-72-388-17) and registered at the Danish Data Protection Agency (2016-051-000001 (706)) and clinicaltrials.gov (NCT03322761).

PwMS were recruited in collaboration with 6 Danish regional MS clinics and The Danish MS Society. Inclusion criteria were (1) 18 to 60 years of age, (2) ≤2 years since clinical diagnosis with RRMS,^16,17 and (3) no relapses or changes in medication status 8 weeks prior to inclusion. Participants was excluded in case of pregnancy or any co-morbidities hindering participation in high-intensity physical exercise. Eligibility was confirmed by project nurses based on patients’ medical records. Age- (±5 years) and sex-matched HC were recruited via MS patients’ network (participants were predominantly partners and friends), the research groups’ network, and via online platforms in that hierarchical order. Inclusion and exclusion criteria for HC were the same as for pwMS besides criteria relating specifically to MS. All participants gave informed written consent prior to inclusion.

Outcomes

All outcomes were assessed 1 time for HC and baseline data for pwMS from the EMSES study^15,18 were used for comparison. All participants underwent a comprehensive test battery including physical- and cognitive tests along with questionaries evaluating HRQoL, fatigue, and physical activity level. Psychometric properties of outcomes can be found in the separate study protocol by Riemenschneider et al.¹⁴

Physical Function

Walking capacity was assessed using 3 different measures of walking; the 25-foot Walk Test (25FWT),¹⁹ a simple short walking test at maximal walking speed, the 6 Spot Step Test (SSST),^20,21 a complex walking test challenging speed, balance, and coordination, and the 6 Minute Walk Test (6MWT),²² a test of walking endurance. Upper limb function was assessed using the 9 Hole Peg Test (NHPT),²³ a measure of hand dexterity. Finally, aerobic capacity was assessed via direct measurement of the maximal rate of oxygen uptake (VO_2max) during an incremental exercise test on a bicycle ergometer (SRM, Jülich, Germany) to voluntary exhaustion. The test was conducted at a self-chosen cadence between 60 and 100 rpm with an initial workload of 45 W for females and 60 W for males. The workload increased by 15 W/minute for females and 20 W/minute for males until voluntary exhaustion. Throughout the test, expired gas was collected in a mixing bag, and the rates of VO₂, VCO₂, and respiratory exchange ratio were continuously determined by an online respiratory gas exchange analyzer. At the point of volitional exhaustion, the maximal workload, time completed, and perceived exhaustion (on a 6-20 Borg scale) were recorded. Maximal VO₂ was determined as the highest average VO₂ recorded over a period of 30 seconds, from which the aerobic capacity was calculated.²⁴

Physical Activity

Two measures of physical activity were applied. The Sport Index of the Baecke Physical Activity Questionnaire was applied as a subjective measure of structured exercise participation. Physical activity level was also assessed objectively by use of thigh-worn accelerometry (Axivity AX3, Axivity Ltd., Newcastle, UK) for 7 consecutive days.²⁵ Raw activity data was sampled at 100 Hz ± 8 g, downloaded using the OMGUI software (version 1.0.0.43), subsequentially exported to an ActiGraph raw binary file (gt3x) and processed into counts using the ActiLife software (version 6.4.11). Data reduction and aggregation were done using the custom-built software (Propero by Jan Christian Brønd, Odense, Denmark). The vector magnitude counts data were analyzed in 60 s epochs over an 18-hour period starting at 6 AM. Non-wear time was defined as time periods of ≥10 min consecutive zeros and was excluded. Eight hours of accepted data had to be reached per day for a minimum of 4 days for the data to be valid and subsequently included. Ultimately, physical activity is presented as counts per minute (corresponding to average daily accumulated counts per average daily wear time in minutes).

Cognitive Function

Cognitive function was assessed by 3 different cognitive tests; the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) both assessing processing speed and attention, and the Selective Reminding Test (SRT) assessing verbal learning and memory. The SRT includes measures of long-term storage, consistent long-term retrieval, and delayed recall.²⁶

Quality of Life

The Short Form-36v2 Health Survey (SF-36) is a multipurpose health survey measuring HRQoL. The questionnaire includes 36 questions used to calculate 2 psychometrically based physical- and mental health summary scores. The SF-36 scores are standardized with a scoring algorithm to obtain a score ranging from 0 to 100, higher scores correspond to better health status.²⁷

Fatigue and Fatigability

Perceived fatigue and performance fatigability are 2 distinct phenomena and should be assessed as such. Therefore, patient-reported fatigue impact was assessed using the Modified Fatigue Impact Scale including sub-measures of physical- and cognitive fatigue. The total score ranges from 0 to 84, with higher scores indicating greater fatigue impact. The sub-scores range from 0 to 36 for the physical component and 0 to 40 for the cognitive component).^28,29 Walking fatigability was assessed as the percentage difference in distance covered between the first and the last minute of the 6MWT.³⁰

Statistical Analysis

As the present study is an addition to the EMSES study, the sample size was determined in relation to the primary outcomes of the EMSES study (relapse rate) as described elsewhere.¹⁴ HC were recruited in a 1:1 age- and sex-matched ratio for this specific study.

All outcomes were assessed for normal distribution and equal variance and presented as means and standard deviations if they approximated the normal model. To investigate differences between pwMS and HC, a linear multiple regression analysis was conducted. Also, differences were evaluated when adjusting for age, sex, and body mass index (for physical function, physical activity, and fatigability outcomes) and age, sex, and education years (for cognitive outcomes; Supplemental Table 2). Cohen’s D effect size was also calculated for normally distributed data and interpreted according to Kinney et al³¹ (empirically-based; small 0.14, medium 0.31, and large 0.61). If the assumption of normality was violated, an appropriate transformation was performed, and differences between pwMS and HC were then analyzed with multiple linear regression. In case transformed data did not follow a normal distribution, a median test was performed to investigate differences between pwMS and HC, and the data were presented as a median and interquartile range. In this case, outcomes could not be adjusted for any variables and no estimate for the difference or effect size could be presented in Table 1.

Table 1.

Overview of Outcomes and Absolute Differences.

Outcome	Mean (SD)/Median [IQR]
Outcome	MS (n = 84)	HC (n = 84)	Mean diff. (95% CI)	P-value	ES
Demographic, anthropometric, and clinical characteristics
Age	37.4 (9.8)	37.3 (10.8)	0.1 (−3.1; 3.2)	.953	0.00
Sex
Women	63	63		1.000	N/A
Men	21	21
Disease duration (mo)	9.4 (6.5)
EDSS	1.4 (0.9)
Height (cm)	173 (9)	172 (8)	1 (−2; 4)	.437	0.12
Body mass (kg)	78.1 (17.3)	69.4 (12.1)	8.8 (4.2; 13.3)	<.001	0.58
BMI (kg/m²)	26.0 (5.3)	23.4 (3.2)	2.6 (1.3; 3.9)	<.001	0.59
Education years	15.2 (2.9)^a	16.0 (2.6)	−0.8 (−1.9; 0.2)	.131	−0.29
Physical function
25FWT (m/s)	2.14 (0.3)	2.46 (0.4)	−0.23 (−0.32; −0.13)	<.001	−0.85
SSST total (s)	5.8 (1.3)	4.4 (0.9)	1.3 (1.0;1.7)	<.001	1.25
6MWT (m)	646 (90)	747 (71)	−102 (−125; −79)	<.001	−1.25
NHPT (s)	18.0 (2.9)	16.5 (1.4)	1.5 (0.9;2.2)	<.001	0.66
Aerobic capacity (mL O₂/kg/min)	28.4 (9.1)	38.2 (6.8)	−10.0 (−12.2; −7.7)	<.001	−1.22
Physical activity
Baecke Sport Index	2.9 (0.8)	3.6 (0.7)	−0.5 (−0.7; −0.2)	<.001	−0.93
Accelerometry (counts/min)	854 (285)	1284 (375)	−436 (−543; −328)	<.001	−1.29
Cognitive function
SDMT	61.6 (13.3)	63.9 (10.5)	−2.3 (−5.9; 1.3)	.209	−0.19
PASAT	48 [40-53]	50 [42-56]	N/A	.037	N/A
SRT LTS	46.0 (11.0)	52.0 (10.2)	−5.8 (−8.8; −2.8)	<.001	−0.57
SRT CLTR	39.0 (12.4)	46.7 (12.1)	−7.6 (−11.1; −4.0)	<.001	−0.63
SRT delay	10 [8-11]	11 [9-12]	N/A	.104	N/A
Health related quality of life
SF-36 MCS	50 [43-56]	56 [52-59]	N/A	<.001	N/A
SF-36 PCS	52 [45-58]	58 [55-60]	N/A	<.001	N/A
Fatigue and fatigability
Walking fatigability (%)	−4.9 (6.2)	−1.4 (6.7)	−3.6 (−5.5; −1.6)	.001	−0.54
MFIS total	23 [13-39]	13 [4-18]	N/A	<.001	N/A
MFIS physical	8 [3-17]	4 [1-7]	N/A	.004	N/A
MFIS cognitive	15 [6-19]	8 [3-11]	N/A	<.001	N/A

Abbreviations: 25FWT, Timed 25-Foot Walk Test; SSST, 6 Spot Step Test; 6MWT, 6 Minute Walk Test; NHPT, 9 Hole Peg Test; VO_2max, Maximal Rate of Oxygen Uptake; SDMT, Symbol Digit Modalities Test; PASAT, Paced Auditory Serial Addition Test; SRT, Selective Reminding Test; LTS, Long Term Storage; CLTR, Consistent Long Term Retrieval; SF36, Short Form-36 Health Survey; PCS, Physical Component Summary; MCS, Mental Component Summary; MFIS, Modified Fatigue Impact Scale; N/A, not applicable; BMI, body mass index, SD, standard deviation.

n = 46.

Correlations (Spearman’s rank) of deficits in physical activity level (counts/minute) and deficits in individual outcomes across domains were also performed (Supplemental Table 1).

To accentuate the differences between pwMS and HC, a percentage deficit was calculated for each pwMS expressed in relation to the paired sex- and age-matched HC for all outcomes. A median percentage deficit was presented for each outcome. Furthermore, the proportion of pwMS performing worse than the fifth percentile of HC was calculated, as this cut-off previously has been used as a measure of impairment in pwMS.³²

All analyses were made in STATA v. 18.0 (StataCorp, College Station, TX, USA) and the figure was made in GraphPad Prism v. 7.0 (GraphPad Software, Boston, MA, USA).

Results

A total of 84 patients with early MS (≤2 years from diagnosis) and 84 age- (±5 years) and sex-matched HC were recruited for the study. Demographic, anthropometric, and clinical characteristics are presented in Table 1. Of note and as previously shown, the characteristics of the MS group were comparable to and thus representable of the sample of the population-based control group regarding characteristics such as age, sex, and disease status. The general MS population was based on data from the Danish MS registry covering all patients diagnosed within the same period as the participants of the present study (see the main paper of the EMSES study¹⁵).

Table 1 presents group means or medians as well as between-group mean differences with 95% CI across physical function, physical activity, cognitive function, HRQoL, and fatigue domains. Generally, pwMS performed worse across all physical function outcomes when compared to HC, as evidenced by large differences and effect sizes. The same pattern was observed across outcomes relating to physical activity behavior, quality of life, cognition (except SDMT and SRT delayed; small difference and effect size for the latter), and fatigue. Importantly, the shown differences as well as the magnitude hereof in physical function, physical activity, and walking fatigability remained almost unaffected after adjusting for BMI (Supplemental Table 2). Also, the shown differences in cognitive function remained essentially unaffected after adjusting for education years, although SDMT was now shown to be different in favor of HC (Supplemental Table 2).

Figure 1 illustrates percentage deficits between pwMS relative to HC, and the proportion of impaired pwMS (ie, performing worse than the fifth percentile of HC). The overall pattern showed deficits across all outcomes for pwMS corresponding to 5-35% in physical function (29%-54% of pwMS being impaired), 17%-38% in physical activity (12%-48% of pwMS being impaired), 4% to 20% in cognitive function (8%-18% pwMS being impaired), 7% to 8% in HRQoL (24%-30% of pwMS being impaired), and 68% to 150% in fatigue (10%-31% of pwMS being impaired).

Figure 1.

Overview of outcomes and deficits (expressed as median deficit of pwMS (≤2 years) and age- and sex-matched HC. Hatched red areas indicate median deficits for pwMS relative to healthy controls regardless of direction. The percentages in the bottom represent percentage of pwMS being outside the fifth percentile of HC.

Discussion

To the best of our knowledge, this is the first study to investigate the impact of early MS (≤2 years since diagnosis) across multiple domains, including physical function, cognitive function, and patient-reported outcomes. When comparing pwMS with age- and sex-matched HC, our findings revealed substantial differences, effect sizes, and deficits across all domains (except SDMT in the cognitive domain), with the physical domain showing the most pronounced impairments.

The pattern of deficits across all domains is consistent with the results from the topical review by our research group. Thrue et al⁹ investigating the impact of the disease across domains in pwMS with a mean time since diagnosis of ≤5 years. Recently, Cattaneo et al⁸ also studied subtle functional impairments in pwMS with no apparent signs of disability in the early phase of the disease (≤5 years; 2.2 ± 1.7 years). An interesting observation was that in pwMS reporting no clinical disability, pronounced walking, and other functional deficits were present. However, Cattaneo et al excluded pwMS having an EDSS >2.5, likely underestimating the deficits in a fully “representative” population of early pwMS. The distinction between early- and mild MS seems important as newly diagnosed (time since diagnosis) does not necessarily equal to being mildly impaired. Interestingly, the present study revealed deficits of comparable magnitude to those reported by both Cattaneo et al and Thrue et al This indicates that the deficits being present within the first 2 years of diagnosis (9.4 ± 6.5 months) resembles those observed 3 to 4 years later.

The present study replicates the findings by Cattaneo et al,⁸ that is, that the most pronounced deficits and impairments relate to the physical domain. Interestingly, results from the present study show that pwMS had a lower physical activity level (38% deficit) and lower participation in structured exercise (17% deficit) which likely contribute to the pronounced physical deficits. However, when calculating the association between deficits in physical activity (counts/minute) level and deficits in individual outcomes across domains from the present study (see Supplemental Table 1), only the 6MWT showed an association, albeit weak (r = .36, P < .01). These findings suggest that deficits at this time of the disease course are caused by MS per se rather than by deconditioning. Several underlying mechanisms may explain this finding, including abnormal central (ie, abnormal connectivity-based nodal strength and network modularity, microstructural damages, and accelerated brain volume loss) and peripheral mechanisms (ie, incomplete activation of motor units, reduced oxidative enzymes, smaller and fewer muscle fibers, and abnormal energy metabolism) as previously reported in pwMS.^33-38

As for the physical outcomes, the SSST showed a striking and quite substantial deficit when comparing pwMS and HC. This is likely due to the complexity of the tests that extensively tax the neuro-muscular interaction (ie, challenging both walking speed, balance, and coordination), at least compared to most other physical tests. Such complex and challenging tests (eg, dual- or multiple tasking involving multiple functional domains at the same time) are known to be particularly potent in detecting early impairments.³⁹ Skjerbæk et al recently showed exactly this in pwMS admitted to a rehabilitation facility, with SSST deficits being observed even in those having “normal physical function” (ie, patient-determined disease step score = 0) as well as in those having time since diagnosis of ≤2 years.²¹ To support the proposal by Skjerbaek et al, the SSST should be prioritized as a key outcome when screening/assessing physical function in newly diagnosed pwMS, as the test is particularly sensitive to detect early changes, and is also quick and easy to administer in clinical settings.

Whilst the cognitive function did not seem to be affected to the same extent as the physical function, SRT targeting short-term- and long-term memory was the most affected. The review by Thrue et al⁹ showed deficits in memory to nearly the same extent as reported here, whereas processing speed and attention (assessed with SDMT and PASAT) were somewhat dissimilar from the results of the review (~13% deficit in the review compared to ~4% deficit in the present study). These findings are suggestive of a rapid decline in cognitive function within the first 5 years of the disease course. This notion is supported by Reuter et al, evaluating the evolution of cognitive impairment during a 5-year follow-up period in 23 patients with CIS with a high risk of developing MS. At 5-year follow-up, they reported cognitive impairments (≥2 standard deviation of HC) in 54% of the patients as compared to 29% at baseline.⁴⁰

Fatigue is recognized as a very frequent and highly disabling symptom in MS.⁴¹ As expected, pwMS in the present study reported worse self-reported levels of fatigue as well as a higher degree of walking fatigability. The differences in median values between pwMS and HC were indeed quite noticeable. However, the very high deficits in the fatigue and fatigability outcomes in pwMS presented in Figure 1 are most likely skewed by comparing values on an ordinal scale, and with HC reporting very low levels of fatigue. Also, pwMS in the present study reported lower HRQoL (7-8% deficit) compared to HC and since most pwMS is diagnosed at a young age, initiatives to increase perceived HRQoL is a highly important prospect for future studies.

Whether the presented deficits are of clinical relevance is difficult to confirm. Established measures of minimal clinical differences and cut-off values of clinical relevance have mostly been established based on more disabled pwMS and are therefore less applicable in these newly diagnosed pwMS. However, in a study by Meca-Lallana et al, a panel of 15 Spanish MS experts established a consensus on the most useful clinical variables for early identification of disease progression.⁴² They concluded that a confirmed minimum of 20% worsening in the performance of selected tests (eg, 25FWT, NHPT, 2-minute walk test, and/or SDMT) was of clinical relevance to the patient. By assuming that our findings represent worsening over time, several outcomes exceeded 20% deficit (SSST, aerobic capacity, physical activity, fatigue, and fatigability), suggesting clinically relevant impairments. While increasing attention has been on the “silent progression” late in the MS disease course,⁴³ less attention has been paid to the silent disability progression in the early phase of the disease course and/or even in the prodromal stage,⁴⁴ where progression is often camouflaged by compensatory mechanisms.

However, regardless of interpreting our findings in the context of proposed clinical cut-off values, we provide novel results that reveal noticeable deficits across all domains. Altogether, this calls for attention and interventions to counteract further declines and/or building of reserve capacities. As highlighted by Marrie et al⁴⁴ identification and validation of clinical, genetic, imaging, and fluid biomarkers of prodromal/early MS in diverse populations are strongly needed. From our point of view, a number of actions should be initiated. First, a comprehensive screening covering several domains seems relevant to introduce as early as possible after diagnosis (or even before) and thereafter on a regular basis (eg, each year), especially since many impairments are not easily detected by the patient or by the treating clinician. Second, early disease-modifying therapies have mainly relied on pharmacological treatments to reduce MS progression. However, combining this with non-pharmacological interventions seems essential, especially when considering the outcomes reported in the present study (ie, physical function, cognitive function, fatigue/fatigability, and HRQoL) which are not very effectively affected by pharmacological treatments. To exemplify, solid evidence supports that exercise therapy is a safe and effective strategy to improve or preserve many of the affected domains.^45-47 Consequently, Dalgas et al have introduced the exercise-induced postponement theory, suggesting that long-term regular moderate- to high-intensity exercise (and/or moderate-to-vigorous physical activity) potentially can postpone the onset of clinical MS diagnosis and postpone the occurrence of disease activity and progression (including symptoms) in pwMS.⁴⁷ In addition to exercise therapy, cognitive rehabilitation clearly has the potential to prevent early loss of cognitive functions in pwMS as evidenced by a recent Cochrane review by Taylor et al⁴⁸ showing marked improvements in memory and learning as well as information processing speed.

Some methodological issues should be considered when interpreting the results of the present study. First, this study is limited by the nature of the cross-sectional design and the trajectory of impairments can therefore not be determined from these results. Second, a selection bias might exist as volunteering for exercise studies may be associated with an undesirable absence of more severely disabled pwMS signing up, and inclusion of pwMS and HC that are more positive toward exercise and physical performance, and therefore likely restrict the generalizability of physical performance in both groups. Third, the present study only included relapsing remitting pwMS. Future studies should seek to include other phenotypes of MS (ie, primary- and secondary progressive MS). Fourth, HC’s were only matched for age and sex, although other adjustments could have been of relevance. Nevertheless, adjusting for BMI when comparing physical function, physical activity, or walking fatigability outcomes did not noticeably affect the differences or magnitude hereof (nor did adjusting for educational years when comparing cognitive function). Fifth, other relevant outcomes were not examined in the present study, such as sleep disorders, pain, bladder dysfunction, neuromuscular function (eg, muscle strength and power) and mental disorders.^49-51 Information across these (and other) outcomes seems needed in order to fully elucidate aspects to target in early pwMS.

Conclusion

This cross-sectional study provides evidence that pwMS in the early stage (≤2 years since diagnosis) of the disease show marked deficits across physical-, cognitive-, and patient-reported outcomes when compared to age- and sex-matched HC. Such substantial early impairments call for better and more frequent early screening programs along with early interventions to counteract further declines.

Supplemental Material

sj-docx-1-nnr-10.1177_15459683251318246 – Supplemental material for Early Phase Multiple Sclerosis Patients Present Substantial Deficits in Physical-, Cognitive-, and Patient-reported Outcomes Compared to Matched Healthy Controls

Supplemental material, sj-docx-1-nnr-10.1177_15459683251318246 for Early Phase Multiple Sclerosis Patients Present Substantial Deficits in Physical-, Cognitive-, and Patient-reported Outcomes Compared to Matched Healthy Controls by Cecilie Thrue, Lars G. Hvid, Mette Diechmann, Tobias Gaemelke, Egon Stenager, Ulrik Dalgas and Morten Riemenschneider in Neurorehabilitation and Neural Repair

Footnotes

Author Contributions

Cecilie Thrue: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Visualization; Writing—original draft; and Writing—review & editing. Lars G. Hvid: Conceptualization; Formal analysis; Supervision; and Writing—review & editing. Mette Diechmann: Investigation; Project administration; Supervision; and Writing—review & editing. Tobias Gaemelke: Data curation; Formal analysis; Investigation; Project administration; Supervision; and Writing—review & editing. Egon Stenager: Supervision and Writing—review & editing. Ulrik Dalgas: Conceptualization; Project administration; Supervision; Visualization; and Writing—review & editing. Morten Riemenschneider: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Visualization; and Writing—review & editing.

Data Availability Statement

Due to European legislation (GDPR) original data cannot be handed out, however, interested researchers are welcome to contact the corresponding author to request summery or group data.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ulrik Dalgas has received research support, travel grants, and/or teaching honoraria from Biogen Idec, Merck Serono, Novartis, Bayer Schering, and Sanofi Aventis, as well as honoraria from serving on the scientific advisory boards of Biogen Idec and Genzyme. Lars G. Hvid has received research support, travel grants, and/or teaching honoraria from Biogen and Sanofi Genzyme. Cecilie Thrue, Mette Diechmann, Tobias Gaemelke, Egon Stenager, and Morten Riemenschneider each declare no potential conflicts of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study is financed by Aarhus University, Faculty of Health (Vennelyst Boulevard 4, 8000 Aarhus C, DK, health@au.dk) and by the following external foundations: “Trygfonden” (grant number: 123878), “Augustinus fonden” (grant number: 17-2194), The Danish MS Society “Scleroseforeningen” (grant numbers: A33634 and A35468), “Direktør Jacob Madsen og Hustru Olga Madsens Mindefond,” “Knud og Edith Eriksens Mindefond.”

ORCID iDs

Cecilie Thrue

Lars G. Hvid

Tobias Gaemelke

Egon Stenager

Ulrik Dalgas

Supplementary material for this article is available on the Neurorehabilitation & Neural Repair website along with the online version of this article.

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