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Sleep Quality, Dysfunctional Sleep Beliefs, and Health-Related Quality of Life and Functioning in People With Multiple Sclerosis

Upper extremity strength and function are rarely assessed in routine multiple sclerosis (MS) care. This study aimed to evaluate hand muscle strength and functionality in individuals with MS and investigate correlations with upper extremity function, cognitive status, health-related quality of life (HRQOL), and balance.

A cross-sectional study was conducted with 45 consecutive individuals with MS between the ages of 18 and 65. Upper limb motor strength was evaluated using a hand grip strength dynamometer. Upper limb functional capacity was assessed using the Nine-Hole Peg Test (9HPT) and the Duruoz Hand Index (DHI). Balance, coordination, and falls were measured with the Berg Balance Scale (BBS), Falls Efficacy Scale (FES), and the 30-Second Chair Stand Test (30CST). Cognitive function was evaluated using the Montreal Cognitive Assessment instrument and the Symbol Digit Modalities Test. Level of HRQOL was assessed using the self-reported 54-item MS Quality of Life-54 questionnaire.

Out of the 45 participants (80% women, mean age 36.6 ± 8.6 years), higher hand grip dynamometer measures were strongly correlated with better DHI, 9HPT, BBS, FES, and 30CST scores. In the regression analysis, a 1-unit increase in dynamometer measures led to a 0.383 increase in overall HRQOL score.

This study demonstrates that increased hand grip strength (HGS) is associated with better hand functionality, balance, and HRQOL in individuals with MS. It provides evidence to support more systematic measurement of HGS in the care of people with MS.

From the Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey (MS, MKA) and the Department of Neurology, Faculty of Medicine, Sakarya University, Sakarya, Turkey (AT). 

 The authors do not have any financial or nonfinancial interests directly or indirectly related to the work submitted for publication.

Multiple sclerosis (MS) is a central nervous system disease characterized by various neurological disabilities resulting from progressive inflammatory and neurodegenerative processes.

 People with MS often experience symptoms that significantly impact their quality of life (QOL), including muscle weakness, sensory deficits, and cognitive impairment.

Approximately 66% of individuals with MS experience upper limb motor impairments, greatly affecting daily activities.

 Hand dysfunction, along with fatigue, ambulation, and cognitive decline, has been associated with increased unemployment, which highlights the importance of addressing these deficits in MS.

 Despite the disabling effects and negative impact on QOL, little is known about the exact frequency and severity of upper extremity dysfunction in individuals with MS. Additionally, accurately assessing upper limb movements is challenging due to their inherent variability.

Hand grip strength (HGS) is a reliable measurement of upper extremity muscle strength to determine functional capacity. It reflects the force generated from the combined contraction of extrinsic hand muscles.

 HGS measurement is recommended as a modality to assess muscle strength and is the simplest method for evaluating muscle functions in clinical practice.

 Previous studies have shown that increased HGS is strongly associated with preserved mobility, functional status, higher levels of daily living activities, and decreased disability.

With an incidence of 40% to 65% in individuals with MS, cognitive impairment is reported to be a predictor of long-term disability. The severity of cognitive decline appears to be related to patients’ ages and levels of physical disability, and certain cognitive aspects can predict functional status in MS.

 Impaired balance is also a disabling symptom that negatively impacts independence and autonomy, leading to falls and injuries. It can be present even in the early stages of the disease course, sometimes even in the absence of physical disability.

 People with MS tend to have lower health-related quality of life (HRQOL) levels.

 Muscle weakness, balance and gait abnormalities, fatigue, and other functional deficits significantly contribute to their lower HRQOL.

This study aims to evaluate HGS and hand functionality in individuals with MS and investigate their correlations with cognitive status, HRQOL, and balance states in these individuals.

This cross-sectional analytical study was conducted in the neurology department of Bursa Yüksek İhtisas Education and Research Hospital (Bursa, Turkey) from February 1, 2020 to May 1, 2020. Ethical approval was obtained from the institutional research committee, and all subjects provided written informed consent.

Physical characteristic data obtained included age, gender, time since diagnosis, and current treatments. Disability was evaluated by a neurologist using the Expanded Disability Status Scale (EDSS).

 The participants had a confirmed diagnosis of relapsing-remitting MS according to the revised McDonald criteria

 and an EDSS score between 0 and 5.5. Participants were between the ages of 18 and 65.

Exclusion criteria were current pregnancy, having an MS relapse within the preceding 3 months, sensorial problems not caused by MS, unilateral sensory perception loss, upper motor neuron injury (eg, stroke survivors), history of peripheral neuropathy, and upper limb orthopedic limitations that could interfere with study procedures.

All assessments were performed by the same physician in a quiet, well-illuminated room.

Upper Limb Functional Capacity: Hand Grip Strength 

Upper limb motor analysis was assessed in a seated position with the patient's feet on the ground. The HGS of the dominant hand was measured by the Jamar Plus+ Digital Hand Dynamometer (Sammons Preston). Since the reliability and validity of the Jamar dynamometer has been evaluated as high, it has been considered a gold standard in the assessment of grip strength.

 Hand dominance was determined by asking the patients which hand they used for writing. The test was performed in a seated position with the shoulder of the tested arm adducted, the elbow flexed at 90°, and the forearm and wrist set in neutral position. Grip strength tests were performed 3 times with 1-minute intervals between each, and the average of the 3 measurements was calculated.

The Nine-Hole Peg Test (9HPT) and the Duruoz Hand Index (DHI) were used to evaluate upper limb functional capacity. The 9HPT is a well-known, standardized, quantitative test of upper limb function. It has a strong test-retest reliability for individuals with MS.

 The test was performed in a seated position with the dominant hand. The chronometer was started as soon as the patient touched the first peg. The chronometer was stopped when the last peg hit the container.

The DHI is an 18-item self-report questionnaire designed to evaluate activity limitations of the hand. It was first developed for individuals with rheumatoid arthritis.

 Questions are grouped in 5 domains: in the kitchen (8), dressing (2), hygiene (2), in the office (2), and other (1). The patient is instructed to answer each question in terms of the level of difficulty they experience when completing various tasks without help from another person or assistive device. Individual items are scored on a 6-point Likert scale where 0 is 

. The 18 individual scores are summed to obtain a composite score. The total score ranges from 0 to 90 with higher scores indicating poorer hand functioning.

The Berg Balance Scale (BBS), Falls Efficacy Scale (FES), and the 30-Second Chair to Stand Test (30CST) were used to assess balance, coordination, and falls. The BBS has been validated in several populations and cutoff scores have been established to identify the risk of falls and the need for a gait aid for ambulation.

The FES questionnaire has 10 listed activities with responses on a Likert scale from 1, 

 at performing the listed activities, to 10, 

l. The total FES score was obtained from the sum of these 10 items, ranging from 10 to 100.

The 30CST was used to evaluate leg strength and endurance. This test was developed to overcome the floor effect that older adults expereinced with the 5 to 10 repetitions of the Sit to Stand Test.

The self-reported 54-item MS Quality of Life questionnaire (MSQOL-54) supplements the generic 36-Item Short Form Health Survey with 18 disease-specific questions that measure social and cognitive functioning, sexual functioning, pain, energy, health anxiety, and overall quality of life. Aggregate scores are generated for mental HRQOL (MCS-54) and for physical HRQOL (PCS-54). The standardized scores range from 0 to 100 and higher scores indicate better HRQOL.

The Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities Test (SDMT) were used to evaluate participants’ cognitive function. The MoCA is a 30-point test that assesses several cognitive domains, including visuospatial/executive functions, naming, memory, attention, language, abstraction, and orientation.

 is a digit substitution test that examines attention, visual scanning speed, perceptual speed, and tracking and is very sensitive to various neurological disorders. It has become the most commonly used neuropsychological test of processing speed in MS.

Statistical analyses were carried out using the SPSS/PC software (version 23.0). Descriptive statistical methods (frequency, percentage, mean, standard deviation, median, min-max) were used to assess the study data. The Shapiro-Wilk test confirmed that the data showed normal distribution. The independent samples 

 test was used to compare quantitative data according to groups. The relationship between the variables in the patient group was examined by the Pearson correlation. Analysis of categorical data according to groups was performed using the χ

 test. Stepwise multiple regression analysis was used to evaluate the relationship among factors. Significance level was taken as 

A total of 80 persons with a diagnosis of relapsing-remitting MS (RRMS) for at least 1 year were screened for eligibility. Of the 80, 35 were excluded from the analysis (32 patients did not meet inclusion-exclusion criteria and 3 declined to participate). Of the 45 persons included, 36 were women (80%); the mean age was 36.6 ± 8.6 (range 21-57) years. The mean disease duration was 7.1 ± 6.1 (range 1-23) years. Forty-two (93.3%) patients were using an MS-immunomodulating therapy: 12 glatiramer acetate, 12 interferon, 16 oral therapies (fingolimod, teriflunamid, dimethyl fumarate), and 2 ocrelizumab. The average EDSS for the RRMS group as a whole was 1.9 ± 1.3 (range 0-5.5).

All parameters were evaluated with the Mann-Whitney U test. The median value of the 9HPT repeated was 22.1 (16.8-21.11) for women and 25.6 (19.7-35.1) for men and showed a significant difference according to sex (

 = .027). The median physical health value was 57.5 (20-100) in women and 90 (35-100) in men, thus, it was significantly higher in men (

 = .048). There was a significant difference between the sexes in terms of sexual function, with a median value of 66.7 (0-100) for women and 100 (8.3-100) for men (

 = .018). The satisfaction in sexual function median was 50 (0-100) for women and 100 (0-100) for men (

 = .046). When the mean value of general QOL was compared by sex, men (72 ± 15) had significantly higher results than women (57.8 ± 18.8) (

 = .041). Women with MS generated less force (45.6 ± 21) than men (70.5 ± 26.7) as measured by the dynamometer grasp performance, demonstrating a strength difference with a moderate effect size (

 = .04). Other variables did not differ according to sex (

Hand grip dynamometer measurements were strongly correlated with DHI (

 = .251) scores. Additionally, the SDMT was significantly correlated with 9HPT (

 = .003) scores, but not with grip strength measurements (

Dynamometer measurements were found to be statistically significant in predicting overall QOL, with each unit increase resulting in an increase in overall QOL score of 0.383 (

 = .001, SI = 0.104, R2 = 0.523 Stepwise Method).

The present study was conducted to draw attention to the hand muscle strength and functionality in people with MS and to investigate its association with balance, cognition, and QOL. We found strong correlations between hand grip dynamometer measures and hand functionality tests (DHI, 9HPT), as well as balance measures (BBS, FES, 30CST). Regression analysis revealed that higher dynamometer scores were significantly correlated with better QOL.

Previous studies have shown that upper limb motor function is significantly affected by the level of disability in people with MS.

 In the Dubuisson et al study, 95% of people with MS considered upper limb function to be more important than lower limb function.

 There are still no standardized, uniform disability scales to evaluate upper limb functionality in people with MS.

 In our study, we used the DHI and 9HPT to assess upper extremity functionality and the Jamar Plus+ Digital Hand Dynamometer to evaluate HGS. Although the HGS test was originally designed for patients undergoing hand surgery, it has been shown to have a strong association with decreased physical fitness and reduced muscle strength.

 We observed that increased HGS was strongly linked to better upper extremity function and balance but not with cognitive status and disability scores. It was positively correlated with QOL.

As reported in previous studies, people with MS generally exhibit lower HGS due to motor weakness.

 It has been demonstrated that a change of 5.5 kg (12 pounds) or more in hand grip strength and 20% or more in the 9HPT falls beyond the range of day-to-day variability and reliably indicates a true change in functionality for people with MS.

 Similar to our study, research has also shown that a deficit in hand grip strength negatively impacts QOL and leads to subsequent dependence for those with MS.

 A study by Aristotelous et al also showed that hand grip strength was not associated with cognitive performance, but was linked to HRQOL, supporting our findings.

 While most studies have focused on evaluating lower extremity strength due to its impact on patients with mild disability, our study highlights the growing importance of upper extremity strength in the later stages of MS, especially when patients require walking aids.

 However, we believe that the earlier stages of the disease are more appropriate for evaluating upper limb strength and functionality. Our study also demonstrates that hand function or upper limb functionality constitutes a separate disability area that is distinct from the EDSS, which can significantly affect QOL and merits further investigation in future studies.

Cognitive impairment has been reported in up to 65% of individuals with MS,

 and in our study, cognitive status was significantly correlated with hand functionality and balance tests, but not with hand muscle strength, similar to the study of Aristotelous et al.

 Previous literature suggests that increased functional capacity is linked to better cognition, possibly due to increased blood flow to the brain, improved cardiometabolic health, and reduced chronic inflammation levels.

 necessitating further studies with larger MS populations, especially focusing on upper limb function evaluations.

Both the mental and physical components of HRQOL are reported to be negatively affected in people with MS.

 Reduced HRQOL was associated with fatigue, depression, and disability in a previous study.

 In addition, cognitive decline was shown to negatively affect HRQOL independent of physical disability.

 Consistent with previous studies, higher disability scores indicated lower sexual functions, satisfaction with sexual function, overall QOL, and physical health composite scores in our study. Increased HGS and younger age indicated a better QOL, as expected.

Some limitations should be considered when interpreting our results, including the cross-sectional design, which limits conclusions about the direction of the association and precludes any inferences of causality or temporality. The study sample consisted of people with MS, so it may not fully represent the entire MS population. Low sample size and inclusion of only ambulatory persons with an EDSS score of up to 5.5 were other limitations.

This study highlights the importance of hand muscle strength and functionality in individuals with MS and its correlation with their cognitive status, balance, and HRQOL. Enhancing hand functionality and muscle strength can significantly impact independence, daily activities, and QOL for people with MS. Loss prevention and early restoration of hand function should be emphasized before the onset of significant morbidity. Further investigations are necessary to identify the most useful hand functionality or muscle strength test as an outcome measure in clinical trials of neuroprotective or neuroreparative therapies in MS. 

Hand Grip Strength as a Predictive Tool for Upper Extremity Functionality, Balance, and Quality of Life in People With Multiple Sclerosis

Decreases in mobility, quality of life (QOL) and cognition are commonly seen in people with multiple sclerosis (MS). Physical therapy (PT) and exercise have been shown to improve many symptoms in ambulatory individuals with MS; however, evidence in nonambulatory people with MS is lacking. Dalfampridine is a US Food and Drug Administration-approved medication for MS that treats impaired ambulation by enhancing nerve conduction. To our knowledge, no study has examined the combined effect of PT and dalfampridine and very few studies have examined dalfampridine's effect on function in individuals with more progressive disease. The purpose of this study was to examine the effectiveness of PT combined with dalfampridine or a placebo on function, QOL, and cognition in nonambulatory individuals with MS. In addition, we explored the benefits of PT in all participants to increase the extremely limited research in this population.

Adults with MS were randomly assigned to receive dalfampridine (n = 13) or placebo (n = 14) for 12 weeks in conjunction with PT treatment 2 times a week. Function, QOL, and cognition were assessed at baseline, 6 weeks, and 12 weeks.

There was a significant time × group interaction for the Multiple Sclerosis Quality of Life-54 favoring the placebo group. Both groups significantly improved on the 9-Hole Peg Test (left arm only), sitting lateral reach (right), transferring from wheelchair to mat, and repeated sit to stand.

The addition of dalfampridine to physical therapy did not improve function, QOL, or cognitive processing speed. Importantly, this study demonstrated an overall benefit in function and QOL with physical therapy 2 times a week for 12 weeks for nonambulatory individuals with MS.

From the Department of Physical Therapy, D’Youville University, Buffalo, NY, USA; and the Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. 

Lacey Bromley, PT, DPT, PhD, NCS, MSCS, Department of Physical Therapy, D’Youville University, 320 Porter Ave, Buffalo, NY 14201; 

This study was envisioned by the late Susan E Bennett. She believed that physical activity would benefit every patient regardless of disease status. Acorda Therapeutics, Inc, provided the funding to complete this protocol. No conflicts of interest exist.

: Preliminary findings from this study were presented at the at the Consortium of Multiple Sclerosis Centers Annual Meeting; May 28-31, 2014; Dallas, Texas.

Multiple sclerosis (MS) presents in individual patients with a variety of clinical manifestations that can impact functional mobility. Substantial progress in treatment of the disease has significantly reduced relapse rates and improved disability outcomes. With the availability of more than 25 disease-modifying therapies time to walking limitation can be delayed for up to 20 years

 and life expectancy has steadily increased.

 Nevertheless, a sizable number of patients, especially those with progressive subtypes, advance to nonambulatory status.

Preserving mobility is consistently ranked as the most important factor impacting quality of life (QOL) in people with MS regardless of disability level or disease duration.

 A strong correlation exists between impaired mobility and the capacity to live independently, complete activities of daily living (ADL), and participate in individual and community-based life roles.

 These limitations can severely decrease QOL in people with MS.

Another concerning and prevalent symptom of MS is cognitive impairment. It is estimated that 34% to 65% of people with MS are affected by cognitive decline; individuals with progressive forms of the disease fall toward the higher end of that range.

 Research suggests that cognitive processing speed, memory, and learning are the faculties most impacted by the MS disease process.

 Slow worsening on the Symbol Digit Modalities Test (SDMT) has been correlated with a decline in cognitive processing and gray matter volume loss due to neurodegeneration.

Physical therapy (PT) and general exercise are well established interventions to preserve mobility and improve QOL in ambulatory individuals with MS.

 In addition, cognitive changes, common in MS, may be impacted by exercise, although more studies are needed to draw definite conclusions. Evidence suggests that physically fit individuals with MS have less gray matter atrophy and, as a result, better cognitive function than their counterparts with MS who are less physically fit.

 Growing evidence from both mouse and human studies shows that exercise impacts the central nervous system by decreasing neuroinflammation and improving both neuroprotection and axonal health.

 Although the research has strengthened the efficacy of exercise in MS, the biggest knowledge gap that remains is to discern how exercise can impact the more progressive forms of the disease.

Dalfampridine (also known as fampridine, 4-aminopryridine, 4-AP) is a broad-spectrum potassium channel blocker that has been shown to improve nerve conduction in demyelinated axons.

 This oral medication binds to open potassium channels and delays repolarization of the nerve cell, extending the duration of the action potential and improving the strength of the nerve signal.

 It has been demonstrated that 9 weeks of dalfampridine treatment results in a significant increase in walking speed as demonstrated by the timed 25-foot walk test in a subset of people with MS.

Because of dalfampridine's mechanism of action, it is reasonable to hypothesize that the drug may impact other bodily functions besides ambulation and could improve functional mobility in people who are not ambulatory. In a small pilot study, 10 mg of dalfampridine given twice a day for 4 weeks was shown to improve upper extremity function in people with MS with an average Expanded Disability Status Scale (EDSS) score of 7.

 The impact of dalfampridine on cognition, with an emphasis on processing speed, fatigue, and depression, has also been explored in a small number of studies with some promising results.

To our knowledge, pairing exercise with dalfampridine treatment has not been explored. Because exercise has neuroprotective qualities and impacts the neuroplasticity of the central nervous system, it is rational to believe there may be potential for an augmented effect if the 2 were combined.

This randomized controlled trial examined the effectiveness of dalfampridine on function, QOL, and cognition in nonambulatory people with MS when it was administered in conjunction with 12 weeks of PT compared to a control group that received PT and a placebo. In addition, a secondary analysis to examine the benefits of PT in all participants was conducted to increase the extremely limited research in this population.

Participants were enrolled consecutively from a tertiary MS care center in Western New York State. Participants were included if they met the following criteria: (1) aged 20 years or older; (2) confirmed MS diagnosis

; (3) no steroid treatment in the last 30 days or a relapse in the last 90 days; (4) MS considered stable; and (5) capable of performing requirements of PT treatment, including at least a 2 of 5 score on the manual muscle test in 50% or more of the major muscle groups. Exclusion criteria were (1) history of seizure disorder; (2) major cognitive or mental illness that prevented ability to provide consent; (3) evidence of another medical cause of cognitive impairment besides MS; and (4) severe joint contractures that limited the ability to move within full active range of motion.

A double-blind, placebo-controlled randomized design was utilized comparing the PT intervention provided 2 times a week for 12 weeks in addition to either 10 mg of dalfampridine or placebo administered twice daily. Participants were randomly assigned in a 1 to 1 ratio to either treatment or placebo, and both the examiner and the physical therapist carrying out the treatments were blinded to the allocation. All participants provided written informed consent and the study was approved by the University at Buffalo, State University of New York Institutional Review Board.

Once eligibility was confirmed and group assignment was complete, the participants underwent outcome measure testing at 4 different time points: twice, 2 weeks apart, with the scores averaged for baseline measurement (PT was scheduled to begin within 1 week after the second measure); at 6 weeks after initiation of PT; and at 12 weeks after completion of PT.

Every testing visit included the primary and secondary outcome measures, as described in the following sections.

The Five Times Sit to Stand Test (5XSTS) was performed 2 times with an interval of 2 minutes of rest between trials and was modified to allow participants to push off of the armrests and steady themselves when upright.

 Using a stopwatch, the time was recorded to the nearest tenth of a second. The average of the 2 times was used for analysis.

Two summary scores (physical health and mental health) and 2 subscales of interest (energy/fatigue and overall) were calculated from the Multiple Sclerosis Quality of Life-54 (MSQOL-54).

To assess cognitive processing speed, the SDMT presents a key of numbers paired with abstract symbols at the top of a page. Participants are asked to fill in the correct numbers on a blank row of symbols using the key. At the conclusion of 90 seconds, the examiner counts the number of correct matches.

Participants performed the 9-Hole Peg Test (9-HPT) 4 times, twice with the right hand, then 2 more trials with the left hand. The average of the trials for each hand was used for analysis.

Performance of transfer (moving from one surface to another) is an item in the Functional Independence Measure used to objectively quantify (scoring from 1 “total dependency” to 7 “complete independence”) an individual's ability to move from a wheelchair to a low mat table and from a low mat table back to a wheelchair.

 This was measured once at each testingpoint.

Seated functional reach, measured in inches (forward and laterally), was tested in 3 trials. The number of inches reached in the 3 tests were averaged, and that result was used for analysis.

Standardized performance scales for static standing have not been published. For this study, the examiner asked the patient to stand up using 2 hands on the parallel bars with the examiner guarding as needed. Once the participant stood upright, the examiner started the stopwatch. The time was stopped when the participant was unable to maintain an upright posture, which was defined as a flexing of the hips and knees or bending the trunk forward more than 75°. Two trials were performed (separated by a 2-minute rest). The average of the 2 times was used for analysis.

After the second baseline measurements, all participants were scheduled for their PT appointments within 1 week. The PT program consisted of 45-minute sessions 2 times a week for 12 weeks. The intervention was carried out by a blinded, licensed physical therapist who provided assistance and facilitation as needed. Progression of each exercise was based off the neurodevelopmental sequence to encourage functional movement. A home exercise program (HEP) was prescribed 3 times a week. The detailed exercises performed in each session and in the HEP are documented in 

(all supplemental material is available in a PDF at the end of the online article).

Using normative data for the main outcome measure,

 a .08 power calculation with α .05 resulted in 17 participants in each group. All data is reported as means plus or minus SD, as analyzed by SPSS software (IBM Corp). A 

 test was utilized for demographic differences between groups. A mixed-factor repeated measures analysis of variance was used to evaluate within subject factor of time (baseline; 6 weeks; 12 weeks) and between subject factors of group (dalfampridine vs placebo). Data was checked for normal distribution and for equality of multiple variances utilizing the Box M test. When data was found to be nonparametric, a Friedman test was employed to determine significance. A 

 value < .05 was used to determine statistical significance for all tests. However, because of the exploratory nature of our study, if interactions had a 

 value < .08, a post hoc analysis of time points was examined.

A total of 35 people were recruited to the study with 29 completing the 3 testing time points. Six participants were lost throughout the project; 2 due to medical reasons and 4 to caregiver issues (completing ADL in time for transportation to pick up participant, absence of caregiver, caregiver unable to assist participant to transport van). Two additional participants were dropped from analysis because they completed less than half of the required PT treatments. Therefore, 27 participants were analyzed (13 on dalfampridine; 14 on placebo), with an average EDSS of 7.35 and a male-to-female ratio of 8:19. There were no significant demographic baseline features (

) and no significant differences in baseline outcome measures between the groups.

Both groups were scheduled to participate in PT 2 times per week and perform an HEP 3 times per week, monitored weekly by the physical therapist. Of the 27 participants who completed the study, 82% attended more than 80% of the treatment sessions and the remaining 18% completed more than 70% of the sessions. Although difficult to truly assess, several of the participants reported impediments to fully adhering to the HEP. Most often the barrier to completion was a lack of caregiver assistance to safely perform the HEP.

There was a significant time × group interaction for both the physical health and mental health summary scores on the MSQOL-54 (

). The placebo group demonstrated significant improvements in QOL after 6 weeks and after 12 weeks of intervention, with the greatest increase in the first 6 weeks of treatment. In contrast, the dalfampridine group tended toward a decrease in QOL during treatment although it did not reach statistical significance. The overall QOL subscale includes 2 questions (“Overall, how would you rate your own quality-of-life?” rated on a visual analog scale of 0 [worst] to 10 [best] and “Which describes how you feel about your life as a whole?” with options from 1 “terrible” to 7 “delighted”). For both groups, scores on this subscale improved significantly after 6 weeks of treatment, however the significance was lost after 12 weeks. In addition, the placebo group demonstrated a greater improvement over time than the group receiving dalfampridine.

 = .06), both groups tended toward improvement on the SDMT (Table 1). The dalfampridine group demonstrated a 1.4-point improvement, while the placebo group achieved a 2.1-point improvement. Secondary to the borderline 

 value, an exploratory post hoc was performed on each time point and a significant difference (

 = .04) was found in the placebo group between the baseline and 6 week testing points.

The functional results are summarized in 

There was a significant improvement on the 9-HPT in the left arm in both groups. Both groups demonstrated approximately a 5-second faster time to task completion throughout the 3 time points. This result was not seen in the right arm.

There was a significant improvement in both groups from baseline to both the 6-week and 12-week time points when transferring from wheelchair to the low mat. The return transfer from the low mat to the wheelchair reached statistical significance at the final 12-week testing in the placebo group only.

No improvements were seen in either group during the anterior functional reach. However, statistical significance was reported for reaching to the right after both 6 weeks and 12 weeks of therapy.

Both groups improved their sit-to-stand times significantly. The group who took dalfampridine improved by 15.8 seconds while the placebo group improved by 3.6 seconds.

Although no statistically significant differences were seen, there was a trend toward increased standing time in both the drug and placebo groups (5.7 and 4.7 seconds, respectively).

The purpose of this study was to evaluate whether nonambulatory individuals with MS would benefit from dalfampridine and PT versus placebo and PT. The dalfampridine group did not demonstrate improvement over the placebo group with any outcomes, however, the overall cohort demonstrated enhancements in functional mobility, cognitive processing, and QOL with PT 2 times a week for 12 weeks. This finding is important, as there are limited studies that show the benefit of PT for nonambulatory people with MS.

A 2017 systematic review identified the need for evidence about exercise in people with MS with moderate-severe disease, with only 19 articles in the final review. Most of these 19 studies had extremely low recruitment numbers with an average of 15 participants; the larger studies included EDSS scores as low as 3.0. Modes of exercise that have been studied in this population include conventional aerobic and resistive training; supported body weight treadmill training; and electric-stimulation–assisted cycling with less evidence in conventional therapy than in the more elaborate modalities.

We were able to recruit 35 people and a total of 27 participants were able to complete the entire protocol. This number of individuals with high EDDS scores is well above the average of other studies. The study budget provided transportation to and from the clinic. We feel that providing transportation increased interest in participation and facilitated better adherence to the regimen once participants were enrolled. However, even with this accommodation, there were barriers to adherence. Due to legal obligations, our transportation company could not help clients out of their homes. Consequently, anyone who could not negotiate 1 step was unable to participate. In addition, participants who could not complete ADL and did not have a caregiver to assist were unable to get ready to travel.

Adherence to the dalfampridine schedule was established with continued monitoring at each PT visit and confirmed by caregivers, when possible. Common adverse effects of dalfampridine include difficulty sleeping, dizziness, nausea, headache, and increased pain. In our cohort, dalfampridine was well tolerated; no adverse effects were noted and there were no serious adverse events reported during the entirety of the study protocol.

Significant differences between the dalfampridine and placebo groups were only seen in 2 outcome measures (functional reach to the left and transferring from low mat to wheelchair), both favoring the placebo group. We attribute this to the small sample size, which was not adequate to perform a proper comparison. In addition, even though EDSS score differences were not statistically significant between groups, and our group comparison showed no statistical significance between outcome measures at baseline, the placebo group appeared to have better functional scores than the group taking dalfampridine. Interestingly, even though the placebo group had a seemingly higher functional status, their QOL measurements were lower at baseline than the dalfampridine group. Their lower QOL improved significantly over the dal-fampridine group by the 6-week mark and remained higher at the 12-week measurement. It is unclear why the dal-fampridine group's QOL measures trended downward throughout the study compared to the placebo group. However, the dalfampridine group's lower function may have resulted in more inconsistency in their symptoms. Throughout the testing procedures, we tried to mitigate the known variability and unpredictability of MS symptoms by averaging multiple trials of the same outcome.

When combining groups, there were significant improvements in 5 outcome measures (overall QOL subscale, functional reaching to the right, 9-HPT on the left hand, transferring from wheelchair to the low mat and back, and 5XSTS). To our knowledge, there is no study that has determined the minimal clinically important difference (MCID) of functional outcome measures in nonambulatory people with MS. The MCIDs of some of the same outcome measures were established in a similar study that examined the effects of slow release fampridine on arm and lower body function in ambulatory people with MS.

 The researchers concluded that the MCID of the 9-HPT was 15.3% (0-15.3) and the 5XSTS was 34.6% (16.9-34.6). In addition to the aforementioned study, the MCID of the 5XSTS has been explored in vestibular disorders with a change of greater than or equal to 2.3 seconds being the threshold for clinical significance

; Møller et al reported a change of 25.5% to be a minimal reliable change in people with MS.

 During our study, the percentage change of the 5XSTS from baseline to 12 weeks was 30%. The change in the dalfampridine group, who began with a poorer time, was 36% (43.45 seconds at baseline to 27.69 seconds at 12 weeks), surpassing the MCID, and the change in the placebo group was 17% (21.30 seconds to 17.68 seconds). The change of the 9-HPT for the left hand in our cohort was 11.1% (46.91 seconds to 41.70 seconds) by the end of the 12-week intervention. We hypothesize that the significant change in only the left was due to the left having more variance and limitation than the right which allowed for an increased opportunity for improvement. The minimal detectable change (MDC) for the lateral functional reach has been established in patients who experienced stroke at 2.3 cm to 2.67 cm.

 Our lateral reach to the right improvement was 2.82 cm, which would surpass the requirement set for MDC in patients with stroke. When reaching to the right, the trunk muscles on the left must eccentrically contract to control the movement, which is followed by a concentric movement to sit back upright. We believe that the improvement seen with the right lateral reach mostly reflects an increase in left (nondominant) trunk muscle control for reasons similar to the improvement seen in the 9-HPT on the left. Although Taheri et al found that a 1.5 (physical) and 2.5 (mental) point change was enough to be considered clinically significant in a population of 265 people with MS,

 MCID cutoffs for QOL scales have been notoriously hard to quantify. Our changes on the MSQOL-54 were much greater than the Taheri MCID, but our sample size was much smaller, so we are cautious about drawing a definite conclusion.

We feel it is important to report qualitative improvements that were not captured in our quantitative analysis. At 6 weeks into the intervention, 1 participant reported the ability to sign checks, which she had not been able to do for the past 2 years. She was in the placebo group, but was benefiting from specific rehabilitation interventions and general exercise. A participant in the dalfampridine group was able to return to ambulating short distances with a 4-wheeled rolling walker after being physically unable to get out of a wheelchair for the previous 2 years. Ambulation was not assessed during this study and thus this impressive finding was not captured. Most participants reported that they enjoyed getting out of the house and attending therapy twice a week. Caregivers also reported improvement in transfer status and ability to complete ADL.

Future studies should be conducted with fewer intervention barriers, for example, a home therapy or inpatient rehabilitation program may be more beneficial for nonambulatory individuals. Outcome measures that can provide a better picture of overall functional status would be ideal, but, at this time, they have not been developed. Another area that may strengthen results would be assessing caregiver burden to assess the subject's functional deficits and/or improvements. With dalfampridine's possible mechanism of improving conduction of action potentials along axons, functional improvements in nonambulatory people with MS is conceivable. Future studies should be conducted to examine the benefits of rehabilitation and dalfampridine to improve functional mobility and QOL for individuals living with a greater level of disability.

There were very few statistically significant differences in function, QOL, or cognitive processing speed between 2 groups of nonambulatory people with MS who received dalfampridine or placebo 2 times a day in conjunction with PT. Importantly, this study demonstrated an overall benefit in function and QOL by engaging in PT 2 times a week for 12 weeks for people who are nonambulatory and who have moderate to severe MS.

Effects of Physical Therapy and Dalfampridine on Function and Quality of Life in Nonambulatory Individuals With Multiple Sclerosis: A Randomized Controlled Trial

The John A. Schafer, MD Multiple Sclerosis Achievement Center (MSAC) conducts wellness programs that include exercise, cognitive stimulation, education, emotional support, and socialization for people with multiple sclerosis and their care partners. Patient-reported outcomes (PROs) are collected annually. Four-year outcomes encompass the COVID-19 pandemic when some of these programs were offered virtually.

Beginning in 2017, baseline data were collected for 110 MSAC day wellness program participants through PRO measures. Of those 110, 52 completed PROs annually through 2021. Outcome measures included the Multiple Sclerosis Impact Scale (MSIS-29); Multiple Sclerosis Self-Efficacy Scale (MSSE-10); Godin Leisure-Time Exercise Questionnaire (GLTEQ); and the Neurology Quality of Life domains of Anxiety, Depression, Emotional and Behavioral Dysregulation, Positive Affect, Cognition, Ability to Participate in and Satisfaction with Social Roles and Activities, and Satisfaction with Social Roles and Activities. Analysis using t tests compared baseline with 4-year data. A separate analysis compared outcomes collected in January 2020 and January 2021.

Analysis of 4-year data demonstrated statistically significant improvement in MSIS-29 and GLTEQ. Statistically significant improvements noted at years 2 and 3 in the Ability to Participate in Social Roles and Activities were no longer significant at year 4. Other notable changes included significant decreases in MSSE at year 4 when compared with baseline and year 3.

Individuals who participated in a weekly, structured day wellness program showed improvements in self-reported disease impact and physical activity at year 4 vs baseline. Decreases in self-efficacy and social domains were seen, corresponding with disruptions caused by the COVID-19 pandemic. Further analysis is needed to understand the effects of the pandemic on program participants.

From the Dignity Health John A. Schafer, MD Multiple Sclerosis Achievement Center, Citrus Heights, CA. 

Tiffany Malone, MSW, MSCS; Dignity Health John A. Schafer, MD Multiple Sclerosis Achievement Center, 7777 Greenback Lane, Suite 108,Citrus Heights, CA 95610; 

Multiple sclerosis (MS) is a chronic disease of the central nervous system most commonly diagnosed in people between 20 and 50 years old. MS debilitates normal body function and can cause serious disruptions to daily living, including “work, physical independence, mobility, social interaction, and participation in leisure activities.”

 In general, people with MS have a normal life span; therefore, many, particularly those who receive a diagnosis early in life, must live a long time with the physical, cognitive, and psychological effects of MS. They often experience isolation from family and friends. As such, interventions to enhance quality of life are essential to helping people with MS live well.

The John A. Schafer, MD Multiple Sclerosis Achievement Center (MSAC) in Sacramento, California, provides adult day services, which, broadly, encompass a system of professionally delivered, integrated, home- and community-based therapeutic, social, and health-related services for individuals to sustain living in the community.

 The wellness programs include individual and group exercise programs, individual cognitive stimulation using activities and applications on a tablet, group discussions in areas of overall health and MS-specific management that are facilitated by a health care professional, emotional support, and socialization with other people with MS. In addition to the day wellness programs, community outings provide other social and recreational opportunities. Some people have been participating since the program's inception in 2014.

Adult day programs also offer respite for caregivers.

 The MSAC provides a professionally facilitated support group for caregivers and loved ones of people with MS. Since its inception in 2016, 91% to 95% of participants in the MSAC support partner program report that they agree or strongly agree that the program is beneficial to their health and well-being.

Research results on day programs are mixed. A scoping review of older adults who participate in activities at adult day centers (ADCs) concluded that ADCs have positive impacts on health-related, social, psychological, and behavioral outcomes.

 In addition, a study found that caregivers showed significant decreases in depression, improvement in their ability to manage memory lapses and difficult behaviors, and improvement in self-perception of overall well-being with participation in an Adult Day Services (ADS) Plus program (a community-based program for adults living at home plus care management services). All these changes were seen at 3 months, but no statistically significant differences were seen long term (up to 12 months).

Investigators in another study did not find clinically significant effects on standardized measures of physical and mental health-related quality of life (HRQOL) or health care utilization after 1 year.

 Scores on the physical component scale of the 12-Item Short Form Health Survey were statistically significant for those with MS attending ADS, but the difference was not considered clinically meaningful. Investigators in a qualitative study from the same data set did conclude that these programs have a profound influence on the participants’ psychosocial health, which the authors attribute to membership in a socially cohesive community.

An evaluation of a concentrated 4-day wellness program for people with MS showed improvements in self-efficacy and self-perceived health-related outcomes. Improvement in these health-related outcomes was not dependent on initial disability as measured by the Expanded Disability Status Scale.

The COVID-19 pandemic affected people with MS in many ways. Several studies have reported increases in depression

 However, results of another study showed improvements in social interactions.

 In a survey of 1145 people with MS, many reported delays in and difficulties with several aspects of their medical care due to the pandemic, including delays to disease-modifying therapy administration and non–MS-related medical procedures, delays to medications and complementary and alternative medicine services, and postponement or cancellation of medical appointments. In addition, more than those who did not self-quarantine, respondents who self-quarantined reported that the pandemic had a significantly negative impact on their diet, personal finances, and exercise.

Alaina G. Tiani, PhD, DBSM

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