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Treatment Satisfaction in Multiple Sclerosis

Migraines are a common comorbidity and source of disability in patients with chronic inflammatory diseases like multiple sclerosis (MS). Recently, therapeutic agents for episodic and chronic migraine known as calcitonin gene-related peptide (CGRP) inhibitors have shown to effectively control migraine attacks and improve quality of life in the general population. This study explored the use of these novel agents in individuals with comorbid MS.

This was a retrospective, population-based cohort study at the University of South Florida's neurology clinic; it evaluated individuals with both MS and migraine.

A total of 27 individuals with MS and chronic or episodic migraine who received treatment with a CGRP monoclonal antibody were identified. Of these, 63% reported a reduction in their migraine frequency of greater than 75%. Concurrent use of a disease-modifying therapy (DMT) for MS occurred in 82% of patients, and in 37% of these, the DMT used was also a monoclonal antibody. Adverse effects from CGRP monoclonal antibodies were mild and occurred in only 11% of patients, and no patient experienced worsening of their MS symptoms during cotreatment over the duration of the study.

Our study showed a significant reduction in migraine frequency and a favorable adverse event profile for individuals with comorbid MS who took CGRP monoclonal antibodies and experienced no worsening of MS symptoms. In individuals with MS, CGRP monoclonal antibodies seem to be a safe and effective therapy for episodic or chronic migraine.

From the Morsani College of Medicine (AM), Department of Neurology (LF, ZT-N, NM, AA, DR, JM), University of South Florida, Tampa, FL, USA. 

 Janice Maldonado, MD, 12901 Bruce B Downs Blvd, MDC 55, Tampa, FL 33612; 

 This data was previously presented at the 2022 Consortium of Multiple Sclerosis Centers Annual Meeting; June 2, 2022; National Harbor, Maryland.

 Janice Maldonado,MD, receives grant support from Genentech for research study. Derrick Robertson, MD, has received grant support from Anokion; Atara Biotherapeutics; Biogen; CorEvitas; EMD Serono; Genentech; GW Pharmaceuticals; Janssen; Mallinckrodt; MedDay; Novartis; Patient-Centered Outcomes Research Institute; PRIME Education, LLC; Sanofi; and TG Therapeutics; consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Greenwich Biosciences, Horizon, Janssen, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics; and honoraria or speaker fees from Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Janssen; PRIME Education, LLC; Sanofi; and TG Therapeutics. The remaining authors report no relevant conflicts of interest.

An enigmatic disorder to treat, migraines can result in severe impairment to sufferers due to symptoms such as pain, difficulty concentrating, and neurological deficits.

 Migraines are thought to arise from nociceptive signals of the trigeminal ganglia, with the neurons of the ganglia releasing vasoactive and inflammatory mediators that elicit pain.

 One of the vasoactive peptides is calcitonin gene–related peptide (CGRP), a 37-amino acid molecule that dilates blood vessels; its presence is markedly increased in individuals with migraines.

 During migraine attacks, CGRPs are found throughout the trigeminal ganglia, cortex, and various nociceptive pathways, promoting pain signaling.

Therapies that inhibit CGRP signaling can improve migraine symptoms during the attack and also serve as prophylaxis.

 Some of these therapies are small-molecule inhibitors of the CGRP receptor, including olcegepant, telcagepant, atogepant, ubrogepant, and zavegepant. In addition, monoclonal antibodies counteract the effects of migraine, including eptinezumab, erenumab, fremanezumab, and galcanezumab.

 Erenumab specifically targets the CGRP receptor while the other monoclonal antibodies bind to CGRP itself to antagonize the vasodilatory effects. Eptinezumab, erenumab, fremanezumab, and galcanezumab are increasingly used for long-term treatment of migraines and have been shown to significantly reduce the number of migraine days.

Anti-CGRP therapy may be beneficial in individuals with comorbid migraines and multiple sclerosis (MS). Some studies have suggested that migraine is a risk factor for developing MS.

 Headaches have been estimated to occur in approximately two-thirds of individuals with MS

 and are associated with a higher prevalence of pain-related MS symptoms such as temporomandibular joint pain, muscle spasms, restless legs syndrome, occipital and trigeminal neuralgia, and Lhermitte sign.

 These MS symptoms can be managed with anti-inflammatory and neuropathic pain agents, but control of the disease itself has been achieved with the expansion of disease-modifying therapy (DMT) options over the past few decades.

 Unfortunately, some DMTs, especially interferon beta, can exacerbate headaches.

Few studies explore how CGRP monoclonal antibodies interact with DMTs, whether their use worsens or improves MS symptoms or, alternatively, whether CGRP monoclonal antibodies improve migraines in individuals with MS.

 Because they may produce both pro- and anti-inflammatory effects and experiments have shown that they reduce microglial-mediated autoimmune reactions,

 CGRP monoclonal antibodies may play a role in reducing autoimmune inflammation in the central nervous system and thus may be beneficial for individuals with MS.

 One series of case studies demonstrated that the use of CGRP monoclonal antibodies for migraines in individuals with MS was associated with only a few adverse effects (AEs): urinary tract infections, sinus infections, and upper respiratory tract infections.

Because CGRP itself has some anti-inflammatory effects, its antagonism may be associated with AEs such as rashes, hepatitis, and drug antibody formation in patients with autoimmune conditions.

 Due to the potential benefits of anti-CGRP therapy in individuals with MS described previously, as well as the possibility of these AEs, we wanted to study the efficacy of CGRP monoclonal antibodies in individuals with comorbid migraines and to see whether those who take CGRP monoclonal antibodies for their migraines experience any AEs as a result.

We conducted a retrospective medical record review at an academic MS center in Tampa, Florida. Individuals with both MS and chronic, episodic, or unspecified migraine who were 18 years of age or older and who had received treatment with a CGRP monoclonal antibody were included (N = 27). Patients whose treatment duration was less than 4 months were excluded. This study collected data from June 2018 to January 2022. Approval for this study was granted by the institutional review board of the University of South Florida.

Patients with diagnoses of MS and migraine were identified using the 

International Classification of Diseases, Tenth Revision

 codes listed in the individuals’ electronic medical records. Data analysis was limited to active patients of the MS study institution and therefore only included notes taken during encounters that were accessible through that institution's health record system.

The primary outcomes were migraine frequency prior to and following the use of CGRP monoclonal antibodies and AEs the participants experienced while on CGRP monoclonal antibodies. Headache reduction was quantified as less than 50% reduction in frequency, between 51% and 74% reduction in frequency, or greater than 75% reduction in frequency.

For each participant visit encounter between June 2018 and January 2022, we extracted MS diagnosis, migraine subtype based on the third edition of the 

International Classification of Headache Disorders

, current use of DMT, type of DMT and CGRP monoclonal antibody, duration of DMT and CGRP monoclonal antibody use, reduction in headache frequency, AEs, other previously trialed CGRP monoclonal antibodies, age, sex, and MS symptoms. This study did not ascertain subtype of MS, as subtype was not typically listed within patients’ charts due to the note templates used for each visit encounter.

Simple statistics were calculated including means and population proportions. To determine any statistically significant difference between the proportions, χ

 analysis was performed. Because of the small sample size, a Fisher exact test was also used to further analyze the data.

The cohort of 27 (88.9% female) with MS and either chronic (88.9%), episodic (7.4%), or unspecified (3.7%) migraine who received treatment with a CGRP monoclonal antibody (ie, fremanezumab, eptinezumab, erenumab, or galcanezumab; 

 had a mean age of 45.6 years. Of the participants, 82% were cotreated with a DMT for their MS (ie, ocrelizumab, glatiramer acetate, siponimod, cladribine, natalizumab, fingolimod, interferon beta-1a, alemtuzumab, dimethyl fumarate, or teriflunomide; see 

The average duration of therapy by CGRP monoclonal antibody subtype was 10 months for fremanezumab, 9 months for eptinezumab, 26 months for erenumab, and 13.5 months for galcanezumab (

). Over the period of the study, the longest duration of treatment with any CGRP monoclonal antibody was 42 months.

Eleven percent reported mild AEs (ie, muscle spasms, constipation, headache) from CGRP monoclonal antibodies. No one demonstrated worsening of their MS symptoms during cotreatment with DMT and CGRP monoclonal antibody. Of those that reported a reduction in headache frequency (n = 25, 92.6% of participants), 7.4% reported between 50% and 75% reduction in headache frequency, while 22.22% reported less than 50% reduction in headache frequency. In total, 63% reported a greater than 75% reduction in migraine frequency. There was no significant difference in reduction of headache frequency between participants who were on dual monoclonal antibody therapy (eg, erenumab plus ocrelizumab) versus those who were not, and this was true for each level of reduction in headache frequency (χ

 = .86). Even when separating into only 2 groups of level of reduction (< 50% and > 50%), there was still no statistically significant difference between participants who were on dual monoclonal antibody therapy versus those who were not (χ

 = .79). Analysis via Fisher's exact test also resulted in a nonstatistically significant difference between participants who were on dual monoclonal antibody therapy versus those who were not (

In a cohort of 27 participants with MS, use of CGRP monoclonal antibodies for migraine prophylaxis was associated with an improvement of migraine symptoms in the form of marked headache reduction for the majority. These findings are in line with the current literature that describes the ability of these medications to improve headaches,

 but more specifically, results show that CGRP monoclonal antibodies can be efficacious in individuals with comorbid MS.

More importantly, this study expanded on the previous letter by Gonzales-Martinez et al to further demonstrate that the CGRP monoclonal antibodies (eg, fremanezumab, eptinezumab, erenumab, galcanezumab) can be safely used in individuals with comorbid MS.

 Participants in this study often were cotreated for migraine while simultaneously receiving a variety of DMTs for MS, and the MS symptoms of the individuals on comorbid DMT and CGRP monoclonal antibodies did not get worse. Furthermore, study participants experienced limited AEs (eg, muscle spasms, constipation, worsened headache), but did not experience any rashes, elevations in liver enzymes suggesting autoimmune hepatitis, drug antibody formation, or other autoimmune-associated reactions to the CGRP monoclonal antibodies, contrary to previous reports.

This study had a few major limitations, including being underpowered. In addition, MS subtypes (eg, RRMS, PPMS) were not ascertained. Most participants had no documented MS exacerbations, which means their MS may not have been active enough to influence the safety of CGRP monoclonal antibody use. We studied CGRP monoclonal antibodies in this population, but not small-molecule inhibitors or gepants, because at the time data was collected, they had not been available on the market for very long. This study is also constrained by limited long-term follow up, with the longest duration of treatment with CGRP monoclonal antibodies being only 42 months. As such, further exploration should aim to address whether long-term use of CGRP monoclonal antibodies has any significant effect on the MS disease course, especially among subtypes. In summary, future research utilizing a cross-sectional or randomized controlled methodology should be pursued to further establish the safety and efficacy of anti-CGRP therapy (including monoclonal antibodies and gepants) in individuals with comorbid migraines and MS.

Use of Calcitonin Gene-Related Peptide Monoclonal Antibodies for the Treatment of Migraines in Individuals With Multiple Sclerosis

People with multiple sclerosis (MS) have an increased risk of falls, which are often associated with changes in movement direction and preceded by head rotation (HR). We aimed to investigate the effects of HR on postural control and gait temporal parameters in people with MS compared with controls (Cs) and to quantify the number of strides required to correct gait after HR.

Eighteen people with MS (44.4 ± 9.9 years; 3.1 ± 1.5 Expanded Disability Scale Score) and 10 Cs (43.6 ± 10.3 years) participated. Postural control during a standing task on a force plate was assessed and quantified by center of pressure displacement. Gait was assessed by 2D sagittal video analysis and analyzed with Kinovea. After30 seconds of unperturbed walking on a treadmill, participants were instructed to turn their head to the left and walk on, followed by a right HR. The 10 strides after the HR were compared with the mean of normal walking strides. Inter- and intragroup comparisons were performed using a mixed model for repeated measurements. Hierarchical testing was used for stride analysis.

While standing, people with MS performed worse in all conditions and increased center of pressure displacement after HR in comparison with Cs (

 ≤ .05). While walking, both groups increased the relative stance phase after HR (

 ≤ .05); however, people with MS reduced stride times (

 ≤ .05), and Cs maintained them. After HR, people with MS needed 3 strides to normalize stride times back to baseline, versus 1 to none for Cs.

People with MS have higher transient imbalance while walking and standing after an HR compared with Cs.

From the Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gemeinnützige GmbH, Berg, Germany (MR, IK); the Department for Clinical Neurosciences and Preventive Medicine, Danube University, Krems an der Donau, Austria (MR); University MS Center, Hasselt Pelt, Belgium (CR, LM, PF); REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, Belgium (CR, LM, PF); freelance instructor in Biomechanics, Kinetae, Barcelona, Spain (JVV-R); Institute of Psychoacoustics and Electronic Music, Faculty of Arts and Philosophy, Ghent University, Ghent, Belgium (LM); Department of Neurology, Ruhr University Bochum, Bochum, Germany (IK). 

 Marianne Rösner, Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gemeinnützige GmbH, Milchberg 21, 82335 Berg, Germany; 

We would like to thank all our colleagues from the diagnostics and medical teams of the Marianne-Strauß-Klinik, especially the physiotherapy team, for their engagement during the patient recruitment period. In particular, we would like to thank M. R. for technical support during the development phase of the study.

This material was previously a poster presentation at the all-virtual Rehabilitation in Multiple Sclerosis conference, November 27-28, 2021.

Peter Feys, PhD, PT, is on the editorial boards of 

. He has been a consultant to Biogen and Neuro-Compass. Ingo Kleiter, MD, has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GSK, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai, and Sanofi. He is an editorial board member of 

. All other authors have declared no relevant conflicts of interest.

Multiple sclerosis (MS) is an inflammatory demyelinating disease with the pathological hallmark of an accumulation of lesions in the white and gray matter of the brain and spinal cord that lead to a wide range of symptoms.

 A frequent complaint among people diagnosed with MS is loss of dynamic and static balance control.

 Approximately half of people with MS report at least 1 fall in a period of 3 months, and 35% report regular falls during a 6-month period.

 Eighty percent of falls can be associated with mobility tasks, and 60% of them occur during walking.

 Furthermore, people with MS usually report falls during activities of daily living, which are preceded by slips, stumbling, or changes in movement directions.

Head rotation (HR) represents a pivotal component in the modification of movement direction, thereby presenting 2 significant challenges that must be surmounted. First, there is the shift of attention from the current to the new situation, which can be interpreted as a dual-task in real-life scenarios. It is well documented that situations that engender such interference can have a detrimental effect on gait and postural control in people with MS.

 Second, the maintenance of movement over time while ensuring balance control is a process governed by brain regions and networks associated with cognition, motor control, and sensory integration, which are frequently impaired in individuals with MS.

 Reweighting processes between sensory systems for intersensory integration is highly related to the reliability of sensory input via the proprioceptive system, the most sensitive and fastest responding system to balance perturbations over time.

 Nevertheless, it has been suggested that people with MS rely more on visual than on proprioceptive sensory input to control balance.

Although studies in the past have concentrated on disease-related changes during unperturbed walking and balance tasks,

 along with the repercussions of assorted extrinsic disturbances on balance maintenance,

 the current study sought to shift the focus to the function of head rotation as a form of self-induced perturbation, discernible in routine activities. We hypothesized that, due to the accumulation of neurological deficits, people with MS would demonstrate an inadequate ability to cope with and/or modulate the perturbation induced by head rotation. We further hypothesized that people with MS would manifest a transitory decline in performance during standing and walking when compared with controls (Cs).

The objectives of this study were to investigate the role of HR on postural control during semistatic balance tasks and on gait temporal parameters during treadmill walking in people with MS compared with Cs. We further aimed to identify the number of strides to adapt and correct walking after the HR in people with MS compared with Cs.

People were recruited from an inpatient MS clinic and had to fulfill the following inclusion criteria: neurologist-confirmed diagnosis of MS according to 2017 McDonald criteria

; 18 years or older; Expanded Disability Status Scale (EDSS) score 1.0 to 5.5; disturbed balance while walking and standing as a main clinical problem stated by the patient and not primarily explained by muscle weakness, ataxia, or spasticity (as assessed by a clinical examination by an experienced physiotherapist); the ability to walk without assistive device for at least 150 m in 3 minutes; and the ability to perform barefoot, free, open-eye quiet standing for 30 seconds. Exclusion criteria were relapse or corticosteroid therapy in the past 3 months, newly prescribed medication with dizziness as a potential adverse effect in the 4 weeks prior to participation, cognitive deficits interfering with direct communication, and the presence of other pathology causing alterations in the locomotor system or balance. Age- and sex-matched healthy controls were recruited from the hospital staff. Written informed consent was obtained from all participants.

Clinical and demographic data of people with MS were obtained from their electronic medical records. All patients were examined following standardized protocols during the first 2 days after hospital admission by a multidisciplinary team, including physicians, physiotherapists, and occupational therapists. All people involved in the conduct and analysis of the study had long-term experience in the diagnosis and treatment of people with MS.

The study was conducted at the Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gemeinnützige GmbH (Germany) in accordance with the Declaration of Helsinki and all applicable regulations. The protocol was approved by the ethics commission of the Bayerische Landesärztekammer (Bavarian Medical Association) in December 2019, and the study was registered at the German Clinical Trials Register (file number DRKS00018076).

Participants with MS had a familiarization session the day before testing to prevent fatigue, to ensure that they would be able to walk safely on the treadmill, and to set a comfortable walking speed. For Cs, familiarization was performed on the day of testing, half an hour before the experimental procedures. The experimental setup is described in 

The Stability Easy force plate (TechnoBody) was used to assess balance control. This rehabilitation training and testing device combines a highly sensitive force plate with an advanced software system for interpretation. Participants were instructed to fix their gaze on a black screen with a white cross, placed in front of them at eye level, while standing along the lines drawn on the plate in a V shape (malleolus medialis is always placed along the central line, coinciding with the axis of movement of the plate). They were asked to perform the standing task in 3 conditions: (1) quiet, standing with eyes open (30 seconds); (2) quiet, standing with eyes open combined with a left head turn at the fifth second and back to the center 3 seconds later until the end of the test (total time: 30 seconds), and (3) same parameters as condition (2), except with a right head turn. Signals were given acoustically (Figure 1B).

Participants were asked to walk on a treadmill (quasar med 50; h/p/cosmos) while secured with a harness and attached to a secure strap. All participants walked at a self-selected comfortable walking speed.

A motion capture system was used for 2-dimensional video recordings. Cameras were placed on the lateral left (Sony Alpha a6400 camera, 120 frames, ISO 100) and dorsal (Nikon 1 J5 camera; 60 frames; ISO 160) while LED-markers (LED-M, Kinetae) were placed on anatomical landmarks of the lower limb (metatarsi-V distal, malleolus lateralis, dorsal calcaneus, lateral knee [interarticular space], lateral thigh [under trochanter major in the line with knee and trunk], second thoracic vertebra [Th2], first sacral vertebra [S1]).

Walking speed was assessed the day before in a training session for people with MS to prevent fatigue, and on the test day, half an hour before testing, for Cs. Individual walking speed remained consistent throughout the trial. Before the video recording, a short warm-up was done for a maximum of 2 minutes until participants said they felt balanced and secure while walking. The experimental procedure consisted of a walking period (unperturbed) followed by walking after head rotations. Participants heard an audio signal, a beep, which instructed them to turn their head. The beep was verbally supported with 

. The first turn was left, and the second turn was right (Figure 1).

Each participant performed the complete standing task 2 times, of which the first execution was analyzed and the second served as a backup in case of inadequate adherence or technical errors.

Balance parameters from the force plate were calculated by the force plate software (ProKin 252 Stability E, TechnoBody, Italy) using the Romberg test application. The displacement of the center of pressure (COP) was used such that COP velocity (mm/s) and area 95% (mm

) provided mean values and a maximum and minimum for each condition for the full length of 30 seconds. The parameters COP displacement (COPd), antero-posterior velocity, and medio-lateral velocity were subjected to statistical analysis.

Raw temporal data from the 3-foot-LEDs were obtained from the video recordings and analyzed using the open-source software Kinovea version 0.9.1 and Microsoft Excel. The LED profiles from the forefoot and the heel were superimposed, so that the time span between maximum and minimum (points of movement inversion) could be read, showing the different gait phases. The initial swing was provided by the forefoot and the initial contact and midswing by the heel, resulting in a stance and a swing phase. The swing phase was further divided into 2 periods, early and late, identified by the turning point at maximal heel speed. A gait cycle was defined as the time span between 2 consecutive initial contacts of the heel of 1 leg, referred to as stride time, and was calculated in milliseconds. Gait phases were given in percentages.

Stride time was the primary outcome measurement, on the assumption that small perturbations could be overcome by adapting phases without the need to change stride time periodicity. The relation between stride times and gait phases provided an idea of the degree of imbalance experienced; the use of adaptive strategies was a secondary outcome. Only the first trial for each HR was analyzed.

For the standing condition, a nonparametric test was used, since values were not normally distributed. A 2-factor analysis of variance with Friedman ranks was used for intragroup analysis, and the Wilcoxon-Mann-Whitney U test was used for intergroup analysis using a pairwise comparison. SPSS (IBM) was used for statistical analysis, as the SPSS Friedman test permitted the analysis of more than 2 time points simultaneously.

For the walking condition, a mixed model for repeated measurements was run via the JMP Pro 15 (SAS Institute) software, with a random effect of subjects in the model. The fixed variables were baseline values given in means and the 10 strides after HR, starting from the first initial contact after completion of the HR.

People with MS and Cs were analyzed separately for the comparison between baseline and perturbed conditions and time points. Afterward, an intergroup comparison of the overall means was done. The mean of the strides from 20 seconds of unperturbed walking was compared with: (1) each one of the 10 following strides (10-fSt) after left and right head rotation (post HRL/post HRR); (2) the mean of the 10-fSt; and (3) between the 10-fSt for the intragroup analysis.

Hypotheses were tested using a hierarchical testing model based on the work of Bauer et al.

 Three test levels were given. For detailed information about the hierarchical testing model, see 

 values for stance and gait parameters were corrected with the Bonferroni correction where applicable. Group-level data are presented as means, SDs, and 95% CIs at a significance level of a less than or equal to .05.

Demographic and clinical data for the 10 Cs and 18 people with MS included in the experimental procedures are shown in 

. Two people with MS were unable to adapt to the treadmill and were excluded after the familiarization session.

Comparison of Balance Tasks at Baseline and After Head Rotation

Intergroup analysis showed that people with MS and Cs differed in baseline values. During still stance, people with MS showed significantly larger COPd and increased anteroposterior velocities than Cs. Furthermore, people with MS performed worse than Cs for all test parameters during the conditions with HR.

Intragroup analysis of people with MS showed a significantly increased COPd and mediolateral velocity for the turn with right HR and a trend toward an increased COPd during the standing condition with the turn with HR left compared with baseline, whereas Cs showed no significant decline in performance. See 

Comparison of Gait at Baseline and After Head Rotation

Compared with Cs, people with MS showed significantly longer stride times while walking normally, with proportionally longer support and shorter swinging phases by a reduction in the relative time span between initial swing and mid swing. This was maintained post HRL and post HRR. Intragroup analysis revealed that people with MS shortened their stride times post HRL, whereas Cs maintained them. Both groups showed an increase in relative time of stance phase post HRL and post HRR, which was more pronounced for Cs (

 .0001) and less so for people with MS, reaching significance post HRL (

Stride-to-Stride Analysis After Head Rotation While Walking

A 1-to-1 stride analysis showed significantly shorter stride times for the first 3 strides post HRL (for stride 1 

 .02) in people with MS compared with baseline values. In contrast, the shortening of strides after HR was much less pronounced, and only the first stride post HRL was significantly shorter in Cs (

In people with MS, stride-1 post HR differed from all other strides, with the shortest stride time. The first stride post HRL differed from all other strides (

≤.02), and the first stride post HRR differed from baseline and strides 4 to 10 (

Left strides 2 and 3 showed no difference in stride time to the following strides after Bonferroni correction (significant value, 

≤ .005), while rightstride-2 had a shorter stride time compared with stride 6 (

.0001), and right stride-3 to stride-10 (

In addition, in people with MS, stride 2 and stride 3 post HRL had relatively longer stance phases in relation to baseline (

.005) and a relatively longer stance phase and shorter swing phase compared with stride-1 (

In Cs, a 1-to-1 stride analysis showed that the first step post HRL was the only step to differ significantly from baseline with a shortened stride time (

 .0031) and increased relative swing time (

 .033). No other differences could be seen.

Falls in people with MS frequently occur during activities of daily living. Nevertheless, little is known about the perturbation effect of inherent activity components, such as HR, for reorientation in space and its impact on balance control. This pilot study investigated the impact of an HR on a semistatic balance task and temporal gait parameter maintenance. We show that people with MS performed worse over almost all investigated parameters during stance and walking conditions in comparison to Cs. Moreover, people with MS showed a notable decline in performance after HR that was more pronounced while walking. People with MS needed 3 strides to regain pre-HR stride time behavior versus 1 to none for Cs. Further, the first stride post HR was significantly the shortest in time compared with almost all other measured stride times for people with MS. The main stance condition difference was an increase in COPd after HR in people with MS that was not seen in Cs.

Two of our study’s observations are novel. First, people with MS showed a decline in performance while walking and an increased number of strides to regain baseline stride time after HR compared with Cs. Second, people with MS had a different adaptive mechanism to overcome the perturbation effect of the HR than Cs. Cs adapted by adjusting their gait phases, while people with MS primarily shortened their stride times, followed by changes in gait phases.

Stride time and gait phase adaptations are both well-known adapting mechanisms in people with MS and Cs.

 If we assume that, in general, people overcome small perturbations by shifting gait phases with no decline in stride time periodicity, for people with MS, HR may present a challenge. Our results suggest that people with MS reacted to the perturbation repercussions, as they had limited control over the ongoing movement itself. It is known
that people with MS show a greater latency in activating adaptive mechanisms.

Although spontaneous external perturbations only allow reactive adaptations, HR is usually a self-initiated movement, which would allow for proactive adaptability. External perturbations are central to perturbation-based balance training, which is a promising tool for fall prevention in healthy and frail older adults as well as in people with Parkinson disease and stroke.

 Perturbation-based training that includes navigating stability-challenging conditions has shown a 48% reduction in fall incidence in older adults, one of the most promising fall interventions.

 People with MS have been shown to benefit from perturbation-based training, although the effect on their fall incidence is not known.

 Thus, perturbation-based training could be considered a promising tool for fall prevention in people with MS, although little is known about what the training should contain.

We believe that adding HR in functional static and dynamic settings could enhance movement planning. Unlike external perturbation, which leads to immediate compensatory mechanisms, self-motivated HR has the capacity to induce reweighting of sensory inputs and planning abilities due to its anticipated nature. Clarifying the role of HR for stability control in people with MS is relevant not only because it can be a precursor to falls, but also because rehabilitation could be implemented in clinical practice at low cost.

The following limitations to our findings should be considered. First, we used an experimental technology to capture balance and gait performance. Video analysis was performed in a clinical setting with a 2D (not 3D) motion analysis system. The 2D recording provides reliable data for the ipsilateral leg in the lateral view, but less for the contralateral side because of image distortion, thus impeding data capture for double stance and segmental kinetics. Nevertheless, the results of previous studies have shown that there is a strong correlation between the spatiotemporal parameters obtained in 2D versus 3D, and that the discrepancy between systems is primarily related to marker size.

 In our study, LED markers were 3 mm instead of 4.5 cm, reducing placement errors significantly. For analysis of the stance phase, an error between 1% and 6% was reported between systems, which can be considered small, and even more so when considering marker size.

Second, we had only 18 participants, who had a notable variability in walking velocity. It is known that a comfortable walking speed equates to the participant having the most stability,

 and when walking at a comfortable speed, the walking performance of people with MS was most similar to that of Cs.

 However, it is also true that temporal changes in the gait phase can be related to walking velocity. We believe that in people with MS, the reduction in walking velocity is due to the disease process, rather than to a voluntary action, and changes in gait phases should be considered adaptations. To overcome this limitation, future studies should include a larger number of participants and a stratification for EDSS (low and moderate) and falls (people with falls versus people without falls), as well as HR repetitions in different situations. Further, over-ground walking allows for a greater variability of adaptive strategies compared with treadmillwalking,

 raising the question of how this might have influenced the findings.

Third, it should be noted that HRs were induced by an audio signal that was not timed to a specific stride phase, unlike a self-initiated movement. Future research should add a marker on the head to calculate the degree of rotation as well as the time between the audio signal and rotation onset. This would also enable an evaluation of the amount of rotation, ie, whether a person with balance problems turns their head sufficiently to see the desired object, but not farther than necessary.

Finally, with the aim of understanding the initial response to HR without motor learning through repetition, we performed only 1 HR analysis for each condition of the study, which may affect data extrapolation.

People with MS experience greater imbalance while standing, have a higher temporary gait disturbance while walking after HR, and a longer time to recovery of temporal gait parameters when compared with Cs. Further research is needed to fully understand the effect of HR on maintaining standing and walking balance to improve the assessment and treatment of balance disorders in people with MS.

Head Rotation Impairs Balance and Walking in People With Mild to Moderate Multiple Sclerosis: A Pilot Study

The Patient-Determined Disease Steps (PDDS) scale is a patient-reported measure of disability used by at least 3 North American multiple sclerosis (MS) registries. We conducted a systematic review of the psychometric properties of the PDDS scale as part of a harmonization effort related to disability measures used in MS registries.

We searched the EMBASE, Ovid Medline, Scopus, Cochrane Database of Systematic Reviews, CENTRAL, CINAHL Plus, and ClinicalTrials.gov databases from database inception through July 28, 2020. Two reviewers independently screened abstracts and full-text reports for study inclusion and data extraction and assessed study quality and risk of bias. We included studies that assessed the validity or reliability of the PDDS scale. We conducted a meta-analysis to quantitatively summarize the findings.

From the 2476 abstracts screened, 234 articles underwent full-text review, of which 5 met the inclusion criteria. These studies assessed criterion validity, construct validity, and test-retest reliability. In all studies, criterion validity was assessed by correlating the PDDS scale score with the Expanded Disability Status Scale score (pooled r = 0.73; 95% CI, 0.66–0.79). Test-retest reliability was high (pooled intraclass correlation coefficient = 0.96; 95% CI, 0.92–0.99).

In this systematic review, the PDDS scale demonstrated criterion and construct validity for assessing disability in individuals with MS who have mild to moderate disabilities. This review also supports the test-retest reliability of the PDDS scale, although further studies with larger samples are needed.

From the Department of Internal Medicine (RAM, CM) and Department of Community Health Sciences (RAM), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, USA (LY); and Section of Statistical Planning and Analysis, Department of Neurology, University of Texas Southwestern University, Dallas, USA (AS). 

: Ruth Ann Marrie, MD, PhD, Health Sciences Centre, University of Manitoba, GF 543-820 Sherbrook St, Winnipeg, MB, R3A 1R9, Canada; 

 This study was funded by the National Multiple Sclerosis Society (SI-1907-34399). Ruth Ann Marrie, MD, PhD, is supported by the Waugh Family Chair in Multiple Sclerosis and a research chair from Research Manitoba. Amber Salter, PhD is supported by a Biostatistics/Informatics Junior Faculty Award from the National Multiple Sclerosis Society.

 Ruth Ann Marrie, MD, PhD, receives research funding from Canadian Institutes of Health Research, the MS Society of Canada, the MS Scientific Research Foundation, the National MS Society, Crohn’s and Colitis Canada, the US Department of Defense, the Arthritis Society, and the Consortium of Multiple Sclerosis Centers. Lauren Yaeger, MA, MLIS, serves as a statistical editor for 

 The remaining authors declare no relevant conflicts of interest.

Multiple registries and observational studies for multiple sclerosis (MS) in North America

 have captured information about disability and disease progression. These data have the potential to be leveraged further by collaboration between these efforts,

 but the studies have different objectives, different methods of data collection (patient-reported vs clinician-reported vs performance-based), and different measures of the same underlying construct, limiting the ability to combine or compare findings across studies. Retrospective data harmonization can improve comparability of similar measures collected across different studies. An initial step to harmonization is to determine what measures are being used and their performance characteristics.

The Patient-Determined Disease Steps (PDDS) scale is a patient-reported measure of disability used by at least 3 North American MS registries. The PDDS scale began as Disease Steps, a clinician-assessed tool initially developed to address challenges with application of the Expanded Disability Status Scale (EDSS) score in clinical practice (eg, poor interrater reliability).

 From there, it became a patient-reported outcome (PRO) measure and has now been used in more than 100 studies. The PDDS scale includes a single item with 9 levels ranging from 0 (normal) to 8 (bedridden).

We conducted a systematic review of the psychometric properties of the PDDS scale as part of a harmonization effort related to disability measures used by MS registries.

We conducted this review according to an a priori published protocol (PROSPERO #CRD42020211745) and report the findings according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria.

 The primary review question was: What are the validity and reliability of disability measures used by North American MS registries participating in the initial phase of the Multiple Sclerosis Metadata Collective (MSMDC, https://www.maelstrom-research.org/network/msmdc)? The participating registries that have listed the measures they use include the Canadian Pediatric Demyelinating Disease Network (CPPDN), iConquerMS People-Powered Research Network (iConquerMS), Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis (JHMS), the Veterans Affairs Multiple Sclerosis Surveillance Registry (MSSR), North American Research Committee on Multiple Sclerosis Registry (NARCOMS), North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) and Pediatric Multiple Sclerosis and other Demyelinating Diseases Database (PeMSDD). The identified measures used were the EDSS or a modified version of the EDSS (NARCRMS, PeMSDD, CPDDN), the Multiple Sclerosis Functional Composite or the related MS Performance Test (NARCRMS, JHMS), and the PDDS scale (NARCOMS, iConquerMS, JHMS). The EDSS has been the subject of previous reviews, as has the Multiple Sclerosis Functional Composite

; therefore, we present findings related to the PDDS scale.

We defined the psychometric or measurement properties of the PRO measure of interest (ie, the PDDS scale) according to the following 6 Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) consensus criteria.

 (1) Content validity refers to the degree to which the content of the PRO adequately reflects the construct being measured. (2) Criterion validity refers to the degree to which the scores on the PRO adequately reflect a gold standard. (3) Construct validity refers to the degree to which the scores on the PRO are consistent with hypothesized associations with other measures or differences between groups. (4) Internal consistency reliability refers to the degree of interrelatedness among the items; this did not apply to the PDDS scale because it is a single-item measure. (5) Responsiveness refers to the degree to which the PRO can detect changes over time in the construct being measured. (6) Test-retest reliability refers to the extent to which scores remain the same on repeated administration for respondents who have not changed.

We included original studies of adults with MS (any disease course) that assessed psychometric properties of disability measures using a noninterventional study design.

A medical librarian (L.Y.) searched the literature for records that included the concepts of MS, disability scales, and validity with modified versions of the Terwee et al filter.

 We did not limit the search to disability measures in North American registries at this stage to ensure a comprehensive search and because work to identify which measures were used by North American registries was concurrent. The librarian created search strategies using a combination of keywords and controlled vocabulary in Embase, Ovid Medline, Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature Plus, and ClinicalTrials.gov. The full search strategies are shown in 

 (All supplemental materials are available in a PDF at the end of this article.). All search strategies were completed on July 28, 2020, with no added database-supplied filters or limits. De-duplication of identified citations was performed using EndNote.

We used a 3-step process for study selection and data extraction. Using EPPI-Reviewer 4 software,

 2 reviewers (R.A.M. and C.M.) independently screened the titles and available abstracts of search results to determine whether they were validation studies of disability measures for individuals with MS. The full text of all reports classified as “include” or “unclear” by either reviewer was retrieved for formal review. In the second step, the 2 reviewers independently assessed the full text of each report by using a standardized form in EPPI-Reviewer 4 that outlined the predetermined inclusion and exclusion criteria. Disagreements were resolved by discussion between the 2 reviewers or by third-party adjudication (A.S.), as needed. At this point we had identified the disability measures used by North American MS registries and thus limited the studies selected for full-text review to those with the aim of validating the PDDS scale.

We developed a data collection tool and implemented it in EPPI-Reviewer 4; data abstraction was completed by 1 reviewer (C.M.) and verified by a second reviewer (R.A.M.). Information extracted included country, setting (eg, specialty clinic), participant inclusion and exclusion criteria, sample size, type of validity or reliability being assessed, the criterion standard (if applicable), and performance of the measure being assessed (eg, correlations, internal consistency reliability, test-retest reliability).

The Quality Assessment of Clinical Measures Research Evaluation Report was used to assess the quality of the studies included. It consists of 12 items that assess (1) the adequacy of the literature review used to establish the research question; (2) explicit inclusion and exclusion criteria; (3) the specific hypotheses or research questions; (4) the appropriate scope of measurement properties considered; (5) the appropriate sample size; (6) the follow-up; (7) how the authors described the measures used and how they were measured; (8) the use of standardized measurement techniques; (9) whether findings are presented for each hypothesis proposed; (10) whether appropriate statistical testing was conducted to obtain point estimates; (11) whether appropriate analyses were completed to estimate precision of the estimates; and (12) whether clear, specific conclusions and recommendations were made.

 Each item is scored as 0, 1, or 2. We summed the scores for each item, divided by the maximum possible score, and multiplied by 100%; this constituted the article’s overall quality score.

 We classified the quality as poor (0%–30%), fair (31%–50%), good (51%–70%), very good (71%–90%), and excellent (>90%).

We also used the COSMIN Risk of Bias Checklist to assess the risk of bias.

 This checklist provides a separate assessment of bias for each component of validity (eg, criterion, construct) and reliability (eg, test-retest). The overall quality of a component of a study is based on the lowest rating of any standard related to that component and may be classified as inadequate, doubtful, adequate, or very good.

We summarized the findings of all included studies using descriptive statistics. Measures of validity (eg, correlation coefficients) were retrieved from the paper when available and pooled using random-effects meta-analysis after the correlations were converted to 

 values using Fisher transformation; the pooled estimates were then converted back to correlation coefficients. We classified correlations of 0.3 or less as weak, 0.4 to 0.6 as moderate, and 0.7 to 1.0 as strong. The amount of heterogeneity was quantified using the 

 and its significance was determined based on the accompanying Q 

Statistical analyses were conducted using Stata Statistical Software: Release 14 (StataCorp LP).

The search identified 4177 citations, of which 1701 were duplicates. Of the remaining 2476 citations, 2242 were excluded at the title/abstract review stage (

). Of 234 articles selected for full-text review, 4 could not be retrieved, and another 92 were excluded. Of the 138 remaining articles, 5 evaluated the psychometric properties of the PDDS scale. Of note, 7 other studies sought to validate another measure and reported correlations between those measures and the PDDS scale.

Details of the included studies are shown in 

. Dates of publication ranged from 2013 to 2019. Study sample sizes ranged from 63 to 103; in total, the studies included 458 participants. Across all studies, most participants were women (n = 332, 72.4%). The median level of disability, based on the PDDS scale, was generally in the mild to moderate range.

Four of the studies evaluated the performance of the PDDS scale after translation to other languages (Portuguese, Turkish, Italian, Spanish); none of these studies formally assessed cross-cultural validity by testing the measurement invariance of the PDDS scale. One study evaluated a telephone-administered version of the PDDS scale rather than a self-administered version.

David J. Rintell, EdD

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