Although detection of new/enlarging multiple sclerosis (MS) lesions is a key metric in clinical practice and research, little is known about how human and automated detection methods compare. We compared findings made by a neuroradiologist to simulate routine practice to those made with a computer-aided technique as used in a clinical trial.

MRIs from a 96-week, progressive MS clinical trial with 255 participants were evaluated for new/enlarging T2 lesions by both a neuroradiologist and a semiautomated method. Readings from 887 paired scans were compared using a paired 

test and inter-rater reliability κ. Selected discordant reads were subsequently reviewed by a second neuroradiologist.

The semiautomated method identified new/enlarging lesions on 19.7% of the paired scans, while the neuroradiologist identified lesions on 5.7%. Of the 185 paired scans with new/enlarging T2 lesions by either method, the semiautomated method detected a mean of 3.4 new lesions, while the neuroradiologist detected 0.4. Overall κ was 0.18 (poor agreement); the κ of only scans with new/enlarging lesions by either method was –0.06. When scans were categorized as active or inactive, κ was 0.18. Unblinded neuroradiologist overread of selected discordant scans found more lesions when using advanced radiology tools such as coregistration.

A large discordance was found between new/enlarging MS lesions identified by a neuroradiologist and a semiautomated identification method. These findings may explain clinical trials reporting new lesions in patients on highly effective therapies, while they are less common in clinical practice. These findings have implications for treat-ment decision algorithms using MRI. Advanced radiology tools such as coregistration may improve lesion detection in routine clinical practice.

From the Cleveland Clinic Lerner College of Medicine (AJW), the Cleveland Clinic Imaging Institute (SEJ, JC), Cleveland Clinic Mellen Center for Multiple Sclerosis, Cleveland Clinic Neurological Institute (RJF), Cleveland Clinic, Cleveland, OH; NeuroRx Research, Montreal, Quebec, Canada (DLA, CE); and Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada. 

: Robert J. Fox, MD, Mellen Center for MS, JJ36, 9500 Euclid Ave, Cleveland, OH 44195; 

Alexandra J. White, MD

Stephen E. Jones, MD, PhD

Jay Costantini, MD

Douglas L. Arnold, MD

Colm Elliott, PhD

Robert J. Fox, MD

Clinical trials typically use semiautomated computer software to identify new lesions on MRI, while clinical practice typically relies on a human radiologist who usually does not have access to lesion identification software.

There is discordance in detecting new lesions using semiautomated methods and human readers; semiautomated software detects many more lesions than a human.

Clinicians should consider this lesion counting discordance when reviewing the new lesion rates reported in clinical trials.

MRI has been a mainstay of multiple sclerosis (MS) clinical practice and research for several decades. New or enlarging hyperintense lesions on T2-weighted images are a key marker of inflammatory injury and disease activity in MS.

 In clinical practice, new lesions are identified by a radiologist or neurologist, while in clinical trials evaluating MS therapies, new lesions are usually identified by an automated or semiautomated evaluation.

 Little is known about how these 2 methods compare, which is important when translating clinical trial results into routine clinical practice. This study aimed to use a combination of qualitative and quantitative methods to compare physician and computer-based identification of new/enlarging brain T2 lesions obtained during a clinical trial.

Ethical approval was obtained from the Cleveland Clinic’s institutional review board. From November 2013 until May 2017, patients with progressive MS enrolled in the phase 2 SPRINT-MS trial (NCT01982942) underwent standardized MRI scans at baseline and every 24 weeks up to 96 weeks for a total of 5 MRIs each.5 MRIs were obtained using Siemens (MAGNETOM Trio or Skyra) or GE (version 12.x or higher) 3T scanners. Image acquisition included T1-weighted 3D-spoiled gradient-recalled echo, proton density weighted and T2-weighted 2D turbo/fast spin-echo, and 2D T2-weighted fluid-attenuated inversion recovery (FLAIR). Gadolinium was not used. Details of the MRI acquisition and overall results of the SPRINT-MS trial have been previously published.

 This analysis was conducted without accounting for treatment assignment.

The semiautomated method (SAM) was performed by a central neuroimaging analysis center, which first conducted quality control on images received from clinical trial sites. Incorrect MRI acquisition parameters, incorrect head angle, and excessive motion were common reasons for scan rejection. T1-weighted, T2-weighted, T2-weighted FLAIR, and proton density weighted images at reference and follow-up time points were all rigidly coregistered to a common patient space at the native resolution of the T2-weighted images (1 × 1 × 3 mm). New/enlarging T2 lesions were automatically segmented by simultaneously considering coregistered T1-weighted, T2-weighted, T2-weighted FLAIR, and proton density weighted images at both reference and follow-up time points, using a voxelwise Bayesian-driven probabilistic classification, followed by random-forest–based classification of individual new/enlarging T2 lesions.

 Automatic segmentation was followed by human visual confirmation by an expert rater and manual correction where necessary.

 New/enlarging T2 lesion counts and volume of each new/enlarging lesion were recorded based on new/enlarging T2 lesion boundaries as determined in the common patient space.

All MRI scans were reviewed by a single, blinded, board-certified neuroradiologist with more than 10 years of experience, who identified new/enlarging T2 lesions relative to previous images using the native, original Digital Imaging and Communications in Medicine (DICOM) images.

The percentage of paired scans with nonzero new/enlarging lesion counts by either method was calculated and compared using a 2-proportion z test. Each paired scan set was treated independently since all comparisons were conducted independently of previous comparisons. To exclude the potential
confounding of small lesions, additional sensitivity analyses excluded lesions less than 50 mm

, as measured by the SAM method. Mean lesion counts per paired scan were compared using the paired 

 test for each subgroup; κ was calculated using the irr package. All analyses were conducted using R software.

To understand the reasons for any significant discordance between SAM and neuroradiologist comparisons, 7 sample paired scans with notable discordance were reviewed by a second neuroradiologist (board-certified neuroradiologist with 15 years of experience) who was unblinded to the previous human and semiautomated identification results. Additional advanced imaging tools were used, including 3D rigid coregistration and an image subtraction module within the DICOM viewer), to assist the second neuroradiologist.	

Of the 255 participants enrolled in the SPRINT-MS trial, 244 patients provided 887 MRI paired scans for analysis. Their average age was 55.6 years, and they were evenly split between diagnoses of primary progressive MS and secondary progressive MS (

). New/enlarging lesions were identified by SAM on 19.7% of paired scans and by the neuroradiologist on 5.2% (

). Of the paired scans, 37 (20% of the 185 paired scans with at least 1 lesion by either method) were identified as having new/enlarging lesions by the human evaluation and by the SAM. In 9 paired scans, the human detected 1 or 2 new/enlarging lesions that were not detected by the SAM. Overall, κ was 0.18 (poor agreement), with 81% raw agreement across the 887 paired scans. Of the 887 MRI paired scans, 702 had no new/enlarging lesions by either method.

Baseline Participant Characteristics (N=255)

From the 185 paired scans with 1 or more lesions identified by either method, the mean number of new/enlarging T2 lesions per scan was 3.4 (median = 2) when identified by SAM and 0.4 (median = 0) on human evaluation (

 .001). Among this subset of 185 paired scans, κ was –0.06, indicating poor agreement, with a raw agreement of 7%. Analysis was also conducted by categorizing paired scans as active (2 or more lesions identified by either method) or inactive (fewer than 2 lesions identified by either method). Of the paired scans, 791 (89.1%) were identified as inactive by both methods, but only 11 (1.2%) were identified as active by both methods. Indicating poor agreement, κ was 0.18, with a raw agreement of 90.4%.

Number of New/Enlarging Lesions Identified

To explore the effect of small lesions, we excluded lesions identified by the SAM with volumes of less than 50 mm

 (approximately 17 voxels on 3-mm–thick slices). After excluding these small lesions, SAM identified new/enlarging lesions in 13.9% of paired scans, compared with the human-observed 5.2% (

). When all scan intervals were considered, κ increased to 0.27 (raw agreement, 87%), but when only paired scans with 1 or more lesions were included, it remained –0.06 (raw agreement, 13%). Much of the discordance was driven by scans with very high numbers of SAM lesions (

). The heat map analysis also shows that significantly fewer lesions were identified by the human method. When the lesion volume cutoff was 14 mm

, SAM identified new/enlarging lesions in 17.5% of paired scans.

Unblinded neuroradiologist review of select discordant paired scans found that more lesions were observed with advanced radiology tools, and the number of lesions was similar to that identified by SAM, including in 3 paired scans where initial neuroradiologist review detected zero new/enlarging lesions (

). This qualitative assessment found that lesions were more likely to be missed on scans with very high total lesion load (data not shown).

Unblinded Second Review by Neuroradiologist


We compared new/enlarging T2 lesion identification by a human reader and by a semiautomated method and found poor agreement (κ = 0.18). Overall, SAM detection identified 3.7-fold more paired scans with new/enlarging T2 lesions than a human and 8.5-fold more lesions per scan that had new/enlarging lesions. This discordance became less pronounced when small lesions were excluded from the SAM analysis, suggesting that the human reviewer overlooked smaller lesions that the automated software was able to detect. Nonetheless, κ remained poor (–0.06) when only paired scans detecting a new lesion by either method were included. It was also poor (κ = 0.18) when paired scans were categorized as active (2 or more new/enlarging lesions) and inactive (fewer than 2 new/enlarging lesions).

These observations have clinical relevance because drug efficacy is typically assessed through clinical trials, which usually use semiautomated lesion identification. Clinical practice usually relies on a radiologist. Based upon these observations, clinicians should recognize that the frequency of new/enlarging lesions derived from clinically read MRIs in routine practice may be much lower than that reported in clinical trials.

Our study used MRI readings conducted by a board-certified neuroradiologist in a busy clinical practice setting, thus reducing variability that may have arisen from multiple human raters.

 Using multiple human reviewers in future studies may better replicate the reality of clinical practice. Our qualitative assessment of 7 discordant paired scans by a second neuroradiologist who was aware of the discordance found more lesions when using advanced radiology tools available on the DICOM viewer. The discordance was greatest in patients with advanced disease, demonstrating the increased difficulty of using the unaided eye to find new lesions with a background of numerous preexisting lesions. This challenge is further complicated when 2 scans that are separated in time are typically acquired in dissimilar slice planes, leaving only a portion of a single image slice in common between the paired scans across time intervals.

Advanced imaging preprocessing tools can aid and augment manual review. Advanced imaging modules can perform a rigid coregistration between 2 studies by interpolating a volumetric scan so common imaging planes are presented for side-by-side review. These advanced tools also often enable the viewer to rapidly alternate (or 

) between coaligned scans, which improves the human eye’s ability to detect differences. Similarly, there are tools that can subtract aligned images, further enabling the visual appreciation of differences.

These findings correspond to previous research data that found a discrepancy in classifying treatment response on MRI between a neuroradiologist and a different semiautomated detection software.

The efficacy of such software and tools should also be rigorously and systematically studied to assess their utility. Further, the advent of artificial intelligence has led to the development of even more sophisticated software for the detection of MS lesions and the analysis of MS progression on MRI, some of which have been demonstrated to be superior to human review.

Our study examined the sum of new and enlarging lesions, as it was a study end point in the trial that provided the dataset, but a further study examining discordance in new lesion detection separately from enlarging lesion detection may yield further insights.

Our study is limited by the fact that our participants all had progressive MS, which has lower event rates of new/enlarging T2 lesions compared with relapsing MS: Only 19.7% of paired scans had 1 or more new/enlarging lesion by semiautomated detection, and only 5.2% had 1 or more new/enlarging lesion by human detection. The detection agreement in people with relapsing MS may be higher due to more numerous and larger-sized new/enlarging T2 lesions. However, the degree of discordance observed even in this population was substantial, underscoring its clinical importance. We only used 1 SAM approach and 1 neuroradiologist, so the generalizability of observations is unknown. We did not use a consensus of experts for lesion detection, and we did not use preprocessing techniques (eg, signal intensity standardization, coregistration). Although some of the discordance could be driven by the SAM detecting artifacts, expert reviewers verified SAM lesion identification, which makes this explanation for the discordance less likely.

We observed a large discordance between new/enlarging lesions identified by a human neuroradiologist and by a semiautomated lesion identification software. Although small lesions contributed to the discordance, the discordance remained even after the exclusion of small lesions. These findings have clinical relevance when applying new/enlarging lesion results from clinical trials to routine clinical practice and in the use of MRI for monitoring            anti-inflammatory therapies.

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New/Enlarging T2 Lesions in a Progressive Multiple Sclerosis Trial Cohort: Computer vs Human Detection

Walking in people with multiple sclerosis (MS) is limited by thermosensitivity, as prolonged activity raises body temperature. Administering a cooling intervention prior to physical activity can improve function; however, there are few data regarding the effect of cooling on walking. The purpose of this study was to compare walking distance in uncooled (control) and cooled conditions in a sample of people with MS. We hypothesized that participants would walk greater distances on a timed walking test after administration of a cooling intervention compared with a condition in which no cooling was administered.

A randomized crossover design was used. Fifteen participants (median Expanded Disability Status Scale score 4, IQR 1.5, range 3-5) underwent a 6-minute walk test (6MWT) in both cooled (CC) and uncooled (UC) conditions in a randomized test order. In CC, participants wore a cooling vest for 30 minutes prior to performing the 6MWT. In UC, participants performed the 6MWT without precooling. Participants returned 1 to 2 weeks later and repeated the 6MWT in the opposite condition. The total and per-minute distances during the 6MWTs were collected.

Participants walked longer distances during the 6MWT in the CC compared with the UC. Post hoc analysis of per-minute distances showed that participants accumulated greater walking distances in minutes 5 and 6 in the CC compared with the UC.

Precooling with a cooling vest had a significant impact on 6MWT performance in this sample of people with MS. The use of a cooling vest should be considered in walking programs for people with MS.

From the Department of Physical Therapy, Hunter College, The City University of New York (CUNY), New York, NY (HK, JR, SR, SS, KR, WY); and the Department of Physical Therapy, Arcadia University, Glenside, PA (EC). 

Herbert Karpatkin, DSc, PT, NCS, Department of Physical Therapy, Hunter College, CUNY, 425 East 25th St, New York, NY 10010;

This study was partially funded by a 2018 Multiple Sclerosis Foundation Quality of Life Grant.

 The authors have reported no conflicts of interest.

 Partial results of this study were presented as a poster in 2021 during the virtual American Physical Therapy Association’s Combined Sections meeting.

Herbert Karpatkin, DSc, PT, NCS

Evan T. Cohen, PhD, PT

Jaya Rachwani, PhD, PT

Sean Riva, DPT, PT

Sandon Stevens, DPT, PT

Kaitlin Russo, DPT, PT

Winnie Yu, DPT, PT

Increased core temperature during exercise can limit the dosage and intensity of exercise performed by people with multiple sclerosis (MS), which can limit the effectiveness of physical therapy.

The use of cooling vests may limit the effects of thermosensitivity in people with MS, as evidenced by improved 6-minute walk test performance compared with an uncooled condition.

Physical therapists working with people with MS should consider using cooling vests to increase exercise dosage and intensity.

Walking impairment is highly prevalent in people with multiple sclerosis (MS), and its remediation is a common rehabilitation goal. Due to the multifactorial nature of MS, walking impairments occur for heterogeneous reasons, making consistent rehabilitation strategies challenging. An intervention to improve walking across a spectrum of MS presentations would therefore be a useful tool.

Thermosensitivity—defined as a transient worsening of neurological function due to increases in core body temperature—is commonly associated with impaired walking in MS. Mobility tasks, such as walking, increase core temperature and limit the amount of exercise that can be tolerated. Lowering core temperature may improve walking performance in people with MS. Cooling has been studied in MS, but its specific impact on walking has not been well examined.

A systematic review identified 6 studies examining the impact of cooling on mobility in those with MS.

 Although the authors concluded that cooling generally resulted in positive outcomes, the studies reviewed had some issues with clinical generalizability. Buoite et al measured walking using distance to fatigue; however, this measurement lacks the validity and reliability of the 6-minute walk test (6MWT). Gonzales et al used an interventional pilot study combining walking and cooling; however, it is not known whether the improvement was due to the training, the cooling, or both. Grahn et al used cooling of 1 hand as an intervention as well as distance to fatigue as an outcome measure. Meyer-Heim and Nilsagård and their colleagues used extremely short walking tests as outcome measures, which may not be valid for assessing gait fatigue in people with MS.

In this study, we investigated the use of an inexpensive, commercially available cooling vest on walking endurance in participants with MS. We hypothesized that they would walk longer distances in the cooled vs the uncooled condition. If successful, this intervention would add a simple, inexpensive, and nonpharmacologic approach to improve walking endurance in people with MS.

We used a randomized crossover design where each participant was randomly assigned (by pulling odd and even numbers out of an envelope during their first session) to either the cooled condition (CC) or the uncooled condition (UC). Participants were then reassigned to the opposite condition in their second session. There were 7 to 14 days between sessions. This study was approved by the Hunter College Institutional Review Board (Protocol #: 2019-0336).

We recruited a convenience sample through flyer distribution to local MS-related medical providers, patient organizations, and support groups. Inclusion criteria included a definitive diagnosis of MS, being at least 18 years of age, the ability to walk 6 minutes without the assistance of another person, with or without an assistive device, and the ability to read and provide informed consent. Exclusion criteria included steroid use within the past 30 days; MS exacerbation (neurologist or self-reported) in the past 30 days; or any orthopedic, cardiovascular, or pulmonary condition that would limit the participant’s ability to complete the intervention.

Once consent was obtained, participant characteristics were collected, including age; sex; years since diagnosis; MS phenotype; and scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale-29 (MSIS-29), Fatigue Severity Scale (FSS), and Multiple Sclerosis Walking Scale-12 (MSWS-12). Validity and reliability in MS for these tests have been established. Tests were administered by the first author (H.K.) except for the EDSS, which was given by the participant’s neurologist in the course of clinical care. These measures were included to better understand the population and allow for appropriate generalizability of study results to patients in the clinic.

Participants in the CC were seated and donned the cooling vest for 30 minutes. We used the Kool Max Adjustable Zipper Cooling Vest (Polar Products, USA). Each vest holds 12 ice packs. In the uncooled cohort, participants sat for
30 minutes without a cooling vest. All participants were instructed to wear a cotton T-shirt, comfortable pants or shorts, and the same shoes for each session. All data were collected in a temperature-controlled room, and no data were collected during the summer months to avoid the possibility of the impact of increased room temperature.

Participants in the CC completed a visual analog scale to measure perceptions of cold (VAS-C), which assessed their current subjective feeling of coldness before and after 30 minutes in the cooling vest. Following the 30-minute period of cooling (CC) or rest (UC), participants completed the 6MWT. During the test, participants were asked to walk in a 100-foot hallway at their fastest comfortable pace for 6 continuous minutes using the assistive device they would normally use. We measured total distance walked as well as the distance walked every minute to assess any slowing over time. Previous research has demonstrated that people with MS often slow down during the 6MWT, suggesting evidence of fatigability.

 Stellman suggested that the 6MWT provided greater ecological validity than shorter walking tests for people with MS. Participants also completed the visual analog scale to measure subjective perceptions of fatigue (VAS-F) before and after the 6MWT.

All analyses were conducted using IBM’s SPSS, version 24.0. The normality of the data was examined using the Kolmogorov-Smirnov test and visually with quantile-quantile plots. The 6MWT and VAS-C scores within each condition were normally distributed. Thus, we used parametric statistics. The differences in VAS-C (Δ VAS-C) from before and immediately after wearing the cooling vest for 30 minutes, and from before to after the 6MWT, were analyzed with a 1-sample t

test comparing the mean change to zero. Distance walked during the 6MWT was analyzed with a 2-way within-subjects analysis of variance comparing cumulative distance walked during each minute of the 6MWT between the UC and CC conditions. The differences in VAS-F scores before and after the 6MWT (Δ VAS-F) were compared between the UC and CC conditions using a within-subjects 

 test. We set α to .05 and used a 2-tailed statistical approach.

We used the G*Power software to calculate the sample size using the effect size from a previous walking study in people with MS with a similar research design and outcome measures.

 = .42, an α of .05, and a desired power of .80, our a priori power analysis showed that a total sample size of 14 would yield sufficient power to detect significant differences in the analysis proposed.

The final sample included 9 women and 6 men, ranging in age from 44 to 71 years (mean [M] = 61.1 years). Years since diagnosis ranged from 5 to 40 years (M = 16.8 years). EDSS scores ranged from 3 to 5 (median [mdn] = 4), FSS scores ranged from 27 to 63 (mdn = 50), and MSIS-29 converted scores ranged from 18% to 99% (mdn = 44.8%). Information about participant characteristics is included in the 

. Eight participants underwent the CC first, followed by the UC, and 7 participants completed the study in the opposite order. Independent 

 tests showed no testing order effects on outcome measures (all 

 shows that the cooling vest had a significant positive effect on participants’ VAS-C. Their perception of cold significantly increased (M = 20.6, SD = +21.2) after wearing the vest for 30 minutes (

 = .97). However, participants felt significantly warmer (M = –12.4, SD = +18.8) after performing the 6MWT (

 = .66). Consequently, participants’ perception of cold after the 6MWT (M = 9.80, SD = +23.8) was similar to how it was when they arrived for the session (

, wearing the cooling vest for 30 minutes prior to the 6MWT showed a significant improvement over time compared with when participants did not wear the cooling vest (

 = .28). Post hoc analyses revealed that during the CC, participants accumulated farther distance at minutes 5 (M = 200.5 meters [m], SD = +138.5) and
6 (M = 242.5 m, SD = +166.5) compared with the UC (M =
186.8 m, SD = +137.9 at minute 5 and M = 228.4 m, SD = +167.7 at minute 6, all 

Minute-By-Minute Accumulated Distance During the CC and UC 6MWT

 shows participants’ change in subjective fatigue from pre- to post 6MWT. The average increase in fatigue in the CC (M = 16.80, SD = +20.31) compared with the UC (M = 22.93, SD = +20.54) was not significantly different (

Difference in the VAS-F After the 6MWT in the CC and UC

We tested an inexpensive, readily available cooling device on walking in people with MS, hypothesizing that the addition would result in improved walking endurance compared with UC. Our results support this hypothesis, as participants in a CC walked longer distances than those in the UC. This finding provides evidence that cooling can improve performance in longer walks, such as a 6-minute walk, in people with MS with the single application of a cooling vest.

Up to 90% of people with MS complain of difficulty with walking.

 This difficulty is multifactorial, and possible limitations are due to impairments in strength, flexibility, sensation, motor control, and fatigue. The heterogeneity of walking dysfunction in MS makes the application of standardized intervention strategies problematic. However, an overarching issue that limits walking in people with MS is fatigability, defined as the magnitude or rate of change in performance over a given time. Pragmatically, fatigability in MS refers to the inability to walk for sufficient periods, and it can restrict functional tasks. Our results provide evidence that cooling can impact fatigability, as evidenced by improvement in the 6MWT, suggesting that cooling may improve walking in people with MS regardless of disease expression. Participants not only walked longer distances overall in the CC, but the majority increased their distances later in the 6MWT test (at minutes 5 and 6). This might suggest that participants were able to maintain their pace in the CC, providing further evidence that cooling decreases fatigability in MS.

Using the 6MWT as a primary outcome measure was essential for our study. Although shorter walking tests commonly used in MS (eg, 10-meter or 2-minute walk tests) may provide useful information regarding walking short distances, they lack the ecological validity of longer walking and may not be of sufficient duration to provoke fatigue. Since the purpose of this study was to examine the impact of cooling on walking fatigue in MS, a measure that was specifically provocative of MS fatigue was indicated. The 6MWT may also be more representative of typical functional walking than shorter measures. Although the psychometric properties of shorter walking tests are robust, they may not provide useful information for MS clinical decisions. An additional advantage of the 6MWT is that it allows measurement of specific time intervals. The slowing of walking over the last 2 minutes in the UC relative to the CC would not have been obtainable using other tests.

Several studies have provided evidence of the effectiveness of cooling in improving mobility in people with MS. However, many modalities may not be feasible (eg, cold water immersion) or too costly (eg, technologically advanced cooling suits) for regular clinical practice. In this study, we intentionally examined an inexpensive and easily obtainable device that is often provided for free in the United States by MS advocacy groups. This represents a means by which MS mobility deficits can be effectively managed at minimal cost.

Despite our positive findings, our study has several limitations. Although diverse, our sample was relatively small. Our study was unblinded, so participants may have simply thought the CC was better for walking. However, since there was no significant difference in perceptions of fatigue between the 2 conditions, unblinding may not have been an issue. This absence of difference may be attributable to objective and subjective fatigue being separate phenomena, or it may represent a limitation in using a self-report fatigue measure. Moreover, unlike previous MS cooling studies, we did not attempt to use sham cooling. Whether sham cooling would have served as an appropriate control condition is questionable—a sham vest could have acted as a layer of insulation, preventing heat loss and elevating core temperature in already thermosensitive people. Therefore, we believed that comparing the cooling vest with an uncooled condition or standard of care resulted in a more valid testing of our hypothesis.

We did not use heat sensitivity as an inclusion criterion, as it is measured exclusively by self-report. It is not known whether self-reports of heat sensitivity actually represent a physiologic limitation in function associated with a rise in temperature, and therefore, it would be unclear as to whether our results would have different effects on those who do and do not report heat sensitivity. Saying that one is heat sensitive is not the same thing as having a worsening performance as body temperature increases. A future research topic may be whether people with MS who do report heat sensitivity perform differently with cooling than those who do not. Thermosensitivity in MS may be a similar phenomenon to MS fatigue, as it may have both subjective and objective components.

This study provides evidence that the use of cooling vests can be effective in limiting the impact of fatigue during walking in people with MS. Treating clinicians should consider the use of cooling vests to improve their patients’ walking endurance.

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Cooling Vests Improve 6-Minute Walk Test Performance in People With Multiple Sclerosis: A Randomized Crossover Trial

Migraine affects approximately 50% of people with relapsing-remitting multiple sclerosis (MS). People with MS and migraine also have greater symptom burden and an increased risk of relapse. Understanding the pathophysiology, symptoms, and approaches to migraine treatment is critical to improving outcomes for this population.

A narrative review was conducted to investigate the pathobiological mechanisms of comorbid migraine in MS, the impact of psychological and cognitive symptoms, and the available treatment options.

The review identified potential reciprocal mechanisms in comorbid migraine and MS, including recurring MS-related inflammation, brainstem lesions, neuroinflammation in migraine, and the disruption of the blood-brain barrier. Shared demographic and endocrine risk factors for MS and migraine were detailed, along with the effect of MS treatments on worsening preexisting migraine. Both disorders were associated with subjective and objective cognitive deficits, particularly affecting processing speed, attention, and executive functions, as well as higher rates of depression and anxiety compared with the general population. In MS, preventive migraine treatments were underprescribed. Selection of prophylactics should include consideration of comorbid symptoms, such as depression and fatigue. Evidence also supports the potential efficacy of behavioral interventions for migraine prevention.

While much remains to be understood, recognizing the comorbid symptoms and appropriate migraine treatments for people with relapsing-remitting MS can guide clinical decision-making and promote quality of life. Further research is needed to evaluate the efficacy of such therapies for people with MS.

From the Department of Neuroscience, Monash University, Melbourne, Australia (PT, HB, JR, AM, EH, RA) and the Department of Neurology, Alfred Health, Melbourne, Australia (HB, JR, EH). 

 Pavika Thevar, MPsych, Level 6, Alfred Centre, 99 Commercial Road, Melbourne VIC 3004; 

Helmut Butzkueven, MBBS, PhD, has received institutional (Monash University) funding from Alexion, Biogen, CSL Limited, F. Hoffmann-La Roche Ltd, Merck, and Novartis; has carried out contracted research for Biogen, F. Hoffmann-La Roche Ltd, Merck, and Novartis; has taken part in speakers’ bureaus for Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Novartis, and UCB (funds received by Monash University); and has received travel support from Merck and Novartis. His research is also supported by the National Health and Medical Research Council (Leadership 1 Investigator Grant), Medical Research Future Fund Grants, the Trish MS Research Foundation, MS Australia, and the Pennycook Foundation. Jason Ray, PhD, MBBS, reports in the last 36 months, he has received honoraria for educational presentations for AbbVie, Novartis, and Viatris. He has served on medical advisory boards for Lilly, Pfizer, and Viatris. His institution has received funding for research grants, clinical trials, and projects supported by AbbVie, Aeon, the BRAIN Foundation, the International Headache Society, Lundbeck, and Pfizer.

Pavika Thevar was supported by an Australian Government Research Training Program stipend.

Pavika Thevar, MPsych

Helmut Butzkueven, PhD, MBBS

Jason Ray, PhD, MBBS

Alissandra McIlroy, PhD

Elspeth Hutton, PhD, MBBS

Rubina Alpitsis, PhD

Individuals with multiple sclerosis (MS) have a higher rate of migraine than the general population. Both conditions are associated with psychiatric comorbidity and cognitive symptoms that should be monitored given the potential for additive burden when MS and migraine co-occur.

Initial migraine assessment should include a headache diary to track migraine symptoms, triggers, frequency, and treatment response. Acute medications should be prescribed, and if migraines occur for more than 4 days per month, preventive treatments should also be considered.

With stress acting as a migraine trigger, psychological interventions should be offered as a nonpharmacological adjunct to migraine management medications.

The co-occurrence of migraine and multiple sclerosis (MS) has become increasingly recognized. Both are disorders of the central nervous system (CNS) and are thought to be the product of a complex interaction between environmental triggers and genetic predisposition.

 Both conditions have a higher prevalence among women, a relatively young age of onset, and are associated with higher rates of cognitive dysfunction, depression, anxiety, pain, and fatigue compared to those of the general population.

 Given the typical age of onset, these disorders tend to affect individuals in the prime of their career development and active family lives.

MS is a chronic autoimmune disease affecting an estimated 2.8 million people worldwide.

 In MS, the T cells and B cells of the immune system are abnormally activated and, once within the CNS, cause inflammation and surround the axons of neurons, resulting in demyelination.

 This disrupts the transmission of signals between neurons to, from, and within the brain, giving rise to neurological and neurocognitive symptoms. There are relapsing and progressive forms of MS. Relapsing-remitting MS (RRMS) constitutes 85% of MS cases.

Migraine is the second-highest cause of disability worldwide.

The International Classification of Headache Disorders (2018) defines a migraine as a headache attack lasting 4 to 72 hours accompanied by at least 2 of the following: unilateral location, a pulsating quality, moderate to severe pain intensity, and/or aggravated by or avoidance of physical activity.

Volume 27, Issue Q3

New/Enlarging T2 Lesions in a Progressive Multiple Sclerosis Trial Cohort: Computer vs Human Detection

Cooling Vests Improve 6-Minute Walk Test Performance in People With Multiple Sclerosis: A Randomized Crossover Trial

Migraine in Multiple Sclerosis: Underlying Mechanisms, Shared Symptoms, and Approaches to Management

Unspoken Challenges: Sexual Health in Sexual and Gender Minority People With Multiple Sclerosis

Feasibility of Aerobic Exercise in People With Advanced Multiple Sclerosis: Characterizing Acute Responses to Inform Exercise Prescription

Experiences of Word-Finding Difficulties in Multiple Sclerosis: A Qualitative Interview Study

Implementation of Cognition, Fatigue, and Mental Health Screening at a Canadian Multiple Sclerosis Center: A Quality Improvement Initiative

Disaster Preparation for People With Multiple Sclerosis: A Scoping Review of Resources

An Updated Assessment of Patient Knowledge in Pregnancy and Multiple Sclerosis

Tumefactive Demyelination in Older Adults: Diagnosis and Misdiagnosis

Virtual Dance Program for Multiple Sclerosis: Feasibility, Quality of Life, and Motor Imagery Outcomes

Apathy in Early Relapsing-Remitting Multiple Sclerosis: Prevalence and Predictors

Effect of a Therapeutic Patient Education Program on the Quality of Life of People With Multiple Sclerosis: A Quasi-Experimental Study