Effects of a Remote Multimodal Intervention Involving Diet, Walking Program, and Breathing Exercise on Quality of Life Among Newly Diagnosed People with Multiple Sclerosis: A Quasi-Experimental Non-Inferiority Pilot Study

Introduction

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects 2.8 million people worldwide.¹ Many people who develop MS first experience a single demyelinating event of the central nervous system; this stage is termed clinically isolated syndrome (CIS). After a second demyelinating event, a relapse, the individual can be described as having relapsing-remitting MS (RRMS) once this diagnosis is confirmed by their treating neurologist through MRI and the 2017 McDonald criteria.² RRMS is the most common type of MS, accounting for approximately 85–90% of new MS cases.³ Over time, people with RRMS experience additional relapses and increased loss of function.⁴

Drug-based disease-modifying therapies (DMTs) significantly lower relapse rates in 29–68% of individuals with MS who have been treated with these therapies;⁵ however, surveys have indicated that up to 31% of people with MS do not start treatment with DMTs.⁶ Reasons for declining DMT treatments include high costs,⁷ concerns about side-effects,⁶ and a lack of insurance coverage.⁸ Among people with MS, there is a trend toward decreased trust in pharmacological interventions and a growing interest in more holistic approaches to treatments, specifically related to diet, exercise, and emotional wellness.⁹ In surveys, most individuals with MS report implementing some form of complementary and alternative care, either combining with DMTs or independently.¹⁰ Understanding the effects of lifestyle programs in people with MS who are voluntarily DMT-naïve will be necessary for predicting the clinical course of patients.

Physical activity recommendations for people with MS encourage greater than or equal to 150 min/week of lifestyle physical activity while adapting exercise activities based on an individual’s needs and capacity, as well as personal preferences.¹¹ Several meta-analyses have shown that physical activity improves cognitive function,¹² depressive symptoms,¹³ and quality of life (QoL).¹⁴ Similarly, mindfulness practices, such as breathing exercises or meditative activities, have been shown to improve fatigue¹⁵ and cognition,¹⁶ as well as reduce self-reported emotion dysregulation.¹⁷ While evidence regarding the value of therapeutic diets alone remains inconsistent,¹⁸ a recent network meta-analysis revealed that patients on the Paleolithic diet showed greater improvements in mental and physical QoL than controls.¹⁹ In people with RRMS, the Paleolithic diet has been associated with significant reductions (both statistically and clinically) in fatigue and increases in mental and physical QoL at 12 and 24 weeks.²⁰ Although each of these interventions individually yields beneficial effects, the combination of these health behavioral modifications has the potential to enhance the QoL for newly diagnosed individuals with MS.

Prior studies investigating the effects of a multimodal intervention consisting of a modified Paleolithic diet, supplementation of specific nutrients, strengthening exercises of core and lower limb muscles along with neuromuscular electrical stimulation, and stress reduction techniques (self-massage and meditation) showed that this approach led to clinically significant improvements in perceived fatigue, mood, gait, and the expression of metabolic biomarkers in people with progressive MS who most adhere to the intervention.^21–23 Although the clinical usefulness of changes in diet, physical activity, and breathing exercises as adjunct therapies for MS symptoms is encouraging, their combined effects on the disease course in the absence of DMTs remain unknown. Thus, the efficacy in people who are newly diagnosed with MS and have declined DMTs remains unclear. This study aimed to assess the effect of a remotely administered, multimodal intervention including study diet, walking program, and breathing exercise on QoL in DMT-naive people newly diagnosed with CIS and RRMS, comparing them to counterparts who had the same diagnosis but opted to receive the standard of care (SOC) treatments.

Participants and Methods

Study Design

A single-center quasi-experimental study was conducted at the University of Iowa Hospitals and Clinics Prevention Intervention Center. A quasi-experimental study design was selected because of ethical concerns about withholding FDA-approved treatments for RRMS.²⁴ Due to the Coronavirus 2019 (COVID-19) pandemic, restrictions prevented in-person research visits during the spring of 2020, when this study was initiated. Thus, planned brain imaging, blood biomarkers, and onsite clinical assessments were omitted from the study procedures. All visits were remote, and outcomes were patient-reported. This study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the University of Iowa Institutional Review Board (IRB #201908778). The study is registered at clinicaltrials.gov, with the identifier: NCT04009005.

Study Participants

Signed documentation of the informed consent process was obtained from all participants before they enrolled. Participants were recruited from the continental United States via social media posts, email blasts, and flyers sent to local neurology clinics. Recruitment started in May 2020 and was completed in August 2021. Inclusion criteria were as follows: 1) a diagnosis of RRMS or CIS according to the 2017 McDonald criteria,² 2) confirmed by the treating neurologist no more than 12 months before the first study visit was completed; 3) between 18 and 55 years of age at the time of consent; 4) consent to share the clinical notes from the primary care and neurology providers during the study period; 5) residence within the continental United States; 6) approval of enrollment by the treating neurologist.

Exclusion criteria for all participants included 1) moderate or severe cognitive impairment as measured by the Short Portable Mental Health Questionnaire;²⁵ 2) use of insulin or Coumadin medication; 3) history of oxalate kidney stones, schizophrenia, or active diagnosis of an eating disorder; 4) time elapsed since initial diagnosis of RRMS or CIS greater than 12 months. Additional group-specific eligibility criteria can be found in Supplemental Table 1. Importantly, participants in the intervention group had to have voluntarily declined DMTs, prior to screening for the study.

For clinical pilot trials, inclusion of more than 10 participants per group is adequate;²⁶ therefore, we aimed to recruit more than 10 individuals per group.

Health Behaviors (HB) Group

Upon enrollment, participants in the HB group received education on the multimodal intervention, which consisted of a modified Paleolithic elimination diet, 4-7-8 breathing exercises, and a moderate-intensity walking program. The HB group participants were scheduled for a medical history review and education session with the study’s principal investigator (PI; TLW). The education module included information on the potential mechanisms by which diet, aerobic exercise, and stress reduction can influence patient-reported symptoms and comorbid disease processes. Participants were subsequently contacted through the Zoom platform by a registered dietitian nutritionist (RDN; LB), who is a credentialed nutrition expert, for the study and provided with an orientation session about the study diet, walking, and stress reduction programs. The RDN was trained in motivational interviewing and self-determination theory,^27–29 which emphasize patient-centered goals through the use of open-ended questions, and applied these frameworks during interactions with all study participants. After the first month was completed, participants were encouraged to attend monthly group support calls with their study peers monitored by the RDN and other research team members. The monthly group support calls entailed participants leading discussions regarding the modifications made during the intervention, such as sharing cooking recipes, offering moral support to other participants, or asking questions. The RDN answered questions and consulted with the study PI, physical therapist (PT; BB), and other study team members whenever needed. Participants received phone, email, and text support from RDN as needed.

Modified Paleolithic Elimination Diet

The study RDN instructed participants in the HB intervention group on the modified Paleolithic elimination diet, which included 6–9 combined servings of fruits and vegetables per day and 9–12 ounces of meat per day for petite women and 12–21 ounces of meat per day for men and tall women, with the exact amount determined based on gender and size. All gluten-containing grains, legumes, eggs, and dairy (except for clarified butter or ghee) were excluded, and nightshades (eg, tomatoes, white potatoes, eggplant, peppers, and seed spices) were excluded following the first three months on the diet. If the participant desired to reintroduce nightshades into the diet, this was done during months 7–9, under observation by the study team, to test tolerance and provide guidance if changes might be necessary. After problematic foods were identified during months 7–9, participants followed their personalized modified Paleolithic elimination diet (months 10–12).

Stress Reduction Using Mindfulness-Based Breathing

The participants were provided a video that provided instructions to reduce stress each day by using the “4-7-8” breathing technique, in which the participant inhales through the nose for a count of 4, holds their breath for a count of 7, and then exhales entirely through the mouth for a count of 8. The video also instructed participants to avoid tightening their muscles while holding their breath. Participants who experienced discomfort while holding their breath for 7 seconds could adjust the breathing pattern for personal comfort while ensuring that the exhalation lasted longer than the inhalation. Participants were instructed to perform this exercise daily for a minimum of 1 minute, but they could do additional 4-7-8 sessions as desired.

Moderate-Intensity Walking Program

Participants were instructed to walk at a moderately brisk pace. To ensure proper form, participants were given access to an instructional video demonstrating walking at a moderate intensity. The video not only illustrated the correct walking technique but also imparted knowledge about the advantages of walking and offered guidance on seamlessly integrating walking into their everyday schedule. Walking for at least 10 minutes was considered one session, and participants could accumulate as many sessions in a day as they would like. Furthermore, participants were advised to aim for a weekly total of 150 minutes of walking and to prevent excessive fatigue by not walking for more than 60 minutes at a time.

Self-Reported Adherence to Study Components

At the 12-month time point, participants in the HB group were asked whether they followed each component throughout the intervention, including the study diet, breathing exercises, and 10-minute walking regimen. This was done using Research Electronic Data Capture (REDCap),^30,31 a secure, web-based software platform designed to support data capture for research studies. Participants who confirmed their compliance with all components were classified as adherent.

Standard of Care (SOC) Group

The SOC group was not provided with advice or education about any component of multimodal intervention. However, to ensure that participants remained engaged with the study team, they were sent monthly emails containing information on the latest MS research that was not related to diet, physical activity, or stress reduction in MS. The study team did not restrict any changes in health-behaviors of SOC participants, if they decide to do so by themselves.

Outcomes

Study outcomes were assessed using validated questionnaires. The primary outcomes were MS-specific physical and mental QoL, which were evaluated using the MS Quality of Life 54 (MSQoL54).³² The secondary outcomes included minutes of physical activity, assessed using the International Physical Activity Questionnaire-Long Form (IPAQ);³³ mood, specifically anxiety and depression, assessed using the Hospital Anxiety and Depression Scale (HADS);³⁴ perceived fatigue, assessed using the Fatigue Severity Scale (FSS)³⁵ and the Modified Fatigue Impact Scale (MFIS);³⁵ and cognitive dysfunction, assessed using the Perceived Deficits Questionnaire (PDQ) including Total PDQ, PDQ – Attention, PDQ – Retromemory, PDQ – Promemory, and PDQ – Planning.³⁶

An adverse event was recorded whenever a participant reported one via phone, text, email, or REDCap online survey, as well as when one was documented in the participant’s medical records. Additionally, side effects were self-reported monthly, via a questionnaire using the MyCap application; this can be downloaded on smartphones, and answers are integrated into the respective REDCap project. Diet-related, serious, and other adverse events determined to require additional attention were forwarded to the medical monitor, who reviewed the issue and determined appropriate follow-up. Self-reported relapses were assessed in the End of Study Survey distributed to participants at 12 months. Self-reported COVID-19 infection was evaluated during the End of Study Call or through email at the 12-month timepoint.

Statistical Analysis

Data were checked for accuracy and possible entry errors. Continuous variables were evaluated for normality by graphical observation. At enrollment, descriptive statistics for each variable were calculated by the treatment group, using frequencies and percentages or means and standard errors (SE). Baseline characteristics of treatment groups were compared using Fisher’s exact test for categorical variables and using a two-sample t-test for continuous variables. Missing observations were omitted from baseline comparisons.

Rates of adverse event outcomes (eg, relapse, COVID-19 infection) were reported as treatment-stratified counts and percentages. Outcome measures collected for the HB and SOC groups were assessed for differences using Fisher’s exact test.

Within- and between-treatment changes in outcomes over time were tested using the linear mixed modeling (LMM)³⁷ framework. All models include fixed effects for the treatment group, time, and their interaction. The models also specify a random effect for participants to account for repeated measures. Point estimates, 95% confidence intervals, and p-values for mean changes in outcome measures over time were generated for each outcome. For all estimates, the significance was assessed at the α = 0.05 level. Cohen’s d, also known as the standardized mean difference, was calculated to assess the magnitude of the within-group changes. A Cohen’s d score of zero means that the treatment and comparison agent have no differences in effect, whereas the absolute value above zero indicates the degree to which one treatment is more efficacious than the other.³⁸

To determine whether the HB intervention was not worse than SOC at 12-months,³⁹ a non-inferiority analysis was conducted for mental and physical QoL, fatigue, mood, and perceived cognitive difficulties outcomes. Margins used for the non-inferiority analysis of each outcome were based on statistical consideration from summarizing the historical evidence; subsequently, a clinical judgment then made by a neurologist (JK) was used to select the margin.⁴⁰ At 12 months, the mean change margin of non-inferiority for mental and physical QoL was 0.25 units,⁴¹ FSS was 0.9 units,⁴² Total MFIS was 8 units,^42,43 HADS – Anxiety was 2.08 units,^44,45 HADS – Depression was 2.8 units,^44,45 and Total PDQ was 3 units.⁴⁶

All analyses were performed with two-sided tests (α = 0.05) using SAS software (version 9.4, SAS Institute, Inc.).

Results

A total of 44 participants enrolled in the trial, including 29 in the HB (n = 29) and 15 in the SOC (n = 15) groups (Figure 1). During the 12-month study period, 5 participants in the HB were lost to attrition; among these, 1 withdrew due to a new health concern (unrelated to the intervention or MS), and 4 were lost to follow-up. In the SOC group, 2 participants were lost to follow-up (Figure 1). At baseline, none of the characteristics assessed differed significantly between the groups (Table 1).

Table 1 Baseline Characteristics of Study Participants in the Health Behaviors (HB) and Standard of Care (SOC) Groupsa

Figure 1 Diagram illustrating participant recruitment and study flow for health behaviors (HB) intervention and standard of care (SOC) groups. *An additional breakdown of ineligibility criteria is available in the Supplemental Material. Reasons for ineligibility or exclusion may not add up to the value of ineligible or excluded because some participants were found ineligible or were excluded for multiple reasons. †Recruitment stopped due to COVID-19 pandemic.

Participants in the HB group self-reported adherence to all components of the study intervention at the end of the study were follows: 95.8% for diet (23/24), 91.7% for physical activity (22/24), and 75% for breathing exercises (18/24). However, 4 participants (16.7%) self-reported starting a DMT during the study course, with 1 of those participants withdrawing from the study due to a new health concern (unrelated to the intervention or MS). In the SOC group, 4 participants reported changing or reducing the dose of their DMTs during the study (Supplemental Table 2), as well as 38.5% (5/13) of participants self-reported beginning a specific diet during the study period, with 15.4% (2/13) starting the Paleolithic diet and 23.1% (3/13) starting the Wahls diet.

In terms of adverse events, at the 12-month timepoint, differences between the groups were non-significant (Supplemental Table 3). Self-reported relapse occurred in 16.7% of participants in the HB group (4/24) and in 7.1% of those in the SOC group (1/14) (p = 0.63). Similarly, the incidence of self-reported COVID-19 cases was 37.5% of participants in the HB group (9/24), and 7.7% of participants in the SOC group (1/13) (p = 0.07). Additionally, no serious adverse events (ie, requiring medical monitoring intervention) were reported for either the HB (Supplemental Table 4) or SOC group (Supplemental Table 5).

The mean scores of the self-reported outcomes were assessed at baseline and 12-months, with within-group changes assessed from baseline to 12-months. The HB group showed a favorable statistically significant mean increase from baseline for mental QoL, as assessed by MSQoL-54 – Mental composite score (4.08 ± 0.13; p = 0.04; Table 2). In contrast, the SOC group exhibited favorable improvements from baseline in physical QoL, as assessed by MSQoL-54 – Physical composite score (2.87 ± 0.04; p = 0.049; Table 2). However, the HB group exhibited an unfavorable reduction in minutes of vigorous activity, as assessed by IPAQ – Vigorous MET (580.00 ± 298.84; p = 0.007; Table 2), whereas the SOC group exhibited a favorable mean decrease in physical activity fatigue, as assessed by MFIS – Physical value (8.54 ± 2.95; p = 0.008; Table 2). For the HB group, the HADS–Anxiety mean value showed a favorable decrease in anxiety (6.63 ± 0.84; p = 0.009); whereas the HADS–Depression value showed a favorable reduction in depressive symptoms in only the SOC group (2.69 ± 0.94; p = 0.02; Table 2). For the HB group, the mean fatigue score favorably decreased, as assessed by Total MFIS and MFIS – Cognitive (25.29 ± 4.28; p = 0.02; 12.75 ± 2.17, p = 0.002; respectively, Table 2), and the mean of cognitive dysfunction was favorably reduced from that at baseline, as assessed Total PDQ, PDQ – Attention, PDQ – Promemory, and PDQ – Planning (p ≤ 0.03 for all; Table 2). Additional mean outcomes for months 3, 6, and 9 are presented in Supplemental Table 6.

Table 2 Baseline and 12-Month Outcome Means and Magnitude of Mean Change for the Health Behaviors (HB) Intervention and Standard of Care (SOC) Groups

The magnitude of mean change for the outcomes was assessed to compare the response of the intervention from baseline to 12-months. For the HB group, the magnitude of mean change had favorable increases for mental QoL, as assessed by MSQoL54 (0.24, 95% CI 0.01, 0.47; p = 0.04; Table 2). In contrast, the SOC group had a favorable magnitude of mean increase for physical QoL, as evaluated by MSQoL54 – Physical (0.12, 95% CI 0.00, 0.24; p = 0.049; Table 2). The HB group had a favorable decrease in the mean magnitude of change for the anxiety score, as assessed HADS – Anxiety value (−1.75, 95% CI −3.08, −0.43; p = 0.009), whereas, only the SOC group showed a favorable reduction in the mean magnitude of change in the depression score, as evaluated by HADS – Depression value (−0.93, 95% CI −2.91, 1.05; p = 0.009; Table 2). In the HB group, the magnitude of mean change in minutes of vigorous activity was unfavorable, as assessed IPAQ – Vigorous MET (0.30, 95% CI 0.12, 0.72; p = 0.007; Table 2). The magnitude of mean change in fatigue differed meaningfully only for the HB group, as evaluated Total MFIS and MFIS – cognitive values (−7.26, 95% CI −13.34, −1.18; p = 0.02; and −4.59, 95% CI −7.56, −1.63; p = 0.002; respectively; Table 2). For the HB group, the magnitude of the change in cognitive dysfunction was favorable, as assessed by Total PDQ and all PDQ subdomains, except for PDQ – Retromemory (p ≤ 0.03 for all). No statistically significant difference in the magnitude of mean between groups was observed for any outcome from baseline to 12-months (p > 0.05), except for PDQ – Planning (p = 0.048; Table 2). A medium effect size was observed for PDQ – Planning with a Cohen’s d of −0.59 (Table 2).

Non-inferiority between-group differences revealed that the 12-month change in mean for the HB group was not worse than that for the SOC for MSQOL54 – Physical QoL by a margin of 0.25 units (p = 0.02), HADS – Anxiety by a margin of 2.08 units (p = 0.02), HADS – Depression by a margin of 2.8 units (p < 0.0001), FSS by a margin of 0.9 units (p = 0.02), and Total PDQ by a margin of 3 units (p = 0.01) (Table 2).

Discussion

The results of the 12-month comparison of a remotely delivered multimodal intervention (diet, breathing exercises, and walking program) for individuals who were newly diagnosed with RRMS or CIS and were voluntarily DMT-naïve revealed that the mean changes for key symptoms of MS, including perceived fatigue, QoL, mood, and cognition, are not worse than those for the participants in the SOC group, who were taking DMTs. Thus, newly diagnosed individuals with RRMS or CIS who voluntarily decline DMTs may benefit from a diet and lifestyle behavioral intervention for the management of MS-related symptoms. However, the mechanisms that contribute to these beneficial effects, as well as whether such a therapy has an impact on relapse rate and disease progression, remain unclear.

This study indicates that interest in therapeutic diet and lifestyle modifications is generally high among individuals with MS. This was evident from the self-reported adherence of the HB participants to the study diet, ie, the modified Paleolithic diet, being 95.8% at the 12-month intervention timepoint. This is higher than a previous study reporting 80% adherence after 3.5 months.⁴⁷ The high adherence to the diet could potentially be explained by the continued support from the study RDNs throughout the duration of the present study. RDNs are qualified to provide personalized medical nutrition therapy; thus, they can help people with MS, especially those newly diagnosed with RRMS or CIS, develop resilience and adaptive strategies regarding food literacy through these patient-centered support strategies.⁴⁸ A second line of support for an interest in diet modifications is that, although members of the SOC group were not provided with information on a special diet, 38.5% reported starting a specific diet during the course of the study. Therefore, newly diagnosed people with RRMS or CIS may benefit from having RDNs as part of their MS care team, regardless of whether they opt to receive a DMT to support diet or dietary modifications, as part of either a complementary or alternative treatment.

The multimodal intervention in the HB group resulted in a significant magnitude of mean changes from baseline to 12 months for perceived fatigue, mental QoL, mood, and cognition. Moreover, the non-inferiority analysis revealed that the 12-month change in mean values for fatigue, mood physical QoL, and cognitive difficulties in HB participants were not worse than that for SOC for the aforementioned outcomes. These findings corroborate the conclusions from a prior multimodal intervention in individuals with MS, ie, that increased engagement in healthy eating habits and physical activity (self-reported) is related to reduced fatigue, perceived stress, and depression, as well as improved cognitive health.⁴⁹ Similarly, results from a study of multimodal lifestyle modifications, which included a plant-based diet very low in saturated fat, omega-3 fatty acids supplementation, increased physical activity, and the use of stress reduction techniques, such as meditation, included improvements in health behaviors outcomes (assessed using mental health and QoL assessments), and maintenance of these lifestyle changes over a 3-year follow-up.⁵⁰ Findings from both a prior multimodal intervention study that included a Paleolithic diet²³ and a study of a low-fat dietary intervention⁵¹ also suggest that lifestyle modifications can have favorable effects on cognitive function. Thus, our study corroborates the notion that interventions based on diet and behavior modifications have the potential to reduce perceived fatigue and cognition problems, as well as improve mental and physical QoL and mood in individuals who are newly diagnosed with RRMS or CIS who decline DMTs.

Although physical activity is an established component of rehabilitation for people with MS,^11,52 the physical activity scores of the HB intervention group in the current study did not improve. Despite the high self-reported adherence to walking program component of the intervention, the HB group participant’s vigorous minutes of activity exhibited a significant unfavorable decrease at 12-months from baseline. It is possible that the COVID-19 pandemic, which coincided with the current study, greatly impacted the participants’ physical activity. This would be consistent with the effects of decreased physical activity observed in people with MS in other studies during the pandemic.^53,54 Additionally, a systematic review of 13 studies evaluating the impact of COVID-19 on physical activity among people with neurological diseases, including MS, reported that COVID-19 had a negative impact on levels of physical activity.⁵⁵ Home isolation and quarantining may have led to decreased physical activity and increased sedentary behavior in the current study.⁵³

This is the first study to have assessed the effects of diet and behavioral interventions on QoL among people with MS who voluntarily decline DMTs. Strengths of this study include high study adherence (to diet, 95.8%; and to physical activity, 91.7%) among participants in the intervention group and robust analytical methods. Although the design did not include randomization, a quasi-experimental study design was necessary because DMTs are efficacious and FDA-approved for reducing relapse risk and slowing disease progression.⁵ Randomizing individuals with MS to a group in which DMTs are withheld would have been unethical.²⁴ Thus, it was necessary to recruit participants who have MS but voluntarily declined DMT treatment prior to enrollment, which is a limitation of the study. Another limitation is the small study size, which may have skewed the outcomes and adverse events measured; further research will be necessary to confirm these results and to understand the physiological underpinnings of the present study’s findings. However, the measures used did capture the perspectives of individuals regarding living with their disease or treatments and perceived wellness, and these may not be captured otherwise.⁵⁶ Moreover, the side effects associated with DMTs may reduce the QoL in the SOC group, contributing to the difference in QoL seen between groups. These side effects underscore the reason why many individuals with MS opt to reject the utilization of DMTs. Additionally, it is important to consider the potential impact of volunteer bias on the initiation of a specific diet concurrent with DMTs within the SOC group. The observed behavior may stem from the high motivation characteristic of individuals inclined to participate in research studies, thereby limiting the generalizability of the findings. However, studies show that around 40% of individuals report making dietary modifications after their diagnosis,⁵⁷ especially 1-year following diagnosis.⁵⁸ Lastly, the fact that the current study coincided with the COVID-19 pandemic likely also affected the perceptions of QoL and other self-reported measures, such as physical activity.⁵⁹ Future investigations would benefit from a combination of self-reporting and clinical and objectively measurable outcomes data. This would provide a more complete understanding of the multimodal intervention’s effects.

Remote delivery of a multimodal diet and lifestyle behavioral intervention may improve perceived QoL, mood, fatigue, and cognition among newly diagnosed individuals with RRMS or CIS who are voluntarily DMT-naive. The implication is that individuals reluctant to use DMTs (because of cost, potential medication related-adverse events, possible pregnancy, or breastfeeding), may benefit from adopting dietary, breathing practice, and physical activity lifestyle behavioral modifications to reduce MS-related fatigue and improve QoL. However, further research is necessary to understand the feasibility and efficacy of diet and lifestyle modifications influence MS relapse rates, disease severity, and disease progression among individuals with newly diagnosed RMSS or CIS who decline DMTs. The results from this study support the need for continued exploration of the impact of diet and lifestyle modifications on MS-related outcomes, disease severity, and disease progression, especially in those who voluntarily decline DMT therapy.