Efficacy of Diet on Fatigue and Quality of Life in Multiple Sclerosis

Abstract

Background and Objective

Emerging evidence suggests a role for diet in multiple sclerosis (MS) care; however, owing to methodological issues and heterogeneity of dietary interventions in preliminary trials, the current state of evidence does not support dietary recommendations for MS. The objective of this study was to assess the efficacy of different dietary approaches on MS-related fatigue and quality of life (QoL) through a systematic review of the literature and network meta-analysis (NMA).

Methods

Electronic database searches were performed in May 2021. Inclusion criteria were (1) randomized trial with a dietary intervention, (2) adults with definitive MS based on McDonald criteria, (3) patient-reported outcomes for fatigue and/or QoL, and (4) minimum intervention period of 4 weeks. For each outcome, standardized mean differences (SMDs) were calculated and included in random effects NMA to determine the pooled effect of each dietary intervention relative to each of the other dietary interventions. The protocol was registered at PROSPERO (CRD42021262648).

Results

Twelve trials comparing 8 dietary interventions (low-fat, Mediterranean, ketogenic, anti-inflammatory, Paleolithic, fasting, calorie restriction, and control [usual diet]), enrolling 608 participants, were included in the primary analysis. The Paleolithic (SMD −1.27; 95% CI −1.81 to −0.74), low-fat (SMD −0.90; 95% CI −1.39 to −0.42), and Mediterranean (SMD −0.89; 95% CI −1.15 to −0.64) diets showed greater reductions in fatigue compared with control. The Paleolithic (SMD 1.01; 95% CI 0.40–1.63) and Mediterranean (SMD 0.47; 95% CI 0.08–0.86) diets showed greater improvements in physical QoL compared with control. For improving mental QoL, the Paleolithic (SMD 0.81; 95% CI 0.26–1.37) and Mediterranean (SMD 0.36; 95% CI 0.06–0.65) diets were more effective compared with control. However, the NutriGRADE credibility of evidence for all direct comparisons is very low because of most of the included trials having high or moderate risk of bias, small sample sizes, and the limited number of studies included in this NMA.

Discussion

Several dietary interventions may reduce MS-related fatigue and improve physical and mental QoL; however, because of the limitations of this NMA, which are driven by the low quality of the included trials, these findings must be confirmed in high-quality, randomized, controlled trials.

Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS)¹ and is associated with increased disability and reduced physical and mental quality of life (QoL).² Pharmacologic treatment options for MS-related fatigue have limited efficacy³; thus, many individuals with MS seek nonpharmacologic therapies to reduce fatigue burden and improve physical and mental QoL.

Surveys consistently observe that half of individuals with MS report implementing dietary modifications.^4,5 However, a recent Cochrane systematic review and meta-analysis found no effect of specific dietary components on MS outcomes including relapse rate, disease progression, or other outcomes.⁶ In addition, a second recent systematic review found that a plant-based diet may be beneficial for fatigue.⁷ However, both reviews included interventions focused on specific dietary components rather than the overall dietary pattern which limits the conclusions that can be drawn about specific dietary patterns. Owing to the lack of evidence demonstrating dietary intervention-related reduced MS disease activity⁸ and the limited role of the neurologist in providing dietary recommendations,⁹ patients with newly diagnosed MS receive little dietary advice¹⁰ which forces this information to be sought from internet sources that are often not evidence based.¹¹

Preliminary trials suggest that dietary interventions may improve physical and mental QoL and reduce MS-related fatigue; however, these studies are generally limited by small sample size, absence of a control group, and an overall lack of consensus regarding the specific dietary intervention investigated.⁸ Owing to the lack of control and heterogeneity of the dietary interventions studied in these preliminary trials, it is not possible to estimate overall effects of specific dietary interventions with standard pairwise meta-analysis. However, network meta-analysis (NMA) is an extension of pairwise meta-analysis that allows for multiple comparisons of several interventions and can overcome some of the limitations of these preliminary trials. NMA combines direct evidence from head-to-head trials and indirect evidence derived from common comparators in a network of trials to estimate overall effects of each intervention.

Therefore, this study assessed the efficacy of different dietary approaches on fatigue and physical and mental QoL among people with MS in a systematic review and NMA of randomized dietary intervention trials.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

This review was registered in PROSPERO International Prospective Register of Systematic Reviews crd.york.ac.uk/prospero/display_record.php?ID=CRD42021262648. The present systematic review was planned, conducted, and reported in adherence to PRISMA standards of quality for reporting systematic reviews and NMA.¹²

Search Strategy

The following databases were searched for eligible citations from inception to May 5, 2021: PubMed, Embase (Elsevier), Cochrane Central Register of Controlled Trials (CENTRAL; Wiley), Cumulative Index of Nursing and Allied Health Literature (CINAHL; EBSCO), Scopus (Elsevier), Web of Science Core Collection, and ProQuest Dissertation and Theses Global (EBSCO). Duplicates in the search results were removed in EndNote using a combination of automated and manual methods. Clinical trial registries searched from inception to May 14, 2021, include ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (who.int/clinical-trials-registry-platform). Furthermore, the reference lists from retrieved articles were screened to search for additional relevant studies. Corresponding authors were contacted for any study that met inclusion criteria but did not provide complete information on outcomes, study sample, or the intervention.

The search strategies were developed and executed by a health sciences librarian trained in systematic literature searching. The full search strategies for all databases and registers are included in eAppendix 1 (links.lww.com/WNL/C436). No language limits were applied to any of the strategies. The strategies were peer-reviewed by another searcher for the potential of missing terms and correct syntax.

Eligibility Criteria

Using the web-based Rayyan application,¹³ 2 reviewers (T.J.T. and J.C.) independently screened all studies for inclusion based on the following criteria:

1. Randomized trial with a dietary approach as intervention.

2. Adults with definitive MS based on McDonald criteria.

3. Patient-reported outcomes of fatigue and/or physical and mental QoL.

4. Minimum intervention period of 4 weeks.

The following studies were excluded:

1. Randomized trials that included pregnant women or individuals age younger than 18 years.

2. Interventions solely based on dietary supplements or single foods.

3. Intervention studies using dietary supplements as control that are not also used with the intervention arm. Supplement use in the intervention group was considered as a component of the dietary approach for this NMA.

4. Studies with a cointervention (e.g., exercise, medication) that was not applied to all groups.

5. Studies using healthy controls or other diseases as the comparative group.

Data Extraction and Synthesis

After study selection, 2 reviewers (J.C. and S.S.F.) extracted the following characteristics: last name of first author, year of publication, study design, sample size, mean participant baseline age, percent female of the study sample, study duration, outcomes instruments, description of the dietary intervention(s), specification of the control group, and baseline and postintervention mean and SD of outcomes. Outcomes data included postintervention mean values with corresponding SDs for fatigue (Fatigue Severity Scale, Modified Fatigue Impact Scale, and Neurologic Fatigue Index-MS) or QoL (physical and mental composite scores of the MSQoL-54 or Short-form-36 or the mobility and emotional well-being subscores of the Functional Assessment of Multiple Sclerosis). Similar dietary interventions were then grouped into similar diet classes based on original published description.

Risk of Bias Assessment

Full articles were assessed for methodological quality using the risk of bias assessment tool from the Cochrane Collaboration¹⁴ for the following sources of bias: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), and reporting bias (selective reporting). Randomized controlled trials in nutrition research are often prone to inherent methodological constraints (e.g., they cannot be controlled with “true” placebos, but rather by a limitation of certain aspects of nutrient compositions, food groups, or dietary patterns). Studies were classified as being at low risk of bias if ≥3 of a maximum of 6 risk of bias subitems were rated with a low risk of bias and ≤1 subitems were rated as high risk of bias (excluding blinding of participants because of the inherent constraints of dietary intervention trials).

Missing Data

We contacted study authors (by email) to obtain relevant missing data from the included randomized trials; 6 corresponding authors sent additional data.

Description of Available Data and Assumption of Transitivity

All available direct comparisons between the different dietary interventions were displayed in a network diagram,¹⁵ where the size of the nodes are proportional to the sample size of each dietary intervention and the thickness of the lines proportional to the number of studies available. We used the contribution matrix to identify the direct comparisons with greater influence in the network relative effects.^15,16 Transitivity is the fundamental assumption of indirect comparisons and NMA, and its violation threatens the validity of findings obtained from a network of studies. We considered the following effect modifiers: mean participant baseline age, body mass index, and MS disease duration.

Statistical Analysis

To synthesize heterogeneous outcome collection methods and minimize effects from baseline differences in studies with small sample size, standardized mean differences (SMDs) of change from baseline were calculated for each arm of each study included in this NMA.¹⁷ First, mean changes from baseline to follow-up were calculated for each diet group. MDs between diet groups were calculated; then, SMDs were calculated by dividing the MDs by the pooled SDs (SD_p). We calculated SD_p with the following formula: SD_p = square root [(n₁ − 1)s₁²] + [(n₂ − 1)s₂²]/[(n₁ − 1) + (n₂ − 1)], where s₁ and s₂ are the end-of-study SD estimates for treatment strata. Before SD_p calculations, in cases where studies reported SEM, SD was estimated using the following formula: SD = SEM × $\sqrt{\left(\mathrm{n}\right)}$, where n is the number of participants. In cases where studies reported outcomes as median and interquartile range, medians were assumed to be equal to means and SDs were estimated from the interquartile range.

For each outcome measure of interest, NMA was used to synthesize all available direct and indirect evidence and enable simultaneous comparisons of multiple interventions forming a connected network while preserving the internal randomization of individual trials. Random effects NMA was conducted for each outcome to estimate all possible pairwise relative effects and clinically meaningful relative ranking of the different dietary interventions was obtained. The relative ranking of the different diets for each outcome is displayed as the ranking probabilities and corresponding P-scores. Pooled SMDs and 95% CIs were presented in league tables. All analyses were fitted in the frequentist framework using the “netmeta” package in RStudio (version 1.4.1106).

Sensitivity Analyses

Sensitivity analyses were conducted excluding trials with high risk of bias, short study duration (<4 months), and mixed MS types.

Assessment of Inconsistency and Heterogeneity

To evaluate the presence of statistical inconsistency (i.e., disagreement between direct and indirect evidence) in the data, we used both local and global approaches.^18,19 Specifically, we used the side-splitting approach²⁰ to detect comparisons for which direct evidence disagrees with indirect evidence from the network. In addition, we used the design-by-treatment interaction model and the I² statistic as global methods to investigate the presence of inconsistency jointly from all possible sources in the network.^21,22

Small Study Effects and Publication Bias

Potential publication bias was explored by visual inspection of funnel plots for asymmetry and with the Egger test.

Credibility of Evidence

The credibility of evidence for each pairwise comparison was evaluated using the NutriGRADE scoring system,²³ which is an extension of the GRADE scoring system that is specific to nutrition studies and comprises the following items: (1) risk of bias, study quality, and study limitations; (2) precision; (3) heterogeneity; (4) directness; (5) publication bias; (6) funding bias; and (7) study design for meta-analyses of randomized trials. This scoring system judges meta-evidence of each pairwise comparison and categorizes scores into 4 classes: high, moderate, low, and very low credibility of evidence.

Data Availability

All data necessary to repeat this analysis are available within this article.

Results

Characteristics

Of the 1,828 publications originally identified, 12 articles reporting on 11 randomized trials (11 for fatigue and 10 each for physical and mental QoL) met inclusion criteria and provided sufficient information to be included in the NMA (eFigure 1, links.lww.com/WNL/C436). Descriptive characteristics of each included study are presented in eTable 1. Excluded studies are presented in eAppendix 2. Included randomized trials were published between 2016 and 2021 and included a total of 608 participants with MS. Seven trials were conducted in the United States, 3 in Iran, and one in Germany. Study durations ranged from 2 to 12 months, and the mean baseline participant age ranged from 34 to 52 years. Included randomized trials were primarily conducted among participants with relapsing remitting MS (RRMS) and included mostly female participants.

Included had heterogeneous definitions for the different intervention diets. For example, one of the low-fat intervention trials used a plant-based, low-fat diet, whereas others were not plant-based. In addition, dietary interventions and support protocols varied among the trials. Hypocaloric, isocaloric, and ad libitum diets were included in this NMA. Furthermore, the definition of a control diet differed across the included trials. Of the 10 trials that included a control group, 5 were based on “no intervention” (usual care or waitlist-control) and 5 were based on minimal intervention (standard dietary advice). Therefore, diets were harmonized across studies to form classes of dietary approaches (eTable 2, links.lww.com/WNL/C436).

Risk of Bias

Four randomized trials were judged to be low risk, 5 were high risk, and 2 were unclear/moderate risk of bias (eTable 3, links.lww.com/WNL/C436). Most (82%) of the included studies indicated a low risk of bias for random-sequence generation, 27% for allocation concealment, 0% for blinding of personnel and participants, 27% for blinding of outcome assessment, 64% for incomplete data outcome, and 55% for selective reporting.

Network Meta-analysis

Figure 1 shows the network diagrams of direct evidence comparisons for fatigue (Figure 1A) and physical and mental QoL (Figure 1B) with the number of studies reflected by the size of the lines and the number of participants reflected by the size of the nodes. The highest number of trials were available for comparison between Mediterranean and fasting diets compared with control (n = 3) for fatigue and for fasting diet compared with control (n = 3) for physical and mental QoL. The statistical contribution of direct and indirect evidence of the different comparisons is summarized in Table 1 and indicates that most of the contribution to the study effects come from indirect comparisons.

Figure 1. Network Diagrams for (A) Fatigue and (B) Physical and Mental QoL.

The size of the nodes is proportional to the total number of participants allocated to each dietary approach and the thickness of the lines proportional to the number of studies evaluating each direct comparison. Abbreviation: QoL = quality of life.

Table 1.

Percentage Contribution of Each Estimate Derived From Direct (Left Column) and Indirect (Right Column) Comparisons

Fatigue
Paleolithic		79%	21%	0%	100%	34%	66%	0%	100%	0%	100%	0%	100%	45%	55%
79%	21%	Low-fat		0%	100%	0%	100%	0%	100%	0%	100%	0%	100%	70%	30%
0%	100%	0%	100%	Mediterranean		0%	100%	0%	100%	0%	100%	0%	100%	100%	0%
38%	62%	0%	100%	0%	100%	Ketogenic		76%	24%	0%	100%	0%	100%	72%	28%
0%	100%	0%	100%	0%	100%	71%	29%	Fasting		0%	100%	83%	17%	95%	5%
0%	100%	0%	100%	0%	100%	0%	100%	0%	100%	Anti-inflammatory		0%	100%	100%	0%
0%	100%	0%	100%	0%	100%	0%	100%	84%	16%	0%	100%	Calorie restriction		80%	0%
49%	51%	66%	34%	100%	0%	80%	20%	96%	4%	100%	0%	79%	21%	Control
Quality of life (QoL)
The values above the dietary approaches correspond to the percentage contribution of direct and indirect comparisons between the row and columns for fatigue (e.g., the percentage contribution of direct comparisons for fatigue between ketogenic and fasting diet is 76%, and 24% for the indirect comparisons). The values below the dietary approaches correspond to the percentage contribution of direct and indirect comparisons between the column and the rows for physical and mental QoL (e.g., the percentage contribution of direct comparisons for QoL between Paleolithic and ketogenic diet is 38%, and 62% for the indirect comparisons).

Abbreviation: QoL = quality of life.

Fatigue

Table 2 summarizes effect size estimates (SMD and 95% CIs) for comparisons of all diets on fatigue. The Paleolithic (SMD −1.27; 95% CI −1.81 to −0.74), low-fat (SMD −0.90; 95% CI −1.39 to −0.42), and Mediterranean (SMD −0.89; 95% CI −1.15 to −0.64) diets showed greater reductions in fatigue compared with control diet (eFigure 2, links.lww.com/WNL/C436). The Paleolithic (SMD −1.20; 95% CI −1.87 to −0.54), low-fat (SMD −0.83; 95% CI −1.46 to −0.21), and Mediterranean (SMD −0.82; 95% CI −1.29 to −0.36) diets showed greater reductions in fatigue compared with the anti-inflammatory diet. The Paleolithic (SMD −1.07; 95% CI −1.76 to −0.38), low-fat (SMD −0.70; 95% CI −1.16 to −0.03), and Mediterranean (SMD −0.69; 95% CI −1.22 to −0.15) diets showed greater reductions in fatigue compared with the fasting diet. Finally, the Paleolithic (SMD −1.62; 95% CI −2.56 to −0.68), low-fat (SMD −1.25; 95% CI −2.17 to −0.33), and the Mediterranean (SMD −1.24; 95% CI −2.07 to −0.41) diets showed greater reductions in fatigue compared with the calorie restriction diet. The Paleolithic diet had the highest P-score for reducing fatigue (0.9748), followed by the Mediterranean (0.7759), low-fat (0.7653), ketogenic (0.5800), fasting (0.3646), anti-inflammatory (0.2694), control (0.2000), and calorie restriction (0.0700) diets.

Table 2.

League Table of the Network Meta-analysis Comparing the Effects (SMD) of all Dietary Approaches and 95% Confidence Intervals (95% CI) on Fatigue Among Individuals With MS (n = 11)

Paleolithic [0.9748]
−0.38 (−0.97 to 0.21)	Mediterranean [0.7759]
−0.37 (−0.05 to 0.79)	0.01 (−0.54 to 0.56)	Low-fat [0.7653]
−0.73 (−1.47 to 0.02)	−0.34 (−1.00 to 0.31)	−0.36 (−1.09 to 0.38)	Ketogenic [0.5800]
−1.07 (−1.76 to −0.38)	−0.69 (−1.22 to −0.15)	−0.70 (−1.16 to −0.03)	−0.34 (−0.93 to 0.25)	Fasting [0.3646]
−1.20 (−1.87 to −0.54)	−0.82 (−1.29 to −0.36)	−0.83 (−1.46 to −0.21)	−0.48 (−1.20 to 0.24)	−0.14 (−0.75 to 0.48)	Anti-inflammatory [0.2694]
−1.27 (−1.81 to −0.74)	−0.89 (−1.15 to −0.64)	−0.90 (−1.39 to −0.42)	−0.55 (−1.15 to 0.05)	−0.21 (−0.68 to 0.26)	−0.07 (−0.46 to 0.32)	Control [0.2000]
−1.62 (−2.56 to −0.68)	−1.24 (−2.07 to −0.41)	−1.25 (−2.17 to −0.33)	−0.90 (−1.82 to 0.03)	−0.55 (−1.33 to 0.23)	−0.42 (−1.30 to 0.47)	−0.35 (−1.14 to 0.44)	Calorie restriction [0.0700]
The values below the dietary approaches correspond to the SMD (95% CI) for fatigue between the column and the row (e.g., the SMD between the Mediterranean diet and the control diet is −0.89). The effect was interpreted as statistically significant (highlighted in bold) if the 95% CIs did not include the null value. The values in the square brackets represent the P-score for fatigue (e.g., for reducing fatigue, the Paleolithic diet was ranked as the best dietary approach, P-score = 0.9748; and the Mediterranean diet was ranked as the second best dietary approach, P-score = 0.7759). Negative SMD values correspond to reductions.

Abbreviations: MS = multiple sclerosis; SMD = standardized mean difference.

Quality of Life

Table 3 summarizes effect size estimates (SMD and 95% CIs) for comparisons of all diets on physical and mental QoL. The Paleolithic (SMD 1.01; 95% CI 0.40–1.63) and Mediterranean (SMD 0.47; 95% CI 0.08–0.86) diets showed greater improvements in physical QoL compared with control diet (eFigure 3, links.lww.com/WNL/C436). The Paleolithic diet showed greater improvements in physical QoL compared with the anti-inflammatory (SMD 1.00; 95% CI 0.20–1.79), fasting (SMD 0.80; 95% CI 0.03–1.58), and low-fat (SMD 0.60; 95% CI 0.10–1.10) diets. The Paleolithic diet had the highest P-score for improving physical QoL (0.9590), followed by the ketogenic (0.7054), Mediterranean (0.6518), low-fat (0.5778), fasting (0.4077), calorie restriction (0.2725), anti-inflammatory (0.2416), and control (0.1842) diets.

Table 3.

League Table of the Network Meta-analysis Comparing the Effects (SMD) of All Dietary Approaches and 95% CIs on Physical and Mental QoL Among Individuals With MS (n = 10, for Both)

Mental QoL
Paleolithic [0.9590, 0.9603]	0.51 (−0.25; 1.28)	0.46 (−0.17; 1.08)	0.51 (0.09; 0.94)	0.84 (0.13; 1.55)	0.70 (−0.25; 1.65)	0.81 (0.13; 1.49)	0.81 (0.26; 1.37)
0.44 (−0.39; 1.28)	Ketogenic [0.7054, 0.5900]	−0.06 (−0.74; 0.63)	0.00 (−0.77; 0.77)	0.32 (−0.98; 0.33)	0.18 (−0.76; 1.13)	0.30 (−0.43; 1.03)	0.30 (−0.32; 0.92)
0.54 (−0.18; 1.27)	0.10 (−0.67; 0.87)	Mediterranean [0.6518, 0.6792]	0.06 (−0.55; 0.66)	0.38 (−0.17; 0.93)	0.24 (−0.59; 1.07)	0.36 (−0.13; 0.85)	0.36 (0.06; 0.65)
0.60 (0.10; 1.10)	0.15 (−0.69; 1.00)	0.06 (−0.64; 0.75)	Low-fat [0.5778, 0.5836]	0.32 (−0.37; 1.02)	0.18 (−0.75; 1.12)	0.30 (−0.36; 0.95)	0.30 (−0.23; 0.82)
0.80 (0.03; 1.58)	0.36 (−0.35; 1.06)	0.26 (−0.38; 0.90)	0.20 (−0.56; 0.96)	Fasting [0.4077, 0.2481]	−0.14 (−0.91; 0.63)	−0.02 (−0.64; 0.59)	−0.02 (−0.49; 0.44)
0.99 (−0.03; 2.02)	0.55 (−0.46; 1.56)	0.45 (−0.47; 1.37)	0.39 (−0.62; 1.40)	0.19 (−0.63; 1.01)	Calorie restriction [0.2725, 0.4171]	0.12 (−0.76; 0.99)	0.12 (−0.67; 0.90)
1.00 (0.20; 1.79)	0.55 (−0.28; 1.39)	0.45 (−0.18; 1.08)	0.40 (−0.37; 1.17)	0.19 (−0.52; 0.90)	0.00 (−0.97; 0.97)	Anti-inflammatory [0.2416, 0.2726]	−0.00 (−0.39; 0.39)
1.01 (0.40; 1.63)	0.57 (−0.10; 1.24)	0.47 (0.08; 0.86)	0.41 (−0.17; 1.00)	0.21 (−0.30; 0.72)	0.02 (−0.81; 0.85)	0.02 (−0.48; 0.52)	Control [0.1842, 0.2492]
Physical QoL
The values below the dietary approaches correspond to the SMD (95% CI) for physical QoL between the column and the row (e.g., the SMD between the Mediterranean and the control diets is 0.47). The values above the dietary approaches correspond to the SMD (95% CI) for mental QoL (e.g., the SMD between the Paleolithic and control diets is 0.81). The effects were interpreted as statistically significant (highlighted in bold) if the 95% CIs did not include the null value. The values in the square brackets represent the P-score for physical and mental QoL, respectively (e.g., for improving physical QoL, the Paleolithic diet was ranked as the best dietary approach, P-score = 0.9590; and for mental QoL the Mediterranean diet was ranked as the second best dietary approach, P-score = 0.6792). Positive SMD values correspond to increases in QoL.

Abbreviations: MS = multiple sclerosis; QoL = quality of life; SMD = standardized mean difference.

For improving mental QoL, the Paleolithic (SMD 0.81; 95% CI 0.26–1.37) and Mediterranean (SMD 0.36; 95% CI 0.06–0.65) diets showed greater improvements compared with the control diet (eFigure 4, links.lww.com/WNL/C436). The Paleolithic diet also showed greater improvements in mental QoL compared with the fasting (SMD 0.84; 95% CI 0.13–1.55), anti-inflammatory (SMD 0.81; 95% CI 0.13–1.49), and low-fat (SMD 0.51; 95% CI 0.09–0.94) diets. The Paleolithic diet had the highest P-score for improving mental QoL (0.9603), followed by the Mediterranean (0.6792), ketogenic (0.5900), low-fat (0.5836), calorie restriction (0.4171), anti-inflammatory (0.2726), control (0.2492), and fasting (0.2481) diets.

Inconsistency

The side-splitting approach indicated no inconsistencies between direct and indirect evidence for fatigue, physical, or mental QoL (eTables 4–6, links.lww.com/WNL/C436). The design-by-treatment models also indicated no significant inconsistency for fatigue (p = 0.62), physical QoL (p = 0.70), or mental QoL (p = 0.93) nor did the I² statistic from primary models for fatigue (I² = 0.0%), physical QoL (I² = 13.9%), or mental QoL (I² = 0.0%).

Sensitivity Analyses

When excluding studies with high risk of bias, fatigue results were generally confirmed; however, the Paleolithic diet was significant when compared with the low-fat (SMD −0.49; 95% CI −0.93 to −0.04) and ketogenic (SMD −0.95; 95% CI −1.78 to −0.11) diets, and the comparisons between the low-fat and Mediterranean diets and control were now attenuated and no longer significant (eTable 7, links.lww.com/WNL/C436). When including only studies among people with RRMS, the results were confirmed (eTable 8). The results of the main analysis were confirmed generally confirmed for fatigue when excluding studies with short duration (<4 months); however, the Paleolithic diet was significant when compared with the low-fat (SMD −0.51; 95% CI −0.98 to −0.04) and ketogenic (SMD −1.25; 95% CI −2.28 to −0.21) diets (eTable 9).

When excluding studies with high risk of bias, the results were generally confirmed for physical QoL; however, comparisons of the Paleolithic diet with low-fat, fasting, and anti-inflammatory diets were attenuated and no longer significant. For mental QoL, the results were generally confirmed; however, comparisons of the Paleolithic diet with the fasting and anti-inflammatory diets were attenuated and no longer significant (eTable 10, links.lww.com/WNL/C436). When including only studies among people with RRMS, the results are generally confirmed for mental QoL; however, for physical QoL, all comparisons were attenuated and no longer significant other than the comparison between the Paleolithic and control diets (SMD 0.91; 95% CI 0.12–1.69; eTable 11). When excluding studies with short duration (<4 months), only the comparisons between the Paleolithic and control diets (SMD 0.83; 95% CI 0.03–1.62) and the Mediterranean and control diets (SMD 0.48; 95% CI 0.12, 0.84) remained significant for physical QoL. For mental QoL, only the comparison between the Mediterranean and control diets (SMD 0.36; 95% CI 0.06–0.65) remained significant (eTable 12).

Publication Bias

The comparison-adjusted funnel plots (eFigure 5, links.lww.com/WNL/C436) and the Egger test (eTable 13) did not indicate publication bias for fatigue, physical QoL, or mental QoL.

Credibility of Evidence

The NutriGRADE credibility of evidence scores were very low for all direct comparisons because of the high risk of bias and small sample sizes of several of the included studies, as well as the relatively few studies included.

Discussion

Eight different dietary approaches (anti-inflammatory, fasting, calorie restriction, ketogenic, low-fat, Mediterranean, Paleolithic, and control) were compared for their effect on fatigue and physical and mental QoL among people with MS. The Paleolithic and Mediterranean diets were consistently shown to be favorable compared with control for reducing fatigue and improving physical and mental QoL. However, owing to the sparse number of studies, small sample sizes, and high risk of bias in several of the trials, the NutriGRADE credibility of evidence is very low for all direct comparisons necessitating caution in interpreting results. Some dietary approaches may be better for reducing fatigue and improving physical and mental QoL compared with no diet; however, large, well-designed randomized trials are urgently needed to confirm these findings.

The results of this study were generally consistent in all sensitivity analyses; however, it is important to highlight a few key similarities and discrepancies. For fatigue, all differences compared with control remained significant in sensitivity analyses. The effect of the Mediterranean diet on physical QoL compared with control was attenuated and no longer significant when including only studies among people with RRMS in the analysis. In addition, the effect of the Paleolithic diet on mental QoL compared with control was attenuated and no longer significant when excluding studies of short duration.

To our knowledge, this is the first NMA investigating the effect of different dietary approaches on MS-related fatigue and physical and mental QoL. To date, we have found no other pairwise meta-analyses on the effect of specific dietary approaches to MS; however, several have investigated specific dietary components. A recent meta-analysis of randomized controlled trials found that vitamin D supplementation had no effect on relapse rate or disability status.²⁴ A second recent meta-analysis of randomized, controlled trials found that probiotic supplementation improved mental health among people with MS.²⁵ Furthermore, omega-3 fatty acid supplementation was found to have no effect on disability status but did significantly reduce serum tumor necrosis factor-α, a marker of inflammation.²⁶ In addition, several observational studies have shown that higher diet quality is associated with reduced risk of MS^27-29 and reduced relapse rate, disability status, brain volume loss, fatigue, cognitive impairment, depression, and increased physical and mental QoL among people with MS.^30-35

Based on the associations of weight with comorbidity burden, weight loss with reduced MS disability, and the microbiome and metabolites with the immune system, the National MS Society recommends “general healthy” diet changes.³⁶ The current state of evidence as of 2019 did not support recommendations for any specific dietary approach,⁸ thus necessitating the Nation MS Society's recommendation for a general healthy diet. However, given the consistent results of this NMA for the Paleolithic and Mediterranean diets on fatigue and physical and mental QoL, it is necessary to consider the similarities of these 2 dietary approaches with general healthy diet recommendations. In accordance with the Dietary Guidelines for Americans (DGA) 2020,³⁷ both the Paleolithic and Mediterranean diets recommend high intake of fruits, vegetables, fish/seafood, nuts/seeds, and healthy fats (rich in monounsaturated and polyunsaturated fatty acids) and avoidance of ultraprocessed foods which are rich sources of added sugar, sodium, and hydrogenated fats. This dietary pattern is also consistent with the diet developed by Dr. Roy Swank which was included in the low-fat diet category that was shown to significantly reduce fatigue in this NMA. Owing to these similarities, it may be prudent to investigate the DGA among people with MS. The DGA have several practical benefits over the specialized diets included in this study as their use would eliminate several conflicts of interest present in the included studies, educational materials for the DGA are freely available, and registered dietitians are trained to help patients implement the DGA.

The mechanism by which a healthy diet improves MS-related fatigue and physical and mental QoL remains unknown; however, comorbidity burden reduction is one possible mechanism.^38,39 Burden of comorbidities is common among people with MS and the prevalence increasing,⁴⁰ likely due to the symptoms of pain, fatigue, and reduced vision, cognition, and ambulation people with MS experience⁴¹ that increase disability burden and reduce their ability to perform activities of daily living such as acquiring and preparing healthy food.⁴² Studies have shown that comorbidity burden is associated with increased risk of relapse, hospitalization, and disability progression in MS.^43-45 Some studies included in this NMA reported significant reductions in weight and metabolic risk factors including serum glucose and cholesterol,^46,47 supporting this possible mechanism. Despite the associations of comorbid obesity with negative outcomes in MS, recent commentaries demonstrate that considerable controversy exists in the MS field regarding the role of dietary approaches for comorbid obesity among patients with MS.^48,49

The strengths of this study include the use of NMA methods which allowed for the comparison and ranking of 8 different dietary approaches for their effect on fatigue and physical and mental QoL among people with MS and the consistency of results in analyses. However, this study also has several limitations. First, the studies included in this NMA are relatively few, and several have small sample sizes, high risk of bias, conflicts of interest, and methodological errors. These limitations reduce the credibility of this evidence and the achieved power, especially for sensitivity analyses. It should be noted that several of the included studies, especially those with small sample size, had large baseline differences between groups which may bias results. Although research on diet and MS is not new, randomized dietary intervention trials are relatively new to the literature. The oldest articles eligible for inclusion in this NMA are from 2016. Second, the number of studies per dietary intervention was relatively few, and most evidence in the NMA is from indirect comparisons. Third, the studies included in this NMA used heterogeneous definitions for the different dietary interventions. To overcome this limitation, we used the dietary intervention descriptions from the original studies to create classes of similar dietary approaches. Fourth, the study samples of the included studies include mostly White females with RRMS which further limits the generalizability of the results to other populations. Fifth, the included studies used heterogeneous methods to collect data on fatigue and QoL which necessitated the use of SMDs to estimate effects and limits clinical relevance of the results. Sixth, the results from this study do not suggest that diet affects MS disease activity as all outcomes evaluated are patient-reported. Finally, NMA methodology has inherent limitations including the inability to include control variables in analyses. Subsequently, confounding because of weight loss or another secondary outcome may explain the suggested beneficial effects of the dietary interventions on fatigue and physical and mental QoL. Owing to these limitations, the NutriGRADE credibility of evidence scores for all direct comparisons in this NMA are very low and necessitate the results from this NMA be interpreted with caution. To increase credibility in this evidence, future well-designed randomized trials with large sample sizes and low risk of bias are needed.

The included studies in this NMA were sparse, had high risk of bias, small sample size, and several limitations; therefore, NutriGRADE credibility of evidence scores is very low for all direct comparisons. Thus, the results of this study must be interpreted with caution and require confirmation with large, well-designed randomized trials with low risk of bias and long duration of follow-up. Despite the limitations of this study, the results provide the first synthesis of the literature and suggest that some diets or diet components may reduce fatigue and improve physical and mental QoL among people with MS. These findings are a necessary step toward highly desired⁵⁰ dietary recommendations for people with MS and justify additional well-designed trials to confirm these findings, elucidate the mechanism by which diet may affect MS-related fatigue and physical and mental QoL, and to evaluate the effect of dietary interventions on MS disease activity.

Glossary

CENTRAL

Cochrane Central Register of Controlled Trials

CINAHL

Cumulative Index of Nursing and Allied Health Literature

DGA

Dietary Guidelines for Americans

QoL

quality of life

NMA

network meta-analysis

MS

multiple sclerosis

RRMS

relapsing remitting MS

SMD

standardized mean difference

Appendix. Authors

Name	Location	Contribution
Linda G. Snetselaar, PhD, RD	Department of Epidemiology, College of Public Health, University of Iowa, Iowa City	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design
Joshua J. Cheek, BS	Department of Kinesiology, Central College, Pella, IA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Sara Shuger Fox, PhD	Department of Kinesiology, Central College, Pella, IA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Heather S. Healy, MA, MLS	Hardin Library for the Health Sciences, University of Iowa, Iowa City	Major role in the acquisition of data; study concept or design
Marin L. Schweizer, PhD	William S. Middleton Memorial Veterans Hospital, Madison, WI	Study concept or design; analysis or interpretation of data
Wei Bao, MD, PhD	Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China	Study concept or design; analysis or interpretation of data
John Kamholz, MD, PhD	Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City	Study concept or design; analysis or interpretation of data
Tyler J. Titcomb, PhD, RD	Department of Epidemiology, College of Public Health, University of Iowa, Iowa City; Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Study Funding

T.J. Titcomb is a research trainee of the University of Iowa Fraternal Order of Eagles Diabetes Research Center (T32DK112751-01) and is supported by the Carter Chapman Shreve Family Foundation and the Carter Chapman Shreve Fellowship Fund for diet and lifestyle research conducted at the University of Iowa. In-kind support was provided by the University of Iowa College of Public Health Preventive Intervention Center.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.