Interventions alimentaires pour les résultats liés à la sclérose en plaques
Résumé scientifique
Contexte
La sclérose en plaques (SEP) est une maladie démyélinisante courante du système nerveux central. Bien que la pathogenèse exacte reste inconnue, la théorie dominante est qu'elle résulte d'une dysrégulation du système immunitaire. Les traitements modificateurs de la maladie approuvés semblent moduler le système immunitaire pour améliorer les critères de jugement liés à la SEP. La capacité des interventions diététiques à influencer les critères de jugement liés à la SEP suscite un intérêt considérable. Ceci est une mise à jour de la revue Cochrane « Interventions diététiques pour la sclérose en plaques » (Farinotti 2003; Farinotti 2007; Farinotti 2012).
Objectifs
Évaluer les effets des interventions diététiques (y compris les plans diététiques avec recommandations pour des aliments complets spécifiques, des macronutriments et des produits de santé naturels) par rapport à un placebo ou une autre intervention sur les résultats de santé (y compris les résultats liés à la SEP et les événements indésirables graves) chez les personnes atteintes de SEP.
Stratégie de recherche documentaire
Le 30 mai 2019, nous avons effectué des recherches dans CENTRAL, MEDLINE, Embase et Web of Science. Nous avons également effectué des recherches sur ClinicalTrials.gov, sur le Système d'enregistrement international des essais cliniques (ICTRP) de l'OMS et sur la bibliothèque numérique en réseau des thèses et des mémoires (Networked Digital Library of Theses and Dissertations, NDLTD). Nous avons vérifié les références bibliographiques des essais identifiés et demandé des informations aux auteurs des essais afin de repérer toute donnée supplémentaire, publiée ou non.
Critères de sélection
Nous avons inclus tout essai contrôlé randomisé (ECR) ou essai clinique contrôlé (ECC) évaluant l'effet d'une intervention diététique par rapport à un placebo ou une autre intervention chez des participants atteints de SEP sur des critères de jugement liés à la SEP, y compris les rechutes, la progression du handicap et les mesures d'imagerie par résonance magnétique (IRM).
Recueil et analyse des données
Nous avons suivi les procédures méthodologiques standard définies par Cochrane. Les critères de jugement principaux prévus étaient le nombre de participants ayant connu une rechute et un changement dans la progression de leur handicap, selon une échelle de handicap validée lors du dernier suivi rapporté. Les critères de jugement secondaires comprenaient l'activité IRM, la tolérance et les critères de jugement rapportés par les patients. Nous avons saisi et analysé les données dans Review Manager 5.
Résultats principaux
Nous avons trouvé 41 articles en texte intégral examinant 30 essais après lecture du texte intégral. Les participants étaient des adultes atteints de SEP, définis selon des critères établis, se présentant dans des cliniques de SEP en Europe, en Amérique du Nord et au Moyen‐Orient. La conception des études variait considérablement, bien que tous les essais présentaient au moins un problème méthodologique entraînant un risque de biais élevé ou inconnu. Essais examinés: supplémentation pour augmenter les acides gras polyinsaturés (AGPI) (11 essais) ; une variété de suppléments antioxydants (10 essais) ; programmes diététiques (3 essais) ; et autres suppléments diététiques (par exemple acétyl L‐carnitine, biotine, créatine, palmitoyléthanolamide, probiotique, riboflavine) (6 essais).
Dans trois essais comparant les AGPI aux acides gras monoinsaturés (AGMI), les données probantes étaient très incertaines concernant la différence de rechutes (risque relatif (RR) 1,02, intervalle de confiance (IC) à 95% 0,88 à 1,20 ; 3 études, 217 participants ; 75% dans le groupe des AGPI contre 74% dans le groupe des AGMI ; données probantes de très faible niveau de confiance). Parmi les quatre essais comparant les AGPI et les AGMI, il pourrait n’y avoir que peu ou pas de différence dans l'impression globale de détérioration (RR 0,85, IC à 95 % 0,71 à 1,03 ; 4 études, 542 participants ; 40 % dans le groupe des AGPI contre 47 % dans le groupe des AGMI ; données probantes de faible niveau de confiance). Dans deux essais comparant les AGPI aux AGMI (102 participants), les données probantes de changement de la progression du handicap étaient très faible niveau de confiance. Aucun des essais AGPI versus AGMI n'a évalué de critères de jugement IRM. Dans un essai comparant les AGPI et les AGMI (40 participants), aucun événement indésirable grave n'a été constaté, sur la base de données probantes de faible niveau de confiance.
Dans deux essais comparant différents AGPI (oméga‐3 contre oméga‐6), il pourrait n’y avoir que peu ou pas de différence dans les rechutes (RR 1,02, IC à 95 % 0,62 à 1,66 ; 2 études, 129 participants ; 30 % dans le groupe oméga‐3 contre 29 % dans le groupe oméga‐6 ; données probantes de faible niveau de confiance). Parmi trois essais comparant les oméga‐3 et les oméga‐6, il pourrait n’y avoir que peu ou pas de différence dans le changement de la progression du handicap, mesurée par le changement moyen de l'échelle EDSS (Expanded Disability Status Scale) (différence moyenne (DM) 0,00, IC à 95 % ‐0,30 à 0,30 ; 3 études, 166 participants ; données probantes de faible niveau de confiance). Dans un essai comparant les oméga‐3 et les oméga‐6, il n'existait probablement pas de différence dans l'impression globale de détérioration (RR 0,99, IC à 95 % 0,51 à 1,91 ; 1 étude, 86 participants ; 29 % dans le groupe oméga‐3 contre 29 % dans le groupe oméga‐6 ; données probantes de niveau de confiance modéré). Dans un essai comparant les oméga‐3 et les oméga‐6 (86 participants), il n'existait probablement pas de différence dans le nombre de nouvelles lésions renforcées par le gadolinium en pondération T1, sur la base de données probantes de niveau de confiance modéré. Dans quatre essais comparant les oméga‐3 et les oméga‐6, il pourrait n’y avoir que peu ou pas de différence dans les effets indésirables graves (RR 1,12, IC à 95 % 0,38 à 3,31 ; 4 études, 230 participants ; 6 % dans le groupe oméga‐3 contre 5 % dans le groupe oméga‐6 ; données probantes de faible niveau de confiance).
Dans quatre essais évaluant la supplémentation en antioxydants par rapport à un placebo, il pourrait n’y avoir que peu ou pas de différence dans les rechutes (RR 0,98, IC à 95 % 0,59 à 1,64 ; 4 études, 345 participants ; 17 % dans le groupe antioxydant contre 17 % dans le groupe placebo ; données probantes de faible niveau de confiance). Dans six essais évaluant la supplémentation en antioxydants par rapport à un placebo, les données probantes concernant le changement dans la progression de l'invalidité, mesurée comme le changement moyen de l'EDSS (DM ‐0,19, IC à 95 % ‐0,49 à 0,11 ; 6 études, 490 participants ; données probantes de très faible niveau de confiance) étaient très incertaines. Dans deux essais évaluant la supplémentation en antioxydants par rapport à un placebo, il pourrait n’y avoir que peu ou pas de différence dans l'impression globale de détérioration (RR 0,99, IC à 95% 0,50 à 1,93 ; 2 études, 190 participants ; 15% dans le groupe antioxydant contre 15% dans le groupe placebo ; données probantes de faible niveau de confiance). Dans deux essais évaluant la supplémentation en antioxydants par rapport à un placebo, les preuves étaient très incertaines concernant la différence dans les lésions réhaussées par le gadolinium (RR 0,67, IC à 95 % 0,09 à 4,88 ; 2 études, 131 participants ; 11 % dans le groupe antioxydant contre 16 % dans le groupe placebo ; données probantes de très faible niveau de confiance). Dans trois essais évaluant la supplémentation en antioxydants par rapport à un placebo, il pourrait n’y avoir que peu ou pas de différence dans les effets indésirables graves (RR 0.72, IC à 95 % 0,17 à 3,08 ; 3 études, 222 participants ; 3 % dans le groupe antioxydants contre 4 % dans le groupe placebo ; données probantes de faible niveau de confiance).
Conclusions des auteurs
Il existe toute une série d'essais contrôlés portant sur les effets des interventions diététiques dans la sclérose en plaques, avec des variations substantielles dans le traitement actif, le comparateur et les critères de jugement d'intérêt. L'administration d'acides gras polyinsaturés pourrait ne pas différer des autres solutions en ce qui concerne le taux de rechute, l'aggravation du handicap ou l'état clinique général des personnes atteintes de sclérose en plaques, mais les données probantes sont incertaines. De même, à l'heure actuelle, il n'existe pas suffisamment de données probantes pour déterminer si la supplémentation en antioxydants ou d'autres interventions diététiques ont un impact sur les résultats de sclérose en plaques.
PICO
Résumé simplifié
Interventions alimentaires pour les résultats liés à la sclérose en plaques
Problématique de la revue
Nous avons évalué les effets de toute intervention alimentaire pour la sclérose en plaques (SEP) (à l'exception de la vitamine D, qui fait l'objet d'une revue Cochrane séparée). Nous avons utilisé les données d'essais contrôlés randomisés, un type d'étude dans laquelle les personnes sont réparties au hasard pour recevoir l'une des interventions cliniques.
Contexte
La sclérose en plaques est une maladie qui se caractérise par une détérioration des fibres de connexion (substance blanche) dans le cerveau et la moelle épinière. Cela peut entraîner divers symptômes neurologiques, notamment des faiblesses, une perte de vision, une altération sensorielle, une incoordination et des problèmes intestinaux et vésicaux. La cause est inconnue, mais la principale théorie est que le système immunitaire de l'organisme joue un rôle dans la maladie. Les traitements approuvés pour la SEP agissent en régulant le système immunitaire. On s'intéresse à la question de savoir si des interventions diététiques, telles que des régimes spécifiques ou des compléments alimentaires, peuvent influer sur la SEP.
Caractéristiques des études
Notre recherche documentaire nous a permis d’identifier 41 rapports en texte intégral de 30 essais, étudiant une variété d'interventions diététiques. Onze essais ont examiné les acides gras polyinsaturés (AGPI), dix ont examiné une variété de compléments antioxydants, trois ont examiné des programmes diététiques et six essais ont examiné d'autres suppléments diététiques.
Principaux résultats et niveau de confiance des données probantes
Parmi les essais cliniques comparant les AGPI aux acides gras monoinsaturés (AGMI), il pourrait n’y avoir que peu ou pas de différence dans les poussées de SEP ou dans l'impression globale de détérioration. L’unique essai comparant les AGPI aux AGMI n'a rapporté aucun événement indésirable grave. Parmi les essais comparant un type d'AGPI à un autre, il pourrait n’y avoir que peu ou pas de différence dans les rechutes de SEP ou dans la progression du handicap. Il n'y avait probablement pas de différence dans l'impression globale de détérioration ou d'aggravation des lésions de SEP selon le type d'AGPI. Il pourrait n’y avoir que peu ou pas de différence dans les événements indésirables graves selon le type d'AGPI. Parmi les études examinant la supplémentation en antioxydants, il pourrait n’y avoir que peu ou pas de différence dans les poussées de SEP ou dans l'impression globale de détérioration. Il existait très peu de données probantes concernant l’effet des antioxydants par rapport au placebo sur l'aggravation du handicap et l'augmentation des lésions de SEP. Il pourrait n’y avoir que peu ou pas de différence dans les effets indésirables graves entre les antioxydants et le placebo. Autrement, les études sur les programmes diététiques et les autres supplément diététiques étaient trop différentes pour être regroupées pour l’analyse. De nombreux essais présentaient des problèmes de conception ou de mise en œuvre pouvant avoir affecter notre confiance dans les résultats. À l'heure actuelle, il n'existe pas suffisamment de données probantes solides permettant de déterminer si les interventions diététiques modifient l'évolution de la SEP.
Les données probantes sont à jour jusqu'en mai 2019.
Authors' conclusions
Summary of findings
| PUFA compared to MUFA for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with MUFA | Risk with PUFA | |||||
| Relapse | Adults with MS: | RR 1.02 | 217 | ⊕⊝⊝⊝ | There may be little to no benefit of PUFA versus MUFA on relapses, although evidence is very uncertain. | |
| 74 per 100 | 75 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Millar 1973 reported no difference in change in EDSS between PUFA and MUFA over two years. Weinstock‐Guttman 2005 reported increase (worsening) in EDSS with MUFA (mean increase 0.35) compared to a decrease (improvement) in EDSS with PUFA (mean decrease 0.07) over one year. | ‐ | 102 | ⊕⊝⊝⊝ | ||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with MS: | RR 0.85 | 542 | ⊕⊕⊝⊝ | There may be little to no benefit of PUFA versus MUFA on global impression of deterioration. | |
| 47 per 100 | 40 per 100 | |||||
| MRI activity ‐ not measured | ‐ | ‐ | ‐ | ‐ | ‐ | |
| SAEs (assessed as number of participants experiencing a SAE) | Pantzaris 2013 reported no adverse events in any of 4 groups, including among 20 participants receiving PUFA and 20 participants receiving MUFA | ‐ | 40 | ⊕⊕⊝⊝ | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded three levels for very serious risk of bias (including high risk of attrition bias in 2 studies and uncertain risk of attrition bias in 1 study) and serious imprecision (small sample size in all studies). | ||||||
| Omega‐3 compared to omega‐6 for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with omega‐6 | Risk with omega‐3 | |||||
| Relapse | Adults with RRMS exposed to DMT (interferon beta or fingolimod): | RR 1.02 | 129 | ⊕⊕⊝⊝ | There may be little to no benefit of omega‐3 versus omega‐6 on relapses. | |
| 29 per 100 | 30 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Adults with RRMS exposed to DMT (interferon beta or fingolimod): | ‐ | 166 | ⊕⊕⊝⊝ | There may be little to no benefit of omega‐3 versus omega‐6 on disability worsening. | |
| Mean EDSS 2.1 | MD 0.00 | |||||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with RRMS exposed to DMT (interferon beta): | RR 0.99 | 86 | ⊕⊕⊕⊝ | Omega‐3 is unlikely to change the global impression of deterioration. | |
| 29 per 100 | 29 per 100 | |||||
| MRI activity | Torkildsen 2012: There was no difference in the number of new T1‐ weighted gadolinium‐enhancing lesions between the omega‐3 and omega‐6 groups at 24 months (P = 0.17). | ‐ | 86 | ⊕⊕⊕⊝ | ||
| SAEs (assessed as number of participants experiencing a SAE) Follow‐up: 3 to 24 months | Adults with MS: | RR 1.12 | 230 | ⊕⊕⊝⊝ | There may be little to no difference between omega‐3 and omega‐6 on serious adverse events. | |
| 5 per 100 | 6 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels for serious risk of bias (including uncertain risk of attrition bias in 2 studies) and serious imprecision (small sample size in both studies). | ||||||
| Antioxidant compared to placebo for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with antioxidant | |||||
| Relapse | Adults with MS: | RR 0.98 | 345 | ⊕⊕⊝⊝ | There may be little to no benefit of antioxidant versus placebo on relapses. | |
| 17 per 100 | 17 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Adults with MS: | ‐ | 490 | ⊕⊝⊝⊝ | There may be little to no benefit of antioxidant versus placebo on progression, although evidence is very uncertain. | |
| Mean EDSS 3.0b | MD 0.19 lower | |||||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with RRMS exposed to DMT (interferon beta): | RR 0.99 | 190 | ⊕⊕⊝⊝ | There may be little to no benefit of antioxidant versus control on global impression deterioration. | |
| 15 per 100 | 15 per 100 | |||||
| MRI activity Follow‐up: 3 to 12 months | Adults with RRMS: | RR 0.67 | 131 | ⊕⊝⊝⊝ | There may be little to no benefit of antioxidant versus control on gadolinium‐enhancing lesions, although evidence is very uncertain. | |
| 16 per 100 | 11 per 100 | |||||
| SAEs (assessed as number of participants experiencing a SAE) Follow‐up: 2 weeks to 1 year | Adults with MS: | RR 0.72 | 222 | ⊕⊕⊝⊝ | There may be little to no difference in serious adverse events between antioxidant and placebo. | |
| 4 per 100 | 3 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels for serious risk of bias (including high risk of attrition bias in 1 study and uncertain risk of attrition bias in 2 studies) and serious imprecision (small sample size in all studies). | ||||||
Background
In this update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012), we assess a broad range of dietary interventions in multiple sclerosis (MS), with the exclusion of vitamin D which is the subject of another Cochrane Review (Jagannath 2018). As conventional therapies are only partially effective, people with MS widely use complementary and alternative medicine (CAM) with dietary interventions among the most popular form of CAM (Pucci 2004; Leong 2009).
Description of the condition
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (Noseworthy 2000). The estimated worldwide prevalence of MS is greater than 2 million, with twice as many females affected as males (Atlas of MS 2013). The prevalence of MS varies by continent, with Europe and North America having the highest prevalence, at more than 100 per 100,000 individuals (Atlas of MS 2013).
Although MS aetiology and pathogenesis remain poorly understood, it is widely accepted that the disease has an immune‐mediated basis (even if the target antigen remains undetermined), and occurs in genetically susceptible individuals (Kamm 2014). Inflammation is believed to result in relapses and focal lesions while neurodegeneration is believed to be responsible for disability progression and brain atrophy (Ziemssen 2016). MS lesions consist largely of T lymphocytes and macrophages with B lymphocytes shown to activate proinflammatory T lymphocytes (Bar‐Or 2010; Lucchinetti 2005).
Approximately 85% of people with MS initially experience relapsing remitting symptoms, while approximately 15% experience gradual progression from symptom onset (Kamm 2014; Noseworthy 2000). Diagnosis of MS is defined by criteria for relapsing remitting MS (RRMS) and primary progressive MS (PPMS) (Lublin 1996; Poser 1983; Schumacher 1965; Thompson 2018). Ongoing description of MS includes assessment of the disease modifiers of activity (relapses or new inflammatory lesions on imaging) and progression (gradual accumulation of disability) (Lublin 2014).
Despite advances in treatments, there is still no cure. MS management is also largely directed at relieving symptoms, which arise variably in the course of the disease. There are a number of disease‐modifying therapies used in the treatment of relapsing forms of MS, including glatiramer acetate, interferon beta, teriflunomide, dimethyl fumarate, fingolimod, natalizumab, alemtuzumab, ocrelizumab, and cladribine (Giovannoni 2018; Hauser 2017; Torkildsen 2016). While disease‐modifying therapies have been shown to reduce inflammatory relapses compared to placebo or an active comparator in randomized controlled trials (RCTs), the long‐term effect on disability progression is less clear, as conclusions are drawn from observational studies (Trojano 2011). In a cohort study, where the majority of individuals with RRMS were treated with glatiramer acetate, or interferon beta, or both, conversion from relapsing remitting to secondary progressive MS (SPMS) was substantially lower than earlier studies conducted before the availability of effective disease‐modifying therapy, at approximately 15 years after disease onset (Cree 2016). There are few disease‐modifying therapies for progressive MS, although ocrelizumab recently demonstrated modest reduction in disability progression in PPMS (Montalban 2017).
Description of the intervention
We assess a broad range of dietary interventions, with the exception of vitamin D, which is the subject of the Cochrane Review 'Vitamin D for the management of multiple sclerosis' (Jagannath 2018). In particular, eligible interventions include dietary programmes with recommendations for specific whole foods, macronutrients (i.e. fats), and supplementation with natural health products (i.e. vitamins, minerals). All interventions could be administered with or without exercise, behavioural support, or other lifestyle interventions.
How the intervention might work
Dietary programmes with recommendations for specific whole foods
We were interested in standardized dietary programmes that have been evaluated in MS. An association between MS and consumption of saturated fats has been reported (Esposito 2018). In addition, vascular risk factors, including hypertension and dyslipidaemia have been associated with disability progression among individuals with MS (Marrie 2010). A diet low in fat may help reduce vascular risk factors. The McDougall and Swank diets are low‐fat diets that have very low consumption of saturated fats (Swank 2003a; Yadav 2016). Swank proposed that saturated fats obstruct capillaries, leading to MS (Swank 2003b). The Mediterranean diet is low in saturated fat, with the main fat source being olive oil (Altowaijri 2017). Olive oil contains phenols, which scavenge free radicals, and may be neuroprotective. The Mediterranean diet is associated with reduced risk of vascular complications (Estruch 2013). The Paleolithic (Paleo) diet promotes consumption of food available to Paleolithic ancestors, including leafy vegetables and lean meats (Altowaijri 2017).
Macronutrients
Polyunsaturated fatty acids (PUFAs) include omega‐6 fatty acids (e.g. linoleic acid) and omega‐3 fatty acids (e.g. alpha‐linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid) (Mehta 2009). In a large prospective study, increased consumption of PUFAs has been associated with reduced risk of MS (Bjornevik 2017). PUFAs may have anti‐inflammatory or immunomodulatory effects (Mehta 2009).
Natural health products
Biotin (vitamin H) is a cofactor in carboxylation reactions that may enhance fatty acid synthesis and support myelin repair (Tourbah 2016). High dose biotin (300 mg per day) may reduce disability progression among individuals with progressive forms of MS.
Cobalamin (vitamin B12) deficiency may result in decreased non‐genomic methylation, including myelin basic protein and membrane phospholipids, possibly contributing to demyelination (Reynolds 2006). Meta‐analysis did not reveal a significant difference in vitamin B12 levels between individuals with MS and controls, although there was higher homocysteine in the blood of individuals with MS compared to controls (Dardiotis 2017). Homocysteine is converted to methionine by methionine synthase which requires vitamin B12 as a cofactor, thus vitamin B12 deficiency results in hyperhomocysteinemia (Dardiotis 2017).
Oxidative stress is proposed to contribute to MS (Adamczyk 2016). Antioxidants neutralize free radicals and prevent oxidation reactions. Antioxidants include beta‐carotene (vitamin A precursor), ascorbic acid (vitamin C), alpha‐tocopherol (vitamin E), selenium, as well as, polyphenols including curcumin found in tumeric and quercetin found in ginkgo biloba (Adamczyk 2016; Esposito 2018).
Why it is important to do this review
Complementary and alternative medicine (CAM) is an area of intense interest for the MS community (Claflin 2018). Among surveyed individuals with MS, use of a CAM therapy ranges from 37% to 100% (Claflin 2018). As the term suggests, CAM is beyond the scope of conventional medicine and includes a range of practices. Dietary interventions are among the most popular form of CAM (Leong 2009; Pucci 2004), with MS patients more likely than other populations to adopt a dietary intervention (O'Connor 2012). The decision to initiate a dietary intervention is due to a broad range of MS symptoms, along with a desire to improve overall well‐being (Leong 2009). To date, there are limited evidence‐based recommendations regarding dietary interventions for MS (Yadav 2014).
Objectives
To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS‐related outcomes and serious adverse events) in people with MS.
Methods
Criteria for considering studies for this review
Types of studies
We considered randomized controlled trials (RCTs) and controlled clinical trials (CCTs) examining the effects of a dietary intervention for MS versus placebo or another intervention (head‐to‐head comparison study design). We considered cluster‐randomized and cross‐over trial designs. For cross‐over trials, to avoid a unit of analysis error, we planned to only include the first period of randomization to intervention or control. We excluded studies with historical controls, ecological studies and uncontrolled pre‐post evaluations (studies that used pretreatment data as the comparison for treatment effect, without randomizing patient allocation), as these provide unreliable data for determining associations.
Types of participants
We included adult individuals with diagnosis of MS, defined by established criteria (Lublin 1996; Poser 1983; Schumacher 1965; Thompson 2018). We included individuals regardless of age, sex, duration of MS, degree of disability, course of the disease and current/prior MS therapy.
Types of interventions
We considered any dietary intervention including dietary plans, specific foods, macronutrients, or natural health products compared to placebo or another intervention. We did not consider vitamin D, as this is examined in another Cochrane Review (Jagannath 2018). We considered trials reporting dietary interventions along with pharmaceutical interventions only if the pharmaceutical intervention was administered to both arms. There was no minimum duration of intervention, although we excluded single doses of an intervention as a single dose was not representative of a dietary intervention. There was no minimum follow‐up interval.
Types of outcome measures
Primary outcomes
Primary outcomes were assessed at the last reported follow‐up.
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Relapse among individuals with MS, within the follow‐up period. Relapse is typically defined as a clinical episode with symptoms and signs typical of MS, with a duration of at least 24 hours, with or without recovery, in the absence of fever or infection (Thompson 2018).
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Change in any validated disability scale, among individuals with MS, over the study period including:
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Expanded Disability Status Scale (EDSS) (Kurtzke 1983); and
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Multiple Sclerosis Functional Composite (MSFC) (Cohen 2012).
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EDSS ranges from 0 (no neurologic abnormality) to 10 (death due to MS). Disability progression is typically defined as an increase of ≥ 1 point in EDSS if baseline score < 5.5 and of ≥ 0.5 points in EDSS if baseline score ≥ 5.5. The EDSS is the most widely accepted measure of MS disability progression (Cohen 2012).
Secondary outcomes
Secondary outcomes were assessed at the last reported follow‐up.
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Number of individuals with MS improved or deteriorated, as determined by a patient or investigator global impression of change, or other applied measure of global assessment. Global impression of deterioration was defined as investigator reported worsening or progression. This included the number of participants experiencing progression according to the study definition of a significant deterioration in EDSS.
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Magnetic resonance imaging (MRI) activity, i.e. new T2‐hyperintense lesions or gadolinium‐enhancing lesions in people with MS during the study period.
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Cognitive function characterized by any validated instrument, i.e.
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Brief Repeatable Battery of Neuropsychological Tests (BRB‐N) (Boringa 2001); and
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Paced Auditory Serial Addition Test (PASAT) (Tombaugh 2006).
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Participant‐reported outcomes
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Health‐related quality of life, characterized by any validated instrument, i.e.
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36‐Item Short Form Health Survey (SF‐36) (Brazier 1992); and
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Multiple Sclerosis Quality of Life‐54 (MSQoL‐54) (Vickrey 1995).
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Fatigue, characterized by any validated instrument, i.e.
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Modified Fatigue Impact Scale (MFIS) (Fisk 1994); and
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Fatigue Severity Scale (FSS) (Krupp 1989).
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Safety
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Number experiencing ≥ one severe adverse event(s) within the follow‐up period. Severe events were defined as:
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fatal
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life‐threatening
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require or prolong hospitalization or
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cause discontinuation of treatment.
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We examined severe events to determine whether there were any significant safety issues associated with dietary interventions or whether adverse events caused discontinuation of the intervention.
Search methods for identification of studies
To improve the comprehensiveness of our search, we worked with a health sciences librarian and revised the search strategy from the previous version of this review. We did not restrict our search by language or publication status. References were imported into Covidence (Covidence).
Electronic searches
On 30 May 2019, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 4) in the Cochrane Library), MEDLINE (1966 to May 2019), Embase (1980 to May 2019), and the Web of Science (1945 to May 2019). We also searched trial registries, including ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) portal for ongoing trials. We searched the Networked Digital Library of Theses and Dissertations (NDLTD) for any relevant trial not published in peer reviewed literature.
Detailed strategies are in the appendices: CENTRAL Appendix 1; MEDLINE Appendix 2; Embase Appendix 3; Web of Science Appendix 4; ClinicalTrials.gov and ICTRP Appendix 5.
Searching other resources
We checked all references in the identified trials and contacted trial authors to identify any additional published or unpublished data.
Data collection and analysis
We allocated studies to one of the following categories based on the intervention: polyunsaturated fatty acid (PUFA) supplementation, antioxidant supplementation, dietary programme, other dietary supplementation.
Selection of studies
Two review authors (NEP, RM, LV) first independently assessed the title and abstract of all studies identified by the searches to determine whether a study satisfied the eligibility criteria for the review. Then, two review authors (NEP, RM, LV, CJT) assessed the full text of all studies selected through this process and made a final decision regarding inclusion of the study. Any disagreement on the eligibility of included studies was managed through discussion and consensus. References were assessed in Covidence (Covidence).
Data extraction and management
Two review authors (NEP, CJT) independently extracted data for studies to be included in the review. The data were extracted using a predefined data extraction form created as a Microsoft Excel spreadsheet and entered into Review Manager (Review Manager 2014); both review authors re‐checked all entries and resolved all disagreements by discussion.
Our standardized data collection form contained the following.
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Study identification information
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Study characteristics, including trial design, inclusion/exclusion criteria, and length of follow‐up
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Participant characteristics, including age, sex, MS subtype, prior/current disease‐modifying therapy, and participants lost to follow‐up
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Intervention characteristics, including type, dose, duration, concomitant treatment, and comparator intervention
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Primary and secondary outcome measures
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'Risk of bias' assessment according to the Cochrane 'Risk of bias' tool for randomized trials (Higgins 2011)
For unreported study data regarding population, intervention, comparator, and outcomes, we attempted to contact the principal investigators of all studies that fulfilled selection criteria to obtain additional trial details.
Assessment of risk of bias in included studies
Two review authors (NEP, CJT, LV) independently evaluated each included study for risk of bias (RoB) using the 'Risk of bias' tool in the Cochrane Handbook for Systemic Reviews of Interventions (Higgins 2011).
We assessed the following domains as 'low risk', 'unclear risk' or 'high risk'.
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Random sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants and personnel (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective reporting (reporting bias)
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Other sources of bias (other bias)
Any disagreement was resolved by discussion among review authors.
Measures of treatment effect
We evaluated each dietary intervention separately. For continuous variables we extracted the number of participants, mean values, and standard deviations (SDs) for the experimental and control groups at baseline and at the end of follow‐up. If studies reported the same continuous outcomes (i.e. EDSS, SF‐36), we calculated the mean differences (MDs) with 95% confidence intervals (CIs). If outcome data were different but measured the same or similar constructs (i.e. cognition or overall quality of life), we calculated standardized mean differences (SMDs) with corresponding 95% CIs. For dichotomous variables, we extracted the number of participants with the outcome of interest and the total number of participants in each group. This was used to calculate a risk ratio (RR) with 95% CIs.
Unit of analysis issues
We did not encounter significant unit of analysis issues. If a study reported different doses of an intervention, we considered the highest dose in the analysis. If there were repeated measurements of outcomes over time, we considered the final measure as the one most relevant to the long‐term course of the participant. In cross‐over trials, we included only the first randomized arm.
Dealing with missing data
Missing data may be due to missing studies, outcomes, and individuals. In the event of missing data, we contacted the principal investigator of the trial with a request for data.
Assessment of heterogeneity
Heterogeneity among interventions was minimized by analysing each intervention separately. We evaluated heterogeneity of the effect of the intervention between trials using the Chi2 test with a significance level at P < 0.1. We also used the I2 statistic to quantify possible heterogeneity with I2 > 50% indicating substantial heterogeneity (Deeks 2017). If possible heterogeneity was detected, we planned to perform subgroup analysis to assess the reasons for heterogeneity.
Assessment of reporting biases
To ensure optimal completeness of identification of published trials, we searched multiple trial databases and reviewed references for relevant articles. To assess reporting bias, we searched trial registries for completed and unreported trials of dietary interventions for MS. In the event of unreported trials, the review authors planned to request results from the trial principal investigator. We used funnel plots to assess for small study bias (Egger 1997). We used caution in the interpretation of funnel plots where there were a small number of trials.
Data synthesis
We performed analysis separately for each intervention. We conducted meta‐analysis using a random‐effects model due to anticipated heterogeneity both within and between studies. Meta‐analysis for continuous outcomes analysed differences in means. Meta‐analysis for dichotomous outcomes analysed RR. We performed all analysis using Cochrane's Review Manager 5 software (Review Manager 2014).
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analysis on participants with diagnosis of relapsing versus progressive subtypes of MS, anticipating that individuals with progressive MS will have greater disability; sex (male versus female), anticipating that men experience greater disability; age (< 55 years versus ≥ 55 years), anticipating that older individuals experience greater disability; dietary recommendations, provided with or without ongoing support in following the intervention, assuming that those who do not have ongoing support are less likely to follow dietary recommendations; and compliance with the dietary intervention, if this information was available. However, lack of data did not permit subgroup analysis.
Sensitivity analysis
We performed a sensitivity analysis to verify the presence of bias due to unequal distribution of losses to follow‐up. We used the total number of randomized participants as the denominator and assumed that all missing participants (lost to follow‐up) experienced the outcome event for dichotomous primary outcomes.
Summary of findings and assessment of the certainty of the evidence
We created 'Summary of findings' tables to summarize the effects of interventions for key outcomes, including relapses, progression, global impression of deterioration, MRI outcomes, and serious adverse events. We rated the evidence for each outcome according to the GRADE approach as high, moderate, low or very low certainty and provided the rationale for these decisions. We downgraded evidence for risk of bias, imprecision, indirectness, unexplained heterogeneity, or publication bias. We upgraded evidence for a large magnitude of effect, if all plausible confounding tended to underestimate an apparent intervention effect, and a dose‐response gradient (Atkins 2004). 'Summary of findings' tables were created using GRADEpro GDT (GRADEpro GDT).
Results
Description of studies
A summary of trial design, participants, interventions, and outcomes of the studies meeting the inclusion criteria are summarized in the 'Characteristics of included studies' tables.
Results of the search
Our search strategy identified 2096 unique references. We found 1070 in MEDLINE, 532 in Embase, 406 in CENTRAL, and 766 in Web of Science, with 2086 unique references. We found nine additional references in ClinicalTrials.gov with three of these references also found in the World Health Organization International Clinical Trials Registry Platform (ICTRP). We identified one additional reference from a review of the literature. We screened the titles and abstracts of all identified references, with 140 papers identified for full‐text review. Finally, we included 30 trials, comprising a total of 41 related full‐text articles.
We recorded the study selection process using a PRISMA flow diagram (Figure 1).
PRISMA Diagram
Included studies
Detailed descriptions of the study design, participant characteristics, and types of interventions used are provided in the Characteristics of included studies table.
Polyunsaturated fatty acid (PUFA) supplementation
We found 11 RCTs on PUFA supplementation (Bates 1977; Bates 1978; Bates 1989; Millar 1973; Pantzaris 2013; Paty 1978; Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012; Weinstock‐Guttman 2005; Zandi‐Esfahan 2017), described below.
Bates 1977 was a parallel group, randomized double‐blind trial of 152 participants with chronic progressive multiple sclerosis (MS) in the United Kingdom. Groups A (linolenic acid and linoleic acid) and C (linoleic acid) received the active treatment (polyunsaturated fatty acid; PUFA) while Groups B and D acted as controls, both receiving oleic acid (monounsaturated fatty acid; MUFA) supplementation. There was no difference in the relapse rate, although additional trial data were not available. After two years of treatment, 24/69 (34.8%) participants receiving PUFA deteriorated and 21/65 (32.3%) receiving MUFA deteriorated. This excluded 18 participants who either died or withdrew during the study, as this information was reported in aggregate form. Funding for this study was obtained from the Multiple Sclerosis Society of Great Britain and Northern Ireland.
Bates 1978 was a parallel group, randomized double‐blind trial of 116 participants with relapsing remitting (RRMS) MS in the United Kingdom. Groups A (linolenic acid and linoleic acid) and C (linoleic acid) received the active treatment (PUFA) while Groups B and D acted as controls, both receiving oleic acid (MUFA). After two years of treatment, 51/58 (87.9%) participants receiving PUFA experienced a relapse and 46/57 (80.7%) receiving MUFA experienced a relapse. Authors reported that at two years, there were significantly more patients in Group A than Group B who had deteriorated according to EDSS, although additional data were not available. Funding for this study was obtained from the Multiple Sclerosis Society of Great Britain and Northern Ireland.
Bates 1989 was a parallel group, randomized double‐blind trial of 312 participants with RRMS in the United Kingdom. The treatment group (PUFA) received fish oil capsules containing eicosapentaenoic acid and docosahexaenoic acid. The control group (MUFA) received capsules containing oleic acid. There was no significant difference in relapse rate although additional data were not available. After two years of treatment, 67/146 (45.9%) participants receiving PUFA and 82/147 (55.8%) receiving MUFA deteriorated, according to EDSS. Funding was obtained from the Multiple Sclerosis Society of Great Britain and Northern Ireland and Action MS ‐ Northern Ireland. The Marfleet Refining Company provided fish oil and control group capsules.
Millar 1973 was a parallel group, randomized double‐blind trial of 87 participants with "inactive MS" in the United Kingdom. The treatment group (PUFA) received sunflower seed emulsion containing linoleic acid. The control group (MUFA) received an emulsion containing primarily oleic acid. After two years of treatment, 25/36 (69.4%) participants receiving PUFA and 30/39 (76.9%) receiving MUFA experienced a relapse. After two years of treatment, EDSS in the treatment group was 3.1 and in the control group was 3.3, with no standard deviation (SD) available. After 2 years of treatment, 13/36 (36.1%) participants receiving PUFA and 18/39 (46.2%) receiving MUFA deteriorated. Funding was obtained from the Multiple Sclerosis Society.
Pantzaris 2013 was a parallel group, randomized double‐blind trial of 80 participants with RRMS in Cyprus. There were four groups: Group A (PUFA, vitamin A, low‐dose vitamin E), Group B (PUFA, vitamin A, high‐dose vitamin E), and Group C (high dose vitamin E), while Group D (olive oil largely composed of oleic acid) was a placebo intervention. There was a significant reduction in annualized relapse rate (ARR) comparing Group B to placebo with ARR 0.40 in Group B and 1.04 in Group D (P < 0.05) after two years of treatment. Group A had ARR 0.85, which was not significantly different from the placebo group. In the intention‐to‐treat analysis at 30 months, disability progression (defined as an increase in EDSS ≥ 1 confirmed at 6 months) occurred among six participants in Group A and seven participants in Group D. No significant adverse events were experienced in any group. Funding was obtained from the Cyprus Ministry of Commerce, Industry and Tourism.
Paty 1978 was a parallel group, randomized double‐blind trial of 96 participants with MS in Ontario, Canada. The treatment group (PUFA) received sunflower seed emulsion containing linoleic acid. The control group (MUFA) received olive emulsion containing primarily oleic acid. After 30 months of treatment, there was no difference in relapse number or severity between groups, although the number of individuals experiencing a relapse in either group was not reported. At 30 months, there was no difference in EDSS between groups, although EDSS attributed to the intervention and control group was unclear and SD was not provided. Funding was obtained from the Multiple Sclerosis Society of Canada.
Ramirez‐Ramirez 2013 was a parallel group, randomized double‐blind trial of 50 participants with RRMS in Mexico taking interferon beta‐1b 250 mcg subcutaneously once every two days ≥ one year prior to study enrolment. The active treatment group (PUFA ‐ omega‐3) received fish oil capsules containing eicosapentaenoic acid and docosahexaenoic acid along with excipient. The control group received placebo capsules containing excipient (glycerin, water, tocopherol, sunflower oil, and titanium dioxide). Sunflower oil is largely composed of linoleic acid (PUFA ‐ omega‐6). There was no difference in relapse rate after one year of treatment between the intervention (0.84, SD 0.9) and control (1.00, SD 1) groups. There was no difference in mean EDSS after one year of treatment between intervention (mean 2.20, SD 1.0) and control (mean 2.20, SD 0.8) groups. Fish oil supplementation was well‐tolerated and no severe adverse events occurred after one year in either group according to the study definition of severe adverse event. There were two participants in the fish oil group and one participant in the control group that discontinued the intervention due to adverse events. There was no reported funding.
Shinto 2016 was a parallel group, randomized double‐blind trial of 39 participants with MS and major depressive disorder taking an antidepressant in the United States. The active treatment group (PUFA‐ omega‐3) received fish oil capsules containing eicosapentaenoic acid and docosahexaenoic acid. The control group received placebo capsules containing soybean oil, which is largely composed of linoleic acid (PUFA ‐ omega‐6). There was no significant difference in the primary outcome of ≥ 50% improvement in the Montgomery‐Asberg Depression Rating Scale (MADRS) at three months. There was no significant difference in change in quality of life between groups, measured using the SF‐36 reported as mean change and standard error of the mean. There were no serious adverse events over three months, according to the study definition of serious adverse event, which was not explicitly stated. There was one participant in the fish oil group and two participants in the soybean oil group who discontinued the intervention due to adverse events. Funding was obtained from National Institutes of Health/National Center for Complementary and Alternative Medicine and National Center for Advancing Translational Research.
Torkildsen 2012 was a parallel group, randomized double‐blind trial of 92 participants with RRMS in Norway. The active treatment group (PUFA ‐ omega‐3) received eicosapentaenoic acid and docosahexaenoic acid. The control group received placebo capsules containing corn oil, which is largely composed of linoleic acid (PUFA ‐ omega‐6). After the first six months, all participants also received interferon beta‐1a 44 mcg three times/week for a further 18 months. There was no significant difference in the primary outcome of new T1‐weighted gadolinium‐enhancing lesions over the initial six months between the active treatment and control groups. In addition, there was no difference in new T1‐weighted gadolinium‐enhancing lesions after 24 months of treatment. At 24 months, 57% of the remaining 45 participants in the omega‐3 group and 58% of the remaining 41 participants in the control group remained relapse free. At 24 months of treatment, there was no significant difference in mean EDSS between the omega‐3 (mean 2.22, SD 1.32) and control (mean 2.19, SD 1.34) groups. Disease progression, although not defined, was reported to have occurred among 13 out of 45 participants in the omega‐3 group and 12 out of 41 in the control group over 24 months. After 24 months of treatment, there was no difference in MSFC, FSS, or SF‐36 scores between the omega‐3 and control groups. There were three participants in the omega‐3 group (fecal incontinence, abortion, anaemia) and one participant in the control group (urinary tract infection/pain) who experienced a serious adverse event according to the study protocol definition of serious adverse event. In addition, one participant in the fish oil group and two participants in the control group discontinued therapy for adverse events. Funding was obtained from Western Norway Regional Health Authority, Norwegian Multiple Sclerosis Society, Pronova Biocare, Amersham Health, and Merck‐Serono.
Weinstock‐Guttman 2005 was a parallel group, randomized double‐blind trial of 31 participants with RRMS in the United States. The active treatment group (PUFA) received capsules containing eicosapentaenoic acid and docosahexaenoic acid. The control group (MUFA) received capsules containing olive oil, which is largely composed of oleic acid. The primary outcome of physical component scale of the SF‐36 was greater in the fish oil compared to the placebo group at six months, but was not significant at 12 months. Unpublished data were obtained indicating 3/13 (23.1%) participants in the PUFA group and 5/14 (35.7%) participants in the MUFA group experienced a relapse after 12 months of treatment. There was a weak trend noted in slight improvement in EDSS in the PUFA group and slight worsening in the MUFA group, although limited data were provided. Fatigue, measured using the MFIS, demonstrated lower fatigue levels in the placebo group at six months compared to the active treatment group, although there was no significant difference between groups at 12 months. Funding was obtained from the National Multiple Sclerosis Society and Mellen Center Foundation.
Zandi‐Esfahan 2017 was a parallel group, randomized double‐blind trial of 50 participants with RRMS receiving fingolimod in Iran. The active treatment group (PUFA ‐ omega‐3) received capsules containing eicosapentaenoic acid and docosahexaenoic acid along with excipient. The control group (PUFA ‐ omega‐6) received capsules containing only excipient (glycerin, water, tocopherol, sunflower oil, titanium dioxide). Sunflower oil contains linoleic acid. The primary outcome was cytokine levels at 12 months, which did not differ between groups. There was no difference in change of EDSS over 12 months of treatment between groups. Over 12 months of treatment, one participant in the active treatment group and one participant in the control group experienced a relapse after which they were removed from the study. Three participants were excluded for hypotension/bradycardia secondary to fingolimod, which was administered to both groups. Funding was obtained from the Vice‐Chancellor for Research and Technology of Isfahan University of Medical Sciences.
Antioxidant supplementation
We found 10 RCTs evaluating antioxidants with a focus on inosine (Gonsette 2010; Markowitz 2009; Munoz Garcia 2015), lipoic acid (Khalili 2012; Khalili 2014; Yadav 2005), vitamin A (Bitarafan 2015), cranberry (Gallien 2014), epigallocatechin‐3‐gallate (Mahler 2015), and coenzyme Q10 (Sanoobar 2015).
Three trials examined inosine. Gonsette 2010 was a parallel group, randomized double‐blind trial of 159 participants with RRMS receiving interferon beta in Europe. The active treatment (antioxidant) group received capsules containing inosine and the control group received placebo. After 24 months of treatment, there was no difference in the number of participants with neurological deterioration between the inosine (14/79) and control (14/78) groups. At 24 months, there was no difference in EDSS between the active treatment (mean 2.30, SD 1.3) and control (mean 2.10, SD 1.3) groups. In addition, there was no difference in MSFC score between groups. After 24 months of treatment, there was no difference in the annual relapse rate between groups, although the number of participants experiencing relapses could not be determined from reported data. Although adverse events were reported, serious adverse events were not defined. Funding was obtained from the Foundation Charcot Stichting, Brussels, Belgium. Markowitz 2009 was a randomized double‐blind, placebo‐controlled cross‐over trial of 16 participants with RRMS in the United States randomized to inosine or placebo for the first six months. EDSS over the initial six months improved on inosine (mean 1.90, SD 0.4) versus placebo (mean 3.10, SD 1.2) although the number of participants remaining in each group at six months was unclear. Also, there were fewer relapses and gadolinium‐enhancing lesions when serum uric acid > 7.0 mg/dL, although we were unable to determine events in the inosine versus placebo group over the initial six months. Four participants over the entire 12‐month study developed renal lithiasis, and three were removed from the study. Funding was obtained from Commonwealth of Pennsylvania Department of Health to Biotechnology Foundation Laboratories and National Institutes of Health. Munoz Garcia 2015 was a parallel group, randomized double‐blind trial of 36 participants with RRMS in Spain treated with interferon beta‐1a randomized to inosine or placebo for nine months. Relapses were experienced by 4/18 in the inosine group and 4/15 in the placebo group after nine months. No participant was felt to have experienced progression by clinical or radiological parameters after nine months of dietary intervention. There were no differences in MRI outcomes at 12 months, including new gadolinium‐enhancing lesions between inosine (mean difference [MD] 1.10, SD 6.1) and placebo (MD ‐1.60, SD 2.4) groups. Three participants withdrew due to adverse events over nine months of interferon beta‐1a plus inosine or interferon beta‐1a plus placebo including one from the inosine group (hyperthyroidism and appendicitis) versus two from the placebo group (1 arthralgias, 1 hypertransaminemia). There was no reported funding.
Three trials examined lipoic acid. Khalili 2012 was a parallel group, randomized double‐blind trial of 50 participants with RRMS in Iran randomized to lipoic acid or placebo for three months. At three months, there was no difference in EDSS between the lipoic acid (mean 1.70, SD 1.3) and placebo (mean 1.70, SD 1.4) groups. In addition, there was no difference in FSS between the lipoic acid (mean 38.40, SD 13.8) and placebo (mean 35.20, SD 10.3) groups. There was conflicting information concerning the number of individuals with new gadolinium‐enhancing lesions at three months. The text indicated one of 22 (4.5%) individuals in the lipoic acid group and four of 17 (23.5%) individuals in the placebo group experienced ≥ one new gadolinium‐enhancing plaque at three months. There was no reported funding. Khalili 2014 was a parallel group, randomized double‐blind trial of 52 participants with RRMS in Iran randomized to lipoic acid or placebo for three months. After three months of treatment, there was no difference in EDSS between the lipoic acid (mean 2.00, SD 0.3) and placebo (mean 1.70, SD 0.3) groups. Funding was obtained from the Vice‐Chancellor for Research of Tehran University of Medical Sciences. Yadav 2005 was a parallel group, randomized double‐blind trial of 37 participants with MS in the United States randomized to lipoic acid (3 different doses) or placebo. Although EDSS was examined at baseline and 14 days, EDSS at follow‐up was not reported. One participant in the lipoic acid 1200 mg twice daily group discontinued treatment due to development of a maculopapular rash associated with fever. Funding was obtained from the National Institutes of Health, Department of Veterans Affairs, Nancy Davis Center WIthout Walls, and Oregon Health & Science University General Clinic Research Centre. Capsules were provided by Pure Encapsulations.
Bitarafan 2015 was a parallel group, randomized double‐blind trial of 101 participants with RRMS in Iran randomized to retinyl palmitate or placebo. After one year of treatment, relapses occurred among 11/47 (23.4%) in the vitamin A group and 6/46 (13.0%) in the placebo group. There was no difference in change in EDSS over one year between the treatment and placebo groups. There was a significantly smaller deterioration in MSFC score over one year in the vitamin A group compared to the control group, which was primarily due to upper limb function and cognition. At one year, gadolinium‐enhancing lesions occurred among 9/46 (19.6%) participants in the treatment group and 6/46 (13.0%) in the placebo group. Funding was obtained from Tehran University of Medical Sciences.
Gallien 2014 was a parallel group, randomized double‐blind trial of 171 participants with MS in France randomized to cranberry extract containing proanthocyanidins or placebo. After one year of treatment, a relapse had occurred among 12/82 (14.6%) participants in the cranberry group and 19/89 (21.3%) in the placebo group. At one year, EDSS was reported to have remained stable, although no data were presented in the publication. Correspondence with the author revealed no significant difference in EDSS between the cranberry group (mean 5.62, SD 1.64) and control group (mean 5.41, SD 1.51) at 1 year. While it was reported that there were no serious adverse events, two participants in the cranberry group and one participant in the placebo group discontinued the intervention due to an adverse event, although these were not attributed to the intervention. Funding was obtained from the French Ministry of Health.
Mahler 2015 was a parallel group, randomized double‐blind, placebo‐controlled cross‐over trial of 20 participants with RRMS in Germany randomized to epigallocatechin‐3‐gallate or placebo for 12 weeks followed by a four‐week washout then the other intervention for 12 weeks. After 12 weeks, there was evidence of improved muscle metabolism among participants receiving EGCG compared to placebo in men to a greater extent than women. Although EDSS was reported at baseline and 12 weeks, the initial randomization group was not clear and values were presented separately for men and women. Funding was obtained from Deutsche Forschungsgemeinschaft.
Sanoobar 2015 was a parallel group, randomized double‐blind trial of 48 participants with RRMS in Iran randomized to coenzyme Q10 or placebo for 12 weeks. Over 12 weeks, two of 24 participants in the coenzyme Q10 group and one of 24 participants in the placebo group were excluded for a relapse. There was no significant difference in change of EDSS over 12 weeks of treatment between the coenzyme Q10 and placebo groups. After 12 weeks of treatment, there was significant improvement in fatigue, measured using the FSS, in the coenzyme Q10 compared to placebo group. Funding was obtained from the Vice‐Chancellor for Research of Tehran University of Medical Sciences.
Dietary programmes
Three RCTs focused on dietary programmes: Paleolithic (Paleo) diet (Irish 2017), Hot‐nature diet (Rezapour‐Firouzi 2013), and a low‐fat plant‐based diet (Yadav 2016).
Irish 2017 was a parallel group trial of 34 participants with RRMS in the United States allocated to the modified Paleo diet or usual diet for three months. Over three months, fatigue measured using the FSS, significantly decreased in the dietary intervention group compared to the control group. Three participants in the dietary intervention group compared to 0 participants in the control group experienced clinically significant improvement in fatigue (FSS > 2 point reduction). There were greater improvements in quality of life measures in the dietary intervention group than control group at three months, according to the Multiple Sclerosis Quality of Life‐54 (MSQoL‐54). All dietary intervention participants experienced an improvement in mental health‐related quality of life compared to three control group participants. In addition, seven dietary intervention participants compared to three control group participants experienced improvement in physical health‐related quality of life. The MSFC revealed no significant change between groups in the timed 25‐foot walk or PASAT although there was improvement in the 9‐Hole Peg Test, using the dominant hand, in the dietary intervention group compared to control group. One participant was withdrawn from the dietary intervention group and two participants from the control group for a flare‐up. No adverse events were reported. Funding was obtained from TZ press which is owned by an author of the study.
Rezapour‐Firouzi 2013 was a parallel group, randomized double‐blind trial of 100 participants with RRMS in Iran randomized to hemp seed oil/evening primrose oil plus Hot‐nature diet (group A), olive oil placebo (group B), or hemp seed oil/evening primrose oil (group C) for six months. EDSS significantly improved over six months in the hemp seed oil/evening primrose oil with and without Hot‐nature diet groups while significantly deteriorated in the placebo group. Over six months, three relapses were experienced in the placebo group, one relapse in the hemp seed oil/evening primrose oil group, and one relapse in the hempseed oil/evening primrose oil with Hot‐nature diet group, although the number of participants experiencing relapses was unclear in the placebo group. There were no serious adverse events, although the definition of a serious adverse event was not provided. Funding was obtained from Tabriz University of Medical Sciences.
Yadav 2016 was a parallel group, randomized single‐blind trial of 61 participants with RRMS in the United States randomized to very low fat, plant‐based diet compared to waiting list over 12 months. After 12 months, there was no difference between groups in MRI measures including new T2 lesions, gadolinium‐enhancing lesions, and brain volume. There was no difference in relapses between groups with seven participants in the diet group and eight participants in the control group experiencing one or more relapse(s). There was no difference between groups in change in EDSS or MSFC over 12 months. There were statistically significant improvements in fatigue in the diet compared to the control group, according to the FSS and MFIS. At 12 months, there was no difference in quality of life between groups, measured using the SF‐36. No severe adverse events were reported, although the definition of severe adverse event was not provided. Funding was obtained from the McDougall Research & Education Foundation which has a study author as president.
Other supplements
Six RCTs focused individually on other supplements including probiotics (Kouchaki 2017), creatine (Malin 2008), riboflavin (Naghashpour 2013), palmitoylethanolamide (Orefice 2016), carnitine (Tomassini 2004), and biotin (Tourbah 2016).
Kouchaki 2017 was a parallel group, randomized double‐blind trial of 60 participants with RRMS in Iran randomized to probiotic versus placebo for 12 weeks. Probiotic contained Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum. After 12 weeks of treatment, EDSS significantly improved in the probiotic group compared to placebo group. There were no relapses or adverse events recorded during the study. Funding was obtained from the Vice‐Chancellor for Research of Kashan University of Medical Sciences.
Malin 2008 was a parallel group, randomized double‐blind cross‐over trial of 12 participants with MS in the United States randomized to creatine monohydrate versus placebo for two weeks in phase 1. There was no significant difference in muscle work or power between the creatine and placebo groups, although data were not provided for phase 1. There was no difference in fatigue between the treatment and control phase, measured using the FSS, although data were not provided for phase 1. There were no adverse events. Funding was obtained from the Department of Health, Nutrition, and Exercise Sciences at the University of Delaware.
Naghashpour 2013 was a parallel group, randomized double‐blind trial of 54 participants with RRMS and secondary progressive MS (SPMS) in Iran randomized to riboflavin versus placebo for six months. After six months of treatment, EDSS decreased in both the riboflavin and placebo groups with no significant difference between groups. Funding was obtained from the Vice‐Chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences and the Academic Center for Education, Culture, and Research‐Khuzestan.
Orefice 2016 was a parallel group, randomized double‐blind trial of 29 participants with RRMS in Italy experiencing side effects from subcutaneous interferon beta‐1a randomized to palmitoylethanolamide versus placebo. While there was a reduction in pain in the active treatment group compared to the control group, measured using a visual analogue scale, there was no difference in injection‐related erythema width after 12 months. Quality of life, measured using the MSQOL‐54, improved in the palmitoylethanolamide versus placebo group at 12 months for two subscales (cognitive function, change in health). EDSS and PASAT remained relatively stable in both groups over 12 months. There were no treatment emergent adverse events. There was no reported funding.
Tomassini 2004 was a parallel group, randomized cross‐over trial of 36 participants with RRMS or SPMS in Italy randomized to acetyl L‐carnitine versus amantadine for three months in phase 1. Overall, there was a significant difference in reduction of fatigue in the acetyl L‐carnitine versus amantadine group, assessed using the FSS. Six participants withdrew from the study in phase 1 due to adverse events, including one participant in the acetyl L‐carnitine group due to insomnia, and five participants in the amantadine group due to nausea and dizziness. There was no reported funding.
Tourbah 2016 was a parallel group, randomized double‐blind trial of 154 participants with PPMS or SPMS in France randomized to biotin (MD1003) versus placebo for 12 months. There was a significant improvement in MS‐related disability, measured using the EDSS or timed 25‐foot walk, at nine months and confirmed at 12 months with improvement noted in 13 participants receiving biotin and 0 participants receiving placebo. After 12 months of treatment, EDSS significantly improved in the biotin group compared to the placebo group. There was no significant difference in change in timed 25‐foot walk between the biotin and placebo groups. Over 12 months, 5/103 (4.9%) in the biotin group and 4/51 (7.8%) in the placebo group experienced a relapse. In a subset receiving MRI, there was no significant difference in new demyelinating lesions on MRI between biotin and placebo group participants after 12 months of intervention. Clinician and subject global impression of change favoured the biotin versus placebo group at 12 months. At 12 months, there was no significant difference in fatigue between groups, measured using the MFIS. In addition, there was no consistent difference in quality of life between groups, measured using the SF‐36. Six participants in the MD1003 group and seven participants in the placebo group discontinued the intervention due to adverse events, including one participant described as having a serious adverse event (mucocutaneous rash) and one death due to suicide, both in the MD1003 group. Funding was obtained from MedDay Pharmaceuticals which are the manufacturers of MD1003.
Excluded studies
We excluded 45 studies following full‐text review and listed reasons for exclusion in the 'Characteristics of excluded studies' table. We excluded 19 studies as the study designs were not RCTs (Cendrowski 1982; Cignarella 2017; Dworkin 1981; Dworkin 1984; Field 1979; Harbige 2007; Lovera 2015; Mertin 1973; Meyer‐Rienecker 1976; Millar 1984; Moccia 2019; Saresella 2017; Schultz 1984; Simpson 1985; Skakonik 1963; Swank 1990; Toncev 2006; Tran 2018; van Rensburg 2006). We excluded nine RCTs as the intervention did not meet the inclusion criteria (Bisaga 2011; Bisaga 2012; Bitarafan 2013; Coe 2017; Kouchaki 2018; Lieben 2017; Loder 2002; Shinto 2008; Wade 2002). We excluded 17 RCTs of dietary interventions with no clinical MS‐related outcomes (Bittner 2016; Eghtesadi 2015; Fitzgerald 2017; Gasperini 2011; Holmoy 2013; Jafarirad 2012; Jafarirad 2013; Lambert 2003; Lopes De Carvalho 2012; Mauriz 2013; Mauriz 2014; Mohammadzadeh Honarvar 2013; Mohammadzadeh Honarvar 2016; Saboor‐Yaraghi 2015; Salari 2015; Spitsin 2010; Tamtaji 2017).
Studies awaiting classification
There are six studies awaiting classification (Bock 2015; Kanter 2014; Khalili 2017; Loy 2018; Shah 2007; Tourbah 2018). Studies examined beta‐alanine (Kanter 2014), biotin (Tourbah 2018), lipoic acid (Khalili 2017; Loy 2018), and dietary plans (Bock 2015; Shah 2007). In a single study, there was ambiguity concerning whether or not the study was randomized (Loy 2018). In a single study, there was limited information concerning co‐interventions (Khalili 2017). In four studies, limited results were available (Bock 2015; Kanter 2014; Shah 2007; Tourbah 2018). Further information is provided in the Characteristics of studies awaiting classification table.
Ongoing studies
There are 10 ongoing studies (see Ongoing studies table). Studies examine biotin (NCT02936037), curcumin (NCT01514370), caprylic triglyceride (NCT01848327), D‐aspartate (NCT03387046) and dietary plans (NCT01915433; NCT02664623; NCT02914964; NCT02986893; NCT03322982; NCT03508414). Dietary plans among individuals with MS include a single study of the Wahls Paleo plus (ketogenic) diet versus Wahls (modified Paleolithic) diet versus usual diet (NCT01915433), a single study of the Swank diet versus Wahls elimination diet (NCT02914964), and a single study of a low‐fat diet versus usual diet (NCT03322982) with all of these studies examining dietary plans having a primary outcome of fatigue. In a single study examining biotin versus placebo among individuals with progressive MS, the primary outcome is proportion of participants improved on either EDSS or TW25 at 15 months (NCT02936037).
Risk of bias in included studies
Risk of bias assessment is summarized in Figure 2 and Figure 3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Among trials comparing PUFA to MUFA, a single study described adequate random sequence generation and allocation concealment (Pantzaris 2013). No other studies comparing PUFA to MUFA described the process for random sequence generation and allocation concealment (Bates 1977; Bates 1978; Bates 1989; Millar 1973; Paty 1978; Weinstock‐Guttman 2005). Among trials comparing different PUFAs, three studies described adequate computer‐generated randomization (Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012). In a single study comparing omega‐3 to omega‐6, random sequence generation was not described (Zandi‐Esfahan 2017). Adequate allocation concealment was reported in three studies (Shinto 2016; Torkildsen 2012; Zandi‐Esfahan 2017). The allocation concealment process was unclear in a single study (Ramirez‐Ramirez 2013).
Among trials examining antioxidant supplementation, five studies described adequate computer‐generated randomization (Gallien 2014; Gonsette 2010; Khalili 2012; Mahler 2015; Yadav 2005). In five studies, the random sequence generation process was unclear (Bitarafan 2015; Khalili 2014; Markowitz 2009; Munoz Garcia 2015; Sanoobar 2015). Adequate allocation concealment was reported in five studies (Gallien 2014; Khalili 2012; Mahler 2015; Markowitz 2009; Yadav 2005), and was unclear in five studies (Bitarafan 2015; Gonsette 2010; Khalili 2014; Munoz Garcia 2015; Sanoobar 2015).
Among trials examining dietary programmes, a single study described adequate random sequence generation, although allocation was not concealed (Yadav 2016). A single study had an unclear process of random sequence generation and allocation concealment (Rezapour‐Firouzi 2013). Additionally, a single study had a high risk of selection bias for randomization by flipping a coin for the first five participants followed by group allocation based on Fatigue Severity Scale (FSS) score with lack of allocation concealment (Irish 2017).
Among trials examining other supplements, two studies reported adequate computer‐generated randomization (Kouchaki 2017; Tourbah 2016). In a single study, participants were randomized based on assay kit number which we judged at high risk for inadequate random sequence generation (Orefice 2016). In three studies, the random sequence generation process was unclear (Malin 2008; Naghashpour 2013; Tomassini 2004). Adequate allocation concealment was described for two studies (Naghashpour 2013; Tourbah 2016), while the other four studies had an unclear process for allocation concealment (Kouchaki 2017; Malin 2008; Orefice 2016; Tomassini 2004).
Blinding
Among trials comparing PUFA with MUFA, three studies described adequate blinding of participants and personnel (Bates 1989; Millar 1973; Pantzaris 2013). Blinding of participants and personnel was unclear in three studies (Bates 1977; Bates 1978; Paty 1978). We considered a single study comparing PUFA to MUFA to be at high risk for unblinding of participants and personnel due to different dietary advice administered to the treatment versus control groups (Weinstock‐Guttman 2005). Adequate blinding of outcome assessment was reported in a single study (Pantzaris 2013). The process of blinding outcome assessment was unclear in five studies (Bates 1977; Bates 1978; Bates 1989; Millar 1973; Paty 1978). We considered a single study to be at high risk of bias in blinding of outcome assessment due to relapses being recorded by the treating physician who was not blinded to the intervention (Weinstock‐Guttman 2005). Among studies comparing different types of PUFAs, adequate blinding of participants and personnel was described in all studies (Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012; Zandi‐Esfahan 2017). Three studies described adequate blinding of outcome assessment (Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012), while the blinding of outcome assessment was unclear in a single study (Zandi‐Esfahan 2017).
Among trials examining antioxidant supplementation, six studies reported adequate blinding of participants and personnel (Gallien 2014; Khalili 2012; Khalili 2014; Mahler 2015; Sanoobar 2015; Yadav 2005), while this process was unclear in a further four studies (Bitarafan 2015; Gonsette 2010; Markowitz 2009; Munoz Garcia 2015). Blinding of outcome assessment was described as adequate in five studies (Gallien 2014; Gonsette 2010; Mahler 2015; Markowitz 2009; Sanoobar 2015), while this process was unclear in a further five studies (Bitarafan 2015; Khalili 2012; Khalili 2014; Munoz Garcia 2015; Yadav 2005).
Among trials examining dietary programmes, all were at high risk of performance bias due to lack or inadequate blinding for dietary intervention (Irish 2017; Rezapour‐Firouzi 2013; Yadav 2016). Blinding of outcome assessment was described as adequate in a single study (Rezapour‐Firouzi 2013), unclear in a single study (Yadav 2016), and unblinded in a single study (Irish 2017).
Among trials examining other supplements, four studies reported adequate blinding of participants and personnel (Kouchaki 2017; Malin 2008; Naghashpour 2013; Tourbah 2016), while this was unclear in two studies (Orefice 2016; Tomassini 2004). Two studies described adequate blinding of outcome assessment (Naghashpour 2013; Tourbah 2016), while this was unclear in four studies (Kouchaki 2017; Malin 2008; Orefice 2016; Tomassini 2004).
Incomplete outcome data
Among trials comparing PUFA to MUFA, all studies had participants who did not complete the study, with loss to follow‐up/missing outcome data ranging from 6% to 49% across studies, leading to an unclear (Bates 1989; Millar 1973), or high (Bates 1977; Bates 1978; Pantzaris 2013; Paty 1978; Weinstock‐Guttman 2005) risk of incomplete outcome data. Similarly, among studies comparing different types of PUFAs, all studies experienced loss to follow‐up ranging from 6% to 22% leading to an unclear (Torkildsen 2012; Zandi‐Esfahan 2017), or high (Ramirez‐Ramirez 2013; Shinto 2016) risk of incomplete outcome data.
Among trials examining antioxidant supplementation, Munoz Garcia 2015 was at low risk of incomplete outcome data as all participants were included in the analysis. Four studies were at high risk of incomplete outcome data, with loss to follow‐up ranging from 22% to 35%, and an imbalance of missing outcome data between groups (Gallien 2014; Gonsette 2010; Khalili 2012; Markowitz 2009). The risk of incomplete outcome data in the remaining five studies was unclear (Bitarafan 2015; Khalili 2014; Mahler 2015; Sanoobar 2015; Yadav 2005).
Among trials examining dietary programmes, all studies were at high risk of incomplete outcome data, with missing outcome data ranging from 13% to 50% (Irish 2017; Rezapour‐Firouzi 2013; Yadav 2016).
Among trials examining other supplements, two studies had a low risk of incomplete outcome data (Kouchaki 2017; Orefice 2016). Two studies were at high risk of incomplete outcome data, as missing participant outcome data ranged from 17% to 46%, and there were unbalanced withdrawals between groups (Naghashpour 2013; Tomassini 2004). Finally, two studies had an unclear risk of incomplete outcome data (Malin 2008; Tourbah 2016).
Selective reporting
Among trials comparing PUFA to MUFA, two studies did not adequately define 'better' or 'deteriorated' as an outcome measure, resulting in a high risk of selective reporting (Bates 1977; Bates 1989). The remaining studies examining PUFA versus MUFA had an unclear risk of selective reporting due to lack of prespecified outcomes (Bates 1978; Millar 1973; Pantzaris 2013; Paty 1978; Weinstock‐Guttman 2005). Among studies comparing different types of PUFAs, two studies reported prespecified outcomes (Shinto 2016; Torkildsen 2012), while two studies had an unclear risk of selective reporting bias due to lack of outcome prespecification (Ramirez‐Ramirez 2013; Zandi‐Esfahan 2017).
Among trials examining antioxidant supplementation, two studies reported prespecified outcomes (Bitarafan 2015; Khalili 2014), while four studies were at high risk of selective reporting bias due to missing outcomes or conflicting reporting of results within the same study (Khalili 2012; Mahler 2015; Markowitz 2009; Yadav 2005). The risk of selective reporting bias was unclear among the remaining four studies (Gallien 2014; Gonsette 2010; Munoz Garcia 2015; Sanoobar 2015).
Among trials examining dietary programmes, a single study adequately reported prespecified outcomes (Irish 2017), with the risk of selective reporting unclear in the remaining two studies (Rezapour‐Firouzi 2013; Yadav 2016).
Among trials examining other supplements, a single study reported prespecified outcomes (Kouchaki 2017). Two studies were at high risk of reporting bias, as the initial randomization group was unclear (Malin 2008; Tomassini 2004), and three studies were at unclear risk of selective reporting (Naghashpour 2013; Orefice 2016; Tourbah 2016).
Other potential sources of bias
Details of other potential sources of bias are reported in the 'Risk of bias' tables.
Effects of interventions
See: Summary of findings 1 Polyunsaturated fatty acid (PUFA) compared to monounsaturated fatty acid (MUFA) for multiple sclerosis (MS); Summary of findings 2 Omega‐3 compared to omega‐6 for multiple sclerosis (MS); Summary of findings 3 Antioxidant compared to placebo for multiple sclerosis (MS)
Polyunsaturated fatty acid (PUFA) versus monounsaturated fatty acid (MUFA)
Relapse
Three trials reported the number of participants experiencing a relapse during the study period (Bates 1978; Millar 1973; Weinstock‐Guttman 2005). Bates 1978 reported that 51/58 (87.9%) participants receiving PUFA and 46/57 (80.7%) receiving MUFA experienced a relapse over two years of treatment. Millar 1973 reported that 25/36 (69.4%) participants receiving PUFA and 30/39 (76.9%) receiving MUFA experienced a relapse over two years of treatment. Weinstock‐Guttman 2005 reported that 3/13 (23.1%) participants receiving PUFA and 5/14 (35.7%) receiving MUFA experienced a relapse over one year of treatment. Overall, when we pooled the data there was no difference in relapse between participants treated with PUFA versus MUFA (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; very low‐certainty evidence; summary of findings Table 1; Analysis 1.1; Figure 4).
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.1 Relapse.
Change in validated disability scale
No trials reported this outcome in a form to allow for meta‐analysis. Millar 1973 reported no significant difference in change in EDSS between the PUFA (+0.2) and MUFA (+0.6) group after 2 years with no SD available. Paty 1978 reported no difference in EDSS between groups after 30 months, although EDSS attributed to the PUFA and MUFA group was unclear and SD was not provided. Weinstock‐Guttman 2005 reported a weak trend toward slight improvement in EDSS in the PUFA group (‐0.07) and slight worsening in the MUFA group (+0.35), although SD was not provided (2 studies, 102 participants; summary of findings Table 1).
Global impression of deterioration
Four trials reported global impression of deterioration during the study period (Bates 1977; Bates 1989; Millar 1973; Pantzaris 2013). Bates 1977 reported 24/69 (34.8%) participants receiving PUFA and 21/65 (32.3%) receiving MUFA deteriorated after two years of treatment. This excluded 18 participants who died or withdrew, as this outcome was reported in aggregate. Bates 1989 reported 67/146 (45.9%) participants receiving PUFA and 82/147 (55.8%) receiving MUFA deteriorated after two years of treatment. Millar 1973 reported 13/36 (36.1%) participants receiving PUFA and 18/39 (46.2%) receiving MUFA deteriorated over two years of treatment. Pantzaris 2013 reported 6/20 (30%) participants receiving PUFA and 7/20 (35%) receiving MUFA experienced deterioration at 30 months according to intention‐to‐treat (ITT) analysis. Overall, pooled data showed no difference in global impression of deterioration between participants treated with PUFA versus MUFA (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; low‐certainty evidence; summary of findings Table 1; Analysis 1.2; Figure 5).
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.2 Global impression of deterioration.
MRI activity
No trial reported this outcome.
Cognitive function
No trial reported this outcome.
Health‐related quality of life
No trial reported this outcome in a form to allow for meta‐analysis. Weinstock‐Guttman 2005 reported global SF‐36 remained unchanged in the PUFA group while it had a tendency to worsen in the MUFA group.
Fatigue
No trial reported this outcome in a form to allow for meta‐analysis. Weinstock‐Guttman 2005 reported no significant difference in MFIS between the PUFA and MUFA groups at 12 months.
Serious adverse events
A single trial reported no serious adverse events among 20 participants receiving PUFA and 20 participants receiving MUFA (Pantzaris 2013; low‐certainty evidence; summary of findings Table 1).
PUFA versus PUFA (omega‐3 versus omega‐6)
Relapse
Two trials reported the number of participants experiencing a relapse during the study period (Torkildsen 2012; Zandi‐Esfahan 2017). Torkildsen 2012 reported 57% of the 45 participants followed in the omega‐3 group and 58% of the 41 participants followed in the omega‐6 group remained free of relapses after two years of treatment. As a result, 19/45 in the omega‐3 group and 17/41 in the omega‐6 group experienced a relapse by two years. Zandi‐Esfahan 2017 reported that one participant was removed from each of the omega‐3 and omega‐6 groups for experiencing a relapse during the study. As a result, 1/22 participants in the omega‐3 group and 1/21 in the omega‐6 group experienced a relapse by one year. Overall, based on these two trials, there was no difference in relapse between participants treated with omega‐3 and omega‐6 supplementation (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; low‐certainty evidence; summary of findings Table 2; Analysis 2.1; Figure 6).
Forest plot of comparison: 2 PUFA (omega‐3) versus PUFA (omega‐6), outcome: 2.1 Relapse.
Change in validated disability scale
Three trials reported change in EDSS (Zandi‐Esfahan 2017), or allowed for a calculation of EDSS change (Ramirez‐Ramirez 2013; Torkildsen 2012). Ramirez‐Ramirez 2013 reported that mean EDSS did not differ between the omega‐3 and omega‐6 group after 12 months of treatment. Torkildsen 2012 reported that mean EDSS did not differ between the omega‐3 and omega‐6 group after 24 months of treatment, while Zandi‐Esfahan 2017 reported no difference in EDSS mean change between the omega‐3 and omega‐6 groups after 12 months. Overall, after pooling the three trials, there was no difference in mean change of EDSS between participants who received omega‐3 versus omega‐6 supplementation (MD 0.00, 95% CI ‐0.30 to 0.30; 3 studies, 166 participants; low‐certainty evidence; summary of findings Table 2; Analysis 2.2; Figure 7).
Forest plot of comparison: 2 Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), outcome: 2.2 Progression (change in EDSS).
Global impression of deterioration
A single trial reported global impression of deterioration (Torkildsen 2012), with deterioration occurring among 13/45 (28.9%) participants receiving omega‐3 and 12/41 (29.3%) receiving omega‐6 after two years of treatment, demonstrating no difference in deterioration between groups (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; moderate‐certainty evidence; summary of findings Table 2; Analysis 2.3).
MRI activity
No trial reported this outcome in a form to allow for meta‐analysis. Torkildsen 2012 reported no difference in the number of new T1‐ weighted gadolinium‐enhancing lesions between the omega‐3 and omega‐6 groups at 24 months (P = 0.17) (1 study, 86 participants; moderate‐certainty evidence; summary of findings Table 2).
Cognitive function
No trial reported this outcome.
Health‐related quality of life
No trial reported this outcome in a form to allow for meta‐analysis. Shinto 2016 reported no difference between groups in SF‐36 quality of life, physical component summary (p = 0.10) and mental component summary (p = 0.06) at 3 months. Torkildsen 2012 reported no difference in SF‐36 quality of life, physical component summary (p = 0.49) and mental component summary (p = 0.85) at 24 months.
Fatigue
No trials reported this outcome in a form to allow for meta‐analysis. Torkildsen 2012 reported no difference between groups in fatigue measured using the FSS at 24 months (p = 0.57).
Serious adverse events
Four trials reported serious adverse events (Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012; Zandi‐Esfahan 2017). Ramirez‐Ramirez 2013 reported that two participants in the fish oil group and one in the control group discontinued the intervention due to adverse events. Shinto 2016 reported that one participant in the fish oil group and two in the soybean oil group discontinued the intervention due to adverse events. Torkildsen 2012 reported four participants in the omega‐3 group and 3 in the omega‐6 group experienced a serious adverse event over two years, while Zandi‐Esfahan 2017 reported no adverse events after one year of treatment. Overall, upon pooling the data, there was no difference in serious adverse events between participants treated with omega‐3 and omega‐6 (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; low‐certainty evidence; summary of findings Table 2; Analysis 2.4).
Antioxidant supplementation versus placebo
Ten trials involving antioxidants had a focus on inosine (Gonsette 2010; Markowitz 2009; Munoz Garcia 2015), lipoic acid (Khalili 2012; Khalili 2014; Yadav 2005), vitamin A (Bitarafan 2015), cranberry (Gallien 2014), epigallocatechin‐3‐gallate (Mahler 2015), and coenzyme Q10 (Sanoobar 2015).
Relapse
Four trials reported the number of participants experiencing a relapse during the study period (Bitarafan 2015; Gallien 2014; Munoz Garcia 2015; Sanoobar 2015). In particular, Bitarafan 2015 reported that 11/47 (23.4%) participants receiving retinyl palmitate and 6/46 (13%) participants receiving placebo experienced a relapse over one year of the intervention. Gallien 2014 reported that 12/82 (14.6%) participants receiving cranberry extract and 19/89 (21.3%) participants in the placebo group experienced a relapse over one year of treatment. Munoz Garcia 2015 reported 4/18 (22.2%) participants in the inosine group and 4/15 (26.7%) participants in the placebo group experienced a relapse over nine months of treatment, and Sanoobar 2015 reported 2/24 (8.3%) participants receiving coenzyme Q10 and 1/24 (4.2%) participants receiving placebo experienced a relapse over three months of the intervention. Overall, there was no difference in relapse between participants treated with a variety of antioxidants versus placebo (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; low‐certainty evidence; summary of findings Table 3; Analysis 3.1; Figure 8).
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.1 Relapse.
Change in validated disability scale
Six trials reported EDSS at the end of the study period (Bitarafan 2015; Gallien 2014; Gonsette 2010; Khalili 2012; Khalili 2014; Sanoobar 2015). Bitarafan 2015 reported there was no difference in change in EDSS over one year between the treatment and placebo groups. Gallien 2014 did not report EDSS values, although correspondence with the author revealed no significant difference in EDSS between the cranberry and placebo group at 12 months. Gonsette 2010 reported no difference in mean EDSS between participants receiving inosine and placebo after two years of treatment. Khalili 2012 and Khalili 2014 reported no difference in mean EDSS between participants receiving lipoic acid and placebo at three months. Sanoobar 2015 reported no difference in mean EDSS between participants receiving coenzyme Q10 and placebo at three months. Overall, our pooled estimate found no difference in mean change of disability, measured using EDSS among participants treated with antioxidants versus placebo (MD ‐0.19, 95% CI ‐0.49 to 0.11; 6 studies, 490 participants; very low‐certainty evidence; summary of findings Table 3; Analysis 3.2; Figure 9).
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.2 Progression (change in EDSS).
Global impression of deterioration
Two trials reported global impression of deterioration (Gonsette 2010; Munoz Garcia 2015). Gonsette 2010 reported that deterioration occurred among 14/79 (17.7%) participants receiving inosine and 14/78 (17.9%) receiving placebo at two years. Munoz Garcia 2015 reported that no participants experienced progression. The meta‐analysis of these trials demonstrated no difference in global impression of deterioration between participants receiving antioxidant versus placebo (RR 0.99, 95% CI 0.50 to 1.93; 2 studies, 190 participants; low‐certainty evidence; summary of findings Table 3; Analysis 3.3).
MRI activity
Among the two trials that reported the number of individuals experiencing gadolinium‐enhancing lesions (Bitarafan 2015; Khalili 2012), Bitarafan 2015 reported 80% of participants receiving retinyl palmitate and 87% of participants receiving placebo had no gadolinium‐enhancing lesions after one year of treatment. Khalili 2012 reported 1/22 (4.5%) participants receiving lipoic acid and 4/17 (23.5%) participants receiving placebo experienced a gadolinium‐enhancing lesion at three months, although there were discrepancies between text and table and after contacting study authors, we were unable to resolve the discrepancy. Overall, there was no difference in gadolinium‐enhancing lesions between participants receiving antioxidant and placebo (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; very low‐certainty evidence; summary of findings Table 3; Analysis 3.4, Figure 10).
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.4 Gadolinium‐enhancing lesions.
Cognitive function
Two trials reported change in cognition assessed using the PASAT (Bitarafan 2015; Gonsette 2010). Bitarafan 2015 reported a significant improvement in PASAT score between vitamin A and placebo groups after one year. Gonsette 2010 reported no significant change in PASAT score between inosine and placebo groups after two years. Overall, there was no difference in change in cognition measured using PASAT between participants receiving antioxidant and placebo (MD 0.66, 95% CI ‐2.50 to 3.82; 2 studies, 250 participants; Analysis 3.5).
Health‐related quality of life
No trial reported this outcome in a form to allow for meta‐analysis. Gallien 2014 measured quality of life using the Qualiveen scale and reported no significant difference between the cranberry and placebo groups at one year.
Fatigue
Three trials reported change in fatigue (Bitarafan 2015; Khalili 2012; Sanoobar 2015). Bitarafan 2015 measured fatigue using the MFIS reporting a significant improvement in fatigue in the vitamin A compared to placebo group at one year. Khalili 2012 measured fatigue using the FSS reporting no significant difference between the lipoic acid and placebo groups at 3 months. Sanoobar 2015 measured fatigue using the FSS reporting a significant improvement in fatigue in the coenzyme Q10 group compared to placebo group at 3 months. Overall, there was no difference in change in fatigue between participants receiving antioxidant and placebo (SMD ‐0.38, 95% CI ‐0.96 to 0.19; 3 studies, 177 participants; Analysis 3.6).
Serious adverse events
Three trials reported serious adverse events (Gallien 2014; Munoz Garcia 2015; Yadav 2005). Gallien 2014 reported no serious adverse events, although two participants in the cranberry group and one in the placebo group discontinued the intervention due to an adverse event. Munoz Garcia 2015 reported three participants who withdrew due to adverse events over nine months of interferon beta‐1a plus inosine or interferon beta‐1a plus placebo, including one from the inosine group and two from the placebo group, while Yadav 2005 reported one participant in the lipoic acid (1200 mg twice daily) group who discontinued due to development of a maculopapular rash associated with fever. Overall, after pooling the reported serious adverse events, there was no difference in events among participants treated with antioxidant versus placebo (RR 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; low‐certainty evidence; summary of findings Table 3; Analysis 3.7).
Dietary programmes versus usual diet/placebo
Three trials examined dietary programmes (Irish 2017; Rezapour‐Firouzi 2013; Yadav 2016). These differed substantially in diet protocol and outcome measures, thus preventing meta‐analysis.
Sensitivity Analysis
There were no differences in relapse between PUFA versus MUFA, omega‐3 versus omega‐6, or antioxidant versus placebo in a sensitivity analysis, assuming that all participants lost to follow‐up experienced the outcome of interest (Analysis 4.1, Analysis 4.2, Analysis 4.3).
Discussion
The purpose of this review was to assess the efficacy and safety of a diversity of dietary interventions among people with multiple sclerosis (MS). We excluded vitamin D which is the subject of a dedicated Cochrane Review (Jagannath 2018).
Summary of main results
This review included 41 full‐text articles reporting the results of 30 trials. Eleven trials examined polyunsaturated fatty acids (PUFAs), 10 trials examined a variety of antioxidant supplements, three trials examined dietary programmes, and six trials examined other dietary supplements.
PUFA supplementation
Trials examining PUFA demonstrated variation in PUFA type, PUFA dose, and comparator intervention. We found seven trials (874 participants) comparing PUFA (including linoleic acid, alpha‐linolenic acid, eicosapentaenoic acid, docosahexaenoic acid) to monounsaturated fatty acid (MUFA) (oleic acid) (Bates 1977; Bates 1978; Bates 1989; Millar 1973; Pantzaris 2013; Paty 1978; Weinstock‐Guttman 2005), and four trials (231 participants) comparing different types of PUFAs: omega‐3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid) versus omega‐6 fatty acids (linoleic acid) (Ramirez‐Ramirez 2013; Shinto 2016; Torkildsen 2012; Zandi‐Esfahan 2017). There was little to no difference between PUFA versus MUFA regarding number of participants experiencing a relapse (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; anticipated absolute effect 75% in the PUFA group versus 74% in the MUFA group) although the evidence was very uncertain. Also, there was little to no difference between PUFA versus MUFA regarding global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 40% in the PUFA group versus 47% in the MUFA group). A single study examining PUFA versus MUFA reported no adverse events (Pantzaris 2013). There was little to no difference between PUFA‐type, omega‐3 versus omega‐6, on number of participants experiencing a relapse (RR 1.02, 95% CI 0.62 to 1.66; 30% in the omega‐3 versus 29% in the omega‐6 group) or mean change of disability measured using EDSS (MD 0.00, 95% CI ‐0.30 to 0.30). There was likely no difference in global impression of deterioration or gadolinium‐enhancing lesions by PUFA type. Also, there was little to no difference in serious adverse events between participants receiving omega‐3 versus omega‐6 (RR 1.12, 95% CI 0.38 to 3.31; 6% in the omega‐3 versus 5% in the omega‐6 group).
Antioxidant supplementation
Studies examining antioxidant supplementation varied considerably in agent, dose and comparator intervention. Antioxidants were defined according to MeSH term "antioxidants [pharmacologic action]". Ten randomized controlled trials (RCTs) involved antioxidants (690 participants) with a focus on inosine (Gonsette 2010; Markowitz 2009; Munoz Garcia 2015), lipoic acid (Khalili 2012; Khalili 2014; Yadav 2005), vitamin A (Bitarafan 2015), cranberry (Gallien 2014), epigallocatechin‐3‐gallate (Mahler 2015), and coenzyme Q10 (Sanoobar 2015). Our pooled analysis of studies examining antioxidant supplementation indicated there was little to no difference in number of participants experiencing a relapse (RR 0.98, 95% CI 0.59 to 1.64; 17% in the antioxidant versus 17% in the placebo group) or global impression of deterioration (RR 0.99, 95% CI 0.50 to 1.93; 15% in the antioxidant versus 15% in the placebo group). There was very uncertain evidence regarding mean change of disability measured by EDSS (mean difference (MD) ‐0.19, 95% CI ‐0.49 to 0.11) or number of participants experiencing gadolinium‐enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 11% in the antioxidant versus 16% in the placebo group). Also, there was little to no difference in serious adverse events between participants receiving antioxidant supplementation versus placebo (RR 0.72, 95% CI 0.17 to 3.08; 3% in the antioxidant versus 4% in the placebo group).
Dietary programmes and other supplements
Studies of dietary programmes and other supplements varied considerably, limiting our ability to perform meta‐analysis. We found three RCTs (195 participants) focusing on dietary programmes, each examining a different diet, namely Paleo (Irish 2017), Hot‐nature (Rezapour‐Firouzi 2013), and low‐fat plant‐based (Yadav 2016) diets. Although the Paleo (Irish 2017) and low‐fat plant‐based (Yadav 2016) diets demonstrated improvement in fatigue outcomes, these trials were at high risk of bias. Six RCTs focused on other supplements individually, including probiotics (Kouchaki 2017), creatine (Malin 2008), riboflavin (Naghashpour 2013), palmitoylethanolamide (Orefice 2016), carnitine (Tomassini 2004), and biotin (Tourbah 2016). High‐dose biotin was associated with improvement in disability, measured using a composite of EDSS and the 25‐foot walk (Tourbah 2016).
Overall completeness and applicability of evidence
A number of small RCTs examine unique dietary interventions in MS, but with very little similarity between studies to allow meaningful meta‐analysis. The greatest number of trials examining a similar agent were for PUFA, although even within this group of studies there was a high degree of variability in PUFA type, PUFA dose, and comparator therapy. In addition to variability in the interventions, there was variability in outcome measures between studies, which further limited our ability to perform meta‐analysis.
Certainty of the evidence
We identified risks of bias in all the studies included in this systematic review. Among 11 studies examining PUFA, eight had unknown risk of selection bias, four had unknown or high risk of performance bias, seven had unknown or high risk of detection bias, 11 had unknown or high risk of attrition bias, and nine had unknown or high risk of reporting bias. Among 10 studies examining antioxidant supplementation, six had unknown risk of selection bias, four had unknown risk of performance bias, five had unknown risk of detection bias, nine had unknown or high risk of attrition bias, and eight had unknown or high risk of reporting bias. Among three studies examining dietary programmes, three studies had unknown or high risk of selection bias, three had high risk of performance bias, two had unknown or high risk of detection bias, three had high risk of attrition bias, and two had unknown risk of reporting bias. Among six studies examining other supplementation, five studies had unknown or high risk of selection bias, two had unknown risk of performance bias, four had unknown risk of detection bias, four had unknown or high risk of attrition bias, and five had unknown or high risk of reporting bias. We conducted a sensitivity analysis for missing outcome data (attrition bias) and found no difference in number of participants experiencing a relapse across interventions, assuming all participants lost to follow‐up experienced the outcome of interest.
Sample sizes were small for all meta‐analyses. We tried to minimize heterogeneity among interventions by analysing different groups of interventions separately, although there remained a substantial degree of heterogeneity (I2 ranged from 0% to 89%) between studies.
Potential biases in the review process
Although there was heterogeneity among interventions and outcomes, the individual study results are consistent with our pooled results, demonstrating little to no difference for any intervention for any outcome. It is possible that there are additional dietary intervention studies with relevant clinical outcome data that we did not obtain. We do not think that we failed to identify a significant dietary intervention study with relapse or progression as a primary outcome. Sensitivity analysis, performed to verify the presence of bias due to losses to follow‐up, did not reveal any effect on relapse between the intervention and control group.
Agreements and disagreements with other studies or reviews
Recently, a systematic review including clinical trials and observational studies examined the effect of diet on risk of MS, with the conclusion that low vitamin D and low vitamin B12 may be associated with increased risk of MS (Bagur 2017). We are not aware of any other comprehensive systematic review assessing dietary interventions for MS outcomes, though there are a number of descriptive reviews covering dietary therapy in MS (Claflin 2018; Esposito 2018; Namaka 2008; Payne 2001; Schwarz 2005; Yadav 2010), with most demonstrating consistent results with our findings. We did not include evidence for vitamin D in MS as this is the subject of a separate Cochrane Review (Jagannath 2018). This review is an updated Cochrane Review (Farinotti 2003; Farinotti 2007; Farinotti 2012). Overall, we reached similar conclusions to the prior versions of this review, whereby there is insufficient evidence from studies of PUFA, antioxidant supplementation, dietary programmes, and other natural health product supplementation to determine whether these interventions have an effect on MS‐related outcomes.
In terms of PUFA supplementation, we did not find a beneficial effect of PUFA supplementation on relapses or disability progression. This is similar to the result reported in the prior version of this review (Farinotti 2012). A systematic review of observational and interventional studies examining fish oil consumption provided a descriptive analysis of seven studies, without performing a meta‐analysis, concluding that omega‐3 supplementation may have a benefit on relapse rate and quality of life (AlAmmar 2019). Evidence‐based guidelines from the American Academy of Neurology conclude that a low‐fat diet with fish oil supplementation is probably ineffective in improving relapses, disability progression, magnetic resonance imaging (MRI) activity, or quality of life measures (Yadav 2014).
In terms of antioxidant supplementation, we did not find a beneficial effect of antioxidant supplementation on relapses, disability progression, or gadolinium‐enhancing lesions. Again, our findings are similar to prior work indicating there is insufficient evidence to determine whether there is a beneficial effect of antioxidant supplementation on MS outcomes (Bowling 2003; Yadav 2010; Esposito 2018).
In terms of dietary programmes, we included three trials each examining a different dietary intervention, including modified Paleo diet, Hot‐nature diet, and low‐fat plant‐based diet. All trials of a dietary programme had issues blinding participants, while two of three trials had incomplete blinding of study personnel. Also, all studies were at risk of attrition bias due to missing outcome data (Irish 2017; Rezapour‐Firouzi 2013; Yadav 2016). No randomized trials addressed the Swank diet, a very low‐fat diet, although an observational study concluded that the Swank diet may be associated with improved survival and mobility (Swank 2003a). There is an ongoing RCT comparing the Wahls Paleo diet to the Swank diet (NCT02914964), with the primary outcome of fatigue.
In terms of other supplements, there was limited evidence to assess the benefit of any individual supplement. High‐dose biotin (MD1003) has shown promise in a small study for decreasing disability progression (Tourbah 2016), and there is an ongoing larger trial to investigate the effects of high‐dose biotin on progressive MS (NCT02936037).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.1 Relapse.
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.2 Global impression of deterioration.
Forest plot of comparison: 2 PUFA (omega‐3) versus PUFA (omega‐6), outcome: 2.1 Relapse.
Forest plot of comparison: 2 Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), outcome: 2.2 Progression (change in EDSS).
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.1 Relapse.
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.2 Progression (change in EDSS).
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.4 Gadolinium‐enhancing lesions.
Comparison 1: Polyunsaturated fatty acid versus monounsaturated fatty acid, Outcome 1: Relapse
Comparison 1: Polyunsaturated fatty acid versus monounsaturated fatty acid, Outcome 2: Global impression of deterioration
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 1: Relapse
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 2: Progression (change in EDSS)
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 3: Global impression of deterioration
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 4: Serious adverse event
Comparison 3: Antioxidant versus placebo, Outcome 1: Relapse
Comparison 3: Antioxidant versus placebo, Outcome 2: Progression (change in EDSS)
Comparison 3: Antioxidant versus placebo, Outcome 3: Global impression of deterioration
Comparison 3: Antioxidant versus placebo, Outcome 4: Gadolinium‐enhancing lesions
Comparison 3: Antioxidant versus placebo, Outcome 5: Cognition
Comparison 3: Antioxidant versus placebo, Outcome 6: Fatigue
Comparison 3: Antioxidant versus placebo, Outcome 7: Serious adverse event
Comparison 4: Sensitivity analysis, Outcome 1: Polyunsaturated fatty acid versus monounsaturated fatty acid: relapse
Comparison 4: Sensitivity analysis, Outcome 2: Omega‐3 versus omega‐6: relapse
Comparison 4: Sensitivity analysis, Outcome 3: Antioxidant versus placebo: relapse
| PUFA compared to MUFA for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with MUFA | Risk with PUFA | |||||
| Relapse | Adults with MS: | RR 1.02 | 217 | ⊕⊝⊝⊝ | There may be little to no benefit of PUFA versus MUFA on relapses, although evidence is very uncertain. | |
| 74 per 100 | 75 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Millar 1973 reported no difference in change in EDSS between PUFA and MUFA over two years. Weinstock‐Guttman 2005 reported increase (worsening) in EDSS with MUFA (mean increase 0.35) compared to a decrease (improvement) in EDSS with PUFA (mean decrease 0.07) over one year. | ‐ | 102 | ⊕⊝⊝⊝ | ||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with MS: | RR 0.85 | 542 | ⊕⊕⊝⊝ | There may be little to no benefit of PUFA versus MUFA on global impression of deterioration. | |
| 47 per 100 | 40 per 100 | |||||
| MRI activity ‐ not measured | ‐ | ‐ | ‐ | ‐ | ‐ | |
| SAEs (assessed as number of participants experiencing a SAE) | Pantzaris 2013 reported no adverse events in any of 4 groups, including among 20 participants receiving PUFA and 20 participants receiving MUFA | ‐ | 40 | ⊕⊕⊝⊝ | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded three levels for very serious risk of bias (including high risk of attrition bias in 2 studies and uncertain risk of attrition bias in 1 study) and serious imprecision (small sample size in all studies). | ||||||
| Omega‐3 compared to omega‐6 for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with omega‐6 | Risk with omega‐3 | |||||
| Relapse | Adults with RRMS exposed to DMT (interferon beta or fingolimod): | RR 1.02 | 129 | ⊕⊕⊝⊝ | There may be little to no benefit of omega‐3 versus omega‐6 on relapses. | |
| 29 per 100 | 30 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Adults with RRMS exposed to DMT (interferon beta or fingolimod): | ‐ | 166 | ⊕⊕⊝⊝ | There may be little to no benefit of omega‐3 versus omega‐6 on disability worsening. | |
| Mean EDSS 2.1 | MD 0.00 | |||||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with RRMS exposed to DMT (interferon beta): | RR 0.99 | 86 | ⊕⊕⊕⊝ | Omega‐3 is unlikely to change the global impression of deterioration. | |
| 29 per 100 | 29 per 100 | |||||
| MRI activity | Torkildsen 2012: There was no difference in the number of new T1‐ weighted gadolinium‐enhancing lesions between the omega‐3 and omega‐6 groups at 24 months (P = 0.17). | ‐ | 86 | ⊕⊕⊕⊝ | ||
| SAEs (assessed as number of participants experiencing a SAE) Follow‐up: 3 to 24 months | Adults with MS: | RR 1.12 | 230 | ⊕⊕⊝⊝ | There may be little to no difference between omega‐3 and omega‐6 on serious adverse events. | |
| 5 per 100 | 6 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels for serious risk of bias (including uncertain risk of attrition bias in 2 studies) and serious imprecision (small sample size in both studies). | ||||||
| Antioxidant compared to placebo for multiple sclerosis | ||||||
| Patient or population: adults with multiple sclerosis, defined by established criteria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with antioxidant | |||||
| Relapse | Adults with MS: | RR 0.98 | 345 | ⊕⊕⊝⊝ | There may be little to no benefit of antioxidant versus placebo on relapses. | |
| 17 per 100 | 17 per 100 | |||||
| Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) | Adults with MS: | ‐ | 490 | ⊕⊝⊝⊝ | There may be little to no benefit of antioxidant versus placebo on progression, although evidence is very uncertain. | |
| Mean EDSS 3.0b | MD 0.19 lower | |||||
| Global impression of deterioration (investigator defined global impression of deterioration) | Adults with RRMS exposed to DMT (interferon beta): | RR 0.99 | 190 | ⊕⊕⊝⊝ | There may be little to no benefit of antioxidant versus control on global impression deterioration. | |
| 15 per 100 | 15 per 100 | |||||
| MRI activity Follow‐up: 3 to 12 months | Adults with RRMS: | RR 0.67 | 131 | ⊕⊝⊝⊝ | There may be little to no benefit of antioxidant versus control on gadolinium‐enhancing lesions, although evidence is very uncertain. | |
| 16 per 100 | 11 per 100 | |||||
| SAEs (assessed as number of participants experiencing a SAE) Follow‐up: 2 weeks to 1 year | Adults with MS: | RR 0.72 | 222 | ⊕⊕⊝⊝ | There may be little to no difference in serious adverse events between antioxidant and placebo. | |
| 4 per 100 | 3 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels for serious risk of bias (including high risk of attrition bias in 1 study and uncertain risk of attrition bias in 2 studies) and serious imprecision (small sample size in all studies). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Relapse Show forest plot | 3 | 217 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.88, 1.20] |
| 1.2 Global impression of deterioration Show forest plot | 4 | 542 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.71, 1.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Relapse Show forest plot | 2 | 129 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.62, 1.66] |
| 2.2 Progression (change in EDSS) Show forest plot | 3 | 166 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.30, 0.30] |
| 2.3 Global impression of deterioration Show forest plot | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.51, 1.91] |
| 2.4 Serious adverse event Show forest plot | 4 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.38, 3.31] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Relapse Show forest plot | 4 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.59, 1.64] |
| 3.2 Progression (change in EDSS) Show forest plot | 6 | 490 | Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐0.49, 0.11] |
| 3.3 Global impression of deterioration Show forest plot | 2 | 190 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.50, 1.93] |
| 3.4 Gadolinium‐enhancing lesions Show forest plot | 2 | 131 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.09, 4.88] |
| 3.5 Cognition Show forest plot | 2 | 250 | Mean Difference (IV, Random, 95% CI) | 0.66 [‐2.50, 3.82] |
| 3.6 Fatigue Show forest plot | 3 | 177 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.38 [‐0.96, 0.19] |
| 3.7 Serious adverse event Show forest plot | 3 | 222 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.17, 3.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Polyunsaturated fatty acid versus monounsaturated fatty acid: relapse Show forest plot | 3 | 234 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.89, 1.06] |
| 4.2 Omega‐3 versus omega‐6: relapse Show forest plot | 2 | 142 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.59, 1.36] |
| 4.3 Antioxidant versus placebo: relapse Show forest plot | 4 | 353 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.65, 1.50] |
