Table 2.

Summary of the characteristics of studies included in the meta-analysis investigating the effects of non-pharmacological interventions on health-related quality of life (HRQoL)—categorized by type of non-pharmacological intervention

Author/year	Region	Sample size (Ix/Cx)a	Participants	Mean age (range)	% Female	Intervention group	Control group	Duration	HRQoL tool	Summary of main outcome related to HRQoL
Physical activity interventions
Ahadi 2013 [23]	Iran—Single Center	31 (10: Treadmill, 11: Yoga, 10: Control)	MS EDSS Score 1–4	34 (19–54)	100	Treatment 1: treadmill training consisted of 24 sessions of treadmill training (30 min), at 40–75% of age-predicted maximum heart rate. Treatment 2: Yoga group subjects participated in a thrice weekly 60–70-min sessions of Hatha yoga intervention	Followed own routine treatment program	8 weeks	MSQOL-54	The treadmill training program subjects showed a significant increase in the PCS. The yoga group also showed a significant increase in PCS (P = 0.02) and MCS (P = 0.00)
Ahmadi, Arastoo 2010 [24]	Iran—Single Center	20 (10, 10)	MS EDSS Score 1–4	37 (19–54)	100	Treadmill training (30 min), at 40–75% of age-predicted maximum heart rate—3 times per week	Wait-list control	8 weeks	MSQOL-54	In the control group, there was no significant change in any of the MSQOL-54 scale scores. Differences between the treadmill training group and the control group were statistically significant in 5 items of the MSQOL-54 scale scores (physical function, pain, energy, health perception and physical health composite)
Ahmadi 2010 [45]	Iran—Single Center	21 (11i, 10c)	MS EDSS Score 1–4	34 (19–54)	100	Hatha yoga classes 60–70 min 3 sessions per week	Wait-list control	8 weeks	MSQOL-54	Significant increase in some of MSQOL-54 scale scores in the yoga group (P ≤ 0.05). No changes for the control group. There was a significant difference found in both the PCS and MCS mean change between the intervention and control groups
Backus 2020 [25]	America—Atlanta—Single Center	12 (6, 6)	MS EDSS Score 7–8.5	55	58	Participants cycled volitionally with assistance from the electrical stimulation (Functional electrical stimulation: FES) as needed and with oversight for safety by the exercise staff. The goal was for participants to train three times a week	Wait list control	3 months	MSQOL-54	Significant increase in the physical health, health perception, health distress, and PCS in the training group
Barclay 2019 [26]	UK—Glasgow-Single Center	24 (15i, 9c)	MS EDSS Score 6–8.5	54	63	30 min of lower limb cycling programme using active passive trainers (2 min passive warm up, 26 min active cycling, 2 min passive cool down), 5 days per week	Usual care	5 weeks	MSQOL-54	Significant increase in both groups in both PCS and MCS. A larger effect size was demonstrated for the intervention group (0.93) and medium effect size in the control group (0.46)
Bjarnadottir 2007 [27]	Iceland	16 (6i, 10c)	MS EDSS Score < 4	37	63	Outpatient aerobic and strength exercise program (60 min) three times a week	Usual care—no change from previous	5 weeks	SF-36	Significant increase in vitality and a trend toward improved QoL in 5 of 8 parameters of SF-36
Carter 2013 [46]	UK—Sheffield—Single Center	30 (16i, 14c)	MS EDSS Score ≤ 5.5	40 (24–49)	87	Pragmatic exercise intervention (2 × supervised and 1 × home-based session per week)	Usual care	10 weeks	MSQOL-54	Significant increase in QoL which was sustained for up to 3 months after the intervention
Dalgas 2010 [33]	Denmark—Single Center	31 (16i, 15c)	MS EDSS Score 3–5.5	48	65	Progressive resistance training of the lower extremities performed twice weekly	Usual activity	3 months	SF-36	PCS QoL was increase significantly more in the intervention arm and this was maintained at follow-up after further 12 weeks
Hebert 2018 [35]	America—Colorado—Single Center	88 (44, 44)	MS	45	85	Balance and Eye-Movement Exercises for People with Multiple Sclerosis (BEEMS) was administered twice weekly with supervision and daily home exercise (phase 1) and in 1 supervised session weekly with daily home exercise (phase 2)	No treatment	4 months	SF-36	The BEEMS group showed a statistically greater increase in MCS compared to controls at 6 and 14 weeks
Jeong 2021 [32]	America-New York	45 (29i, 16c)	MS EDSS Score 5.5–7.5	57	73	Custom home exercise program with additional assistance by the telerehabilitation system	Usual care—custom daily home exercise plan	3 months	MSQOL-54	Patients in the telerehabilitation group showed significant improvement in pain and cognitive function symptoms in comparison with the control group
Kargarfard 2012 [47]	Iran—Isfahan	21 (10i, 11c)	RRMS (relapse remitting MS) EDSS Score ≤ 3.5	33	100	Supervised aquatic exercise in a swimming pool (3 times a week, each session lasting 60 min)	Usual care	8 weeks	MSQOL-54	Patients in the aquatic exercise group showed significant increases in QoL at 4 and 8 weeks compared with the control group
Langeskov-Christensen [34]	Denmark-multicentre	86 (43, 43)	MS EDSS score 0–6	45	60	Supervised progressive aerobic exercise (PAE) sessions with one continuous and one interval exercise session performed each week	Habitual lifestyle	24 weeks	SF-36	No differences in the SF-36 were found
Oken 2004 [36]	America—Oregon	57 (15: Exercise, 22: Yoga, 20: control)	MS EDSS Score ≤ 6	49	93	Group 1: weekly exercise class using a stationary bicycle along with home exercise Group 2: Weekly 90-min Iyengar yoga class along with home practice	Wait-list control	6 months	SF-36	Exercise and Yoga both significantly increase vitality on the SF-36 more as compared to the control group
Pappalardo 2016 [43]	Italy—Catania—Single Center	146 (49: outpatient, 49: inpatient, 48: control)	MS EDSS Score 4–8	46 (25–74)	64	Group A—Outpatient rehabilitation: once daily, 6 days per week, each session 60 min Group B—Inpatient rehabilitation: twice-daily, 6 day per week, each session 60 min	Wait-list control	5 weeks	SF-36	Outpatient rehabilitation significantly improved all sub scales of the SF-36 and was found to be more effective at improving QoL than inpatient rehabilitation
Patti 2002 [44]	Italy—Catania—Single Center	111 (58i, 53c)	MS EDSS Score 4–8	46 (25–60)	58	Outpatient rehabilitation program, 6 days a week	Wait-list control	6 weeks	SF-36	QoL increase significantly in the intervention group and this was seen at 6 and 12 weeks. The difference was significant between the intervention and control for all 8 subscales
Romberg 2005 [28]	Finland—Single Center	95 (47i, 48c)	MS EDSS Score 1–5.5	44	64	Progressive exercise program, mainly consisting of resistance training, it combined resistance training (3–4 times a week) with aerobic endurance training (once a week)	No treatment	6 months	MSQOL-54	“There was no effect seen in the MSQOL-54. The scores on the PCS and MCS of the MSQOL-54 were stable with no differences between groups”
Behavioral and psychological interventions
De Giglio 2015 [37]	Italy—Rome—Single Center	35 (18i, 17c)	RRMS	44	74	Dr. Kawashima’s Brain Training (DKBT): How Old Is Your Brain video game 30 min/day, 5d/wk	No treatment	8 weeks	MSQOL-54	DBKT improved QoL significantly in the MCS, role limitations due to emotional problems, emotional wellbeing, and cognitive function when compared to the control
Jongen 2019 [48]	Netherlands—Single Center	158 (79, 79)	RRMS EDSS score ≤ 4	40	88	Intensive 3-day social cognitive treatment (can do treatment)	No treatment	3 days	MSQOL-54	In the intervention arm PCS and MCS were improved significantly at 1 month but this was not sustained at 3 and 6 months
Momenabadi 2019 [49]	Iran—Kermin—Single Center	80 (40, 40)	RRMS EDSS score ≤ 5	30 (20–35)	85	18 training sessions based on the main constructs of the health-promoting self-care behaviors system. Training class twice a week in 45–60 min sessions. In addition to holding in person training sessions, patients in the intervention group were followed up by phone calls and texts during the training period	No treatment	3 months	MSQOL-54	There was a significant increase in 14 subscales of QoL, MCS and PCS in the intervention arm and this was not observed in the control arm
O'Hara 2002 [38]	UK—Greater London	169 (73i, 96c)	MS	51 (28–81)	70	Self-care programme primarily comprised a discussion of self care strategies supported by an information booklet developed for the study in line with consumer priorities—2 discussion lasting 1–2 h over the month	No treatment	1 month	SF-36	There was a significant improvement in MCS in the intervention arm as compared to the control arm
Stuijbergen 2003 [39]	America—Community setting southwestern US	113 (56i, 57c)	MS	46 (25–60)	100	Lifestyle-change classes weekly for 90 min, then telephone follow-up	No treatment	8 weeks and then telephone follow-up for 3 months	SF-36	A significant improvement in the intervention arm was seen in mental health on the SF36 when compared to the control. There was no significant difference between the intervention and control for vitality, physical function, role–physical or role–emotional, social functioning, or general health
Nutraceutical/supplement interventions
Ashtari 2016 [29]	Iran	94 (47, 47)	RRMS EDSS score ≤ 4	33	85	50,000 IU vitamin D3 every 5 days	Placebo	3 months	MSQOL-54	A significant increase in Mental Health QoL was seen in the intervention arm and this was not seen in the control arm
Etemadifar 2013 [50]	Iran—Isfahan—Single Center	54 (26, 26)	RRMS EDSS score < 5	34	100	250-mg Korean ginseng tablets twice daily after breakfast and evening meal	Placebo	3 months	MSQOL-54	A significant increase in most of the domains of the MSQOL were seen in the intervention arm as compared to the control arm
Namjooyan 2019 [40]	Iran—Khuzestan	51 (26i, 25c)	MS EDSS score 2–5.5	47	63	Two parts of ajwain and one part of Iranian borago were soaked in water for 24 h and one part of cinnamon was soaked in water for 72 h then were distilled—patients given 15 cc total per day (split in four capsules per day)	Placebo	3 months	MSQOL-54	A significant increase was seen in the physical and mental components of QoL in the intervention arm as compared to the control arm and this was sustained at 3 months
Nozari 2019 [30]	Iran—single centre	50 (25, 25)	RRMS	30	54	5 mg daily folic acid tablets and three divided doses of 1 mg injective vitamin B12	Placebo	2 months	MSQOL-54	A significant difference was seen in the physical and mental components of QoL in the intervention arm as compared to the control arm
Siahpoosh 2018 [51]	Iran—single centre	66 (33, 33)	MS	32	68	Capsules with powder of grape seed extract (plus excipients 50 mg) twice a day	Placebo	1 month	MSQOL-54	A significant difference was seen in the physical and mental components of QoL in the intervention arm as compared to the control arm
Diet interventions
Moravejolahkami 2020 [41]	Iran—single centre	147 (68i, 79c)	RRMS EDSS score ≤ 3	39	83	A modified version of Mediterranean Diet (mMeD), based on higher intake of fresh fruits and vegetables, whole grains, monounsaturated fatty acids, fish, and low to moderate consumption of dairy products, meat, and poultry	Traditional Iranian diet	6 months	MSQOL-54	A significant increase was seen in the physical components of QoL in the intervention arm, however, this was not seen in the MCS
Tissue manipulation
Doğan 2021 [52]	Turkey-multi center	66 (33, 33)	MS EDSS score < 5.5	38	NA	Reflexology was applied on each patient in the intervention group for 3 sessions a week	No treatment	3 months	MSQOL-54	A significant increase in the combined physical and mental health scores were found in the intervention group
Other interventions
Shinto 2008 [31]	America—Oregon—Single Center	45 (15, 15, 15)	RRMS EDSS score ≤ 6	44	87	Intervention 1: naturopathic medicine which entailed 8 visits with a naturopath including daily supplements, Vitamins, diet intervention and counseling Intervention 2: MS education which entailed 8 visits with a nurse trained in MS care	Usual care	6 months	SF-36	“There were no significant differences between groups on any outcome measure”
Vermöhlen 2017 [42]	Germany—Multi Center	56 (25i, 31c)	MS EDSS 4–6.5	51	81	Hippotherapy once a week	Usual care	3 months	MSQOL-54	A significant increase was seen in the PCS and MCS in the intervention arm

^aIn the sample size column ‘i’ refers to the intervention arm and ‘c’ is in reference to the control arm