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Evaluating functional electrical stimulation (FES) cycling on cardiovascular, musculoskeletal and functional outcomes in adults with multiple sclerosis and mobility impairment: A systematic review

Published:October 30, 2019DOI:https://doi.org/10.1016/j.msard.2019.101485

      Highlights

      • Functional electrical stimulation (FES) cycling is used by people with MS (PwMS).
      • A systematic review evaluated FES cycling in PwMS with a mobility impairment.
      • 9 studies met the inclusion criteria, with outcome data for n = =76 unique participants.
      • Overall study quality was poor, with limitations in study protocols and outcomes.
      • There is insufficient evidence to support FES cycling for cardiovascular risk.

      Abstract

      Background

      People with Multiple Sclerosis (PwMS) are at an increased risk of diseases associated with low levels of physical activity (PA). Deconditioning may lead to an acceleration in the development of secondary complications from MS, impairing physical function and exacerbating disease progression. Functional Electrical Stimulation (FES) Cycling may provide a suitable lower limb exercise intervention for PwMS with mobility impairment. The effects of FES cycling on cardiovascular, musculoskeletal and functional outcomes for PwMS with mobility impairment are yet to be investigated to date.

      Objective

      The objective of this review was to systematically examine the outcomes of PwMS with mobility impairment following FES cycling intervention.

      Methods

      A systematic search of four electronic databases (MEDLINE, Web of Science, CINAHL and PEDro) from their inception to 8th January 2019 was performed. Inclusion criteria was (1) include human participants with definite diagnosis of MS (2) participants had to be aged 18 years or older (3) include participants with mobility impairment (determined as an average participant EDSS ≥ 6.0) (4) evaluate FES cycling as an intervention study.

      Results

      Initial searches found 1163 studies. 9 of which met the full inclusion criteria: 5 pre-post studies with no control group, 2 randomised controlled trials (RCTs), 1 retrospective study and 1 case study. Two studies had the same participant group and intervention but reported different outcomes. Outcome data was available for n = =76 unique participants, with n = =82 completing a FES cycling intervention. Of the n = =4 papers with clear dropout rates, pooled dropout rate was 25.81%. Two papers reported non-significant improvements in aerobic capacity following a FES cycling intervention. Four papers reported no change in lower limb strength and two papers reported significant reductions in spasticity post training. Four studies failed to provide information regarding adverse events with the other studies reporting n = =10 adverse events across 36 participants.

      Conclusion

      Findings suggest FES cycle training may reduce CVD risk alongside trends for a reduction in spasticity post training, however the low quality of the literature precludes any definitive conclusions. FES cycle training appears to be well tolerated in PwMS with mobility impairment, with no serious adverse events.

      Keywords

      1. Introduction

      Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the Central Nervous System (CNS) and is characterised by inflammation and neurodegeneration of the myelin sheath, axons and grey and white matter (
      • Kierkegaard M.
      • Lundberg I.E.
      • Olsson T.
      • Johansson S.
      • Ygberg S.
      • Opava C.
      • et al.
      High-intensity resistance training in multiple sclerosis - An exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition.
      ;
      • Motl R.W.
      • Sandroff B.M.
      • Pilutti L.A.
      • Klaren R.E.
      • Baynard T.
      • Fernhall B.
      Physical activity, sedentary behavior, and aerobic capacity in persons with multiple sclerosis.
      ;
      • Motl R.W.
      Ambulation and multiple sclerosis.
      ;
      • Klaren R.E.
      • Motl R.W.
      • Dlugonski D.
      • Sandroff B.M.
      • Pilutti L.A.
      Objectively quantified physical activity in persons with multiple sclerosis.
      ;
      • Wens I.
      • Eijnde B.O.
      • Hansen D.
      Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.
      ). MS presents as symptoms of fatigue and impairment of both autonomic and somatic systems which have a deleterious impact on walking performance (and other types of physical activity), overall health, quality of life and ability to complete activities of daily living (ADLs) (
      • Motl R.W.
      • Sandroff B.M.
      • Pilutti L.A.
      • Klaren R.E.
      • Baynard T.
      • Fernhall B.
      Physical activity, sedentary behavior, and aerobic capacity in persons with multiple sclerosis.
      ;
      • Motl R.W.
      Ambulation and multiple sclerosis.
      ).
      In line with these limitations, people with MS (PwMS) frequently fail to engage in the recommended amounts of moderate-to-vigorous physical activity (MVPA) necessary to accrue health benefits (
      • Klaren R.E.
      • Motl R.W.
      • Dlugonski D.
      • Sandroff B.M.
      • Pilutti L.A.
      Objectively quantified physical activity in persons with multiple sclerosis.
      ). Moreover, studies of PwMS also report that they experience both real and perceived barriers to engaging in physical activity (PA), which when combined with reductions in physical function, may promote an inactive lifestyle resulting in physical deconditioning (
      • Wens I.
      • Eijnde B.O.
      • Hansen D.
      Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.
      ;
      • Stroud N.
      • Minahan C.
      • Sabapathy S.
      The perceived benefits and barriers to exercise participation in persons with multiple sclerosis.
      ).
      The consequences of insufficient PA and deconditioning may be particularly problematic in this cohort. PwMS are not immune to the increased risk of cardiovascular disease (CVD) occurring as a result of low levels of PA (
      • Heine M.
      • Wens I.
      • Langeskov-Christensen M.
      • Verschuren O.
      • Eijnde B.O.
      • Kwakkel G.
      • et al.
      Cardiopulmonary fitness is related to disease severity in multiple sclerosis.
      ;
      • Marrie R.A.
      • Reider N.
      • Cohen J.
      • Stuve O.
      • Trojano M.
      • Cutter G.
      • et al.
      A systematic review of the incidence and prevalence of cardiac, cerebrovascular, and peripheral vascular disease in multiple sclerosis.
      ;
      • Jadidi E.
      • Mohammadi M.
      • Moradi T.
      High risk of cardiovascular diseases after diagnosis of multiple sclerosis.
      ). Indeed, deaths from secondary chronic conditions such as hypertension, increased cholesterol and diabetes are common, and the mortality rate in PwMS is estimated as being between 1.7 to 3.5 times greater than that of the general population (
      • Lalmohamed A.
      • Bazelier M.T.
      • Van Staa T.P.
      • Uitdehaag B.M.J.
      • Leufkens H.G.M.
      • De Boer A.
      • et al.
      Causes of death in patients with multiple sclerosis and matched referent subjects: a population-based cohort study: causes of death in patients with MS.
      ;
      • Jick S.S.
      • Li L.
      • Falcone G.J.
      • Vassilev Z.P.
      • Wallander M.-A.
      Mortality of patients with multiple sclerosis: a cohort study in UK primary care.
      ). In addition, deconditioning may lead to an acceleration in the development of secondary complications from MS in an interdependent manner. Deconditioning has been suggested to impair physical function and exacerbate disease progression, resulting in further reductions in levels of PA, and an associated cycle of decline in health (
      • Wens I.
      • Eijnde B.O.
      • Hansen D.
      Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.
      ;
      • Sandroff B.M.
      • Sosnoff J.J.
      • Motl R.W.
      Physical fitness, walking performance, and gait in multiple sclerosis.
      ;
      • Sandroff B.M.
      • Pilutti L.A.
      • Motl R.W.
      Does the six-minute walk test measure walking performance or physical fitness in persons with multiple sclerosis?.
      ). Indeed, disease progression has been significantly correlated to reductions in aerobic capacity, muscular strength and walking performance (
      • Heine M.
      • Wens I.
      • Langeskov-Christensen M.
      • Verschuren O.
      • Eijnde B.O.
      • Kwakkel G.
      • et al.
      Cardiopulmonary fitness is related to disease severity in multiple sclerosis.
      ;
      • Sandroff B.M.
      • Sosnoff J.J.
      • Motl R.W.
      Physical fitness, walking performance, and gait in multiple sclerosis.
      ;
      • Pilutti L.A.
      • Sandroff B.M.
      • Klaren R.E.
      • Learmonth Y.C.
      • Platta M.E.
      • Hubbard E.A.
      • et al.
      Physical fitness assessment across the disability spectrum in persons with multiple sclerosis: a comparison of testing modalities.
      ;
      • Motl R.W.
      • Learmonth Y.C.
      Neurological disability and its association with walking impairment in multiple sclerosis: brief review.
      ).
      Disease progression in MS is monitored and assessed utilising the Expanded Disability Status Scale (EDSS) (
      • Kurtzke J.F.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      ). The scale describes different levels of impairment and ranges from 0 to 10, with 0 representing no symptoms and 10 representing death (
      • Kurtzke J.F.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      ). An EDSS score of 6.0 is an identifiable milestone on the scale, whereby the individual can walk a maximum of 100 m without stopping, even with the support of a unilateral assistive device (
      • Confavreux C.
      • Vukusic S.
      Natural history of multiple sclerosis: a unifying concept.
      ). As EDSS increases, PwMS are likely to participate in reduced amount of PA in comparison to those with lower EDSS, thus PwMS of disability levels of EDSS ≥ 6.0 are less likely to meet MVPA guidelines and have a greater risk of experiencing CV comorbidities (
      • Beckerman H.
      • de Groot V.
      • Scholten M.A.
      • Kempen J.C.E.
      • Lankhorst G.J.
      Physical activity behavior of people with multiple sclerosis: understanding how they can become more physically active.
      ). For example, vascular comorbidities have been significantly correlated to an increased risk of mobility impairment and speed of disability progression (
      • Marrie R.A.
      • Rudick R.
      • Horwitz R.
      • Cutter G.
      • Tyry T.
      • Campagnolo D.
      • et al.
      Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.
      ). Furthermore, whilst there is evidence that exercise has a multitude of health benefits for PwMS (
      • Latimer-Cheung A.E.
      • Pilutti L.A.
      • Hicks A.L.
      • Martin Ginis K.A.
      • Fenuta A.M.
      • MacKibbon K.A.
      • et al.
      Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development.
      ;
      • Platta M.E.
      • Ensari I.
      • Motl R.W.
      • Pilutti L.A.
      Effect of exercise training on fitness in multiple sclerosis: a meta-analysis.
      ;
      • Ewanchuk B.W.
      • Gharagozloo M.
      • Peelen E.
      • Pilutti L.A.
      Exploring the role of physical activity and exercise for managing vascular comorbidities in people with multiple sclerosis: a scoping review.
      ), few intervention studies have evaluated the effects of PA in persons with greater levels of impairment (e.g. EDSS of 6.0 and above).
      Sensorimotor impairments in MS typically impact on the lower limbs, with up to 75% of PwMS experiencing a gait impairment (
      • Lee Y.
      • Chen K.
      • Ren Y.
      • Son J.
      • Cohen B.A.
      • Sliwa J.A.
      • et al.
      Robot-guided ankle sensorimotor rehabilitation of patients with multiple sclerosis.
      ). This can make the use of upper body exercise appealing (
      • Skjerbæk A.
      • Næsby M.
      • Lützen K.
      • Møller A.
      • Jensen E.
      • Lamers I.
      • et al.
      Endurance training is feasible in severely disabled patients with progressive multiple sclerosis.
      ). Whilst both upper body and lower body exercises may have the potential to elicit cardiovascular adaptions in PwMS, it is important to note that the peripheral adaptation and conditioning of the lower limbs remain vital for PwMS's mobility and contribute to their ability to complete personal and instrumental ADLs (
      • Paltamaa J.
      • Sjogren T.
      • Peurala S.H.
      • Heinonen A.
      Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.
      ). Lower body function is of particular importance in enabling PwMS to remain independent since it supports the completion of personal ADLs such as self-care, transfer and locomotion (
      • Månsson E.
      • Lexell J.
      Performance of activities of daily living in multiple sclerosis.
      ).
      Functional Electrical Stimulation (FES) cycling is a suggested lower limb exercise intervention for individuals who have higher levels of impairment (
      • Davis G.M.
      • Hamzaid N.A.
      • Fornusek C.
      Cardiorespiratory, metabolic, and biomechanical responses during functional electrical stimulation leg exercise: health and fitness benefits.
      ). FES cycling can be used where individuals are unable to propel a cycle ergometer independently due to reduced physical function (
      • Davis G.M.
      • Hamzaid N.A.
      • Fornusek C.
      Cardiorespiratory, metabolic, and biomechanical responses during functional electrical stimulation leg exercise: health and fitness benefits.
      ). The intervention applies electrical stimulation to the lower limb muscles, which is appropriately timed to generate cyclical contractions to propel the cycle ergometer (
      • Duffell L.D.
      • Donaldson N.
      • de N.
      • Perkins T.A.
      • Rushton D.N.
      • Hunt K.J.
      • Kakebeeke T.H.
      • et al.
      Long-term intensive electrically stimulated cycling by spinal cord-injured people: effect on muscle properties and their relation to power output.
      ). This intervention has reported to benefit other neurological conditions, such as persons with incomplete or complete spinal cord injury (SCI), including increased lower limb skeletal muscle mass, muscular strength, and endurance whilst also improving aerobic capacity, and glucose metabolism (
      • Davis G.M.
      • Hamzaid N.A.
      • Fornusek C.
      Cardiorespiratory, metabolic, and biomechanical responses during functional electrical stimulation leg exercise: health and fitness benefits.
      ;
      • Thrasher T.
      • Ward J.
      • Fisher S.
      Strength and endurance adaptations to functional electrical stimulation leg cycle ergometry in spinal cord injury.
      ;
      • Griffin L.
      • Decker M.J.
      • Hwang J.Y.
      • Wang B.
      • Kitchen K.
      • Ding Z.
      • et al.
      Functional electrical stimulation cycling improves body composition, metabolic and neural factors in persons with spinal cord injury.
      ). In PwMS, FES cycling may support higher exercise intensities, enabling greater engagement with the level of MVPA than would be otherwise possible with passive leg cycling; increasing the potential for cardiovascular conditioning (
      • Edwards T.
      • Motl R.W.
      • Pilutti L.A.
      Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment.
      ). This methodology therefore, may be a feasible option for reducing comorbid CVD risk.
      Over the last decade, FES cycling has attracted an increased number of investigations due to the potential benefit this intervention has for PwMS, both in terms of supporting their physical functioning, and reducing CVD risk. To date, the evidence remains unclear as to the efficacy of FES cycling to support PwMS in maintaining cardiorespiratory and musculoskeletal health, and preventing the development of further comorbidities. No systematic evaluation has been conducted in this group. Given that FES cycling is a more appropriate intervention for those with higher levels of mobility impairment, the aim of this review is to systematically examine cardiovascular, musculoskeletal and functional outcomes in PwMS with mobility impairment following a FES cycling intervention.

      2. Methodology

      2.1 Search strategy

      This systematic review was conducted was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) statement (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the prisma statement.
      ). A comprehensive literature search was performed in order to examine the effect of FES cycling on cardiovascular, musculoskeletal and functional outcomes in PwMS. Four electronic databases (MEDLINE, Web of Science, CINAHL and PEDro) were searched from their inception to 8th January 2019. Search terms used were as follows: (“Multiple Sclerosis” OR “Progressive MS” OR “Relapsing Remitting MS”) AND (“NMES” OR “FES” OR “ESAC” OR “neuromuscular stimulation” OR “electrical stimulation” OR “stimulation-assisted cycl*” OR “assisted cycl*”). Table 1 provides an example of the search strategy. Filters were applied so that only research articles and articles that were peer-reviewed would be retrieved.
      Table 1Sample search strategy.
      #1“Multiple Sclerosis” OR “Progressive MS” OR “Relapsing Remitting MS” [all fields]
      #2“NMES” OR “FES” OR “ESAC” OR “neuromuscular stimulation” OR “electrical stimulation” OR “stimulation-assisted cycl*” OR “assisted cycl*” [all fields]
      #3#1 AND #2
      NMES = =Neuromuscular Electrical Stimulation, FES = =Functional Electrical Stimulation, ESAC = =Electrical Stimulation-Assisted Cycling.

      2.2 Description of the intervention

      FES cycling utilises a commercially available motorised ergometer (e.g. RT300, Restorative Therapies Inc, Baltimore, MD, USA), typically accessed from a seated position (
      • Thrasher T.
      • Ward J.
      • Fisher S.
      Strength and endurance adaptations to functional electrical stimulation leg cycle ergometry in spinal cord injury.
      ). This enables the user to remain on their wheelchair, reducing the requirement for transferring (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ). Stimulation electrodes are placed on the skin, typically above the quadriceps, hamstrings and glutei and a bilateral current is delivered to the muscles providing timed and cyclical stimulation necessary to produce a cycling motion (
      • Duffell L.D.
      • Donaldson N.
      • de N.
      • Perkins T.A.
      • Rushton D.N.
      • Hunt K.J.
      • Kakebeeke T.H.
      • et al.
      Long-term intensive electrically stimulated cycling by spinal cord-injured people: effect on muscle properties and their relation to power output.
      ;
      • Fornusek C.
      • Davis G.M.
      Cardiovascular and metabolic responses during functional electric stimulation cycling at different cadences.
      ). A target cadence is predetermined on the ergometer with suitable software amending the electrical stimulation and ergometer's resistance based on muscle fibre recruitment and fatigability (
      • Griffin L.
      • Decker M.J.
      • Hwang J.Y.
      • Wang B.
      • Kitchen K.
      • Ding Z.
      • et al.
      Functional electrical stimulation cycling improves body composition, metabolic and neural factors in persons with spinal cord injury.
      ). Where a participant has leg function, their individual volitional efforts will contribute to attaining the target cadence (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ).

      2.3 Inclusion criteria

      To be included in this review, the study had to (1) include human participants with definite diagnosis of MS (2) participants had to be aged 18 years and over (3) include participants with an average EDSS 6.0 or above, or an equivalent mobility impairment (4) evaluate FES cycling as an intervention study. Since the number of qualifying studies was anticipated to be small, no restrictions were placed on the type of study included in this review, and all qualifying studies were included regardless of study quality.

      2.4 Study selection

      Following searches of the relevant databases, results were imported into bibliographic software (Zotero: V 5.0.60, Fairfax, VA, USA). Subsequently, articles were screened to remove duplicates. Two authors (JS and NS) independently conducted a literature search and screened the title and abstracts of relevant papers to remove studies which clearly did not meet the inclusion criteria. Where it was not clear in the title or abstract if the study was suitable for inclusion, the full text was read. Using the inclusion criteria, both authors independently generated a list of eligible studies.

      2.5 Data extraction

      In addition to bibliographic data, the following information was extracted from each article by JS and verified by NS: (i) participant data (Table 2) (ii) intervention protocols (Table 3) (iii) intervention outcomes (Table 4).
      Table 2Summary of papers’ participant data.
      StudyStudy designnDrop outParticipant characteristicsMS Related measuresAnthropometric measures
      SexAge (Years)EDSS RangeMean EDSSDisease duration (Years)Type of MSHeight (cm)Body mass (kg)Body mass index (kg m−2)
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      )
      Pre-Post No Control14NRF = =7 M = =755.28 ± 10.98NRNR15.29 ± 7.35PP = =2 SP = =7 RR = =5NR
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      and
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      15
      RCTCON = =5, FES = =6CON = =1, FES = =2CON: F = =4, FES: F = =3 M = =1CON: 48.5 ± 7.7, FES: 57.3 ± 6.05.5–6.5CON: 6.3 ± 0.9, FES: 6.3 ± 0.5CON: 20.8 ± 8.5, FES: 22.3 ± 5.3CON: P = =2 RR=2, FES: P = =2 RR=2CON: 160.5 ± 9.2, FES: 161.1 ± 10.4CON: 85.8 ± 46.0, FES: 70.6 ± 19.5CON: 32.1 ± 13.9, FES: 27.2 ± 7.4
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      )
      Pre-Post No Control81F = =839 ± 146.5–8.57.3 ± 0.7NRSP = =8NR
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      )2
      RetrospectiveCON = =10, FES = =30NRF = =27 M = =1354.7 ± 122.5–7.56.0 ± 1.416.8 ± 12.7PP = =12 SP = =14 RR = =14NR
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      Case Study1NRM = =1467.5NRSP = =1NR
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      )
      Pre-Post No Control51F = =2 M = =350 (median) (range 46–60)6.0–6.56.5 (median)13 (median) (range 6–21)PP = =2 SP = =3NR
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      )3
      Pre-Post No Control14NRF = =1 M = =754.5 ± 13.9NRNR16.8 ± 6.9PP = =2 SP = =4 RR = =2NRNR24.7 ± 3.3
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      )4
      Pre-Post No Control124F = =1 M = =1150.9 ± 6.94.0–8.06.5 ± 1.115.3 ± 8.2P = =8NR
      Inclusion criteria of all papers equated to mean EDSS ≥ 6.0. 1, demographic data only given for those that completed the intervention; 2, demographic data not split by control and intervention; 3, demographic data only given for those for those with measurable mVO2; 4, EDSS unknown for n = =1; 5; two papers appear to be same participants and same intervention and have been grouped to prevent double counting; F, female; M, male; PP, Primary Progressive; RR, Relapsing Remitting; SP, Secondary Progressive; P, Progressive; Con, Control Group; FES, FES Cycling Group; NR, Not Reported. Data are mean ± SD unless otherwise stated.
      Table 3Summary of papers’ intervention protocols.
      StudyStudy designApparatusMuscles stimulatedTarget cadence (rpm)Stimulation settingsSession duration (mins)FrequencyStudy duration (weeks)Total number of sessionsTotal training volume (mins)Continuous stimulation (C)/Intervals of stimulation (I)ProgressionSettingSupervised (Y/N)Notes
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      )
      Pre-Post No ControlRT300Quadriceps, Hamstrings & Gluteals35–50PW = =200 μs; F = 50 Hz303 x a week412360C↑ 0.14 Nm Increments (if 3 sessions for 30 mins continuously)ClinicalYIf participant was unable to cycling for 30-mins, the cycle entered a passive mode for remainder of session
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      and
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      1
      RCTRT300Quadriceps, Hamstrings & Gluteals40–50PW = =250 μs; F = 50 Hz10 → 303 x a week24721800C↑10 min after 4 weeks (until 30 min reached)ClinicalYCON completed on same apparatus.
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      )
      Pre-Post No ControlMotomed Viva 1.5 & Custom Muscle StimulatorQuadriceps, Hamstrings & Gluteals10PW = =300 μs; F = 35 Hz; Initial SA = =30 = mA40≈ 1.8 x a week≈ 1018720C↑ SA at constant rate to reach predetermined level at 20 min. Then 20 mins at SAClinicalYParticipants instructed not to push voluntarily during the training.
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      )
      RetrospectiveRT300, MotoMed FES Ergometer, Portable Neuromuscular Electrical Stimulation Units 300PV & SWISS Stim among othersNRNRNR≥60≈ 4.4 h total ABRT a month≈ 8≈ 16≈ 960NRNRClinicalYPart of wider ABRT program. The average prescribed 12-month ABRT consisted of two 3-hour sessions per week administered in two blocks of 4 weeks each.
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      Case StudyConstant Current 8-channel StimulatorQuadriceps, Gluteals & Femoral BicepsNRSA: 30 → 90 mA≥301 x a week22≈ 60IStimulation increased with toleranceClinicalYShort breaks of 3–5 mins
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      )
      Pre-Post No ControlRT300Quadriceps, Hamstrings & GlutealsNRInitial PD = =250 ± 25% = %μs; Initial F = 33–45 = Hz≥60≈ 3.8 x a week24NR≈ 5472NRNRHomeNAsked to use at least 3 times per week for at least an hour per session
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      )
      Pre-Post No ControlRT300Quadriceps, Hamstrings & Gluteals40–50NR30≈ 3 x a week4–512360C↑ 0.14 Nm Increments (if 3 sessions for 30 mins continuously)ClinicalYStimulation gradually increased to cause cycling at 50 rpm. If participant was unable to cycling for 30-mins, the cycle entered a passive mode for remainder of session
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      )
      Pre-Post No ControlTheravital Cycle Ergometer & Constant Current 8-channel StimulatorQuadriceps & HamstringsNRF = 20 Hz; Max SA = =127 mA, Constant PW = =300 μs12–183 x a week2672–108INRClinicalYn = =11 received conventional physiotherapy 5 times a week, and outpatient n = =1 attended conventional physiotherapy sessions twice a week. Highest cycling resistance was selected that would allow the subject to tolerate well 12–18 min of active ergometric pedalling (with and without stimulation), but at the same time not become too exhausted.
      1, two papers appear to be same participants and same intervention and have been grouped to prevent double counting; F, frequency; PW, pulse width; PD, phase duration; SA, stimulation amplitude; NR, not reported; ABRT, Activity Based Restorative Therapy; RT300, Restorative Therapies Inc, Baltimore, MD, USA; Motomed Viva 1.5, Reck Medixintechnik GmBH, Betzenweiller, Germany; Motomed FES Ergometer, Reck Medixintechnik GmBH, Betzenweiller, Germany; Portable Neuromuscular Electrical Stimulation Units 300PV, Empi, St Paul, MN, USA; SWISS Stim, Valmed, Sion, Swizerland; Constant Current 8-channel Stimulator, Krauth + Timmermann, Germany; Theravital, Medica-Medizintechnik Ltd, Hochdorf, Germany.
      Table 4Summary of papers’ objective outcome measures.
      StudyOutcome Measures Pre-Post InterventionAdverse EventsType of Adverse Events Reported
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      )
      Resistance or Time during FESC Power during FESC, Lower Limb Strength (Combined MMT of Bilateral HF, KF, KE and AD), Spasticity (MAS), Fatigue (MFIS), Pain (MOS PES), Mental Health (MHI), QOL (MSQLI)0
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      and
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      1
      T25FW, MSWS-12, 2MW, TUG, VO2peak, WRpeak, KE Strength, KF Strength, Leg FFM, Leg FM, Leg % Fat, Leg BMD, Cognition (SDMT), Fatigue (FSS, MFIS), Pain (SF-MPQ), QOL (MSIS-29)7 (6 Min, 1 Mod)Min (n = =6): Skin Irritation/Redness n = =3, Non-Debilitating Fatigue n = =2, Increased Muscle Spasticity n = =1 Mod (n = =1): Fall Outside of Training
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      )
      Left and Right Thigh CircumferenceNRNR
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      )
      Lower Extremity Motor (ISNCSCI) ↔ Upper Extremity Motor (ISNCSCI), Light Touch (ISNCSCI), Pin Prick (ISNCSCI)NRNR
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      Spasticity (MAS)NRNR
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      )
      GDNF, IFNγ, IL-8, MIP-1α, MCP-1 EDSS, 2MW, T25FW, 9HPT, PASAT, TUG, KE Strength, KF Strength, HE Strength, HF Strength, FD Strength, Lower Limb Sensation, Spasticity (LLSMS), Gait, QOL (SF-36), Mental Health (SCL-90), Other cytokines, chemokines and growth factors3 (2 Min, 1 Mod)Min (n = =2): Bowel Incontinence n = =1, Increased Muscle Spasticity n = =1 Mod (n = =1): Fall Outside of Training
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      )
      Resistance or Time during FESC, mVO20
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      )
      Power during FESC, Smoothness during FESC, 10MWT (ST & LT), KE Strength, KF Strength, Spasticity (MAS, LT) Spasticity (MAS; ST)NRNR
      ↑, significant increase (p ≤ 0.05); ↔, no significant change; ↓, significant decrease (p ≤ 0.05); 1, two papers appear to be same participants and same intervention and have been grouped to prevent double counting; Min, minor adverse event; Mod, moderate adverse event; FESC, functional electrical stimulation cycling; HE, hip extensor; HF, hip flexor; KF, knee flexor; KE, knee extensor; AD, ankle dorsiflexor; FD, foot dorsiflexor; MMT, manual muscle test; MAS, modified ashworth scale; MFIS, modified fatigue impact scale; SDMT, symbol digit modalities test; SF-MPQ, short-form McGill pain questionnaire; MOS PES, medical outcomes study pain effects scale; MHI, mental health inventory; QOL, quality of life; MSQLI, multiple sclerosis quality of life index; SF-36 = =short-form 36; SCL-90, symptom checklist-90; FSS, fatigue severity scale; T25FW, timed 25-foot walk test; 2MW, 2-minute walk; MSWS-12, 12-item multiple sclerosis walking scale; TUG, timed up-and-go; FFM, fat-free mass; FM, fat mass; BMD, bone mineral density; MSIS-29, 29-item multiple sclerosis impact scale; ISNCSCI, international standards for neurological classification of spinal cord injury; 9HPT, 9-hole peg test; PASAT, paced auditory serial addition test; LLSMS, lower limb spasticity measurement system; GDNF, glial cell-derived neurotrophic factor; IFNγ, interferongamma; IL-8, interleukin-8; MIP-α, macrophage inflammatory protein-1 alpha; MCP-1, monocyte chemotactic protein-1; 10MWT, 10 m Walk Test; ST, Short-Term; LT, Long-Term.

      2.6 Study quality assessment

      Study quality was appraised using four different tools based on study type. The majority of studies were evaluated using the tools designed by the National Heart, Lung and Blood Institute (NHLBI), specifically cohort studies (
      Quality Assessment for Before-After (Pre-Post) Studies With No Control Group [Internet]
      National Heart, Lung and Blood Institute (NHLBI).
      ) and RCTs (
      Quality Assessment of Controlled Intervention Studies [Internet]
      National Heart, Lung and Blood Institute (NHLBI).
      ). Case studies were evaluated using the tools developed by
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      ) and retrospective studies using the Newcastle-Ottawa Scale (
      • Wells G.A.
      • Shea B.
      • O'Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non Randomised Studies in Meta-Analyses [Internet].
      ).

      3. Results

      Fig. 1 denotes the literature search and screening process undertaken. The initial search found 1162 potential articles supplemented with 1 study from an external source; with 9 of these meeting the inclusion criteria. Of these, 5 were pre-post studies with no control group (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ), two were Randomised Controlled Trials (RCTs) (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ), one was a retrospective study (
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ) and one was a case study (
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). Two papers reported different outcomes on the same participant group following the same intervention (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). As a result, there was a total of 9 papers which underwent quality assessment, however these 9 papers describe 8 different interventions. For clarity, the remainder of this review will refer to papers, not interventions.
      Fig. 1
      Fig. 1PRISMA flow diagram of literature search and review process.

      3.1 Demographic information

      The mean participant EDSS in each study was ≥6.0. Of the 9 selected papers, four did not exclusively feature participants with EDSS ≥ 6.0 (
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). Two papers did not report participant EDSS however their inclusion criteria approximately equated to that of participants with mobility impairment and EDSS ≥ 6.0 (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). The highest level of impairment reported in participants was EDSS 8.5 (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ). Six papers utilised participants with both progressive and relapsing remitting MS (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). Three exclusively recruited participants with progressive MS (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). One study only provided age range therefore from the other 8 papers with extractable data, the mean participant age was 50.77 ± 10.21 years and disease duration 17.14 ± 8.35 years. Two papers, which reported on the same participants reported body height and mass (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Three papers reported BMI in kg/m2 (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ).
      In three papers, data were only provided for participants who completed the FES cycling intervention (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). The same three papers failed to identify the number of participants recruited and drop outs (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). Whilst one of the remaining papers was a case study, the other 5 papers reported dropout rates (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Two of these papers failed to provide demographic data for participants who withdrew (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). In the four remaining papers a total of 23 out of 31 participants who started the FES cycling protocol completed and 8 dropped out; resulting in a pooled dropout rate of 25.81% (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ).
      One paper only provided demographic information for those participants where the main outcome, muscle oxygen consumption (mVO2), was successfully measured (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). Resting and Peak Heart Rate (HR) was provided in one paper, however these were from baseline assessments and not measured pre and post intervention (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ).

      3.2 Protocols

      Intervention duration ranged between 2 and 24 weeks. Eight papers were completed under supervision in a clinical exercise setting (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ) and the remaining paper was undertaken unsupervised at home (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ). Seven papers conducted 2/3 sessions per week for a range of 2–24 weeks (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). The other two papers were once every week for 2 weeks (
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ) or completed in two blocks of 4 weeks (
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ).
      In two papers, the protocol was unclear (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). The protocol of five papers was to cycle continuously for a minimum of 10–60 min utilising FES (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Of these, the protocol for four papers was to reach a point where a participant could complete 30 min of FES cycling at a target cadence of 35–50 rpm (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Two papers utilised periods of stimulation interspersed with periods of rest (
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ).

      3.3 Cardiorespiratory performance

      One paper investigated mVO2 and reported no improvement following a FES cycling intervention (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). One paper measured peak aerobic capacity (VO2peak) across control and intervention groups and measured no change (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Peak work rate (WRpeak) was measured in one paper, with no improvement following the intervention (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Two papers measured power generation during FES cycling across the duration of the intervention, reporting no change (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ). In two papers, where participants could cycle continuously for 30 min, the resistance at which they could cycle significantly increased (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). Conversely, in the same two papers, where participants were unable to cycle continuously for 30 min, active cycling time significantly increased (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ).

      3.4 Functional performance

      Walking performance was measured in three papers in a variety of tests; 2-min walk test (2MW) (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ), timed 25-foot walk test (T25FW) (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ), 10 m Walk Test (10MWT) (
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ) and 12-item MS Walking Scale (MSWS-12) (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). All three papers reported insignificant changes (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Timed Up-and-Go (TUG) performance was measured in two papers; with no change post FES cycling (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ).

      3.5 Musculoskeletal outcomes

      Lower body strength was commonly measured in the Knee Extensors (KE), Knee Flexors (KF), Hip Extensors, Hip Flexors and/or Dorsiflexors or in combined tests (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Three papers found no improvement in either KE or KF strength (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Combined strength testing of the Hip Flexors, KE, KF & Dorsiflexors did not change (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ). One study, that observed a significant increase in thigh volume failed to measure changes in muscle mass or fat free mass in order to ascertain the cause of such increase (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ).
      The most frequently measured parameter was spasticity (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). Three papers utilised the Modified Ashworth Scale (MAS) (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). One study utilised the Lower Limb Spasticity Measurement System (LLSMS) (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ). One study used self-reporting (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ). Three papers reported a reduction in spasticity post FES cycling; two papers described significant improvements in spasticity directly post FES cycling (
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ) and one paper described self-evaluated measures on an unspecified time frame (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ). Four papers reported no longer term improvements when measures were taken on different days (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ).

      3.6 Psychological outcomes

      Two papers evaluated mental health finding no change utilising the Mental Health Inventory (MHI) and Symptom Checklist-90 accordingly (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ). Quality of Life was measured in three papers with no significant change post FES cycling (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ).

      3.7 Adverse events

      Four papers did not explicitly report any information regarding adverse events (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). Of the five remaining papers, a total of 36 participants reported 10 adverse events; none of which were described as serious (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Only two papers specifically discuss MS-related adverse events and in both cases, none were reported (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). Two papers reported 8 minor events which included skin irritation, increased spasticity, bowel dysfunction and fatigue (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). Two papers both reported a moderate adverse event which caused a participant to drop out; both of which were falls noted by researchers as unrelated to the intervention (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ).

      3.8 Study quality

      The study quality assessment tools indicated that papers consistently had unclear or insufficient sample sizes to provide confidence in the findings (Table 5, Table 6, Table 7, Table 8). The largest sample size was that of a retrospective study, which contained 40 participants (
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ). Of the 8 other papers, sample size ranged from 1 to 14 (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). Across all nine papers, 82 participants were reported to complete a FES cycling intervention, but outcome data was only provided for 76 (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). Only two papers had a blinded assessment of outcome measures (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Across the 7 papers with cohort study designs (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ), only 2 reported a dropout rate ≤20% (
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ). None of the papers included in this review recorded outcome measures multiple times following a FES cycling intervention (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ;
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ).
      Table 5NHLBI quality qssessment tool for before-after (Pre-Post) studies with no control group.
      StudyResearch question clear?Participant eligibility criteria clear?Participants representative of clinical population of interest?Were all eligible participants enrolled?Was sample size sufficiently large to provide confidence in the findings?Was the intervention clearly described and delivered consistently?Outcome measures prespecified, clear, valid and reliable? Assessed consistently?Blinded assessment of outcomes?Loss to follow-up after baseline ≤20%Did the statistical method examine changes pre and post intervention? p values provided?Outcome measures taken multiple times pre and post intervention?
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      )
      YYYYUCYYNNRYN
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      )
      YYYYUCYNNYNN
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      )
      YYYYNYYNYNN
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      )
      YYYYUCYYNNRYN
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      )
      YYYYUCYYNNYN
      Y, yes; N, no; UC, unclear; NR, not reported.
      Table 6Quality assessment of case reports and case series.
      StudyDomain
      SelectionAscertainmentCausalityReporting
      Patient represent whole experience of the investigator or is the selection method unclear to the extent that other patients with similar presentation may not have been reported?Exposure adequately ascertained?Outcome adequately ascertained?Other alternative causes that may explain the observation ruled out?Challenge/rechallenge phenomenon?Dose–response effect?Follow-up long enough for outcomes to occur?Case described with sufficient details to allow other investigators to replicate the research or to allow practitioners make inferences related to their own practice?
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      UCYYNNNYY
      Y, yes; N, no; UC, unclear.
      Table 7NHLBI quality qssessment for controlled intervention studies.
      StudyStudy described as RCT?Method of randomisation adequate?Treatment allocation concealed?Study participants and providers blinded to treatment group assignment?Outcome assessors blinded to participants' group assignments?Groups similar at baseline on important characteristics that could affect outcomes?Drop out rate at endpoint ≤20% or lower of number allocated to treatment?Differential drop-out rate at endpoint ≤15%High adherence to intervention protocols for each treatment group?Were other interventions avoided or similar in the groups?Were outcomes assessed using valid and reliable measures, implemented consistently across all participants?Sample size sufficiently large to detect difference in main outcome between groups with ≥80% power?Outcomes reported or subgroups analysed prespecified?All randomised participants analysed in group to which they were originally assigned?
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      and
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      1
      YYYNYYNYYNRYNYN
      Y, yes; N, no; NR, not reported; 1, two papers appear to be same participants and same intervention and have been grouped to prevent double counting.
      Table 8Newcastle-Ottawa quality assessment scale for case control studies.
      StudyDomain
      SelectionComparabilityOutcome
      Case Definition Adequate?Representativeness of casesSelection of controlsDefinition of controlsComparability of cases and controls on basis of design or analysisAscertainment of exposureSame ascertainment for cases and controlsNon-response rate
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      )
      one star.
      one star.
      one star.
      one star.
      one star.

      4. Discussion

      The aim of this systematic review was to conduct a comprehensive literature search examining the effect of FES cycle training on cardiovascular, musculoskeletal and functional outcomes in PwMS and EDSS ≥ 6.0. The heterogeneity in outcome measures across the nine papers prevented a meta-analysis. The low quality of the literature base precludes any definitive conclusions regarding the efficacy of FES cycle training in improving cardiovascular health in PwMS and higher EDSS scores. In the present review, one of the main findings is that FES cycle training appears to be well tolerated in PwMS with mobility impairment, with no serious adverse events.

      4.1 Cardiorespiratory performance

      Aerobic capacity is a strong indicator of cardiovascular fitness and associated CVD risk in PwMS (
      • Heine M.
      • Wens I.
      • Langeskov-Christensen M.
      • Verschuren O.
      • Eijnde B.O.
      • Kwakkel G.
      • et al.
      Cardiopulmonary fitness is related to disease severity in multiple sclerosis.
      ). CVD is of particular risk for PwMS, with papers demonstrating that PwMS are more likely to have CVD in comparison to healthy controls (
      • Wens I.
      • Eijnde B.O.
      • Hansen D.
      Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.
      ;
      • Mincu R.I.
      • Magda S.L.
      • Mihaila S.
      • Florescu M.
      • Mihalcea D.J.
      • Velcea A.
      • et al.
      Impaired cardiac function in patients with multiple sclerosis by comparison with normal subjects.
      ). Although definitive data is lacking, it is plausible that those with the greatest level of mobility impairment are subject to an increased risk of CVD, with a significant correlation between disease progression and aerobic capacity (
      • Heine M.
      • Wens I.
      • Langeskov-Christensen M.
      • Verschuren O.
      • Eijnde B.O.
      • Kwakkel G.
      • et al.
      Cardiopulmonary fitness is related to disease severity in multiple sclerosis.
      ;
      • Pilutti L.A.
      • Sandroff B.M.
      • Klaren R.E.
      • Learmonth Y.C.
      • Platta M.E.
      • Hubbard E.A.
      • et al.
      Physical fitness assessment across the disability spectrum in persons with multiple sclerosis: a comparison of testing modalities.
      ). Whilst aerobic training has been demonstrated to reduce this CVD in PwMS (
      • Howe J.-A.A.
      • Gomperts M.A.
      Aerobic testing and training for persons with multiple sclerosis: a review with clinical recommendations.
      ); the majority of this work has been in those with EDSS < 6.0, whereas those with higher mobility impairment (e.g. EDSS ≥ 6.0) have been poorly researched in the literature (
      • Howe J.-A.A.
      • Gomperts M.A.
      Aerobic testing and training for persons with multiple sclerosis: a review with clinical recommendations.
      ). FES cycling has the potential to increase the dose of exercise attainable in PwMS with higher mobility impairment, and could therefore increase aerobic capacity and PA (
      • Edwards T.
      • Motl R.W.
      • Pilutti L.A.
      Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment.
      ;
      • Dolbow D.R.
      • Gorgey A.S.
      • Ketchum J.M.
      • Gater D.R.
      Home-based functional electrical stimulation cycling enhances quality of life in individuals with spinal cord injury.
      ). However, despite this potential, from the evidence of this review, the effectiveness of FES cycling in improving aerobic capacity is equivocal. Only two papers recorded valid objective measures of aerobic capacity (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). One paper found a significant increase in peripheral oxygen consumption (mVO2) following 360 min of FES cycle training across 4 weeks while the other study reported trends for improvement in VO2peak that fell short of statistical significance (
      • Wells G.A.
      • Shea B.
      • O'Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non Randomised Studies in Meta-Analyses [Internet].
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ). In both cases, the samples were small (n ≤ 8) and the studies were underpowered, making it difficult to draw definitive conclusions.
      Walking tests are associated with aerobic capacity in PwMS (
      • Sandroff B.M.
      • Sosnoff J.J.
      • Motl R.W.
      Physical fitness, walking performance, and gait in multiple sclerosis.
      ). In the present review, walking performance was the most frequently utilised functional test (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ) however no papers reported any improvements. This apparent limited effectiveness may be due to the lack of specificity since walking performance is also reliant on balance and lower limb strength asymmetries (
      • Sandroff B.M.
      • Sosnoff J.J.
      • Motl R.W.
      Physical fitness, walking performance, and gait in multiple sclerosis.
      ). Moreover, whether different doses of exercises would be more effective (e.g. longer duration or higher intensity) remain to be determined. Indeed, the high level of variability within the FES cycling interventions makes it difficult to attribute any changes to a specific protocol. While four of the nine papers had similar protocols (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ), only two had matched training volumes and outcome measures in both papers had a high level of variability (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Fornusek C.
      • Hoang P.
      Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis.
      ).

      4.2 Cardiovascular risk factors

      Obesity, typically measured utilising BMI, is a well-accepted and independent risk factor for CVD (
      • Poirier P.
      • Giles T.D.
      • Bray G.A.
      • Hong Y.
      • Stern J.S.
      • Pi-Sunyer F.X.
      • et al.
      Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American heart association scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism.
      ). Given the increased risk of CVD in PwMS compared to the general population, it is surprising that only two papers provided BMI data (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). One paper gave baseline measures for BMI (
      • Reynolds M.A.
      • McCully K.
      • Burdett B.
      • Manella C.
      • Hawkins L.
      • Backus D.
      Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis.
      ). The other paper provided more nuanced assessment of fat free mass, fat mass and bone density (measured utilising a bone densitometer) and reported no change following FES cycle training (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ). The overall poor reporting of BMI and small sample size in
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ) makes it difficult to assess the role of FES cycle training in preventing obesity as a CVD risk factor.
      However, the accuracy of standard BMI thresholds for persons with lower limb impairment have been questioned since BMI does not distinguish between muscle and fat compartments (
      • Bandini L.
      • Danielson M.
      • Esposito L.E.
      • Foley J.T.
      • Fox M.H.
      • Frey G.C.
      • et al.
      Obesity in children with developmental and/or physical disabilities.
      ). Consequently, in persons with reduced lower limb muscle tone and bone density, BMI thresholds designed for able bodied persons may underestimate the risk of increased body fat (
      • Bandini L.
      • Danielson M.
      • Esposito L.E.
      • Foley J.T.
      • Fox M.H.
      • Frey G.C.
      • et al.
      Obesity in children with developmental and/or physical disabilities.
      ). Notably, in this regard FES cycling has been reported to improve body composition including increase in lean tissue in persons with SCI (
      • Frotzler A.
      • Coupaud S.
      • Perret C.
      • Kakebeeke T.H.
      • Hunt K.J.
      • Donaldson N.N.
      • et al.
      High-volume FES-cycling partially reverses bone loss in people with chronic spinal cord injury.
      ). However, the potential of FES cycling to produce similar effects in PwMS is yet to be investigated.

      4.3 Spasticity

      Spasticity is a common and debilitating symptom for persons with MS (
      • Haas J.
      Pathophysiology, assessment and management of multiple sclerosis spasticity: an update.
      ;
      • Pozzilli C.
      Overview of MS spasticity.
      ). In particular, this is important for PwMS since disease progression and duration are both strongly correlated with spasticity and reductions in mobility (
      • Pozzilli C.
      Overview of MS spasticity.
      ;
      • Tintoré M.
      Advances in the management of multiple sclerosis symptoms: pathophysiology and assessment of spasticity in multiple sclerosis.
      ). Alongside a reduction in mobility and associated independence, spasticity can also be a direct source of MS-related pain (
      • Truini A.
      • Barbanti P.
      • Pozzilli C.
      • Cruccu G.
      A mechanism-based classification of pain in multiple sclerosis.
      ). FES cycling has been suggested as a possible support mechanism for spasticity since it is associated with a reduction in spastic muscle tone in persons with SCI (
      • Jain N.B.
      • Higgins L.D.
      • Katz J.N.
      • Garshick E.
      Association of shoulder pain with the use of mobility devices in persons with chronic spinal cord injury.
      ) but the degree to which this is the case with PwMS remains to be determined.
      Spasticity was the most commonly recorded measure, and FES cycle training appears to acutely improve symptoms of spasticity but this does not appear to translate into medium term effects (defined as approximately 48 h after training) (
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Krause P.
      • Szecsi J.
      • Straube A.
      FES cycling reduces spastic muscle tone in a patient with multiple sclerosis.
      ). No papers evaluated longer term effects of FES cycling and thus the effect of FES cycle training in reducing spasticity > 48 h remains unclear. The MAS was the most frequently utilised measurement within this review and is commonly used to measure spasticity in persons with MS (
      • Tintoré M.
      Advances in the management of multiple sclerosis symptoms: pathophysiology and assessment of spasticity in multiple sclerosis.
      ). That being said, a number of limitations are reported with the MAS related to inter-rater reliability, sensitivity to change and insufficient guidelines regarding its use (
      • Frotzler A.
      • Coupaud S.
      • Perret C.
      • Kakebeeke T.H.
      • Hunt K.J.
      • Donaldson N.N.
      • et al.
      High-volume FES-cycling partially reverses bone loss in people with chronic spinal cord injury.
      ;
      • Pozzilli C.
      Overview of MS spasticity.
      ). Future studies should look to use more robust measures of spasticity with less subjectivity.

      4.4 Lower limb muscular strength

      Lower Limb Muscular Strength is correlated to walking performance in PwMS and is important in enabling PwMS to complete personal and instrumental ADLs (
      • Månsson E.
      • Lexell J.
      Performance of activities of daily living in multiple sclerosis.
      ;
      • Kjølhede T.
      • Vissing K.
      • Dalgas U.
      Multiple sclerosis and progressive resistance training: a systematic review.
      ). Clearly, one aim of FES cycling is to stimulate the musculature of the lower limbs thus aiming to increase strength, reduce the rate of decline and preserve function in the lower body; with the potential to support PwMS's ability to maintain ADLs. Moreover when this lower limb function is lost, this in turn translates into greater loads being placed on the upper body and a higher risk of chronic upper body injury (
      • Jain N.B.
      • Higgins L.D.
      • Katz J.N.
      • Garshick E.
      Association of shoulder pain with the use of mobility devices in persons with chronic spinal cord injury.
      ;
      • Haubert L.L.
      • Gutierrez D.D.
      • Newsam C.J.
      • Gronley J.K.
      • Mulroy S.J.
      • Perry J.
      A comparison of shoulder joint forces during ambulation with crutches versus a walker in persons with incomplete spinal cord injury.
      ). Four papers assessed this outcome, however no improvements in lower body muscular strength following FES cycle training were found within the present review (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ).
      Clearly, cycling is generally considered to be aerobic in nature and may be considered to produce modest increases in muscular strength. Indeed, to elicit skeletal muscle hypertrophy in healthy populations using aerobic exercise, the optimum exercise intensity is suggested as a minimum of 70% HR reserve (HRR), 4 times a week for 30 min (
      • Konopka A.R.
      • Harber M.P.
      Skeletal muscle hypertrophy after aerobic exercise training.
      ). Given that none of the papers included in this review had sufficient exercise volume to equate to this, nor was %HRR or %VO2peak set as a target within the interventions, it is perhaps not surprising that no changes in strength were noted. Moreover, FES cycling can be considered as a dynamic training modality with moderate speeds of muscle contraction. However, in all cases, strength was assessed isometrically using semi-quantitative (
      • Backus D.
      • Burdett B.
      • Hawkins L.
      • Manella C.
      • McCully K.K.
      • Sweatman M.
      Outcomes after functional electrical stimulation cycle training in individuals with multiple sclerosis who are nonambulatory.
      ;
      • Szecsi J.
      • Schlick C.
      • Schiller M.
      • Pöllmann W.
      • Koenig N.
      • Straube A.
      Functional electrical stimulation-assisted cycling of patients with multiple sclerosis: biomechanical and functional outcome – a pilot study.
      ), static (
      • Hammond E.R.
      • Recio A.C.
      • Sadowsky C.L.
      • Becker D.
      Functional electrical stimulation as a component of activity-based restorative therapy may preserve function in persons with multiple sclerosis.
      ) or isokinetic (
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ) methods. It is well established that changes in strength are specific to the speed and type of contraction used in training, and outcome measures should reflect the training mode (
      • Baker D.
      • Wilson G.
      • Carlyon B.
      Generality versus specificity: a comparison of dynamic and isometric measures of strength and speed-strength.
      ). Indeed, strong correlations only existed between isometric and dynamic strength using large forces, or explosive power as anticipated (
      • Juneja H.
      • Verma S.K.
      • Khanna G.L.
      Isometric strength and its relationship to dynamic performance: a systematic review.
      ), which was not the case in the interventions used in the papers.
      Consequently, the conclusion that FES cycling does not improve strength in PwMS with EDSS ≥ 6.0 should be viewed with caution, and must be re-evaluated with more appropriate protocols, given the mismatch between training stimulus and outcome assessment. Evidence has shown that PwMS and mobility impairment can reach higher %HRpeak during an acute bout of FES cycling in comparison to passive leg cycling (76.4%HRpeak vs 55.5%HRpeak) (
      • Edwards T.
      • Motl R.W.
      • Pilutti L.A.
      Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment.
      ). This supports the theory that FES cycling protocols have the potential to provide increases in strength. A further limitation is that of the papers in this review, only two interventions were longer than 10 weeks and in both cases, sample sizes were too small to make meaningful interpretations (n = =4 completed in both cases) (
      • Ratchford J.N.
      • Wendy S.
      • R H.E.
      • Gregory R.J.
      • Robert R.
      • Pingting N.
      • et al.
      A pilot study of functional electrical stimulation cycling in progressive multiple sclerosis.
      ;
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      • Pilutti L.A.
      Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.
      ;
      • Pilutti L.A.
      • Edwards T.
      • Motl R.W.
      • Sebastião E.
      Functional electrical stimulation cycling exercise in persons with multiple sclerosis: secondary effects on cognition, symptoms, and quality of life.
      ). Another consideration for those papers that measured muscular strength, is that the majority had no control group. As disease progression is correlated to reductions in lower limb muscular strength, future research should look to determine if maintenance of muscular strength is clinically meaningful over time in comparison to controlled counterparts (
      • Sandroff B.M.
      • Sosnoff J.J.
      • Motl R.W.
      Physical fitness, walking performance, and gait in multiple sclerosis.
      ).

      4.5 Adverse events & adherence

      Accurate reporting of adverse events is particularly important in this group since there are few intervention papers evaluating the benefits of PA in persons with EDSS ≥ 6.0 (
      • Latimer-Cheung A.E.
      • Pilutti L.A.
      • Hicks A.L.
      • Martin Ginis K.A.
      • Fenuta A.M.
      • MacKibbon K.A.
      • et al.
      Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development.
      ;
      • Platta M.E.
      • Ensari I.
      • Motl R.W.
      • Pilutti L.A.
      Effect of exercise training on fitness in multiple sclerosis: a meta-analysis.