Physical Fitness and Exercise Training on individuals with Spina Bifida: a 1 systematic review 2

ABSTRACT


RESEARCH HIGHLIGHTS
• Individuals with SB have impaired physical fitness; • Data on body composition, flexibility and neuromotor fitness in SB are scarse; • Exercise training improve cardiorespiratory endurance and muscle strength.

Introduction
Spina Bifida (SB) is a consequence of a malformation in the caudal neural tube, which results in a heterogeneous range of structural defects affecting the spinal cord, cerebrum and brainstem (Botto, Moore, Khoury, & Erickson, 1999;Mitchell, et al., 2004).The worldwide incidence is on average 2-8 per 10000 live births, and, due to medicine advances, aproximetly 60% of individuals with SB are expected to survive until early adulthood (Chamberlain & Kent, 2005;Kondo, Kamihira, & Ozawa, 2009).The four most common types of SB are SB occulta, SB cystica, meningocele, lipomyelomeningocele (LMMC) and myelomeningocele (MMC), being MMC the most severe and common presentation of the disease (Botto, et al., 1999;Jenkinson, et al., 2011;National Health Service, 2011).
Depending on the type and level of the lesion, impairments related to defits in cognition, motor function and sensory function may arise (Özek, Cinalli, & Maixner, 2008;Vinck, et al., 2010).These imparments place individuals with SB at an increased risk of developing inactive lifestyles (Roebroeck, Jahnsen, Carona, Kent, & Chamberlain, 2009).Recent studies have shown that individuals with SB have reduced physical fitness levels compared with their healthy peers, potentiating the risk of developing obesity and cardiovascular diseases (Buffart, Roebroeck, et al., 2008;Buffart, van den Berg-Emons, Burdorf, et al., 2008).However, data on physical fitness components (cardiorespiratory endurance, muscle strength, body composition, flexibility and neuromotor fitness) in individuals with SB are dispersed in the literature, which makes difficult to draw strong conclusions (American College of Sports Medicine, 2009;Garber, et al., 2011).

Study selection
Two reviewers independently assessed all the potential studies identified.A third reviewer was consulted to solve any disagreements.The studies were selected based on their titles and abstracts; when the title and abstract were relevant to the purpose of the review, the full-text article was read carefully to decide its inclusion.

Quality Assessment and Data Extraction
Two independent reviewers assessed the methodological quality of the studies with a checklist adapted by Petticrew and Roberts (2006) based on the 'Crombie criteria' to assess cross-sectional studies (Crombie, 1996).This checklist has been used in previous systematic reviews (Barnard, Thomas, Royle, Noyes, & Waugh, 2010)

Data Syntheses and Analysis
Data from the physical fitness components of participants with SB were, whenever possible, compared with values from age-matched healthy peers.
This was possible for peak oxygen consumption (VO2peak) and six minute walk distance (6MWD), since the included studies assessed participants with SB and healthy participants.However for muscle strength, flexibility and body fat (BF), data from healthy peers was not always available.In the absence of these data, comparisons with established reference values were performed.
Due to the great amount of diverse measures used in the selected studies, a meta-analysis was not possible to conduct.Instead, a summary of the results was performed using a best-evidence synthesis (Slavin, 1995;van Tulder, Furlan, Bombardier, & Bouter, 2003).This rating system takes into account the number, methodological quality and consistency of outcomes of the studies, in 5 levels of evidence: i) strong evidence, provided by generally consistent findings in multiple (≥2) high-quality studies; ii) moderate evidence, provided by generally consistent findings in 1 high-quality study and 1 or more low-quality studies or in multiple low-quality studies; iii) limited evidence, when only 1 study is available or findings are inconsistent in multiple (≥2) studies; iv) conflicting evidence, provided by conflicting findings in case-control studies (<75% of the studies reported consistent findings) and v) no evidence, when no case-control studies are found (Slavin, 1995;van Tulder, et al., 2003).

Study selection
The databases search identified 1196 records.After duplicates removal, 587 records were screened for relevant content.During the title and abstract screening, 537 articles were excluded.The full-text of 50 potentially relevant articles was assessed and 28 articles were excluded due to the following reasons: i) did not provide quantitative data on physical fitness (n=15); ii) did not individualize the results of participants with SB (n=7); iii) assessed the validity and reliability of outcome measures in physical fitness (n=3); iv) did not include participants with SB (n=2) and v) were systematic reviews (n=1).Therefore, 22 original articles were selected.The search for relevant articles within the reference list of the selected articles retrieved 1 study.Therefore, a total of 23 studies were included in this review (figure 1).
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Study characteristics
All studies assessing physical fitness were cross-sectional (n=20), seventeen studies provided information on cardiorespiratory endurance, nine on muscle strength, seven on body composition and three on flexibility.No studies on neuromotor fitness were found.In total, 625 participants with SB (52% male) enrolled in the included studies, 475 diagnosed with MMC, 28 with LMMC and 122 not specified.All studies included children (≤18yrs old) and eight also included adults.Most studies described the participants' ambulatory status according to the classification of Hoffer, Feiwell, Perry, Perry, and Bonnett (1973), which defines 4 levels: i) community -independent outdoor ambulation with or without use of braces or assistive devices and/or use of wheelchair for longer distances; ii) household -use of braces or assistive devices for indoor ambulation and/or use of wheelchair for outdoor locomotion; iii) nonfunctionalwalking only in therapeutic situations and iv) none -wheelchair dependent.Garber, & Longmuir, 1991)] and one was a true experimental ( de Groot, Takken, van Brussel, et al., 2011).A total of 53 participants with SB (55% male), age ranging from 8 to 17.5 years old, were included in these studies.

Quality assessment
As presented in table 1, all studies presented an appropriate research design, used objective measures and appropriate statistical analysis.One study failed in reporting the recruitment strategy used (Agre, et al., 1987) and eleven did not report the response rate.Only the studies conducted by de Groot, et al. used a representative sample ( de Groot, Takken, van Brussel, et al., 2011) and performed a power calculation ( de Groot, et al., 2009;de Groot, Takken, van Brussel, et al., 2011) (table 1).The agreement between the two reviewers was substantial (k=0.78;95% CI 0.54-1; p<0.001).
(insert table 1 about here) 3.4.Synthesis of the results

Physical fitness
Results on physical fitness components are summarized in table 2.

Cardiorespiratory endurance
Cardiorespiratory endurance was assessed using supramaximal, maximal or submaximal tests.Only de Groot, et al. (2009)  ).Conflicting evidence regarding VO2peak levels and ambulatory status was found.Five studies reported that participants with higher levels of ambulatory status had significantly higher VO2peak.Three other studies, however, did not reach a statistically significant difference.Similarly to healthy population, male participants had a higher VO2peak than female participants (table 2).
The maximum workload capacity (maximum workload achieved during an exercise test) found in participants with SB was 48.9-158W, 13-25% lower than values from healthy peers (table 2).
Five studies reported the distance walked in the 6MWT.In this test, a higher distance walked indicates higher cardiorespiratory endurance.Results ranged from 391 to 424m (approximately 60-62% of the predicted for healthy peers).
Studies found significant i) lower 6MWD in participants with SB compared to reference values and ii) higher 6MWD in participants with SB with normal ambulation compared with community ambulation (408.5-473m vs. 333.4-357m).Schoenmakers, et al. (2009) also found that the 6MWD was higher in participants with LMMC than in those with MMC (424m vs. 353m) (table 2).
According to a best-evidence synthesis, there is moderate evidence on decreased cardiorespiratory endurance in individuals with SB compared to healthy peers.

Muscle strength
The methods and protocols used to evaluate muscle strength varied considerably across studies, i.e., manual muscle testing, using scales ranging from 1 to 5 and from 0 to 5 (higher scores imply high strength); maximal handgrip strength; isometric strength, "break" testing method and peak dynamic strength (table 2).
Muscle groups assessed also varied.The upper extremity group muscles  , et al., 2009).For all these muscles groups, males presented higher values than females, both in healthy participants and participants with SB (Widman, et al., 2007).Hand grip strength was assessed in three studies and varied from 38N to 686N.Norrlin, Strinnholm, Carlsson, and Dahl (2003) found that hand grip strength of participants with MMC was 71.03±23.3% of the predicted for healthy peers (table 2).
Conflicting evidence regarding muscle strength and ambulatory status was found.Danielsson, et al. (2008) and Norrlin, et al. (2003)  Moderate evidence supports that individuals with SB have higher values of BF when compared with healthy peers.

Flexibility
Studies provided data on flexibility through three different procedures: i) passive mobilization of the hip and knee joints while participants were lying supine and passive mobilization of the ankle joint while participants were sitting, ii) hip and knee joints degrees according to Cole (1982) recommendations and iii) hip, knee and ankle joints degrees according to the American Academy of Orthopedic Surgeons (table 2).Approximately, 26.3-61% of the participants had mobility restrictions in at least one of the following joints: hip, knee or ankle.
Non-ambulators were those with more contractures and flexibility was more impaired in females (females 67% vs. males 54%).
Moderate evidence exists on decreased flexibility in individuals with SB compared to healthy peers (table 2).

Neuromotor fitness
None of the included studies assessed neuromotor fitness.
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2011) (table 3).
There is moderate evidence that exercise training increase cardiorespiratory endurance and muscle strength and that it does not change body composition in participants with SB.No studies were found regarding exercise training effects on flexibility or neuromotor fitness.
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DISCUSSION
The purpose of the present systematic review was to provide a critical synthesis Cardiorespiratory endurance was found to be lower in individuals with SB compared with age-matched healthy peers.Some of the included studies also shown that individuals with high levels of ambulatory status (normal or community ambulators) have better levels of cardiorespiratory endurance.Poor cardiorespiratory endurance in childhood has been described as having important consequences for the development of cardiovascular disease in later life (Berenson, 2002).Moreover, moderate and high levels of cardiorespiratory fitness have been associated with lower risk of mortality from all-causes regardless of gender, age and body composition (Lee, Artero, Sui, & Blair, 2010).Therefore, to prevent cardiovascular diseases and reduce mortality rates, it is crucial to enhance cardiorespiratory endurance in individuals with SB since early childhood.This review found moderate evidence that exercise training programs increase cardiorespiratory fitness in individuals with SB.
Therefore, a key factor to enhance cardiorespiratory endurance in this population, and thus their survival, might be the integration of aerobic training in their treatment plans since early life.
Lower levels of muscle strength, in both upper and lower extremities, were found in individuals with SB when compared with age-matched healthy peers.
As expected, muscle strength was higher in individuals with better ambulatory status, nevertheless conflicting evidence was found.The relatively better performance of non-ambulators compared to ambulators, together with similar elbow muscle strength in individuals with SB and healthy peers, might be explained by the relatively higher muscle strength in the upper extremities due to their routine use for wheelchair propulsion (Buffart, van den Berg-Emons, van Wijlen-Hempel, et al., 2008).Nevertheless, lower levels in hand grip strength were found in individuals with SB, regardless of ambulatory status.This is an important result, because upper extremity limbs are essential to perform daily life activities independently and grip strength is a powerful predictor of disability and morbidity (Bohannon, 2008;Syddall, Cooper, Martin, Briggs, & Aihie Sayer, 2003).Exercise training programs, including upper extremity strength training, significantly improved the muscle strength of the upper extremity muscle groups (Andrade, et al., 1991;de Groot, Takken, van Brussel, et al., 2011).Therefore, upper extremity strength training should be added to the health management of individuals with SB to prevent functional deterioration and physical dependence.
Subnormal muscle strength in hip abductors, knee extensors and ankle dorsal flexors tended to be linked with non-ambulators, whereas normal strength was more frequently observed in ambulators.One of the main reasons of low muscle strength in individuals with SB is muscles disuse, causing deconditioning (Buffart, van den Berg-Emons, van Wijlen-Hempel, et al., 2008).
Therefore, strength training of the lower extremity muscles could be a strategy to preserve and improve muscle strength.This specific training might prevent non-ambulatory status and potentiate independent ambulation.
Body composition was assessed mainly with thickness of skinfolds.This measure is one of the most recommended as it provides an estimate of the total amount of subcutaneous fat and has been considered a better predictor of high BF than body mass index (Bedogni, et al., 2003;Nooyens, et al., 2007).
However, controversy exists regarding reliability and accuracy of thickness of skinfolds.Some studies reported good accuracy (Grogan & Ekvall, 1999;Shurtleff, Walker, Duguay, Peterson, & Cardenas, 2010), while others showed poor test-retest and inter-rater reliability (Shurtleff, 1986).More research should, therefore, be conducted to test the reliability of skinfold measures and to develop useful regression equations.An increased BF in individuals with SB was found.As expected, BF was higher in female, non-ambulators and in those with no participation in sports.Several factors may contribute to these findings, such as i) physiologic mechanisms associated with the disorder itself (e.g., excessive BF has been linked to hormonal and metabolic imparments) (Buffart, Roebroeck, et al., 2008;Mita, et al., 1993); ii) decreased levels of sport participation and iii) reduced self-efficacy toward physical exercise (Bandini, Schoeller, Fukagawa, Wykes, & Dietz, 1991;Cairney, et al., 2005;Kelly, Altiok, Gorzkowski, Abrams, & Vogel, 2011).The conjugation of these factors may result in an energy imbalance, whereby energy expended is less than energy consumed, leading to accumulation of BF (Tsiotra, Nevill, Lane, & Koutedakis, 2009) Considering that only three studies provided data on flexibility through different measuring instruments, assumptions on this fitness component are limited.This lack of data is also observed in other chronic diseases such as Cerebral Palsy (Hombergen, et al., 2012).Nevertheless, in this review, a tendency for decreased flexibility, ultimately resulting in rigidity, was found (Agre, et al., 1987;Norkin & Levangie, 1992).As flexibility is essential to move efficiently and to perform daily activities independently, such as personal hygiene and transfer abilities (Agre, et al., 1987)

LIMITATIONS
This systematic review has some limitations that need to be acknowledged.
Firstly, the different study designs, measures used to assess the physical fitness components hampered the results synthesis and impaired the conduction of a meta-analysis.Secondly, different ambulatory classifications were used, which weakens the associations between physical fitness and the ambulatory levels of individuals with SB.Thirdly, the same sample appears to have been used in more than one study and thus the results need to be interpreted with caution.Fourthly, the studies mainly included young participants and with MMC.    de Groot, et al. (2011) Body fat de Groot, et al. (2011) Maximum workload Widman, McDonald, and Abresch (2006) 6MWD de Groot, et al. (2011) 9' run modified form Andrade, et al. (1991) Neuromotor No studies found exercise training and/or motor skills training.However, the effect of these interventions was analyzed only in one physical fitness component -muscle strengthand in one SB subtype -MMC.Therefore, the benefits of exercise training on the main components of physical fitness are not systematically documented.A systematic review would be valuable to provide health professionals with the best evidence available on exercise training and guide interventions for individuals with SB.The present systematic review provides a critical synthesis on physical fitness components and on the effects of exercise training on these components in individuals with SB.
assessed were: shoulder flexors and extensors, elbow flexors and extensors and hand flexors.Participants with SB presented lower strength on shoulder flexors (-10-23%) and on shoulder extensors (-23-34%) than reference values from healthy peers (Danneskiold-Samsoe, et al., 2009; Widman, Abresch, Styne, & McDonald, 2007).Regarding elbow muscles, no differences were observed between participants with SB and reference values of healthy peers (Danneskiold-Samsoe extensors, abductors and flexors, knee extensors and flexors, calf muscles and plantar and dorsal ankle flexors.Hip extensors strength ranged from 2 to 5 in manual testing and from 9±36N to 161±31N during isometric contractions (normative values range from 202N in females and 326N in males (Danneskiold-Samsoe, et al., 2009)).Hip flexors and hip abductors were only evaluated through manual testing and presented values between 4-5 and 2-5, respectively.Knee extensors strength was generally above 4 in manual testing and between 4±16N and 161±31N during isometric contractions (normative values range from 96.6N in females and 424N in males (Danneskiold-Samsoe, on physical fitness components and on the effects of exercise training on these components in individuals with SB.Two moderate findings emerged from this systematic review: i) individuals with SB have impaired cardiorespiratory endurance, muscle strength, body composition and flexibility compared with healthy peers/normative data and ii) cardiorespiratory endurance and muscle strength components seem to improve with exercise training.
. It is not clear if exercise training influences BF, as only one study assessed its effects in this fitness component.However the participation in sports activities and exercise training programs with adequate intensities may aid to control this energy imbalance and therefore, reduce BF and improve overall health.More studies addressing the influence of these activities in BF are needed to provide evidence based recommendations.

Table captions 1Table 1 -
Quality assessment based on the 'Crombie criteria'.2

Table 2 -
Assessment of physical fitness components in subjects with Spina Bifida. 1

Table 4 -
Evidence for physical fitness in people with Spina Bifida compared 1 with age matched healthy peers/normative values. 2

Table 5 -
Evidence for the effect of exercise training on the physical fitness of people with Spina Bifida.