The effects of increased dose of exercise-based therapies to enhance motor recovery after stroke: a systematic review and meta-analysis

  • Emma V Cooke1,

    Affiliated with

    • Kathryn Mares2,

      Affiliated with

      • Allan Clark3,

        Affiliated with

        • Raymond C Tallis4 and

          Affiliated with

          • Valerie M Pomeroy2Email author

            Affiliated with

            BMC Medicine20108:60

            DOI: 10.1186/1741-7015-8-60

            Received: 21 September 2010

            Accepted: 13 October 2010

            Published: 13 October 2010

            Abstract

            Background

            Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. To determine the strength of current evidence for provision of a higher dose of the same types of exercise-based therapy to enhance motor recovery after stroke.

            Methods

            An electronic search of: MEDLINE, EMBASE, CINHAL, AMED, and CENTRAL was undertaken. Two independent reviewers selected studies using predetermined inclusion criteria: randomised or quasi randomised controlled trials with or without blinding of assessors; adults, 18+ years, with a clinical diagnosis of stroke; experimental and control group interventions identical except for dose; exercise-based interventions investigated; and outcome measures of motor impairment, movement control or functional activity. Two reviewers independently extracted outcome and follow-up data. Effect sizes and 95% confidence intervals were interpreted with reference to risk of bias in included studies.

            Results

            9 papers reporting 7 studies were included. Only 3 of the 7 included studies had all design elements assessed as low risk of bias. Intensity of the control intervention ranged from a mean of 9 to 28 hours over a maximum of 20 weeks. Experimental groups received between 14 and 92 hours of therapy over a maximum of 20 weeks. The included studies were heterogeneous with respect to types of therapy, outcome measures and time-points for outcome and follow-up. Consequently, most effect sizes relate to one study only. Single study effect sizes suggest a trend for better recovery with increased dose at the end of therapy but this trend was less evident at follow-up Meta-analysis was possible at outcome for: hand-grip strength, -10.1 [-19.1,-1.2] (2 studies, 97 participants); Action Research Arm Test (ARAT), 0.1 [-5.7,6.0] (3 studies, 126 participants); and comfortable walking speed, 0.3 [0.1,0.5] (2 studies, 58 participants). At follow-up, between 12 and 26 weeks after start of therapy, meta-analysis findings were: Motricity Arm, 10.7 [1.7,19.8] (2 studies, 83 participants); ARAT, 2.2 [-6.0,10.4] (2 studies, 83 participants); Rivermead Mobility, 1.0 [-0.6, 2.5] (2 studies, 83 participants); and comfortable walking speed, 0.2 [0.0,0.4] (2 studies, 60 participants).

            Conclusions

            Current evidence provides some, but limited, support for the hypothesis that a higher dose of the same type of exercised-based therapy enhances motor recovery after stroke. Prospective dose-finding studies are required.

            Background

            Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. There is strong clinical opinion that if higher doses of exercise-based therapy could be provided then motor outcome would be improved.

            The possibility of a dose-response relationship between exercise-based therapy and motor recovery is supported by the findings of several systematic reviews [15]. However, some of the included trials in all of the published systematic reviews were not designed primarily to evaluate different doses of the same therapy. Rather, they were designed to evaluate either different types of therapy, augmentation of one therapy with another or even the effects of a therapy compared with no treatment. Consequently, the results of these systematic reviews are confounded by examination of different types as well as different intensities of therapies. Differentiation of the effects of different types and different intensities of exercise-based therapies is required.

            In contrast to widely-held clinical opinion and conclusions of systematic reviews an increased dose of constraint-induced movement therapy (CIMT) given early after stroke resulted in a worse outcome than either a smaller dose of CMIT or a smaller dose of conventional therapy [6]. This unexpected finding echoes those from animal model studies which indicate that a high usage of a paretic forelimb early after experimental stroke is associated with a poorer motor outcome and an increase in size of the brain lesion [79] if it is provided early after stroke [10]. It is possible, therefore, that high doses of exercise-based therapy could be detrimental for motor recovery after stroke. This is not the only possibility, however, as experimental animal model studies indicate that more activity, provided in enriched environments, enhances motor recovery more than a standard housing environment [11]. In addition, preliminary investigation suggests the existence of a moderate relationship (r = 0.45, p < 0.01) between the number of repetitions of an exercise and improvement in motor function[12], post-hoc analysis of three separate research studies of the same therapy suggests greater benefit for a higher dose [13] and an exploratory study suggests benefit from higher dose of CIMT for people who were later after stroke [14] than were participants in the recent trial [6].

            Whether an increased dose of exercise-based therapy is beneficial, detrimental or makes no difference to motor recovery after stroke needs to be elucidated. Well designed studies of different doses of the same therapy at different times after stroke in well characterised groups of stroke survivors are required. Before undertaking such studies a systematic review specifically investigating the effect of increased dose of exercise therapy is required to establish the current evidence-base. This paper reports a systematic review and meta-analysis designed to determine the strength of current evidence for providing a higher intensity of the same types of exercise-based therapy to enhance motor recovery after stroke.

            Methods

            Design

            The design of this systematic review followed recommendations of the Cochane Collaboration. The review protocol was not published prior to this report other than as part of a PhD thesis [15].

            Search strategy

            The following databases were searched electronically; US National Library of Medicine Database (MEDLINE); European Medical Database (EMBASE); Cumulative Index to Nursing and Allied Health Literature (CINHAL); Allied and Complementary Medicine Database (AMED); and Cochrane Central Register of Controlled Trials (CENTRAL). An example of the search strategy used is given in Table 1. The initial search was conducted to cover the time period from induction of the databases to November 2008 and this was updated in a subsequent search to include the period up to October 2009. The updated search (December 2008 to October 2009) did not include CINHAL because the host had changed from OVID. A decision was made not to update the CINHAL search because records identified through it in the initial search were also found in other databases.
            Table 1

            Search strategy for electronic databases

            1. exp Stroke/

            2. stroke.mp.

            3. cerebrovascular diseas$.mp.

            4. cerebral vascular diseas$.mp.

            5. cerebral vascular accident$.mp.

            6. cerebrovascular accident$.mp.

            7. (hemipleg$ or hemipar$).mp.

            8. 6 or 4 or 1 or 3 or 7 or 2 or 5

            9. exp Physical Therapy Modalities/

            10 physiotherapy.mp.

            11. physical therapy.mp.

            12. 11 or 10 or 9

            13. randomized controlled trial.pt.

            14. controlled clinical trial.pt.

            15. randomised controlled trials.sh.

            16. random allocation.sh.

            17. double-blind method.sh.

            18. single-blind method.sh.

            19. 18 or 16 or 13 or 17 or 12 or 15 or 14

            20. clinical trial.pt.

            21. exp Clinical Trial/

            22. ((singl$ or doubl$ or treb$ or trip$) adj25 (blind$ or mask$)).ti, ab.

            23. (clin$ adj25 trial$).ti, ab.

            24. placebo$.ti, ab.

            25. placebo.sh.

            26. random$.ti, ab.

            27. research design.sh.

            28. 27 or 25 or 21 or 26 or 20 or 22 or 24 or 23

            29. comparative study.sh.

            30. exp Evaluation Studies/

            31. follow up studies.sh.

            32. (contro$ or prospectiv$ or volunteer$).ti, ab.

            33. 32 or 30 or 31 or 29

            34. 33 or 28 or 19

            35. exercis$.mp.

            36. exercis$.sh.

            37. exp Exercise/

            38. functional strength train$.mp.

            39. activities of daily living.mp.

            40. neuro facilitation.mp.

            41. bobath therap$.mp.

            42. motor relearn$.mp.

            43. rehabilitation.mp.

            44. rehabilitation.sh.

            45. exp Rehabilitation/

            46. restoration of function$.mp.

            47. 35 or 39 or 40 or 36 or 41 or 38 or 42 or 46 or 45 or 37 or 43 or 44

            48. intensit$.mp.

            49. intensit$.sh.

            50. frequenc$.sh.

            51. frequenc$.mp.

            52. duration.mp.

            53. duration.sh.

            54. dose.mp.

            55. dosage.mp.

            56. amount.mp.

            57. quantit$.mp.

            58. how much.mp.

            59. dos$.mp.

            60. dosing.mp.

            = .doses.mp.

            62. amounts.mp.

            63. 63. 50 or 53 or 57 or 61 or 51 or 58 or 48 or 59 or 52 or 60 or 56 or 49 or 62 or 54 or 55

            64. 64. 8 and 63 and 34 and 12 and 47

            Abbreviations

            mp = title, original title, abstract, name of substance word, subject heading word

            Reference lists of all articles reporting included trials were searched for any extra possibly relevant records. If any records were identified from the hand searching of reference lists and they came from journals not included on the CENTRAL data base, the contents pages of those journals were hand searched. A hand search of our own private databases of references was also undertaken. In addition authors of included articles were contacted for any unpublished data.

            Criteria for inclusion of trials

            Types of trial

            Randomised or quasi randomised controlled trials with or without blinding of assessors;

            Types of participants

            Adults, aged over 18 years, with a clinical diagnosis of stroke

            Types of interventions

            • Experimental and control group interventions identical except for dose. Therapy dose can be described in terms of time spent in therapy and/or of effort expended [16]. Description of time includes: minutes per session; sessions per day/week; and number of days/weeks [16]. Description of effort can be made in terms of the work or power required to perform an exercise for example, resistance training and the amount of weight used [16]. For this systematic review dose refers to the total time spent in exercise-based therapy.

            • Interventions investigated were exercise-based (no electrostimulation, splinting or orthotics) to facilitate muscle activity or functional ability;

            Types of outcome measures

            • Measure of motor impairment - muscle function. For example. Motricity Index, muscle tone, joint range of motion;

            • Measures of motor impairment - movement control. For example. co-ordination, reaction time;

            • Measure of motor activity. For example. Modified Rivermead Mobility Index, Action Research Arm Test, Functional Ambulation Categories, 9 Hole Peg Test.

            Trial selection

            The identification of relevant trials was undertaken by two reviewers independently using the pre-set inclusion criteria set out on a predesigned form. Reviewers assessed the record titles and categorised each as 'definitely relevant', 'possibly relevant' or 'definitely irrelevant'. Any title that both reviewers ranked 'definitely irrelevant' was excluded. The reviewers repeated the categorisation process for abstracts and full papers in turn. They did not use the category 'possibly relevant for the full papers. Any disagreements between the reviewers were resolved through referral to full papers and discussion. Trials reported in full papers which were categorised as 'definitely irrelevant' by both reviewers were excluded and reasons documented. Trials which both reviewers categorised as 'definitely relevant' were classified as included trials for evaluation in this systematic review.

            Assessment of risk of bias

            Assessment of the risk of bias in included trials was undertaken by two reviewers independently for design features using the tool developed by the Cochrane Collaboration [17]. Any disagreements between reviewers were resolved by discussion, referral to full papers and contact with authors for clarification where necessary. A risk of bias plot was produced for the review using categories of low, unclear or high risk.

            Data Extraction

            Data extraction was undertaken by two reviewers independently using a predesigned form. Any disagreements were resolved by discussion and referral to the original full papers. Trial authors were contacted to clarify results when this was necessary and possible. Data was extracted on:

            • Trial design, sample size and attrition;

            • Participant characteristics' e.g. age, gender, site of lesion, stroke classification;

            • Type of interventions;

            • Dose of interventions (sum of treatment hours);

            • Measures made at outcome (end of intervention period) and follow-up time-points in terms of average scores for trial groups.

            Statistical analysis of outcome and follow-up data

            Analysis was undertaken, where possible, on an intention- to-treat basis. Trials were not excluded if data was unavailable for subjects who did not complete all the outcome measures. Data analysis was undertaken using the Cochrane statistical package RevMan 4.2.

            Effect sizes were calculated as odds ratios (OR) and 95% confidence interval (CI) for dichotomous outcomes and as weighted mean differences (WMD and 95% CI) for continuous outcomes. WMDs were determined initially using a Fixed Effect Model. Where two or more trials had used the same outcome measure, however, and if there was evidence of heterogeneity, the WMDs were estimated from a Random Effects Model. Where it was not possible to combine and compare the outcome measures reported in different trials, then statistical results were described and tabulated individually. Sub-groups were formed by each follow-up time point. No overall analysis was done since this would involve combining subgroups based on the same individuals and could bias the results.

            Synthesis and interpretation

            The results of the statistical analysis were interpreted with reference to the risk of bias in trials, and comparability of participants, types of interventions and dose of interventions.

            Results

            Full details of the number of records screened and studies included in this review are given in Figure 1. In summary, 940 potentially relevant records were screened and 31 potentially relevant records were identified. Twenty-two records did not meet the inclusion criteria and are listed in Table 2 alongside the reasons for their omission from this review. The remaining nine records were articles reporting seven studies (three articles reported different aspects of the same study [1719]. Therefore nine articles reporting seven studies have been included in this review [1826] (Fig 1).
            http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-8-60/MediaObjects/12916_2010_Article_319_Fig1_HTML.jpg
            Figure 1

            Flow Diagram for this systematic review (note: 3 full-text articles reported the same study).

            Table 2

            Excluded Studies

            Study

            Reason for Exclusion

            Ada 2006

            Not a randomised controlled trial.

            Barreca 2004

            Treatment interventions between control and experimental group differed in content.

            Dromerick 2009

            Interventions included different time periods for wearing of mitt (not an exercise based intervention) and different doses of shaping, therefore, unable to determine which aspect of this intervention would contribute to functional outcomes.

            Duncan 2003

            Treatment interventions between control and experimental group differed in content.

            Fang 2003

            Control group received no intervention, therefore study investigated effects of physiotherapy rather than an increased intensity of physiotherapy.

            Feys 1998

            Investigated the effects of an intervention not intensity.

            Fisher 2001

            Not a randomised controlled trial.

            Green 2002

            Investigated the effect of an intervention in a specific setting not intensity.

            Kuys 2008

            Not a randomised controlled trial.

            Kwakkel 2002

            Examination of a subgroup of the original trial (Kwakkel 1999).

            Moreland 2003

            Progressive resisted exercise - not the definition of intensity used in this review.

            Nugent 1994

            Not a controlled or randomised controlled trial.

            Page 2004

            Investigated the effect of an intervention not intensity.

            Richards1993

            Treatment interventions between control and experimental group differed in content.

            Richards 2008

            Not a randomised controlled trial.

            Sivenius 1985

            Extra therapy incorporated components of physical, occupational and speech therapy. It was not possible to isolate the effects of exercise-based therapy.

            Slade 2002

            Therapy analysed included physical, perceptual and cognitive, washing and dressing, daily living activities, group treatment, joint treatment and splinting and this was analysed as 'a package'. It was not possible to isolate the effects of exercise-based therapy.

            Smith 1981

            No specific treatment techniques described. Intensive therapy involved multi disciplinary treatment and therefore difficult to isolate the effects of exercise-based therapy. Control group also given extra treatment if deemed necessary.

            Sunderland 1992

            Treatment interventions between control and experimental group differed in content. The experimental group also included EMG biofeedback.

            Wade 1992

            Subjects received physiotherapy immediately or after three months delay, therefore effectively the first half of a crossover study - physiotherapy versus no treatment. Therefore not different intensities of the same physiotherapy treatment.

            Werner 2002

            Treatment interventions between control and experimental group differed in content.

            Wolf 2007

            Not a randomised controlled trial.

            Study designs

            Of the 7 included studies three used a multi-centre, observer-blind randomised controlled design. The remaining four studies used a single-centre, observer-blind randomised controlled design (Table 3)
            Table 3

            Included studies design, participants and attrition

            Study

            Design

            Participants

            Attrition

            (cumulative)

              

            Number & gender

            Mean (SD)

            age (years)

            Stroke lesioned hemisphere

            Stroke classification

            Mean (SD) time

            after stroke (days)

              
              

            Control

            Extra

            Control

            Extra

            Control

            Extra

            Control

            Extra

            Control

            Extra

            Control

            Extra

            Cooke 2009

            Multi-centre

            Observer- blind

            RCT

            38 (21 M)

            35 (22 M)

            66.4 (13.7)

            67.5 (11.3)

            17 right

            13 right

            All anterior circulation stroke

            36.8 (22.5)

            32.4 (21.3)

            7 by 6 weeks

            21 by 6 weeks

            3 by 6 weeks

            10 by 12 weeks

            Donaldson 2009

            Single centre

            Observer- blind

            RCT

            10 (5 M)

            10 (5 M)

            72.7 (14.5)

            73.0 (8.6)

            5 right

            4 right

            All anterior circulation stroke

            13.4 (4.4)

            25.6 (15.5)

            2 by 6 weeks

            7 by 12 weeks

            0 by 6 weeks

            4 by 12 weeks

            GAPS 2004

            Multi-centre

            Observer- blind

            RCT

            35 (17 M)

            35 (24 M)

            67 (10)

            68 (11)

            15 right

            15 right

            TACI = 7

            PACI = 18

            LACI = 8

            POCI = 1

            unsure = 1

            TACI = 6

            PACI = 15

            LACI = 10

            POCI = 2

            unsure = 2

            25 days

            (range 6-71)

            0 by 4 weeks

            1 by 3 months

            1 by 6 months

            1 by 4 weeks

            3 by 3 months

            4 by 6 months

            Lincoln 1999

            Single centre

            Observer- blind

            RCT

            95 (45 M)

            94 (51 M)

            Median 73

            (IQR 64-80)

            Median 73

            (IQR 65-81)

            38 right

            47 right

            TACI = 7

            PACI = 29

            LACI = 13

            POCI = 0

            unsure = 46

            TACI = 9

            PACI = 31

            LACI = 11

            POCI = 0

            unsure = 43

            1-5 weeks after stroke

            5 by 5 weeks

            11 by 3 months

            14 by 6 months

            7 by 5 weeks

            10 by 3 months

            13 by 6 months

            Kwakkel 1999 & 2002

            Multi-centre

            Observer- blind

            RCT

            37 (14 M)

            Arm group

            33 (16 M)

            64.1 (15)

            Arm group

            69 (9.8)

            24 right

            Arm group

            19 right

            TACI = 25

            PACI = 9

            LACI = 3

            POCI = 0

            unsure = 0

            Arm group

            TACI = 19

            PACI = 11

            LACI = 3

            POCI = 0

            unsure = 0

            7.5 (2.9)

            Arm group

            7.2 (2.8)

            3 by 20 weeks

            3 by 26 weeks

            4 by 52 weeks

            Arm group

            4 by 20 weeks

            4 by 26 weeks

            5 by 52 weeks

              

            Leg group

            21 (13 M)

              

            Leg group

            64.5 (9.7)

             

            Leg group

            18 right

             

            Leg group

            TACI = 17

            PACI = 13

            LACI = 1

            POCI = 0

            unsure = 0

             

            Leg group

            7.0 (2.5)

             

            Leg group

            5 by 20 weeks

            5 by 26 weeks

            6 by 52 weeks

            Partridge 2000

            Single centre

            Observer- blind

            RCT

            60

            54

            76.5 (range 60 - 90)

            53 right

            No data provided in paper

            No data provided in paper

            4 by 6 weeks

            11 by 6 months

            2 by 6 weeks

            10 by 6 months

              

            (52 M)

                      

            Rodgers 2003

            Single centre

            Observer- blind

            RCT

            61 (30 M)

            62 (28 M)

            Median 75 (no range provided)

            Median 74 (no range provided)

            35 right

            34 right

            TACI = 13

            PACI = 17

            LACI = 29

            POCI = 2

            unsure = 0

            TACI = 8

            PACI = 17

            LACI = 34

            POCI = 3

            unsure = 0

            Median of 5 days after stroke

            10 by 3 months

            13 by 6 months

            8 by 3 months

            14 by 6 months

            Participants

            The seven studies included 680 participants (range 20-189) who completed baseline measurements (Table 3). One trial provided additional therapy from a qualified therapist and an assistant, but only the subjects treated by the qualified therapist are included in this review to ensure comparability with the other studies [22]. The mean age of participants in the seven studies ranged from 65.9 years [1820] to 76.5 years [22] and time since stroke on admission to studies ranged from a median of 5 days [24] to a mean of 35 days [26](Table 3). Full details of participant characteristics are provided in Table 3.

            Interventions

            Four of the studies described the intervention as a 'normal movement' (Bobath) approach [2124], two studies investigated conventional physical therapy as used in the UK [25, 26] and one study based the intervention on an eclectic approach involving task specific training regime following stroke [1820] (Table 4). The dose of the exercise-based intervention was described in terms of intensity (minutes per day), frequency (times per week), duration (number of weeks). From this the total dose was calculated. The dose of the control intervention was not provided in two studies [22, 23]. The dose of the control intervention in the remaining five studies ranged from a mean of 9.2 hours [26] to 27.5 hours [1820]. The mean dose received by the experimental groups (control plus extra) ranged from 13.8 hours [25]D to 91.8 hours [1820]. Details are provided in Table 4.
            Table 4

            Included studies interventions, intensity and outcome measures

            Study

            Intervention

            Intensity - mean hours delivered (SD)

            Measurement time points

            Outcome measures

             

            Control

            Extra

            Control

            Extra

            Baseline

            Outcome

            Follow-up 1

            Follow-up 2

             

            Cooke 2009

            Conventional physical therapy - lower limb from usual staff

            9.2

            (6.9)

            23.0 (10.4)

            Pre-intervention

            After 6 weeks of intervention

            12 weeks after end treatment

            NA

            ▪ Walking speed

            ▪ Ability to walk at 0.8 m/s or more

            ▪ Modified Rivermead Mobility Index

            ▪ Knee flexion peak torque

            ▪ Knee extension peak torque

              

            Extra from research staff

                   

            Donaldson 2009

            Conventional physical therapy - upper limb from usual staff

            2.81

            (3.7)

            13.8

            (27.1)

            Pre-intervention

            After 6 weeks of intervention

            12 weeks after end treatment

             

            ▪ Action Research Arm Test

            ▪ 9 hole peg test

            ▪ Hand grip force

            ▪ Pinch grip force

            ▪ Elbow flexion force - isometric

            ▪ Elbow extension force - isometric

              

            Extra from research staff

                   

            GAPS 2004

            Treatment broadly based on 'normal movement' (Bobath approach) from usual staff.

            Average 21

            (no data)

            Average 34

            (no data)

            Pre-intervention

            After 4 weeks of intervention

            3 months after start treatment

            6 months after start treatment

            ▪ Rivermead Mobility Index

            ▪ Motricty Index

            Lincoln 1999

            Treatment based on the Bobath approach from usual staff

            No data

            Median 9.58 extra to control

            (IQR 4.7-10)

            Pre-intervention

            After 5 weeks of intervention

            3 months after start treatment

            6 months after start treatment

            ▪ Rivermead Arm Assessment

            ▪ Action Research Arm Test

            ▪ Rivermead Motor Assess - gross function

            ▪ 10-hole Peg Teat

            ▪ Maximum grip strength

              

            Extra from research staff

                   

            Kwakkel 1999 & 2002

            Routine arm & leg training using evidenced-based guidelines from usual staff

            27.5 arm

            &

            23.2 leg*

            Arm group

            91.8*

            Pre-intervention

            After 20 weeks treatment

            26 weeks after start treatment

            52 weeks after start treatment

            Arm group

            ▪ Action Research Arm Test

            ▪ Frenchay Activities Index

              

            Arm group

            Arm training from usual staffLeg group

            Leg training from usual staff

            leg*

            Leg group

            84.2*

                

            Leg group

            ▪ Comfortable walking speed

            ▪ Maximum walking speed

            ▪ Functional Ambulation Categories

            Partridge 2000

            Bobath method of treatment from usual staff

            No data

            No data

            Pre-intervention

            After 6 weeks of intervention

            6 months after start treatment

            NA

            ▪ Functional reach

            ▪ 5-metre timed walk

            ▪ Timed sit-to-stand

            Rodgers 2003

            Normal movement approach (Bobath) within meaningful activity and task analysis from usual staff

            17.4

            24.9

            Pre-intervention

            None

            3 months after stroke

            6 months after stroke

            ▪ Action Research Arm Test

            ▪ Upper Limb Motricity Index

            ▪ Frenchay Arm Test

            * calculated using minutes/day data 20 weeks each with 5 treatment days

            $ calculated using median 30 days with 0.58 hours a day for control and 0.83 hours a day for extra

            Assessment of potential bias

            The results of the assessment of potential bias are presented in Table 5. In summary, only 3 of the 7 included studies had all design elements assessed as low risk of bias. Of note are:
            Table 5

            Risk of bias for included studies

             

            Cooke 2009

            Donaldson 2009

            GAPS 2004

            Lincoln 1999

            Kwakkel 1999 & 2002

            Partridge 2000

            Rodgers 2000

            Sequence generation

            low

            low

            low

            low

            low

            low

            low

            Allocation concealment

            low

            low

            low

            unclear

            unclear

            low

            low

            Blinding (participants, personnel and assessors)

            low

            low

            low

            low

            low

            low

            high

            Incomplete outcome data

            low

            low

            low

            unclear

            low

            unclear

            low

            Selective outcome reporting

            low

            low

            low

            low

            low

            high

            low

            Other sources of bias

            low

            low

            low

            low

            low

            low

            low

            1. 1.

              The blinding procedure used in one study [24] was assessed as presenting a potential high risk of bias because in the discussion section of the paper it is stated that clinical therapists were not blind to treatment allocation and therefore gave more uni-disciplinary treatment to those participants who were receiving less therapy in the trial.

               
            2. 2.

              Allocation concealment procedures used in two studies [1820, 22] were unclear as there were no specific statements about this aspect of randomisation procedure e.g. use of sealed opaque envelopes

               
            3. 3.

              Incomplete outcome data is possibly present in two studies [22, 23] but this is unclear from information presented in the papers. In one trial [22] it was reported that a number of participants died yet there was no reference to the process used for analysis for drop outs. Indeed the results tables suggest that all participants were included in the outcome analysis. One trial [23] provided no reasons for withdrawals and no methods for dealing with participants who withdrew before measurement time-points.

               
            4. 4.

              One trial appeared to report outcomes selectively [23]. Specifically step-time ratio was included in list of outcomes to be measured yet was not reported in the results section. Also sit-to-stand time, timed walk and functional reach were not measured at baseline yet there was no explanation as to why these were omitted.

               

            Outcomes

            Extraction of data for one study [1820] was undertaken considering its 3-group design of placebo, extra arm therapy and extra leg therapy and that all participants undertook all measures. In this present review we considered that the placebo group would act as a control for both experimental groups but that data extracted for the arm group would be that specific to the upper limb and data extracted for the leg group would be that specific to the lower limb. Consequently data analysed in this present review does not include upper limb measures reported for the leg group and vice versa. Two other studies also used a 3-group design [25, 26] to compare different types and different doses of physical therapy. The data extracted from these for this review consists of that for the groups receiving the routine amount and extra amount of conventional physical therapy.

            The time-points for outcome measures were mostly comparable as they were made between 4 and 6 weeks after the start of therapy except for one study where treatment was provided for 20 weeks [1820] (Table 4) At follow-up 1 there was more variety between studies with time-points ranging from 12 to 26 weeks after the start of treatment and also 3 months after stroke (Table 4). Follow-up 2 time-points were either 6 months after start of treatment, 52 weeks after start of treatment or 6 months after stroke (Table 4)

            1. Motor impairment - muscle function (Table 6)
            Table 6

            Motor impairment - muscle function

            Time-point

            Study

            Measure used

            Augmented therapy

            Standard therapy

            Mean difference

               

            Number subjects

            Mean (SD)

            Number subjects

            Mean (SD)

            Effect size

            [95% CI]

            Outcome

                    

               4 weeks after start therapy

            GAPS

            Motricity arm + leg

            33

            119.0 (46.0)

            34

            111.0 (45.0)

            8.0

            [-13.8,29.8]

               20 weeks after start therapy

            Kwakkel

            Motricity leg

            26

            68.2 (25.8)

            34

            45.2 (24.8)

            23.0

            [10.0,35.9]

               20 weeks after start therapy

            Kwakkel

            Motricity arm

            29

            53.1 (32.0)

            34

            28.9 (28.5)

            24.2

            [9.2,33.1]

               6 weeks after start therapy

            Donaldson

            Hand grip force

            10

            71.9 (49.5)

            8

            64.8 (39.3)

            7.1

            [-34.0,48.1]

               5 weeks after start therapy

            Lincoln

            Hand grip strength

            87

            0 (25.19)

            90

            11.0 (36.3)

            -11.0

            [-20.2,-1.8]

             

            Subtotal - hand grip force/strength

            97

             

            98

             

            -10.1

            [-19.1,-1.2]

               6 weeks after start therapy

            Donaldson

            Pinch grip force

            10

            31.5 (23.1)

            8

            24.5 (19.7)

            7.0

            [-12.8,26.8]

               6 weeks after start therapy

            Donaldson

            Elbow extend force

            10

            64.5 (44.6)

            8

            68.6 (39.6)

            -4.1

            [-43.1,34.8]

               6 weeks after start therapy

            Donaldson

            Elbow flexion force

            10

            76.1 (58.7)

            8

            75.0 (38.7)

            1.1

            [-44.1,46.3]

               6 weeks after start therapy

            Cooke

            Knee extend torque

            26

            45.3 (33.2)

            25

            27.8 (26.3)

            17.5 a

            [1.1, 33.9]

               6 weeks after start therapy

            Cooke

            Knee flexion torque

            26

            34.0 (23.1)

            25

            19.0 (17.8)

            15.0 a

            [3.7, 26.3]

            Follow-up 1

                    

               3 months after start therapy

            GAPS

            Motricity arm + leg

            32

            130.0 (44.0)

            33

            120.0 (42.0)

            10.0

            [-10.9,30.9]

               26 weeks after start therapy

            Kwakkel

            Motricity leg

            26

            68.2 (25.3)

            34

            27.2 (26.8)

            41.0

            [27.7,54.3]

               26 weeks after start therapy

            Kwakkel

            Motricity arm

            29

            48.6 (31.1)

            34

            31.1 (30.1)

            17.5

            [2.3,32.7]

               3 months after stroke

            Rodgers

            Motricity arm

            54

            85.0 (20.0)

            51

            78.0 (36.3)

            7.0

            [-4.3,18.3]

             

            Subtotal - Motricity arm

            83

             

            85

             

            10.7

            [1.7,19.8]

               18 weeks after start therapy

            Cooke

            Knee extend torque

            19

            56.4 (36.3)

            18

            37.9 (27.8)

            18.5a

            [-2.3, 39.3]

               18 weeks after start therapy

            Cooke

            Knee flexion torque

            19

            41.7 (28.8)

            18

            25.2 (22.9)

            16.5a

            [-0.2, 33.2]

               3 months after start therapy

            Lincoln

            Hand grip strength

            84

            9.0 (28.2)

            84

            19.0 (43.0)

            -10.0

            [-19.5,1.8]

            Follow-up 2

                    

               6 months after start therapy

            Lincoln

            Hand grip strength

            81

            23.0 (40.7)

            81

            25.0 (45.2)

            -2.0

            [-15.3,11.3]

               6 months after stroke

            Rodgers

            Motricity arm

            48

            83.0 (28.2)

            48

            77.0 (25.9)

            6.0

            [-4.8,16.8]

               6 months after start therapy

            GAPS

            Motricity arm + leg

            30

            124.0 (42.0)

            34

            121.0 (51.0)

            3.0

            [-19.8,25.8]

            a = fixed effect model used; b = random effect model used; FU = Follow-up; * = < 0.05

            Heterogeneity between studies in use of specific measures limited meta-analysis. At outcome there was a trend towards benefit for a higher dose of therapy but effect sizes for 5 of the 10 comparisons were not statistically significant. Significant effect sizes found for individual comparisons were: Motricity Index Leg score, 23.0 [10.0,35.9]; Motricity Index Arm score, 24.1 [9.2,33.1]; knee extension torque, 17.5 [1.1,33.9], knee flexion torque, 15.0 [3.7,26.3]; and hand grip strength, -11.0 [-20.2,-1.8]. Meta-analysis was only possible for hand grip force/strength (2 studies) and this found a benefit for the standard dose of therapy, -10.1 [-19.1,1.2].

            At follow-up 1 the trend toward benefit for a higher dose of therapy remained but only two of the seven individual effects sizes were significant. These were both from the same study [1820] Motricity Index Leg score, 41.0 [27.7,54.3]; and Motricity Index Arm score, 17.5 [2.3,32.7]. Meta-analysis was only possible for Motricity Index Arm score (two studies) and the effect size was 10.7 [1.7,19.8].,

            No significant differences were found between the two doses of therapy at follow-up 2 (three studies). Meta-analysis was not possible.

            2. Motor impairment - movement control (Table 7)
            Table 7

            Motor impairment - movement control

            Time-point

            Study

            Measure used

            Augmented therapy

            Standard therapy

            Mean difference

               

            Number subjects

            Mean (SD)

            Number subjects

            Mean (SD)

            Effect size

            [95% CI]

            Outcome

                    

               6 weeks after start therapy

            Cooke

            Symmetry step time

            19

            18.8 (35.6)

            15

            28.6 (33.1)

            9.7a

            [-32.9, 13.5]

               6 weeks after start therapy

            Cooke

            Symmetry step length

            19

            13.5 (15.8)

            15

            25.0 (36.6)

            11.5a

            [-31.3, 8.3]

            Follow-up 1

                    

               18 weeks after start therapy

            Cooke

            Symmetry step time

            19

            19.4 (29.9)

            14

            23.0 (23.5)

            3.6a

            [-21.9, 14.6]

               18 weeks after start therapy

            Cooke

            Symmetry step length

            19

            23.7 (49.9)

            14

            12.3 (11.0)

            -11.4a

            [-11.8, 34.6]

            a = fixed effect model used; b = random effect model used; FU = Follow-up; * = = < 0.05

            Note: symmetry values represent difference from total symmetry therefore a higher value indicates a worse outcome.

            All of the outcome measures were made at 5 or 6 weeks after the start of therapy but heterogeneity in measures used between studies prevented meta-analysis. Effect sizes were insignificant for all individual comparisons and no trends were discernable in the data.

            3. Functional activity (Table 8)
            Table 8

            Effect sizes for functional activity

            Time-point

            Study

            Measure used

            Augmented therapy

            Standard therapy

            Mean difference

               

            No. subjects

            Mean (SD)

            No. subjects

            Mean (SD)

            Effect size

            [95% CI]

            Outcome

                    

               6 weeks after start therapy

            Donaldson

            ARAT

            10

            41.8 (17.8)

            8

            45.0 (14.0)

            3.2

            [-17.9,11.5]

               20 weeks after start therapy

            Kwakkel

            ARAT

            29

            9.0 (28.9)

            34

            0.0 (1.5)

            9.0

            [-1.5,19.5]

               5 weeks after start therapy

            Lincoln

            ARAT

            87

            1.0 (25.9)

            90

            5.0 (28.2)

            -4.0

            [-12.0,4.0]

             

            Subtotal - ARAT

            126

             

            132

             

            0.1

            [-5.7,6.0]

               6 weeks after start therapy

            Donaldson

            9 Hole Peg Test

            10

            0.2 (0.2)

            8

            0.2 (0.1)

            0.0a

            [-0.1,0.1]

               5 weeks after start therapy

            Lincoln

            10 Hole Peg Test

            87

            0.0 (19.3)

            90

            0.0 (41.5)

            0.0a

            [-9.5,9.5]

               5 weeks after start therapy

            Lincoln

            Rivermead arm

            87

            3.0 (5.9)

            90

            4.0 (5.2)

            -1.0

            [-2.6,0.6]

               6 weeks after start therapy

            Cooke

            Rivermead mobility

            31

            36.6 (10.4)

            32

            34.6 (10.8)

            2.0

            [-3.2,7.2]

               6 weeks after start therapy

            Cooke

            Walk 0.8 m/s or more

            31

            11

            32

            4

            3.9 c

            [1.1,13.9]

               6 weeks after start therapy

            Cooke

            Comfort walk speed

            32

            0.6 (0.5)

            31

            0.3 (0.4)

            0.3

            [0.1,0.5]

               20 weeks after start therapy

            Kwakkel

            Comfort walk speed

            26

            0.7 (0.5)

            34

            0.4 (0.4)

            0.3

            [0.1,0.5]

             

            Subtotal - comfort walk speed

            58

             

            65

             

            0.3

            [0.1,0.5]

               20 weeks after start therapy

            Kwakkel

            Max walk speed

            26

            0.9 (0.7)

            34

            0.5 (0.6)

            0.4

            [0.1,0.7]

               20 weeks after start therapy

            Kwakkel

            FAC

            29

            4 (1.5)

            34

            3 (2.2)

            1.0

            [0.1,2.0]

               6 weeks after start therapy

            Partridge

            5 metre walk time

            33

            49.2 (32.0)

            22

            39.9 (29.9)

            9.3

            [-7.3,25.9]

               5 weeks after start therapy

            Lincoln

            Rivermead Gross Function

            87

            3.0 (4.4)

            87

            5.0 (5.2)

            -2.0

            [-3.4,-0.6]

            Follow-up 1

                    

               26 weeks after start therapy

            Kwakkel

            ARAT

            29

            4.0 (28.2)

            34

            0.0 (1.85)

            4.0

            [-6.3,14.3]

               3 months after stroke

            Rodgers

            ARAT

            54

            53.0 (27.4)

            51

            54.0 (41.5)

            -1.0

            [-14.5,12.5]

             

            Subtotal - ARAT

            83

             

            85

             

            2.2

            [-6.0, 10.4]

               18 weeks after start therapy

            Cooke

            Rivermead mobility

            28

            36.6 (9.8)

            23

            39.7 (5.7)

            -3.1

            [-7.4,1.2]

               3 months after start therapy

            GAPS

            Rivermead mobility

            32

            9.7 (3.3)

            34

            8.1 (3.6)

            1.6

            [-0.1,3.3]

             

            Subtotal - Rivermead mobility

            60

             

            57

             

            1.0

            [-0.6,2.5]

               18 weeks after start therapy

            Cooke

            Comfort walk speed

            27

            0.6 (0.5)

            23

            0.4 (0.4)

            0.2

            [-0.1,0.5]

               26 weeks after start therapy

            Kwakkel

            Comfort walk speed

            26

            0.6 (0.5)

            34

            0.4 (0.4)

            0.2

            [-0.0,0.4]

             

            Subtotal - Comfort walk speed

            59

             

            61

             

            0.2

            [-0.1,0.4]

               3 months after stroke

            Rodgers

            Frenchay Arm Test

            54

            4.0 (2.2)

            51

            4.0 (3.7)

            0.0

            [-1.2,1.2]

               3 months after start therapy

            Lincoln

            Rivermead arm

            84

            3.0 (5.9)

            84

            5.0 (5.2)

            -2.0

            [-3.7,-0.3]

               6 months after start therapy

            Partridge

            5 metre walk time

            27

            35.8 (16.5)

            33

            49.4 (32.1)

            -13.6

            [-26.2,-1.0]

               3 months after start therapy

            Lincoln

            Rivermead Gross Function

            84

            5.0 (5.2)

            84

            6.0 (5.9)

            -1.0

            [-2.7,0.7]

               26 weeks after start therapy

            Kwakkel

            FAC

            26

            5.0 (0.7)

            34

            4.0 (2.2)

            1.0

            [0.2,1.8]

               18 weeks after start therapy

            Cooke

            Walk 0.8 m/s or more

            27

            10

            23

            4

            2.8

            [0.8,10.6]

               26 weeks after start therapy

            Kwakkel

            Max walk speed

            26

            0.9 (0.7)

            34

            0.6 (0.6)

            0.3

            [-0.0,0.6]

            Follow-up 2

                    

               6 months after start therapy

            Lincoln

            ARAT

            81

            3.0 (28.9)

            81

            19.0 (33.3)

            -16.0

            [-25.6,-6.4]

               52 weeks after start therapy

            Kwakkel

            ARAT

            28

            6.0 (31.3)

            33

            1.0 (21.1)

            5.00

            [-8.6,18.7]

               6 months after stroke

            Rodgers

            ARAT

            48

            55.0 (31.9)

            48

            56.0 (23.7)

            -1.0

            [-12.2,10.2]

             

            Subtotal - ARAT

            157

             

            162

             

            -6.4

            [-12.8,0.0]

               6 months after start therapy

            Lincoln

            10 Hole Peg Test

            81

            0 (40.7)

            81

            0 (45.2)

            0.0

            [-13.3,13.3]

               6 months after stroke

            Rodgers

            Frenchay Arm Test

            48

            5.0 (3.0)

            48

            4 (3.0)

            1.0

            [-0.2,2.2]

               6 months after start therapy

            Lincoln

            Rivermead arm

            81

            4.0 (6.7)

            81

            6.0 (5.9)

            -2.0

            [-4.0,-0.1]

               6 months after start therapy

            Lincoln

            Rivermead Gross Function

            81

            6.0 (5.9)

            81

            7.0 (3.7)

            -1.0

            [-2.5,0.5]

               52 weeks after start therapy

            Kwakkel

            Max walk speed

            25

            0.9 (0.6)

            33

            0.7 (0.6)

            0.2

            [-0.1,0.5]

               52 weeks after start therapy

            Kwakkel

            FAC

            25

            5 (0.7)

            33

            4 (1.48)

            1.0

            [0.4,1.6]

               6 months after start therapy

            GAPS

            Rivermead mobility

            30

            10.2 (3.1)

            34

            9.1 (4.0)

            1.1

            [-0.6,2.8]

               52 weeks after start therapy

            Kwakkel

            Comfort walk speed

            25

            0.6 (0.5)

            33

            0.5 (0.4)

            0.1

            [-0.1,0.3]

            a = fixed effect model used; b = random effect model used; c = odds ratio used; FU = Follow-up; * = = < 0.05; ARAT = Action Research Arm Test; FAC = Functional Ambulation Category

            At outcome, data from one trial relating to Rivermead Mobility Index was omitted because only 3 of 35 participants in the extra therapy group appear to have been included in the outcome data compared to all participants in the control group [22]. Therefore values provided may not have been representative of the entire group. Meta-analysis was undertaken for Action Research Arm Test (3 studies) and comfortable walking speed (2 studies) with effect sizes of 0.1 (-5.7,6.0] and 0.3 [0.1,0.5] respectively. For other measures, the individual study comparisons found a trend towards a better outcome with higher dose for most comparisons but this was weaker than for motor impairment- muscle function. Significance was only found in individual study comparisons in favour of extra therapy for: ability to walk at 0.8 m/sec or more with an odds ratio of 3.9 [1.1,13.9] and maximal walking speed effect size, 0.4 [0.1,0.7]. A significant benefit for standard dose therapy was found for one individual study comparison for the Rivermead Gross Function score with effect size -2.0 [-3.4,-0.6].

            At follow-up-1 meta-analysis was undertaken for Action Research Arm Test (2 studies), Rivermead Mobility Score (2 studies) and comfortable walking speed (2 studies) with non-significant effect sizes of 2.2 [-6.0,10.4], 1.0 [-0.6,2.5] and 0.2 [-0.1,0.4] respectively. For other measures the significant effect sizes from individual studies were: Rivermead Arm score, -2.0 [-3.7,-0.3]; 5 metre walk time, -13.6 [-26.2,-1.0]; Functional Ambulation Categories, 1.0 [0.2,1.8]; and ability to walk at 0.8 m/sec or more, 2.8 [0.8,10.6].

            The follow-up-2 meta-analysis (3 studies) found a significant benefit for standard dose therapy for ARAT, subtotal of -6.4 [-12.8,0.00]. A significant benefit in favour of standard dose therapy was also found from an individual study in respect of the Rivermead Arm score with an effect size of -2.00 [-4.0,-0.1]. The benefit for higher dose therapy was, however, maintained for Functional Ambulation Category, 1.0 [0.4,1.6].

            Discussion

            This systematic review provides limited support for the hypothesis that a higher dose of exercise-based therapy enhances motor recovery after stroke. There are some indications from the present meta-analysis for benefit from a higher dose for: comfortable walking speed; maximum walking speed; and upper limb muscle function. Meta-analysis was, however, limited by heterogeneity between studies in the measures used and therefore most estimates of effect size were derived from single studies. Those single study sample estimates that were statistically significant were mostly in favour of a higher dose of therapy. In contrast, there are also some indications from meta-analysis for benefit from a standard dose for hand grip force/strength and upper limb functional ability at outcome (Table 6) and for ARAT score at follow-up 2 (Table 8). Caution in interpretation of the results of the present review is also raised by the finding that only three of the seven included studies had all design elements assessed as low risk of bias. Clearly there are limitations to the current evidence base that restrict the provision of clear guidance for whether an increased dose of exercise-based therapy enhances recovery after stroke.

            This finding differs from the results of benefit from extra therapy of: earlier systematic reviews [15] and experimental human studies (for example [12]). But, maybe this result is not so surprising considering that animal model studies and a clinical trial found that higher doses of therapy produced worse outcomes early after stroke [610]. Interestingly the detrimental effect found in the present systematic review on hand grip force/strength (Table 6) and upper limb function as measured by the ARAT (Table 8) emanate from trials conducted early after stroke [21, 24]. It is possible therefore that there is a negative interactional effect between time from stroke and dose. However, other trials included in the present review were also conducted with participants early after stroke and detrimental effects were not found for either upper limb or lower limb motor impairment or activity. Prospective robust clinical trials are needed to investigate whether time after stroke influences motor response to different doses of exercise-based therapies.

            A starting dose for subsequent trials is suggested by an earlier systematic review which concluded that a 16-hour difference in treatment time between experimental and control groups provided in the first 6 months after stroke is needed to obtain significant differences in activities of daily living" [3]. Investigation of the data reported here for a potential dose-response relationship is limited by the relatively small number of comparisons that can be included in a meta-analysis because of the variation in measures used in included studies. We were concerned to avoid undertaking analyses of sets of heterogeneous measures in a single meta-analysis. However, visual inspection of outcome time-point data (Tables 6,7 and 8) and data on dose (Table 4) suggests a trend for better outcome with higher dose. The highest doses, however, were of task-specific interventions [1820] whereas the smaller doses consisted of UK conventional physical therapy [25, 26]. This difference could have influenced the results of the present review. It is also possible that differences in effect sizes between studies could be due to differences in underlying standard care. The study by Kwakkel and colleagues [1820] was conducted in the Netherlands whereas the other four studies took place in the United Kingdom. This could have influenced the results of the present review because there may be important differences in underlying routine care between centres and countries [27]. There may also be differences in standard therapy over time [28]. Therefore the differences in clinical setting for studies may also be influential on outcome. Consequently, this present review which restricted included studies to those investigating different doses of the same therapy to avoid the confound of different types of therapy may itself be confounded by the inclusion of different types as well as different intensities of therapy. Essentially this systematic review highlights the need for prospective dose-ranging studies of specific interventions before undertaking efficacy studies.

            None of the doses investigated in included studies emerged from preliminary dose-finding studies. The same observation emerged from in a systematic review and meta-analysis of electrostimulation [29]. Indeed dose-finding has not featured prominently as a precursor to stroke rehabilitation trials [30, 31] Without precursor dose-finding studies it is possible that the studies included in this review investigated sub-optimal doses of exercise-based therapies. The case for prospective dose-finding studies as precursors to Phase II and phase III trials of rehabilitation has been made already [30, 31]. Nevertheless, we are aware of only one study designed to investigate the relative efficacy of three or more doses of the same rehabilitation therapy [Hunter SM, Hammett L, Ball S, Smith N, Anderson C, Clark A, Tallis R, Rudd A, Pomeroy VM. Appropriate dose of Mobilisation and Tactile Stimulation to enhance upper limb recovery early after stroke: a randomised controlled trial. Submitted]. Dose-finding has not featured prominently as a precursor to phase II and phase III trials of rehabilitation therapies.

            A potential limitation to the present review is the examination of multiple data sets from the same study participants. Therefore bias is potentially present through the repeated use of results arising from the same group of participants. In recognition of this possibility the present review did not combine data from the same studies within meta-analyses.

            Another potential limitation is that the present review may be influenced by a publication bias as the literature search excluded studies written in a language other than English. A strong publication bias is, however, unlikely to be present the studies included in this present review were also included in previous meta-analyses. In addition, authors of included studies were contacted for any unpublished data.

            Conclusions

            The findings indicate that there is limited empirical evidence to inform clinical decisions on how much exercise-based therapy is needed to enhance motor recovery after stroke. To the best of our knowledge the present systematic review of the effects of dose of therapy is the first to control for the potential confounder of different types of intervention. It has refined and updated knowledge of the effects on motor recovery of the provision of an increased dose of exercise-based therapy after stroke. It has highlighted the clinical uncertainty around dose. Further systematic reviews are unlikely to resolve this clinical uncertainty because of the heterogeneity between exercise-based therapies in included studies and the apparent lack of dose-finding studies undertaken as precursors to robust clinical trials. The results of the present systematic review therefore indicate a need to undertake dose-finding studies of specific exercise-based interventions as precursors to robust clinical trials.

            Declarations

            Acknowledgements

            We gratefully acknowledge: funding provided by The Healthcare Foundation and St George's Charitable Foundation that enabled us to undertake this study.

            Authors’ Affiliations

            (1)
            Academic Dept of Geriatric Medicine, St George's University of London
            (2)
            Health and Social Sciences Research Institute, Queen's Building, University of East Anglia
            (3)
            Health and Social Sciences Research Institute, MED Building, University of East Anglia
            (4)

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            32. Pre-publication history

              1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1741-7015/​8/​60/​prepub

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            © Cooke et al. 2010

            This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.