|Year : 2019 | Volume
| Issue : 3 | Page : 138-150
ULIS (Upper Limb International Spasticity), a 10-year Odyssey: An international, multicentric, longitudinal cohort of person-centered spasticity management in real-life practice
Lynne Turner-Stokes1, Klemens Fheodoroff2, Jorge Jacinto3, Pascal Maisonobe4, Stephen Ashford5
1 Department of Palliative Care, Policy and Rehabilitation, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London; Regional Hyper-Acute Rehabilitation Unit, Northwick Park Hospital, London, UK
2 Neurorehabilitation, Gailtal-Klinik, Hermagor, Austria
3 Centro de Medicina de Reabilitação de Alcoitão, Serviço de Reabilitação de adultos 3, Estoril, Portugal
4 Ipsen Pharma, Boulogne-Billancourt, France
5 Department of Palliative Care, Policy and Rehabilitation, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London; Regional Hyper-Acute Rehabilitation Unit, Northwick Park Hospital; Centre for Nursing and Midwifery Research, University College London Hospital, London, UK
|Date of Submission||12-Jan-2019|
|Date of Decision||10-Apr-2019|
|Date of Acceptance||19-Apr-2019|
|Date of Web Publication||10-Oct-2019|
Prof. Lynne Turner-Stokes
Regional Hyper-Acute Rehabilitation Unit, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ
Source of Support: None, Conflict of Interest: None
Homer's Odyssey, one of the major Greek epic poems, tells the story of the hero Odysseus (or Ulysses in Roman versions) and his journey home to his wife Penelope. An epic poem is a long, narrative poem that is usually about heroic deeds and events that are significant to the culture of the poet. In keeping with this classic storytelling style, we describe the journey that the Upper Limb International Spasticity Study (ULIS) program has taken. The program was started in 2008 and has encountered a number of trials and obstacles along the way. This article sets out the history of development through its 10-year “Odyssey.” We use the benefit of hindsight to discuss how conducting large-scale, international observational studies can inform and influence routine practice in an area as diverse and complex as spasticity rehabilitation. We focus on the clinical pearls found within the now extensive ULIS dataset and how continually building upon the insights from each study can provide a real impetus for change.
Keywords: Botulinum toxin, observational study, spasticity, upper limb
|How to cite this article:|
Turner-Stokes L, Fheodoroff K, Jacinto J, Maisonobe P, Ashford S. ULIS (Upper Limb International Spasticity), a 10-year Odyssey: An international, multicentric, longitudinal cohort of person-centered spasticity management in real-life practice. J Int Soc Phys Rehabil Med 2019;2:138-50
|How to cite this URL:|
Turner-Stokes L, Fheodoroff K, Jacinto J, Maisonobe P, Ashford S. ULIS (Upper Limb International Spasticity), a 10-year Odyssey: An international, multicentric, longitudinal cohort of person-centered spasticity management in real-life practice. J Int Soc Phys Rehabil Med [serial online] 2019 [cited 2020 Jul 2];2:138-50. Available from: http://www.jisprm.org/text.asp?2019/2/3/138/268797
| Foreword|| |
The Odyssey is one of the major Greek epic poems and is thought to have been composed by Homer sometime near the end of the 8th century BC. It focuses on the hero Odysseus (“Ulysses” in Roman versions), King of Ithaca, and his journey home to his wife Penelope. In his book, The Hero With A Thousand Faces (1949), Joseph Campbell describes the “monomyth” and expounds the theory that many mythological narratives share the same fundamental structure. Christopher Vogler expands on this to describe 12 stages in the Hero's Journey, as set out in [Table 1].
We have chosen to base this article on the above framework because of certain similarities between the ULIS program and the Odyssey, which are described as follows:
- The names Upper Limb International Spasticity (“ULIS”) and “Ulysses”
- The duration of the journeys (10 years)
- The fact that we have encountered challenges along the way that have required the learning of new skills
- The promise of a final position. We bring to day-to-day clinical practice a new perspective and approach to improve the management of upper-limb spasticity (ULS) for patients across the world.
| Introduction|| |
Spastic movement disorder, commonly referred to as “spasticity,” is a common consequence of damage to the central nervous system which has been estimated to affect up to 42% of stroke survivors, 75% of people with a traumatic brain injury, and 60% of people living with multiple sclerosis.
When present, spasticity can be painful, can be distressing, and can be a potentially costly cause of disability. If left untreated, unopposed contraction (spastic dystonia) in the affected muscle groups may lead to abnormal limb postures, soft-tissue shortening, and further biomechanical changes resulting in contracture and deformity. Secondary complications include impaired movement, difficulty in maintaining hygiene and self-care, poor self-esteem and body image, pain, and pressure ulcers. However, the presentation is highly diverse, and approaches to management must be customized around the individual needs of each patient.
While physical management (to maintain muscle length and optimize function) forms the backbone of treatment, some patients will also require pharmacological intervention incorporating oral antispasmodics and/or chemodenervation techniques such as botulinum toxin type-A (BoNT-A). There is now a well-established body of evidence demonstrating that BoNT-A is a safe and effective focal intervention for reduction of spasticity, and it is now widely recommended for use in standard clinical practice.,, Controlled studies,,,, have demonstrated the benefits of BoNT-A at the level of impairment, but functional gains have been harder to demonstrate. In many cases, this may be because active function continues to be limited by the underlying motor dysfunction, but there may also be methodological reasons for failure to capture functional gains, as follows:
- Earlier trials tended to apply generic measures of global function which would not necessarily be expected to capture local changes arising from focal intervention
- The timing of assessments was sometimes premature (e.g., 1 month in the BOTULS study). A meta-analysis has demonstrated that there is often a time lag between reduction in spasticity and maximum functional gain, due to the need for time to practice and develop new skills in the hemiparetic arm after spasticity has been relieved. As such, functional gains may be missed if outcomes are measured just at a single early time point.
Measuring functional outcome is challenging in this context because of wide diversity in patient presentation, potential for rehabilitation, and individual goals for treatment. Current guidelines for the use of BoNT-A in the management of spasticity advocate the application of focused outcome evaluations, targeted on the attainment of priority goals that are relevant to the treatment intentions and important to the individual.
The ULIS Study program represents a series of large international observational studies to describe the current clinical practice in the application of BoNT-A in ULS and to work toward the development of a common dataset for prospective systematic recording of longitudinal person-centered outcomes. The program was started in 2008 and has encountered a number of trials and obstacles along the journey. This article sets out the history of development through its 10-year “Odyssey.” We use the benefit of hindsight to discuss how conducting large-scale, international observational studies,,, can inform and influence routine practice in an area as diverse and complex as spasticity rehabilitation. We focus on the clinical pearls found within the now extensive ULIS dataset [Box 1] and how continually building upon the insights from each study can provide a real impetus for change.
Stage 1 – “The Ordinary World”
In 2005, an international working group of rehabilitation experts was convened to try to reach consensus on a common approach to the management of ULS using BoNT-A on the following:
- How to identify the patients most likely to respond to BoNT-A treatment
- Which muscles to inject, with what doses, to best treat spasticity
- What outcome measures to record to measure outcome.
Delegates from over 15 countries participated in a series of meetings in London and Paris. It was generally acknowledged that there is a group of patients who make extraordinary functional improvement following treatment (the so-called “best responders”), but the various experts disagreed on how to identify these. A group from Germany had identified five different patterns of spasticity, each with a distinct posture. They proposed a standard approach to clinical prioritization, with a structured regimen of muscle injection for each pattern. However, other experts at the meeting believed that, while potentially useful as a basic framework, patterns of spasticity alone were insufficient to identify “best responders,” and that in addition a person-centered approach was needed.
Opinion also varied on injection techniques, including dosage and dilution; single or multiple injection points: how to locate the correct muscle(s) and whether it was necessary to target the muscle end point (motor end plate); postinjection interventions – exercise and therapy; and which outcome measures to use. There was clearly a wide range of strongly held opinion, and no consensus could be reached. It was, therefore, agreed to undertake an international observational study to determine what clinicians from across the world actually do in real-life clinical practice – this was the start of the ULIS program on the way to identify best practice strategies in different clinical situations.
Stage 2 – “The Call to Adventure – the start of the Upper Limb International Spasticity program”
Phase IV studies complement data from randomized controlled trials (RCTs) by evaluating treatment over a longer period for a greater number of patients. Phase V studies provide additional information about the benefits and optimal use of interventions. Both types of investigation can be conducted in the course of routine clinical practice to gain insights into the effectiveness of an intervention as it is applied in real life, as opposed to the more restrictive confines of an RCT. Large international observational studies are well placed to identify which treatment approaches work best for which patients and to examine any geographic variations in usage in between different countries, which may, for example, reflect differences in local licensing rules or health-care culture. Such data are increasingly required by decision makers and payers to understand the real-life effectiveness of interventions.,
The Upper Limb International Spasticity-I
The ULIS-I was conceptualized in 2008 as an international, cross-sectional, noninterventional survey of reported practice designed to document the clinical profiles and treatment goals of patients with ULS and requiring BoNT-A therapy (any agent) to inform future research. A total of 122 investigational sites from across 31 countries throughout Europe, the Middle East, Pacific Asia, and South America took part. Each center recruited a maximum of ten consecutive patients for whom a decision had already been made to inject BoNT-A. The investigators reported on how they assessed and treated their patients and how they planned to evaluate the outcome. Data collection was performed at a single time point on the day of treatment.
The survey population consisted of 974 patients. In all geographic areas, the emphasis was primarily on measuring the impairments, rather than the activity limitations due to the ULS. A very wide range of outcome measures were reported, but the most common were the Modified Ashworth Scale (MAS) (83%) and active and passive range of movement (87% and 92%, respectively). Although primary and secondary treatment goals were identified for most patients, their formal assimilation into Goal Attainment Scaling was used by only a minority of investigators (5%) working at a few centers. “Active function” and “pain” were the most common primary goals when patients were treated in the first 3 months, and “passive function” was the most common reason for treatment in the chronic phase of ULS. Release, grasp, and reach were the most frequently selected items when active function was the treatment goal.
A weakness of the ULIS-I was that it only captured what clinicians said they would do. Thirteen UK sites also included a follow-up arm to record what they actually did. This was revealing – analysis of data from 95 UK patients showed that formal assessment of goal attainment and outcome measurement occurred as planned in only 65% of UK patients. This left almost a third for whom either no follow-up measures were recorded, or different measures were used from those recorded at baseline, leaving no opportunity for comparison. Similarly, about a third of the patients had not received the planned concomitant therapy. It was clear that a more formal “before-and-after” evaluation was required.
Stage 3 – “Refusal of the Call”
Before any formal evaluation could take place, it was necessary to agree at least a minimum set of agreed measures. Persuading clinicians from many different backgrounds and health cultures to adopt a common set of outcome measures has never been an easy task. As the ULIS program is noninterventional, it was not possible to impose the use of formal measures that were not part of the normal clinical practice. However, almost all clinicians said that they set goals for treatment, and so Goal Attainment Scaling (GAS) was chosen as the primary outcome measure for the program, and we set about training and engaging clinicians in its use.
Goal Attainment Scaling
GAS is a method of assimilating achievement in a number of individually set goals into a single “goal attainment score.” Originally developed in the context of mental health, it is increasingly taken up in clinical practice, and it has been applied in various areas of complex intervention including rehabilitation, and treatment for the ULS., Attainment for each goal is rated on a 5-point achievement scale where 0 = as expected, 1 = a little more than expected, 2 = a lot more than expected, −1 = a little less than expected, and −2 = a lot less. Although other numerical models for the scale have been proposed (e.g., adding a −3 score to include worsening), these have not been found to provide added value and are not commonly applied. The sum of the scores for each goal (with optional weighting for the patient-rated importance of the goal and the team-rated anticipated difficulty of achieving it) is combined into a single T-score. The mathematical formula to derive the T-score is such that, if goals are set in an unbiased fashion so that results exceed and fall short of expectations in roughly equal proportions, under- and over-achievement are equally balanced, the mean GAS T-score will be 50 with a standard deviation (SD) of 10.
In addition to providing a semi-quantitative (ordinal) assessment of goal attainment, GAS provides qualitative information regarding the patient's priority goals for treatment. Moreover, the very process of goal setting and rating supports dialog and negotiation between the patient and his/her treating team, to establish agreed expectations for outcome. However, the GAS is not a measure of outcome per se, but a measure of the achievement of intention. It, therefore, does not replace standardized measures, but is a useful adjunct to use alongside them.
The GAS has its critics, however. Concerns have been raised in some quarters about nonlinearity of the scaling and lack of uni-dimensionality, and some authors have proposed the development of standardized goals or “item banks.”, The World Health Organization (WHO) International Classification for Functioning Disability and Heath (ICF) offers a common language for categorizing goals into different domains of personal experience. A previous secondary analysis of a multicentric controlled trial from Australia, mapped a total of 165 goals onto the ICF domains to identify the key goal areas for the treatment of ULS to inform the future development of standardized goal sets. The key goal areas were as follows:
- Bodily functions:
- Maintaining joint range
- Reducing involuntary movements (associated reactions and spasms).
- Activities and participation:
- Passive function (caring for the affected upper limb)
- Function (using the limb to perform functional tasks)
- Mobility (using the upper limb for support/balance while walking).
The authors recommended further research with a priori categorization of goals in large prospective cohort studies to describe the full value of BoNT-A in the management of ULS.
A further concern about the GAS was the length of time that it took to negotiate and set individualized goals. The original authors proposed the use of a “follow-up guide” defining the levels of attainment for each of the five possible scores, which was extremely time-consuming. It was clear that the GAS would not be suitable for wholesale adoption in the ULIS program in its original form.
Stage 4 – “Meeting the Mentor”
The breakthrough came in a collaboration between the UK and colleagues in Australia. We had already started to explore a simpler approach in which the effort of goal setting is focused only on the expected outcome (i.e., the condition scoring “0”) and wording this as a Specific, Measurable, Achievable, Realistic, and Timed (SMART) goal. At review, the patient and the team then agree by consensus whether this has been achieved, exceeded (“a little” or “a lot”), partially achieved (−1), or not at all. A 6-point verbal rating scale that reflects the way clinicians actually think translates to a 5-point numerical scale depending on the baseline score and supports the capture of a worse condition. Side-by-side comparison with the original GAS method demonstrated results that were highly comparable but were obtained within a fraction of time.
During a series of workshops organized by Ipsen Australia in 2008 with a view to making GAS practical in the context of a busy clinic, this shortened version was dubbed the “GAS-Light” (Gavin Assauw and Robert McGregor). This approach has since been widely adopted as the preferred method for application of GAS in clinical practice.
We, therefore, decided to adopt the GAS-Light method for evaluation of goal attainment for the ULIS-II. However, before we could do this, it was necessary to ensure that all the centers were using GAS consistently. This also proved harder than might be supposed. Using GAS came quite naturally to the centers which ran a spasticity service in the context of a multidisciplinary team setting. However, it came less easily to doctors working in the unidisciplinary model of a medical outpatient clinic, some of whom who found it hard to engage with the flexible nature of functional goal setting as a valid form of measurement over the traditional impairment-based measures.
A comprehensive rater training program for clinical GAS was carried out for all the participating centers. This program not only educated clinicians who were unfamiliar with the routine use of GAS in its application, but also formed part of the validation process for the use of GAS in the ULIS II. The program was ambitious in that it trained centers not only to use GAS, but to understand how it worked.
Validation of Goal Attainment Scaling goal statements
In addition to the prestudy training, the project steering group continued to monitor the quality of goal statements at various stages of the ULIS-II study. Statements for the primary goal were independently evaluated by three leading investigators. Formal evaluations were carried out in two rounds, approximately three-quarters of the way through (Round 1) and at the end (Round 2) of the recruitment.
Goal statements were examined independently by each of the three investigators who were blinded to country and center. They were assessed on two criteria: the WHO-ICF domain and SMART description, as shown in [Table 2].
|Table 2: Quality rating criteria for primary goal statements - World Health Organization International Classification of Functioning domain and Specific, Measurable, Achievable, Realistic, and Timed description used during the Upper Limb International Spasticity Study II validation process|
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While it was accepted that goal statements would be impairment related for some patients (e.g., prevention of contractures), it was expected that at least some goals from each center would be related to function. After evaluation, an overall center quality rating for WHO ICF domain (A, B, or C) and SMART description (++, + or−) was reached by consensus, and results were fed back to the centers. Centers with lower rates (B, C, or−) were invited to submit revised goal statements to improve quality. If not, these centers were asked to discontinue recruitment.
By the end of the study, 37 centers submitted revised goal statements (of which 21 [57%] had improved their rating). [Figure 1] shows the percentage of centers achieving the higher quality ratings for SMART-ness and functionality of goal statements. Evaluation of goal statements had clearly helped centers to improve the quality and function-related focus of goal statements, supporting the validity of GAS as the primary outcome measure. It is important to recognize, however, that the process of goal refinement would have made goals harder to achieve, resulting in lower overall levels of goal attainment.
|Figure 1: Percentage of centers achieving high-quality ratings in rounds 1 and 2 during validation of GAS statements. See Table 2 for the description of WHO ICF domains A, B, and C, and SMART descriptor ratings ++, +, and −. GAS: Goal Attainment Scaling, ICF: International Classification of Functioning, SMART: Specific, Measurable, Achievable, Realistic, and Timed, WHO: World Health Organization|
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Stage 5 – “Crossing the Threshold”
The Upper Limb International Spasticity-II – what did we learn?
The ULIS-II was a large, international, observational, 18-month, cohort study to describe real-life practice and outcomes in the treatment of poststroke ULS with BoNT-A. Its primary objective was to assess the responder rate (as defined by the achievement of the primary goal from GAS) following one BoNT-A injection cycle delivered in the context of routine clinical practice.
The secondary objectives were to provide a detailed description of clinical practice with respect to:
- Demographics, duration and pattern of spasticity, concomitant therapies/medication, etc.
- Injection practices (muscle identification, dosage, dilution, etc.)
- Describe and categorize the common goals for treatment to identify those that are most often achieved
- Evaluating the overall attainment using the GAS T-score as a patient-centered measure of outcome and evaluating this in relation to other standardized measures, including global benefits as perceived by the investigator and the patient
- Identify any prognostic factors for response.
Recruitment took place (84 centers in 22 countries spanning Europe, Pacific Asia, and South America) between January 2010 and May 2011 and once again, the number of patients was limited to 5–12 patients per treatment center to limit the potential bias from overrecruiting sites. Participants were consenting adults ≥18 years with poststroke ULS in whom a decision had already been made to inject BoNT-A and who had had no previous treatment with BoNT-A or BoNT-B within the last 12 weeks. Agreement on an achievable goal set and ability to comply with the prescribed treatment were also required. The efficacy population (n = 456) included all participants who received one cycle of BoNT-A injection and who underwent a postinjection visit including an assessment of GAS.
The mean age was 56.7 years, and the median time since the onset of stroke was just over 3 years. At baseline, over half of the participants (57%) had no useful hand function and 46% had sensory impairment. These findings confirmed that this was a relatively young population of whom the majority had chronic spasticity with severe impairment and therefore little potential for recovery of useful motor function. Approximately two-thirds of the participants (67%) had received a previous injection of BoNT-A for ULS. The median time since the last injection was 5 months. Some had had treatment spanning several years.
Goal attainment in the Upper Limb International Spasticity-II
Primary efficacy findings showed that, despite wide variations in the approach to clinical practice, a large majority (80%) of the patients with ULS achieved their primary goal following a single injection of BoNT-A. The most common goals for treatment were passive function and maintaining range and active function [Figure 2]. Although reduction of pain was less commonly set as the primary target for treatment, goals in this area were more likely to be achieved (83.6%), while goals for active function were achieved in 72.1% of the patients for whom they were set.
|Figure 2: The six main primary goal areas set and achieved in Upper Limb International Spasticity-II program|
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At follow-up, the mean (SD) weighted GAS T-score was 52.0 (10.1), giving a mean change from baseline of 17.6 (11.0; 95% confidence interval [CI]: 16.6–18.6) (P< 0.001). This confirmed the rates of goal achievement as beyond expectation – the minimal clinically important change in GAS scores is 10. Overall, 90.1% of the investigators and 85.8% of the patients considered BoNT-A treatment to be of benefit.
Importantly, GAS T-scores were significantly correlated with global benefit (Spearman's ρ = 0.38; P < 0.0001) as well as other standard measures such as the MAS (Spearman's ρ = 0.28; P < 0.0001), suggesting that the clinical gains occurred due to a reduction in spasticity. These results provided robust “real-life” evidence that BoNT-A injections can contribute to an improvement in the daily life of patients and their caregivers beyond simple reduction of tone or spasticity.
As the ULIS-II was an observational study, physicians were free to use any BoNT-A preparation and to give this in accordance with their usual practice. This design allowed us to capture important information on how experienced clinicians were using BoNT-A in real life, including the most commonly targeted muscles and injection techniques.
Post hoc subgroup analyses showed that, as expected, patients with primary goals focused on active function had less motor impairment (P = 0.0001), contracture or soft-tissue shortening (P< 0.0001), spasticity (P< 0.0001), and shorter time since stroke (P = 0.001), while those with primary goals for passive function had the opposite. Whereas patients without contractures were more likely to achieve goals relating to active function and improved passive range of motion, those with severe contractures still achieved goals related to pain and passive function. These findings directly challenged the common perception that BoNT-A is not suitable for patients with contractures – even those with severe contractures may benefit from treatment if the goals are appropriately selected – for example, the reduction of pain.
Dosing for all three main BoNT-A brands tended to be on the low side compared to the respective prescribing information, and there was wide variation in clinical practice with respect to injection parameters, including the selection of muscles. The most frequently injected muscles were the long-finger flexors, followed by biceps and brachioradialis, regardless of the distribution of spasticity across the limb [Figure 3].
It is important that these data are considered in the context of routine practice. For example, even though shoulder spasticity is reported to be a major cause of hemiplegic shoulder pain, and shoulder movement is critical for many active and passive tasks, the shoulder muscles were relatively rarely injected with the exception of the pectoralis major. Other muscles such as the subscapularis have been suggested as useful BoNT-A targets for shoulder pain and function,, and it is not clear why the pectoralis major was injected so much more frequently (19.3% of patients were injected in the pectoralis, whereas only 3.1% received subscapularis injections). Similarly, it could be questioned why the biceps brachii was injected so frequently (59%) and perhaps disproportionately when compared to the brachialis (29%), which is a more potent elbow flexor. Other studies have also shown that muscle selection and BoNT-A dosage are not significantly associated with spasticity severity or with patient-identified goals and that the principal driver of injection technique is the study site. From the authors' own experiences in BoNT-A injection training, it becomes apparent that many injectors require greater in-depth training on functional anatomy (which may change their injection paradigm). Indeed, it is likely that some investigators simply listed the biceps when they actually injected the brachialis. The ULIS-II thus highlighted the need for further systematic research into which approaches are likely to be most effective for which patients, as well as continued injector training and medical education in order to maximize the utility of BoNT-A injections.
Use of standardized measures
Reflecting common impairment, the range of active (56%) and passive (54%) motion were the most commonly recorded standardized measures of ULS used at baseline. Approximately one-third (34%) of the patients also used a visual analog rating to reflect symptoms such as pain or carer burden. However, only a very small minority (7%) had a standardized measure of functional outcome recorded, such as the Arm Activity Scale (ArmA – a self-report measure of active and passive function) (6%) or the Leeds Adult Spasticity Impact Scale (an investigator-reported measure of passive function) (1%). Because of the wide range of measures used, the ULIS-II did not attempt to capture the actual scores within each measure, but simply whether they were “the same,” “better,” or “worse.” Rated in this way, the change in these standardized measures (wherever they were measured) correlated strongly with the GAS T-score (Spearman's ρ = 0.41–0.76, P < 0.001).
Many previous studies fail to record detail on concomitant therapies – the ULIS-II at least collected some data. Nearly two-thirds (61.6%) of the patients were receiving physiotherapy in association with the BoNT-A treatment at follow-up and 39.5% also received occupational therapy. However, there was wide variation in the number of sessions received. At baseline, the frequency of concomitant treatments ranged from 18% (functional electrical stimulation) to 92.8% (passive stretching). By follow-up, the overall frequency of concomitant therapies had diminished, although the range of modalities remained similar. Notably, the proportion of patients on antispasmodic medication fell from 46.1% to 28.5%, suggesting that these were no longer needed in some patients – or at least in not such high doses.
Although the study did not collect sufficiently detailed information to determine how the type of therapy affected goal attainment, a post hoc analysis categorized patients into those who received higher intensity (>10 sessions, 53%) and lower intensity therapeutic input (≤10 sessions, 47%) between BoNT-A treatment and goal evaluation at follow-up. The overall rate of primary goal achievement was significantly greater in the higher intensity group than the lower (83.6% vs. 74.6%; P = 0.0260), although patients receiving higher intensity therapy also had a significantly shorter time since the onset of stroke (median difference of 11.4 months; P = 0.0002) and so were possibly still in the recovery phase. While this fairly crude analysis does not show causality of effect, our findings support the idea that therapy input is critical for functional goal attainment. However, more work was needed to understand whether intensive therapeutic input is more important for some goal than others, and if so, which types and amount.
Potential prognostic factors
Step-wise logistic regression modeling was used to identify prognostic factors for achievement of the primary goal. Potential covariates included etiology of the stroke, primary goal area, duration and severity of spasticity, time interval to follow-up, presence of confounding factors (including the presence of contractures; impaired motor, sensory, cognitive, emotional, cortical function, etc.). Backward elimination analysis showed primary goal area, primary goal score at baseline, first administration of BoNT-A, and cortical function to be the strongest predictors of outcome. When these were entered into the multivariate logistic model, the results indicated that patients with impaired cortical function were half as likely to respond to treatment (odds ratio [OR]: 0.48 [95% CI: 0.26–0.89]). The most likely explanation for this is that patients with dyspraxia, neglect or poor visuospatial perception are more likely to have difficulty complying with and carrying through any treatment program.
A nonsignificant trend was also seen for poorer goal achievement in patients receiving their first administration of BoNT-A, compared with those who had had previous injections (OR: 0.69 [95% CI: 0.43–1.12]). This may reflect the fact that patients who already received BoNT-A benefited from their prior experience to better define their treatment goals and expectations for outcome.
Stage 6 – “Tests, allies, and enemies”
Learning from the Upper Limb International Spasticity-II
By 2012/2013, the findings from the ULIS-II had considerably enhanced our understanding of the main goals that were likely to be achieved through BoNT-A and how clinicians were using it in their normal clinical practice.
However, there is still much that we did not know:
- The ULIS-II focused only on poststroke spasticity – It did not tell us anything about spasticity in other conditions such as traumatic brain injury and spinal cord injury.
- It recorded only one cycle of treatment. We did not know anything about the response to repeated cycles of treatment
- Neither did we know how clinicians conduct repeated cycles; for example, if they change their practice between one injection and another and choose different goals, different muscles, different doses, different outcome measures, etc., as the patient progresses, or whether they simply tend to repeat the same injections using the same approach
- Although the quality of goal statements had improved considerably during the course of the ULIS-II, only 12 centers (24%) had achieved a maximum possible combined rating of “A++.” It was clear that still work has to be done on GAS training
- We were starting to see some narrowing of the range of different outcome measures used, but we still had not got actual data from the standardized measures
- Although the ULIS-II recorded therapy input crudely in terms of the number of sessions by clinical discipline (physiotherapy or occupational therapy), it did not capture sufficient detail to describe or cost the rehabilitation program
- We had not yet captured any measure of quality of life.
In the course of the ULIS-II, we had recruited a number of spasticity services who were now fully engaged in the use of GAS and the ULIS tools as a process for systematic recording of outcomes. While we hope not to have made any actual “enemies,” we acknowledge that some centers found the flexible nature of goal setting and GAS conceptually too hard and would have preferred a more structured approach to outcome measurement.
Learning from the above, the ULIS-III is a longitudinal study that will expand the patient cohort and capture the benefits of treatment in reallife clinical practice, over several treatment cycles. It uses a more structured approach to outcome measurement incorporating both GAS and standardized measures in a targeted way that is feasible to implement in clinical practice. In addition, it also assesses the wider benefits of BoNT-A treatment for ULS by evaluating economic and quality-of-life data, as well as the concurrent therapy rehabilitation program provided.
Stage 7 – “Approach to the Inmost Cave”
Before we could “approach the inner cave” of the ULIS-III, there were some further refinements to be made to the measurement tools and dataset. A proof-of-principle study was conducted in the UK (Ashford and Turner-Stokes) to develop a battery of assessments designed to capture the diversity of presentation, goals, and outcomes inherent in populations of patients with ULS, while targeting measurement on the priority areas of treatment for that individual. The resulting tool is known as the ULS Index.
The Upper Limb Spasticity Index
The ULS Index is a battery of assessments that can be used to evaluate both patient-and clinician-rated components of outcome measurement in ULS. Its three main components are as follows:
- Severity of presentation and confounders to recovery, including:
- Distribution and severity of spasticity and soft-tissue contractures
- Severity of impairment:
- Local to upper limb (e.g., motor control, sensory loss, and neglect)
- General (e.g., cognitive, behavioral, communicative, and mood).
Individual GAS using a structured approach, including:
- GAS-evaluation of outcome in ULS (GAS-eous): SMART goal setting supported by targeted goal parameters or measures according to goal areas
- Patient satisfaction with and engagement in goal setting.
A limited set of standardized measures
- The measures applied are determined by the goal areas, so a standard measure is rated ONLY when that category is one of the goals for treatment.
The Goal Attainment Scaling-evaluation of outcome in upper limb spasticity
The GAS-eous tool was designed to provide a structured framework for the application of GAS alongside standardized measures in the context of ULS. Its development was based on the six main goal domains described in the ULIS-II but corroborated by similar goal analysis across four other single- and multicentric studies.,,,,
As with the standard GAS, the patient and/or their family identify one primary and up to two secondary goals for treatment, but each goal is classified into one of the six key goal areas. The SMART goal statements are then agreed between the team and the patient/family, using one or more of the recommended goal parameters (wherever possible) to frame the statement [Figure 4]. The chosen goal areas determine which of the standardized measure(s) (selected from the limited range of measures for use alongside GAS within the ULS Index - see below) are to be recorded. The baseline and outcome GAS scores are then recorded using the verbal rating scale in the GAS-Light model.
The GAS-eous method offers several potential advantages over the traditional GAS. The more structured approach is designed to streamline goal setting in busy clinical settings, reducing the time taken to apply GAS. In addition, targeted selection of relevant standardized outcome measures reduces the time that would otherwise be spent recording numerous, less relevant measures. Importantly, the GAS-eous retains the individualized nature of patient-centered goal setting focused on the patient's own priorities.
Standardized measures in the Upper Limb Spasticity Index
Standardized outcome measures were selected on the basis that they were supported by published evidence of validity and were already used in clinical practice by centers in the ULIS-II.
- The MAS, which reports variations in muscle tone during flexion and extension, measures the severity of spasticity
- The ULS-adapted version of the Neurological Impairment Scale measures the severity of functional impairment and was used in the ULIS-II
- A verbal rating/10 or Visual Analog Scale is used to record the severity of symptoms including pain, ease of care, ease/difficulty in performing a task, and sleep quality, among others. The Numbered Graphic Rating Scale and the Scale of Pain Intensity are available to support self-report for patients with communication problems
- The Associated Reaction Rating Scale is used to measure involuntary movements such as arm posturing associated with walking
- The ArmA measure is a standardized scale for measuring and determining active and/or passive function
- The Functional Ambulation Category and the 10-m walk test record walking ability.
Spasticity Quality of Life Tool-6D
Generic health utility measures have generally proven insensitive for evaluating change in quality of life with focal intervention for ULS., Although meeting the patient's own priority goals for treatment may to some extent be considered a proxy for quality of life, other areas of clinical practice have developed targeted quality-of-life tools for specific conditions (e.g., the Multiple Sclerosis Quality of Life inventory-54). The Spasticity Quality of Life-6D (SQoL-6D) is another novel tool that was designed for the ULIS program to further assess the quality-of-life benefits of BoNT-A treatment in ULS. It is a self-completed 6-item questionnaire, based on the EuroQoL-5D, intended to evaluate the quality of life in relation to ULS within the six key goal areas defined for GAS-eous. It is still undergoing development and evaluation in its original language (English) and has not yet been translated into other languages. The ULIS-III includes piloting of the self-completed SQoL-6D in the subset of native English-speaking countries (Australia and the USA).
The ULS Therapy Recording Schedule
The ULS Therapy Recording Schedule (ULSTR), a novel instrument designed for the ULIS program, records the actual intervention and intensity of the physical treatments used to manage ULS, and so has the potential to relate concurrent rehabilitation therapies to specific goal achievement. Like the SQoL-6D, the ULSTR is still undergoing full evaluation, but is being used in the ULIS-II as part of that process.
Patient and family engagement
Recent trends in rehabilitation emphasize the importance of self-management. Engaging patients in their own goal management is shown to be an effective therapeutic intervention in itself. The negotiation of goals that mirror the patient's own priorities may encourage positive engagement in rehabilitation. Alongside GAS-eous, the ULIS-III records patient engagement in goal setting and their satisfaction with the goals.
[Figure 5] summarizes the process for the application of measures in the ULIS-III.
|Figure 5: Process of application of measures in the Upper Limb International Spasticity-III study|
Click here to view
Stage 8 – “The Ordeal”
The Upper Limb International Spasticity-III
The ULIS-III is an international, multicentric, observational, prospective, longitudinal cohort study which has enrolled 1004 individuals in 57 study centers across 14 countries. Once again, the study design is noninterventional and reflects real-life clinical practice. Patients with ULS arising from any neurological condition and receiving any licensed BoNT-A product are included. A maximum of 30 patients per center were included.
The primary objective is to assess the attainment of patient-centered and function-related goals following repeated BoNT-A injections (where used) and alongside integrated ULS management in real-life settings over a 2-year period. The primary outcome is the cumulated GAS T-score, defined as the mean of the individual GAS T-scores for all cycles per patient.
The secondary objectives are to:
- Describe injection practices and additional treatment strategies and to record clinical decision-making in the serial approach to spasticity management over time
- Assess the attainment of patientcentered goals by goal area following each cycle of BoNT-A injections and overall attainment after repeated cycles, alongside standardized measures of symptoms, impairment, disability (activity limitation), and participation selected on an individual basis according to the goals for treatment
- Describe and quantify concomitant therapy use and explore its relationship with goal attainment.
In addition to the use of the novel tools described above, the ULIS-III includes an analysis of health-care resource utilization, including direct clinical costs and indirect costs associated with spasticity and concomitant medications. These are assessed at baseline and at every subsequent visit. They include assessment of changes in concomitant treatments, such as medications associated with spasticity and pain, changes in employment status, and maintenance of health care, for example, nurse or caregiver. The ULSTR data are used to determine health-care resource use associated with ULS-related physical therapy.
Quality of goal setting
Part of the rationale for development of the GAS-eous tool was to improve the quality of goal setting, and the recruiting centers (many of which also recruited for the ULIS-II) underwent further training for the ULIS-III. Goal reviews, validation, and feedback by the Steering Group were also conducted at more frequent intervals throughout the recruitment phase to facilitate a high standard of goal setting.
The participants were recruited between January 14, 2015, and May 4, 2017. Goal setting data were quality checked, and the centers were given a rating based on the WHO ICF and SMART guidelines, as for the ULIS-II. By the end of the recruitment, 76.5% of the centers had achieved the highest rating (A++). This included 33 centers who had not participated in the ULIS-II and were new to the program. This finding supports the view that the more structured approach of the GAS-eous can help improve the quality of goal setting, even for novel users.
Preliminary findings and change in clinical practice
The ULIS-III is still underway, and the final results will not be available until 2020. However, recruitment is complete, and some interesting preliminary findings are emerging, even from the baseline data.
[Figure 6] compares the frequency of primary goals set across the six main areas in the ULIS-II and ULIS-III. Pain is now the second most common goal for treatment (25%), while active function and range of movement have decreased correspondingly. Similarly, the frequency of injections into shoulder muscles has increased from 18% to 38%. These findings suggest that clinicians have learned that hemiplegic shoulder pain is an important goal for treatment, while goals related to active function are less likely to be achieved. Recent observational studies have suggested that patient-reported outcomes are best seen after the third or fourth injection cycle. The longitudinal collection of data in the ULIS-III will allow a better understanding of when patients meet their treatment goals and how treatment goals may evolve over time as different issues are addressed. It will also inform our understanding of how patterns of injection (e.g., muscles for shoulder pain) change over time.
|Figure 6: Frequency of primary goal areas in Upper Limb Spasticity-II and Upper Limb International Spasticity-III programs|
Click here to view
The journey continues
The ULIS program has been a 10-year odyssey of learning and building on the insights of each successive study while drawing upon other innovations from the fast-moving field. Our quest has changed somewhat in the course of the program. At the outset, our aim was to identify “best responders,” but over the course of the program, this mission has expanded to the broader objective of learning how to identify meaningful, realistic goals for each patient and to deliver best practice in different clinical situations. The program has not only provided important information about what clinicians do in real-life clinical practice, but it has also improved their understanding of what does and does not work, and so it has already started to change approaches to the management of ULS.
Our journey has been undertaken against a changing backdrop of clinical knowledge, and through our various publications (both from within and outside the ULIS program), we have contributed to that knowledge base. Goal setting and GAS are now much more widely recognized as useful clinical tools for guiding intervention as well as evaluating outcome. They are increasingly incorporated into clinical practice and clinical trial design.,,
Even after 10 years, our odyssey is far from over. We are just starting to reap the beginnings of “The Reward,” but there is much to do before we start our “Return Journey” – so, for now, we must continue to travel onward in pursuit of further adventure. The results from the ULIS-III are still awaited, and work has already begun to extend the exploration to lower-limb spasticity. The ULIS program sets in train a methodology that is practical for use in routine clinical practice and in future studies. We hope that developments such as the GAS-eous, the ULS Index, the ULSTR, and the SQoL-6D will enable other studies also to expand their clinical dataset to one of the sufficient sizes to elucidate important findings, including which patients are most likely to benefit from what types of treatment and how best to capture the outcomes.
The authors thank all patients involved in the study, as well as their caregivers, care team, investigators, and research staff in the participating institutions. We are particularly indebted to Australian colleagues Steve De Graaff, Ian Baguley, and Gavin Assauw (Ipsen Australia) for assistance with the development of the GAS-Light. We also acknowledge the work of the ULIS project managers at Ipsen over the years. The authors thank Anita Chadha-Patel PhD of ACP Clinical Communications Ltd (Hertfordshire, UK) for providing medical writing support, which was funded by Ipsen (Paris, France) in accordance with the Good Publication Practice guidelines. Ipsen Pharma provided financial support for this assistance. Financial support for manuscript preparation was also provided through the Dunhill Medical Trust and Northwick Park Hospital.
Financial support and sponsorship
The ULIS program was sponsored by Ipsen.
Conflicts of interest
Lynne Turner-Stokes, Stephen Ashford, Klemens Fheodoroff, and Jorge Jacinto all received honoraria and conference attendance fees from Ipsen for undertaking this research. Lynne Turner-Stokes and Stephen Ashford have a specific interest in outcome evaluation and have published extensively on the use of GAS in this context, as well as a number of other standardized measures; all of which are freely available. However, they have no personal financial interest in any of the materials mentioned in this article. Stephen Ashford received funding from the National Institute of Health Research (NIHR) in the form of a Clinical Lectureship award and an NIHR CLAHRC Northwest London Fellowship. Klemens Fheodoroff has a specific interest in outcome evaluation and the use of the International Classification of Function in clinical settings. Jorge Jacinto has a particular interest in clinical and instrumental spasticity evaluation methods, goal setting, treatment strategies/techniques, and outcome measurement.
| Ulis Study Group|| |
Australia: Ian Baguley, Arun Aggarwal, John Olver, John Estell, Stephen Faux, Edwin Luk, Clayton King, Katya Kotschet, Andrew Hughes, Rachael Nunan, Michael Pollack, Brian Zeman. Austria: Bernhard Haslinger, Petra Baum, Cornelia Mobius, Urban Fietzek, OA Johann Rappold, Chi Wang Ip. Belgium: Thierry Deltombe, Thierry Lejeune, Geert Vanhooren, Els Van Tichelt. Brazil: Tae Mo Chung, Régina Helena Chueirem, Carla Heloisa Cabral Moro. Czech Republic: Martin Bares, Edvard Ehler. Denmark: Helge Kasch, Stephen Worlich Pedersen, Thomas Truelsen. Finland: Petteri Maunu, Niko Tieranta, Jari Ylinen. France: Claire Aymard, Nicolas Bayle, Djamel Bensmail, Laurent Bensoussan, Isabelle Bonan, François Boyer, Emmanuelle Chaleat-Valayer, Flavia Coroian, Claire Delleci, Anne-Laure Ferrapie, Marie-Eve Isner-Horobeti, Serdar Kocer, Philippe Marque, Bernard Parratte, Dominic Perennou, Joanna Rome, Christophe Roth, Marc Rousseaux, Jean-Yves Salle, Alexis Schnitzler. Germany: Dirk Dressler, Peter Kossmehl, Beate Patzner Gerhard Reichel, Stefan Unglaub, Hartwig Woldag, Karlheinz Werner Hong Kong: Leonard Sheung Wai Li, Ching Man Leung. Italy: Michela Cosma, Carlo Caltrairone, Giovanni Checchia, Carmelo Chisari, Manuela Diverio, Paolo Girlanda, Giancarlo Ianeri, Mario Manca, Marzia Millevolte, Franco Molteni. Korea: Min Ho Chun, Han Young Chung, Deog Young Kim, Yun Hee Kim, Sang Jee Lee, Nam Jong Paik. Malaysia: Goh Khean-Jin, Mak Choon Soon. Mexico: Carlos Cuevas, Jorge Hernandez Franco, Juan Francisco Javier Gomez Hernandez, Francisco Jiménez, Sandra Quinones Aguilar, Laura Patricia de la Lanza Andrade. Poland: Dariusz Koziorowski, Anna Potulska, Monika Rudzinska, Philippines: Raymond Rosales, Jeanne Flordelis. Portugal: Eduarda Afonso, Maria João Andrade, Eduarda Afonso, Renato Nunes, Ana Rolo Duarte. Russia: Ludmila Antipova, Elena Arefyeva, Denis Karpov, Dina Khasanova, Svetlana Khatkova, Alexey Korenko, Andrey Korolev, Dmitry Pokhabov, Dmitry Popov, Larisa Sperling. Singapore: Keng He Kong, Yee Sein Ng. Spain: Juan Vicente Lozano Guadalajara, Lourdes López de Munaín, Inmaculada Máñez Añón, Susana Moraleda Pérez. Sweden: Tor Ansved, Ann Axelsson, Bo Danielsson, Hans Naver. Taiwan: Tsai Ching Piao, Yi-Chung Lee, Sen-Wei Tsai, Chou Li Wei. Thailand: Witsanu Kumthornthip, Areerat Suputtitada. UK: Magid Bakheit, Prabal Datta, T Lal Landham, Rama Prasad. USA: Jessica Tate, Thomas L. Davis, Cynthia Marciniak, Atul Patel.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]