Delphi consensus study and clinical practice guideline development for functional electrical stimulation to support upright mobility in people with an upper motor neuron lesion.

PURPOSE: A Clinical Practice Guideline (CPG) is required to provide guidance on optimal service delivery for Functional Electrical Stimulation (FES) to support upright mobility in people living with mobility difficulties due to an upper motor neuron lesion, such as stroke or multiple sclerosis. A modified Delphi consensus study was used to provide expert consensus on best practice. METHODS: A Steering Group supported the recruitment of an Expert Panel, which included a range of stakeholders who participated in up to three survey rounds. In each round, panelists were asked to rate their agreement with draft statements about best practice using a 6-point Likert scale and add free text to explain their answer. Statements that achieved over 75% agree/strongly agree on the Likert scale were included in the CPG. Those that did not were revised based on free text comments and proposed in the next survey round. RESULTS: The first round included 82 statements with seven substatements. Sixty-five people (84% response rate) completed survey round 1 leading to 62 statements and four substatements being accepted. Fifty-six people responded to survey round 2, and consensus was achieved for all remaining statements. CONCLUSION: The accepted statements are included within the CPG and provide recommendations about who can benefit from FES and how they can be optimally supported through FES service provision. As such the CPG will support advocacy for, and optimal design of, FES services.

Patient research priority setting partnership in human T-cell lymphotropic virus type I.

INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) is a chronic infection affecting 5-10 million people worldwide. Ten percent develop HTLV-1-associated diseases, and 3%-5% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis. Low health-related quality of life (HRQoL) is a significant concern for those with HTLV-1, and little is known about how it impacts daily life or what patients need from healthcare services. To address this, we report on patient involvement workshops aimed at identifying research priorities for HTLV-1 health service provision. METHODS: Participants recruited through HTLV-1 clinics in England attended six 90-min virtual workshops over 10 months, and two 60-min consolidation workshops. Content developed iteratively from topic focussed group discussions. All workshops were video-recorded with consent, transcribed verbatim and thematically analysed. Using consensus voting rounds, participants individually ranked their top six and then collectively their top three research priorities from the themes inferred from the analysis. A final feedback session explored the experiences of participating in the workshops. FINDINGS: Twenty-seven people with HTLV-1 engaged with the workshops with up to 22 participants attending each meeting. The majority were diagnosed with HAM (n = 22). The top three research priorities were identified as understanding disease progression, psychosocial wellbeing, and information and knowledge. Participants valued being asked to set research priorities that directly addressed their needs and enjoyed the workshops. They stressed the importance of patient advocates for promoting research that positively impacts everyday life. CONCLUSION: This is the first of this type of research engagement with people with HTLV-1 in the United Kingdom. Participants identified several avenues of investigation that could lead to improvements in healthcare services and HRQoL. Participants believed the workshops signified the start of a conversation to progress person-centred and meaningful research in HTLV-1. PATIENT OR PUBLIC CONTRIBUTION: People living with HTLV-1 were involved in the iterative design, conduct, analysis, writing and dissemination of this project through the patient involvement workshops. As a result of this engagement, a patient led advisory group has been set up to assist with the dissemination of the findings.

Implementing functional electrical stimulation clinical practice guidelines to support mobility: A stakeholder consultation.

Functional Electrical Stimulation (FES) has been used to support mobility for people with upper motor neuron conditions such as stroke and multiple sclerosis for over 25 years. Recent development and publication of clinical practice guidelines (CPGs) provide evidence to guide clinical decision making for application of FES to improve mobility. Understanding key barriers to the implementation of these CPGs is a critical initial step necessary to create tailored knowledge translation strategies. A public involvement and engagement consultation was conducted with international stakeholders including researchers, clinicians and engineers working with FES to inform implementation strategies for CPG use internationally. Reflexive thematic analysis of the consultation transcripts revealed themes including inconsistent use of CPGs, barriers to implementation such as limited access to FES and low clinician confidence, and the need for a tiered education approach with ongoing support. Insights derived from this consultation will inform the development of knowledge translation strategies to support the next steps to implementing FES use for mobility.

A qualitative systematic review and thematic synthesis exploring the impacts of clinical academic activity by healthcare professionals outside medicine.

BACKGROUND: There are increasing opportunities for healthcare professionals outside medicine to be involved in and lead clinical research. However, there are few roles within these professions that include time for research. In order to develop such roles, and evaluate effective use of this time, the range of impacts of this clinical academic activity need to be valued and understood by healthcare leaders and managers. To date, these impacts have not been comprehensively explored, but are suggested to extend beyond traditional quantitative impact metrics, such as publications, citations and funding awards. METHODS: Ten databases, four grey literature repositories and a naïve web search engine were systematically searched for articles reporting impacts of clinical academic activity by healthcare professionals outside medicine. Specifically, this did not include the direct impacts of the research findings, rather the impacts of the research activity. All stages of the review were performed by a minimum of two reviewers and reported impacts were categorised qualitatively according to a modified VICTOR (making Visible the ImpaCT Of Research) framework. RESULTS: Of the initial 2704 identified articles, 20 were eligible for inclusion. Identified impacts were mapped to seven themes: impacts for patients; impacts for the service provision and workforce; impacts to research profile, culture and capacity; economic impacts; impacts on staff recruitment and retention; impacts to knowledge exchange; and impacts to the clinical academic. CONCLUSIONS: Several overlapping sub-themes were identified across the main themes. These included the challenges and benefits of balancing clinical and academic roles, the creation and implementation of new evidence, and the development of collaborations and networks. These may be key areas for organisations to explore when looking to support and increase academic activity among healthcare professionals outside medicine. The modified VICTOR tool is a useful starting point for individuals and organisations to record the impact of their research activity. Further work is needed to explore standardised methods of capturing research impact that address the full range of impacts identified in this systematic review and are specific to the context of clinical academics outside medicine.

Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life.

BACKGROUND: HTLV-1 is a neglected sexually transmitted infection despite being the cause of disabling neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is no treatment for this infection and public health policies are essential to reduce its transmission. However, there are no data to support adequate cost-effective analysis in this field. The aim of this study was to obtain health state utility values for individuals with HAM/TSP and HTLV-1 asymptomatic carriers (AC). The impact of both states on quality of life (QoL) is described and compared to other diseases. METHODS: A cross-sectional observational study of 141 individuals infected with HTLV-1 (79 with HAM/TSP and 62 AC) from three Brazilian states (Rio de Janeiro, São Paulo and Alagoas) and from the United Kingdom. Participants completed a validated general health questionnaire (EQ-5D, Euroqol) from which country specific health state utility values are generated. Clinical and epidemiological data were collated. PRINCIPAL FINDINGS: Health state utility value for HAM/TSP was 0.2991. QoL for 130 reported clinical conditions ranges from 0.35 to 0.847. 12% reported their quality of life as worse as death. Low QoL was associated with severity rather than duration of disease with a moderate inverse correlation between QoL and Osame's Motor Disability Score (-0.4933) Patients who are wheelchair dependent had lowest QoL whilst those still walking unaided had the highest. AC also reported impaired QoL (0.7121) compared to general population. CONCLUSION: HTLV-1 and its associated neurological disease has a marked impact on QoL. This study provides robust data to support the development of cost-utility analysis of interventions for HTLV-1.

Evidence of Brain Inflammation in Patients with Human T-Lymphotropic Virus Type 1-Associated Myelopathy (HAM): A Pilot, Multimodal Imaging Study Using 11C-PBR28 PET, MR T1-Weighted, and Diffusion-Weighted Imaging.

HTLV-1-associated myelopathy (HAM; HTLV-1 is human T-lymphotropic virus type 1) is a chronic debilitating neuroinflammatory disease with a predilection for the thoracic cord. Tissue damage is attributed to the cellular immune response to HTLV-1-infected lymphocytes. The brains of HTLV-1-infected patients, with and without HAM but no clinical evidence of brain involvement, were examined using a specific 18-kDa translocator protein ligand, 11C-PBR28, and T1-weighted and diffusion-weighted MRI. METHODS: Five subjects with HAM and 2 HTLV-1 asymptomatic carriers were studied. All underwent clinical neurologic assessment including cognitive function and objective measures of gait, quantification of HTLV-1 proviral load in peripheral blood mononuclear cells, and human leukocyte antigen-antigen D related expression on circulating CD8+ lymphocytes. 11C-PBR28 PET and MRI were performed on the same day. 11C-PBR28 PET total volume of distribution and distribution volume ratio (DVR) were estimated using 2-tissue-compartment modeling. MRI data were processed using tools from the FMRIB Software Library to estimate mean diffusivity (MD) and gray matter (GM) fraction changes. The results were compared with data from age-matched healthy volunteers. RESULTS: Across the whole brain, the total volume of distribution for the subjects with HAM (5.44 ± 0.84) was significantly greater than that of asymptomatic carriers (3.44 ± 0.80). The DVR of the thalamus in patients with severe and moderate HAM was higher than that in the healthy volunteers, suggesting increased translocator protein binding (z > 4.72). Subjects with more severe myelopathy and with high DR expression on CD8+ lymphocytes had increased DVR and MD (near-significant correlation found for the right thalamus MD: P = 0.06). On the T1-weighted MRI scans, the GM fraction of the brain stem was reduced in all HTLV-1-infected patients compared with controls (P < 0.001), whereas the thalamus GM fraction was decreased in patients with HAM and correlated with the disease severity. There was no correlation between neurocognitive function and these markers of central nervous system inflammation. CONCLUSION: This pilot study suggests that some patients with HAM have asymptomatic inflammation in the brain, which can be detected and monitored by 11C-PBR28 PET together with structural and diffusion-weighted MRI.

Assessing Walking Ability in People with HTLV-1-Associated Myelopathy Using the 10 Meter Timed Walk and the 6 Minute Walk Test.

BACKGROUND: Five to ten million persons, are infected by HTLV-1 of which 3% will develop HTLV-1-associated myelopathy (HAM) a chronic, disabling inflammation of the spinal cord. Walking, a fundamental, complex, multi-functional task is demanding of multiple body systems. Restricted walking ability compromises activity and participation levels in people with HAM (pwHAM). Therapy aims to improve mobility but validated measures are required to assess change. STUDY DESIGN: Prospective observational study. OBJECTIVES: To explore walking capacity in pwHAM, walking endurance using the 6 minute walk (6MW), and gait speed, using the timed 10m walk (10mTW). SETTING: Out-patient setting in an inner London Teaching hospital. METHODS: Prospective documentation of 10mTW and 6MW distance; walking aid usage and pain scores measured twice, a median of 18 months apart. RESULTS: Data analysis was completed for twenty-six pwHAM, (8♂; 18♀; median age: 57.8 years; median disease duration: 8 years). Median time at baseline to: complete 10m was 17.5 seconds, versus 21.4 seconds at follow up; 23% completed the 6MW compared to 42% at follow up and a median distance of 55m was covered compared to 71m at follow up. Using the 10mTW velocity to predict the 6MW distance, overestimated the distance walked in 6 minutes (p<0.01). Functional decline over time was captured using the functional ambulation categories. CONCLUSIONS: The 10mTW velocity underestimated the degree of disability. Gait speed usefully predicts functional domains, shows direction of functional change and comparison with published healthy age matched controls show that these patients have significantly slower gait speeds. The measured differences over 18 months were sufficient to reliably detect change and therefore these assessments can be useful to detect improvement or deterioration within broader disability grades. Walking capacity in pwHAM should be measured using the 10mTW for gait speed and the 6MW for endurance.

Effect of Pulsed Methylprednisolone on Pain, in Patients with HTLV-1-Associated Myelopathy.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune mediated myelopathy caused by the human T-lymphotropic virus type 1 (HTLV-1). The efficacy of treatments used for patients with HAM/TSP is uncertain. The aim of this study is to document the efficacy of pulsed methylprednisolone in patients with HAM/TSP. Data from an open cohort of 26 patients with HAM/TSP was retrospectively analysed. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. Treatment was well tolerated in all but one patient. Significant improvements in pain were: observed immediately, unrelated to duration of disease and maintained for three months. Improvement in gait was only seen on Day 3 of treatment. Baseline cytokine concentrations did not correlate to baseline pain or gait impairment but a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Until compared with placebo, treatment with pulsed methylprednisolone should be offered to patients with HAM/TSP for the treatment of pain present despite regular analgesia.

Timed walk as primary outcome measure of treatment response in clinical trials for HTLV-1-associated myelopathy: a feasibility study.

BACKGROUND: To advance the treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), randomised controlled therapeutic studies with appropriate and sensitive outcomes are reuired. One candidate outcome is the 10-metre walk test (10MWT), a patient-centred, simple and functional measure. To calculate sample size based on 10MWT as the primary outcome, variability within and between subjects must be known. METHODS: Data on 10MWT from 76 patients with HAM/TSP were prospectively collected from four specialist centres in Brazil, Japan, USA and UK. Data, collected at two time points, 6 months apart, were log transformed and subjected to analysis of covariance. RESULTS: Baseline mean (standard deviation = SD), median 10MWT were 23.5 (18.9), 16.3 s/10 m and at 6 months 24.9 (23.9), 16.4 s/10 m. The mean (SD) % increase in walk time was 5.74 % (28.2 %). After logarithmic transformation, the linear correlation between baseline and 24 weeks 10MWT was r = 0.938. Using these data, it was determined that a randomised controlled trial with 30 participants per group would have 90 % power to detect a 19 % decrease or a 23 % increase in 10MWT. CONCLUSIONS: The intra-patient variability of 10MWT is relatively small in HAM/TSP over 6 months. 10MWT is a feasible outcome measure for a clinical trial in HAM/TSP. To our knowledge, this is the first ever recommendation for the sample size required for trials in HAM/TSP patients.

Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis.

INTRODUCTION: Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. MATERIALS AND METHODS: Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with 'early' (50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. RESULTS: All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. CONCLUSIONS: These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.