Adine Adonis

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 agents safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.

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.

Treatment of patients with HTLV-1-associated myelopathy with methotrexate

The lifetime risk of developing HTLV-1 associated myelopathy (HAM) is 0.25-3%. The main pathological feature is an immune-mediated response leading to chronic inflammation of the spinal cord. The optimal long term treatment has yet to be determined although clinical improvement with ciclosporin has been shown in a pilot study. Methotrexate, commonly used for autoimmune diseases, was introduced for the treatment of HAM at the National Centre for Human Retrovirology, London, UK as an alternative to ciclosporin.

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.

A proof of concept study of Infliximab for the treatment of HTLV-1-associated myelopathy

Background Disease modifying treatment options for patients with HAM are limited. Most studies have included all patients regardless of duration, disability or disease activity. The Medical Research Council UK funded a series of proof of concept studies for patients with early (50% deterioration during preceding 3 months). The results of the first study of ciclosporin have been published. The second study, of the anti-TNF monoclonal antibody Infliximab, is presented.

Evidence of brain inflammation in patients with Human T Lymphotropic Virus type 1 associated myelopathy (HAM): A pilot, multi-modal imaging study using [11C] PBR28 PET, MR T1w and DWI

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.

Using the 6 minute walk to investigate endurance in patients with HTLV associated myelopathy

Patients with HTLV-Associated-Myelopathy (pwHAM) predominantly have proximal leg weakness, and reduced activities of daily living (ADLs). 92% of pwHAM attending NCHR use a walking aid and experience difficulty with walking long distances, thus many are housebound, or community ambulators. The 6 minute walk test (6MWT) measures walking endurance and was measured at 2 timepoints (T1 & T2), 1 year(yr) apart. We retrospectively analysed 36 patients’ notes (26♀: 10♂; mean age 56.8yrs; mean duration of HAM 10.7yrs). We correlated, regressed and t-tested 10m timed walk (10mTW), walking aid used, pain scores, distance covered, time taken and velocity. Significant differences were found between T1T 6MWVelocity p=0.04 & 10mTW p=0.04. 6MW is reliable (ICC: 0.83).10mTW inversely correlated with the 6MWTDistance covered T1p=0.002 & T2 p=0.022 & 6MWTVelocity T1p=0.000 & T2 p=0.002.10mTW at T1 predicted 6MWDistance (p=0.004), T1 6MWVelocity predicted T2 distance walked. Walking aids predicted 10mTW time (p=0.00 at T1 & T2); 6 MWDistance covered (T1=p=0.002;T2:p=0.00) and velocity (T1&T2:p=0.00). Duration of disease (p=0.34), interval between tests (p=0.57) & age (p=0.75) did not predict the 6 MWT (distance or time) or the 10mTW. Average pain score changed 8.3% between T1&T2 (p=0.75). No element of the 6 MW test or the 10mTW correlated with pain at either time point. Walking endurance is an important component of walking capacity. The 6MWT appears to be a reliable measure to use in patients with HAM. The results demonstrate that pwHAM are more dependent in their ADLs, are a falls risk, walk limited distances & have limited endurance.

Evidence of Brain Inflammation in Patients with Human T-Lymphotropic Virus Type 1-Associated Myelopathy (HAM)

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.

Comparison of walking measures in patients with HTLV-1 Associated Myelopathy

Walking, a fundamental, complex, multifunctional task, is demanding of multiple body systems, interactively affecting walking capacity. Due to their restricted walking ability, activity and participation levels in patients with HTLV-1-Associated Myelopathy (pwHAM) are compromised. Primarily, the applicability of walking endurance using the 6 minute walk (6MW) and gait speed using the timed 10m walk (10mTW), in pwHAM, were explored. Distance covered, change over one year and the influence of pain were documented. Retrospectively, case notes were abstracted for gait (6MW; 10mTW) and pain, for all pwHAM, walking a minimum of 10m, at least 11 months apart. 26 pwHAM, (8-; 18-) met the assessment criteria. Mean age 58.5 years and disease duration was 10.46years ±6.02years. Observed distance walked (55m at T1 and 71m at T2) was shorter (p<0.01) than expected for age, gender and height (610m). Using a patients 10mTW velocity to predict the 6MW distance overestimates the actual distance walked in 6 minutes (p=.00 ;p=.00). Initially the 10mTW velocity, accounted for 35% of the variance of the 6MWdistance (F=.59; p=.00), improving to 63% (F=.00; p=.00). Patients’ 10mTW velocities versus healthy age matched controls differed at baseline (p=0.00)and follow-up (p=0.00). Using a walking aid strongly correlated with the 10mTW at both time points (rs=.78 p= .00; rs=.85 p= .00). Change in pain was not significant over time. 23%(baseline)- 42%(followup) of our pwHAM, completed the 6MW. Acting as their own controls, the distance covered for the 6MW is much shorter compared to predicted values. The 10mTW velocity underestimated the degree of disability, usefully predicted functional domains and highlighted functional decline. The 6MW, independent of the 10mTW velocity, provides a functional measure of endurance. Walking capacity in pwHAM can be measured using the 10mTW for gait speed and the 6MW for endurance. These appear to represent different indicators of walking efficacy in pwHAM.