Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1.

OBJECTIVES: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures. METHODS: Assessments included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), CMTNSv2-Rasch modified, nerve conduction studies, quantitative sensory testing, intraepidermal nerve fibre density (thigh), computerised myometry (lower limbs), plasma 1-deoxysphingolipid levels, calf-level intramuscular fat accumulation by MRI and patient-based questionnaires (Neuropathic Pain Symptom Inventory and 36-Short Form Health Survey version 2 [SF-36v2]). RESULTS: 35 patients with HSN1 were recruited. There was marked heterogeneity in the phenotype mainly due to differences between the sexes: males generally more severely affected. The outcome measures that significantly changed over 1 year and correlated with CMTNSv2, SF-36v2-physical component and disease duration were MRI determined calf intramuscular fat accumulation (mean change in overall calf fat fraction 2.36%, 95% CI 1.16 to 3.55, p=0.0004), pressure pain threshold on the hand (mean change 40 kPa, 95% CI 0.7 to 80, p=0.046) and myometric measurements of ankle plantar flexion (median change -0.5 Nm, IQR -9.5 to 0, p=0.0007), ankle inversion (mean change -0.89 Nm, 95% CI -1.66 to -0.12, p=0.03) and eversion (mean change -1.61 Nm, 95% CI -2.72 to -0.51, p=0.006). Intramuscular calf fat fraction was the most responsive outcome measure. CONCLUSION: MRI determined calf muscle fat fraction shows validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials.

Revolution in acute ischaemic stroke care: a practical guide to mechanical thrombectomy.

Rapid, safe and effective arterial recanalisation to restore blood flow and improve functional outcome remains the primary goal of hyperacute ischaemic stroke management. The benefit of intravenous thrombolysis with recombinant tissue-type plasminogen activator for patients with severe stroke due to large artery occlusion is limited; early recanalisation is generally less than 30% for carotid, proximal middle cerebral artery or basilar artery occlusion. Since November 2014, nine positive randomised controlled trials of mechanical thrombectomy for large vessel occlusion in the anterior circulation have led to a revolution in the care of patients with acute ischaemic stroke. Its efficacy is unmatched by any previous therapy in stroke medicine, with a number needed to treat of less than 3 for improved functional outcome. With effectiveness shown beyond any reasonable doubt, the key challenge now is how to implement accessible, safe and effective mechanical thrombectomy services. This review aims to provide neurologists and other stroke physicians with a summary of the evidence base, a discussion of practical aspects of delivering the treatment and future challenges. We aim to give guidance on some of the areas not clearly described in the clinical trials (based on evidence where available, but if not, on our own experience and practice) and highlight areas of uncertainty requiring further research.

Stability and sensitivity of water T2 obtained with IDEAL-CPMG in healthy and fat-infiltrated skeletal muscle.

Quantifying muscle water T2 (T2 -water) independently of intramuscular fat content is essential in establishing T2 -water as an outcome measure for imminent new therapy trials in neuromuscular diseases. IDEAL-CPMG combines chemical shift fat-water separation with T2 relaxometry to obtain such a measure. Here we evaluate the reproducibility and B1 sensitivity of IDEAL-CPMG T2 -water and fat fraction (f.f.) values in healthy subjects, and demonstrate the potential of the method to quantify T2 -water variation in diseased muscle displaying varying degrees of fatty infiltration. The calf muscles of 11 healthy individuals (40.5 ± 10.2 years) were scanned twice at 3 T with an inter-scan interval of 4 weeks using IDEAL-CPMG, and 12 patients with hypokalemic periodic paralysis (HypoPP) (42.3 ± 11.5 years) were also imaged. An exponential was fitted to the signal decay of the separated water and fat components to determine T2 -water and the fat signal amplitude muscle regions manually segmented. Overall mean calf-level muscle T2 -water in healthy subjects was 31.2 ± 2.0 ms, without significant inter-muscle differences (p = 0.37). Inter-subject and inter-scan coefficients of variation were 5.7% and 3.2% respectively for T2 -water and 41.1% and 15.4% for f.f. Bland-Altman mean bias and ±95% coefficients of repeatability were for T2 -water (0.15, -2.65, 2.95) ms and f.f. (-0.02, -1.99, 2.03)%. There was no relationship between T2 -water (ρ = 0.16, p = 0.07) or f.f. (ρ = 0.03, p = 0.7761) and B1 error or any correlation between T2 -water and f.f. in the healthy subjects (ρ = 0.07, p = 0.40). In HypoPP there was a measurable relationship between T2 -water and f.f. (ρ = 0.59, p < 0.001). IDEAL-CPMG provides a feasible way to quantify T2 -water in muscle that is reproducible and sensitive to meaningful physiological changes without post hoc modeling of the fat contribution. In patients, IDEAL-CPMG measured elevations in T2 -water and f.f. while showing a weak relationship between these parameters, thus showing promise as a practical means of quantifying muscle water in patient populations.

Putting pontine anatomy into clinical practice: the 16 syndrome.

The anatomical localisation of brainstem syndromes is the domain of the clinical neurologist, though MRI has made an encyclopaedic knowledge of neuroanatomy less crucial. Isolated pontine syndromes comprise ∼20% of the brainstem lacunar syndromes. Typical presentations such as pure motor hemiparesis and ataxic hemiparesis are easily recognisable but atypical syndromes, particularly when bilateral, may present with puzzling signs. We discuss a patient with an unusual acute bilateral brainstem syndrome, in whom MRI was contraindicated. We use the relevant neuroanatomy to support the likely diagnosis of bilateral caudal pontine tegmentum infarction due to occlusion of a single paramedian pontine tegmental perforating artery.

A practical approach to the genetic neuropathies.

Charcot-Marie-Tooth disease is the commonest inherited neuromuscular disease. It is characterised by degeneration of peripheral sensory and motor nerves and can be classified into axonal and demyelinating forms. This review provides a diagnostic approach to patients with suspected inherited neuropathy and an algorithm for genetic testing that includes recent advances in genetics such as next-generation sequencing. We also discuss important aspects of the long-term management of patients with inherited neuropathy.

Development of an initial training and evaluation programme for manual lower limb muscle MRI segmentation.

BACKGROUND: Magnetic resonance imaging (MRI) quantification of intramuscular fat accumulation is a responsive biomarker in neuromuscular diseases. Despite emergence of automated methods, manual muscle segmentation remains an essential foundation. We aimed to develop a training programme for new observers to demonstrate competence in lower limb muscle segmentation and establish reliability benchmarks for future human observers and machine learning segmentation packages. METHODS: The learning phase of the training programme comprised a training manual, direct instruction, and eight lower limb MRI scans with reference standard large and small regions of interest (ROIs). The assessment phase used test-retest scans from two patients and two healthy controls. Interscan and interobserver reliability metrics were calculated to identify underperforming outliers and to determine competency benchmarks. RESULTS: Three experienced observers undertook the assessment phase, whilst eight new observers completed the full training programme. Two of the new observers were identified as underperforming outliers, relating to variation in size or consistency of segmentations; six had interscan and interobserver reliability equivalent to those of experienced observers. The calculated benchmark for the Sørensen-Dice similarity coefficient between observers was greater than 0.87 and 0.92 for individual thigh and calf muscles, respectively. Interscan and interobserver reliability were significantly higher for large than small ROIs (all p < 0.001). CONCLUSIONS: We developed, implemented, and analysed the first formal training programme for manual lower limb muscle segmentation. Large ROI showed superior reliability to small ROI for fat fraction assessment. RELEVANCE STATEMENT: Observers competent in lower limb muscle segmentation are critical to application of quantitative muscle MRI biomarkers in neuromuscular diseases. This study has established competency benchmarks for future human observers or automated segmentation methods. KEY POINTS: • Observers competent in muscle segmentation are critical for quantitative muscle MRI biomarkers. • A training programme for muscle segmentation was undertaken by eight new observers. • We established competency benchmarks for future human observers or automated segmentation methods.

Prolonged Ventilatory Support for Patients Recovering From Guillain-Barré Syndrome.

BACKGROUND: Recovery from Guillain-Barré syndrome (GBS) may be protracted, and patients may need prolonged ventilatory support. We present clinical data from a tertiary referral weaning center managing patients with GBS requiring prolonged ventilatory support. METHODS: A retrospective review of patients managed in a 34-bed specialist ventilator weaning facility in London, United Kingdom, between 2006 and 2017. Data including demographics, initial presentation, and ventilatory support were collected. Functional recovery and outcome data were collected between 12 months and 3 years following disease onset. RESULTS: Twenty-nine patients with severe GBS requiring prolonged ventilation were included. In several patients, coexisting conditions or complications affected the course. Seventy-six percent (n = 22) were successfully weaned from invasive ventilation with a median time to tracheostomy decannulation of 193 days (range: 49-527 days). Use of noninvasive ventilation (NIV), as part of the weaning program, was applied in 59% (13/22), with 14% (3/22) requiring long-term nocturnal NIV. Twenty-four percent (7/29) were not decannulated, with 14% (4/29) supported on long-term invasive ventilation. Forty-five percent (10/22) weaned from invasive ventilation were able to achieve short distance-assisted ambulation. Mortality at 36 months was 17% (5/29), with 3 of these deaths occurring in patients invasively ventilated during their acute admission. CONCLUSIONS: GBS with severe respiratory muscle weakness and bulbar dysfunction may require prolonged invasive ventilation. However, there is potential for complete weaning from invasive mechanical ventilatory support with associated function recovery. These data highlight the importance of maintaining ongoing support and rehabilitation for patients with GBS requiring prolonged ventilation.

Semi-Automated Analysis of Diaphragmatic Motion with Dynamic Magnetic Resonance Imaging in Healthy Controls and Non-Ambulant Subjects with Duchenne Muscular Dystrophy.

Subjects with Duchenne Muscular Dystrophy (DMD) suffer from progressive muscle damage leading to diaphragmatic weakness that ultimately requires ventilation. Emerging treatments have generated interest in better characterizing the natural history of respiratory impairment in DMD and responses to therapy. Dynamic (cine) Magnetic Resonance Imaging (MRI) may provide a more sensitive measure of diaphragm function in DMD than the commonly used spirometry. This study presents an analysis pipeline for measuring parameters of diaphragmatic motion from dynamic MRI and its application to investigate MRI measures of respiratory function in both healthy controls and non-ambulant DMD boys. We scanned 13 non-ambulant DMD boys and 10 age-matched healthy male volunteers at baseline, with a subset (n = 10, 10, 8) of the DMD subjects also assessed 3, 6, and 12 months later. Spirometry-derived metrics including forced vital capacity were recorded. The MRI-derived measures included the lung cross-sectional area (CSA), the anterior, central, and posterior lung lengths in the sagittal imaging plane, and the diaphragm length over the time-course of the dynamic MRI. Regression analyses demonstrated strong linear correlations between lung CSA and the length measures over the respiratory cycle, with a reduction of these correlations in DMD, and diaphragmatic motions that contribute less efficiently to changing lung capacity in DMD. MRI measures of pulmonary function were reduced in DMD, controlling for height differences between the groups: at maximal inhalation, the maximum CSA and the total distance of motion of the diaphragm were 45% and 37% smaller. MRI measures of pulmonary function were correlated with spirometry data and showed relationships with disease progression surrogates of age and months non-ambulatory, suggesting that they provide clinically meaningful information. Changes in the MRI measures over 12 months were consistent with weakening of diaphragmatic and inter-costal muscles and progressive diaphragm dysfunction. In contrast, longitudinal changes were not seen in conventional spirometry measures during the same period. Dynamic MRI measures of thoracic muscle and pulmonary function are, therefore, believed to detect meaningful differences between healthy controls and DMD and may be sensitive to changes in function over relatively short periods of follow-up in non-ambulant boys with DMD.

Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A.

OBJECTIVE: To translate the quantitative MRC Centre MRI protocol in Charcot-Marie-Tooth disease type 1A (CMT1A) to a second site; validate its responsiveness in an independent cohort; and test the benefit of participant stratification to increase outcome measure responsiveness. METHODS: Three healthy volunteers were scanned for intersite standardization. For the longitudinal patient study, 11 patients with CMT1A were recruited with 10 patients rescanned at a 12-month interval. Three-point Dixon MRI of leg muscles was performed to generate fat fraction (FF) maps, transferred to a central site for quality control and analysis. Clinical data collected included CMT Neuropathy Score. RESULTS: Test-retest reliability of FF within individual healthy calf muscles at the remote site was excellent: intraclass correlation coefficient 0.79, limits of agreement -0.67 to +0.85 %FF. In patients, mean calf muscle FF was 21.0% and correlated strongly with disease severity and age. Calf muscle FF significantly increased over 12 months (+1.8 ± 1.7 %FF, p = 0.009). Patients with baseline FF >10% showed a 12-month FF increase of 2.9% ± 1.3% (standardized response mean = 2.19). CONCLUSIONS: We have validated calf muscle FF as an outcome measure in an independent cohort of patients with CMT1A. Responsiveness is significantly improved by enrolling a stratified patient cohort with baseline calf FF >10%.

Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

OBJECTIVE: A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function. METHODS: 15 non-ambulant DMD boys (mean age 13.3 y) and 10 age-gender matched healthy controls (mean age 14.6 y) were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.). Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation. RESULTS: Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001). A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7), accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9) and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8). CONCLUSIONS: These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.