Issue 1 - March 2022
Ambulatory Duchenne muscular dystrophy children: cross-sectional correlation between function, quantitative muscle ultrasound and MRI
Duchenne muscular dystrophy (DMD) is a progressive genetic muscle disease. Quantitative muscle ultrasound (US), muscle MRI, and functional tools are important to delineate characteristics of muscle involvement. We aimed to establish correlations between clinical/functional and above-named imaging tools respecting their diagnostic and prognostic role in DMD children. A cross-sectional retrospective study of 27 steroid-naive, ambulant male children/adolescents with genetically-confirmed DMD (mean age, 8.8 ± 3.3 years). Functional performance was assessed using motor function measure (MFM) which assess standing/transfer (D1), proximal (D2) and distal (D3) motor function, and six-minute walk test (6MWT). Imaging evaluation included quantitative muscle MRI which measured muscle fat content in a specific location of right rectus femoris by mDixon sequence. Quantitative muscle US measured right rectus femoris muscle brightness in standardized US image as an indicator of muscle fat content. We found a highly significant positive correlation between the mean MFM total score and 6MWT (R = 0.537, p = 0.007), and a highly significant negative correlation between fat content by muscle US and MFM total score (R = -0.603, p = 0.006) and its D1 subscore (R =-0.712, p = 0.001), and a significant negative correlation between fat content by US and 6MWT (R = -0.529, p = 0.02), and a significant positive correlation between muscle fat content by mDixon MRI and patient’s age (R = 0.617, p = 0.01). Quantitative muscle US correlates significantly with clinical/functional assessment tools as MFM and 6MWT, and augments their role in disease-tracking of DMD. Quantitative muscle US has the potential to act as a substitute to functional assessment tools.
Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked inherited disease that affects 1 in 3600-6000 live male births 1. DMD occurs as a result of mutations (mainly exon deletions) in the dystrophin gene (DMD; locus Xp21.2). The most common presenting feature is secondary deterioration of the motor milestones typically recognized at mid childhood. With time, untreated progressive muscle weakness, joint contractures, and cardio-pulmonary compromise affect quality of life. The disease eventually runs a fatal course by approximately 20 years of age 1,2. This is especially true for untreated or steroid- naïve patients, whereas steroid-administered patients may show some amelioration of their clinical course. The management of DMD requires a multidisciplinary approach to improve the quality of life 2-4.
Therapeutic interventions have recently demonstrated intense upswings in modifying the natural history of DMD. These interventions include; therapies that slow the decline in muscle strength and function as glucocorticoids and therapies that target the pathology of DMD or improve muscle growth and regeneration 1,5. Furthermore, gene therapies as gene-addition, exon-skipping, stop codon read through and genome-editing therapies aim at improving the expression and functionality of dystrophin protein. Other therapies work on a cellular level and aim at replacement of damaged muscle tissue. Both of the above therapies yielded encouraging preliminary results 6,7. Nevertheless, these therapeutic gains have accentuated the need for consistent, valid and reliable assessment tools/outcome measures to monitor responses to treatment and to act as prognostic indicators. Widely used clinical scales that measure the motor function and activities of ambulatory and non- ambulatory patients with DMD exist 8-10. Recently significant interest in the use of magnetic resonance imaging (MRI) of muscles as whole-body MRI, quantitative MRI and magnetic resonance spectroscopy (MRS) to monitor disease progression has evolved 11-13. MRI is a valuable non-invasive tool to reveal distinct pathologic patterns of various hereditary muscular diseases such as facioscapulohumeral muscular dystrophy 14, sarcoglycanopathies 15, congenital myopathies 14, muscular dystrophies 16, including DMD 14,17. The use of quantitative muscle MRI and whole-body MRI have also been shown valuable to draw clinical-imaging-genetic correlations and identify ideal sites for muscle biopsy 11,14,16,17. The combined use of quantitative muscle US and MRI showed promising results in regard to delineating disease stage and its relevance to functional status in facioscapulohumeral muscular dystrophy patients 18,19. In DMD quantitative muscle MRI 20-22, and quantitative muscle ultrasound (US) 23,24, were found to be a satisfactory substitute to clinical/functional assessment tools as timed function tests and so forth in regard to monitoring disease progression.
Nevertheless, we are not aware of studies that investigated the clinical utility of quantitative muscle US and quantitative muscle MRI when used simultaneously with clinical functional tests in patients with DMD. The objectives of this study are: a) to assess the role of quantitative muscle US and muscle MRI as a potential diagnostic and prognostic tool in a series of ambulatory children with genetically-confirmed DMD; b) to draw relevant correlations between these two imaging modalities and clinical outcomes namely 6-minute walk test and motor function measure.
Materials and methods
This was a cross-sectional retrospective study. Twenty-seven steroid-naive, ambulant male children/adolescents with genetically-confirmed DMD were enrolled. The mean age of patients was 8.8 ± 3.3 years (range, 3.1 to 18). Exception to the reading frame rule occurred in one patient (18 years) with frameshift deletion of exon 3-7, who presented with Becker phenotype. This was likely due to either the presence of an alternative translation initiation site in exon 8 that was activated by the mutation, or due to genetic modifiers 25-27. The functional performance of patients was assessed using the motor function measure (MFM) 28, and six-minute walk test (6MWT) 8. MFM consists of 32 items (20 items for children < 7 years). It assesses all three dimensions of motor performance including standing and transfer (D1) subscore, axial and proximal motor function (D2), and distal motor function (D3). 6MWT is a commonly used timed functional test that also sufficiently monitors changes in muscle function. The imaging evaluation included quantitative muscle MRI, which measured muscle fat content in the right rectus femoris at the junction of the proximal 1/3 - distal 2/3 of thigh by mDixon sequence, and quantitative muscle US which measured muscle brightness in standardized US image as an indicator of muscle fat content. Twenty-five patients completed both functional tests; 21 patients completed the muscle US examination and 16 completed the muscle MRI examination. The study was approved by the Medical Ethics Research Committee of Faculty of Medicine, Ain Shams University, Egypt, number FMASU R 110 / 2021. Informed consent from participants was waived by the regulatory authority.
The imaging and functional evaluation took place over two consecutive days where imaging evaluations were done prior to the functional tests. The patients who had sufficient cognitive ability to comply with verbal commands pertaining to the functional tests, were evaluated by the same examiner and approximately at the same time-point of the day. The functional tests were performed uniformly in the following order: MFM followed by 6MWT.
Motor function measure (MFM)
Items of the MFM-32 and MFM-20 are classified in three domains: D1: standing and transfers (13 items for the MFM-32 and 8 items for the MFM-20); D2: axial and proximal motor function (12 items for the MFM-32 and 8 items for the MFM-20); D3: distal motor function (7 items for the MFM-32 and 4 items for the MFM-20). Scores ranged from 0 to 3 as follows: (0) cannot perform the task, or cannot maintain the starting position, (1) initiated the task, (2) performs the movement incompletely, or completely but imperfectly (compensatory movements, position maintained for an insufficient duration of time, slowness, uncontrolled movement) and (3) performs the task fully and “normally” namely the movement is controlled, mastered, directed and performed at constant speed. The calculation of scores was expressed as a percentage in relation to the maximum score (for furthers details see https://mfm-nmd.org/).
Six-minute walk test
6MWT was performed according to the ATS guidelines, modified by having two examiners, one recording time and distances, and one staying close to the patient for safety issues 29.
Quantitative muscle MRI
mDixon sequence was taken using Achieva 1.5-T MR machine (Philips Medical Systems, The Netherlands) with the following parameters; (Slice thickness 10 mm, Spacing 5 mm, Number of phase encoding steps: 268, Acquisition matrix 272/0/0/268, Flip angle 15), the images were transferred to workstation (ViewForum R 6.3). mDixon sequence was done and the workstation was used to generate the four sequences (fat, water, in phase and out of phase). The mean fat and water signal of a region of interest (ROI) within the right rectus femoris muscle were measured at the junction between the proximal 1/3 and distal 2/3, between its origin (from the anterior inferior iliac spine) and its insertion (at the upper pole of the patella).
Quantitative muscle US
US in axial plane of the right rectus femoris muscle was taken at the junction between the proximal 1/3 and distal 2/3 between its origin (from the anterior inferior iliac spine) and its insertion (at the upper pole of the patella), using GE Logiq p7 machine (GE Healthcare, Waukesha, Wisconsin, USA) with high resolution linear probe 7-12 MHz. All the imaging parameters (including the probe frequency, depth, and gain) were constant, the images were transferred to a personal PC and mean grayscale (i.e. muscle echogenicity) was calculated using image histogram analysis software (ImageJ), and was used as an indication of muscle fat content. The quadriceps is a large proximal muscle which is frequently and severely involved by fatty infiltration in DMD and at a relatively early stage. Technique-wise its examination is practical 17.
Data was revised for its completeness and consistency. Data entry was done on Microsoft Excel workbook. Quantitative data was summarized by mean, standard deviation while qualitative data was summarized by frequencies and percentages. The program used for data analysis was IBM SPSS statistics for windows version 23 (IBM Corp., Armonk, NY, USA). Chi-square test, student t test, and Pearson correlation coefficient were used in analysis of this study. Kappa test was done to measure level of agreement. A “P value” of less than 0.05 was considered statistically significant.
Six patients (22%) were < 7 years of age. 19 patients (70%) had exon deletions, 2 (7%) had exon duplications, and 6 (22%) had small variants, two of which were nonsense and four were small deletions. Comparatively, patients with exon deletions had a lower mean MFM score without statistical significance. Tables I and II show the descriptive statistics of all clinical and imaging assessment tools used. We found a highly significant positive correlation between 6MWT and the mean total MFM score (R = 0.537, p = 0.007) and its D1 subscore (R = 0.751, p = 0.000) (Figs. 1,2). We found a highly significant negative correlation between fat content by muscle US and total MFM score (R = -0.603, p = 0.006) and its D1 subscore (R = -0.712, p = 0.001) (Figs. 3-5). Additionally, we found a significant negative correlation between fat content by muscle US and 6MWT score (R = -0.529, p = 0.02) (Tab. S3). This denotes that the higher the fat replacement in muscles of the thigh, the lower the scores of MFM and its D1 subscore and the lower meters achieved by patients in 6MWT. We found a significant positive correlation between patient’s age and muscle fat content by mDixon MRI (R = 0.617, p = 0.01). However, we did not find a statistically significant correlation between both muscle fat content and muscle water content by mDixon MRI and neither total MFM score nor 6MWT (Tab. S4) (Figs. 6,7) (Fig. S9). Statistical correlations between age and both mean total MFM scores and subscores, and 6MWT scores were non-significant. For additional information, see (File S1). A graphical abstract of results is shown in Figure 8.
Corticosteroids remain the mainstay of treatment in DMD children whereas gene therapeutic modalities are emerging 30,31, among others 32. Some of these gene therapeutics have received regulatory approval in the USA, Europe and Japan 33. Both treatment modalities aim at improving the child’s functional status. Recent advances in therapeutics for the treatment of DMD children have sparked significant interest in finding reliable clinical and imaging assessment tools to monitor responsiveness to these treatment modalities. The current study has incorporated various clinical and imaging assessment tools to explore their diagnostic and prognostic role in genetically-confirmed ambulatory and steroid-naïve DMD children and adolescents. Whereas quantitative US depends on measuring muscle echogenicity using the mean gray scale of a ROI within a selected muscle 23, quantitative MRI depends on measuring muscle fat replacement 22,34. Both quantitative imaging tools have proved to aid clinical assessment fundamentally.
Our study implications are twofold. Firstly, it confirmed the widely acknowledged role of MFM and 6MWT as reliable and clinically meaningful assessment tools in DMD children 8,21,28. Secondly, our study introduced statistically significant positive correlations between scores of these clinical assessments tools, namely MFM and 6MWT on the one hand and quantitative muscle US in DMD children. This highlights the potential clinical utility of quantitative muscle US for DMD monitoring, and underscores the role of quantitative muscle US as an important complement to clinical functional assessment tools. This role has been elucidated in both cross-sectional 35 and longitudinal 23 study designs capable of monitoring disease progression in DMD children. Contrastingly, quantitative muscle fat content measured by US did not show a statistically significant correlation with patient’s age.
Quantitative muscle MRI -as per T2 mapping and mDixon- has been found helpful for delineating upper 12,36 and lower extremity 22,37,38 muscle involvement, and to be a satisfactory predictor of both strength of the investigated muscles or of the overall function of the investigated extremity in DMD children. However, our results did not establish a similarly significant correlation between the scores of these clinical assessments tools, namely MFM and 6MWT and quantitative muscle MRI namely muscle fat content and muscle water content by mDixon MRI. This may be attributed to the limitations of our study. Including the genotype profile in the analysis would have been insightful for interpreting the clinical-imaging results. However, this was beyond the scope and objectives of this study, and is reserved for a separate study. Missing data of some tests were sporadic and attributed to patient-related transport barriers among others.
North Star Ambulatory Assessment and Performance of the Upper Limb Module are reliable outcome tools which are designed to assess functional mobility 39 and upper limb performance 40,41 among DMD children. Both outcome tools have been used to better characterize natural history, responsiveness to treatment and genotype-phenotype correlations in ambulatory 39,40 and non-ambulatory DMD children 41. Although these outcome tools were not implementedin our cross-sectional study, we believe they represent valid substitutes for such.
Our study contained multiple clinical and imaging assessment tools (dependent variables). Additionally, its retrospective and cross-sectional nature does not allow for complete bias control in terms of standardization of patient characteristics among others. Moreover, longitudinal study designs have a greater potential to consolidate evidence for the use of both quantitative muscle US and muscle MRI as a substitute or a supplement to functional assessment tools in disease tracking and monitoring response to treatment of DMD patients. Further, the diversity of clinical assessment tools in general and functional tools in specific used across studies, need to be considered when interpreting the imaging-clinical correlation results 42. Interestingly, quantitative muscle fat content measured by mDixon MRI showed a statistically positive correlation with patient’s age. This is a clinically meaningful correlation, and it supports the assumption that the above-noted non-significant correlations between the clinical MFM and 6MWT scores, and quantitative fat content by mDixon MRI is mainly due study limitations. Additionally, of note is that statistical significance does not necessary equate to clinical significance. Consequently, all findings should be interpreted cautiously, and within clinical context. Results from the assessment of a single muscle by quantitative MRI and US, may not be fully representative of the overall muscle pathology.
Quantitative muscle US correlates significantly with clinical/functional assessment tools as MFM and 6MWT, and augments their promising role in disease tracking in DMD children. In that regard, quantitative muscle US has the potential to act as a complement to functional assessment tools. The presence of multiple clinical and imaging assessment tools (dependent variables) and study design-related limitations may have underpowered our statistical correlations of quantitative muscle MRI.
The Authors thank Dr Khaled M. Abd Elaziz, Professor of Public Health, Ain Shams University for his help in performing the statistical analysis. Part of the material in this work has been submitted and accepted as a poster presentation at Parent Project Muscular Dystrophy 20121 Annual Conference/Virtual Meeting (June 23-26 June, https://www.parentprojectmd.org/events/ppmds-2021-annual-conference).
The current manuscript has been posted on a preprint server (https://doi.org/10.1101/2021.08.17.21262119).
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