Of the patients who were not available for systematic analysis of lung function, 2 had normal VCmax (E1: 54-year-old woman, onset at age 47, VCmax% 75%; F1: 54-year-old woman, onset at age 50, VCmax% 82%). A 38-year-old man required nocturnal continuous positive airway pressure ventilation 2 years after disease onset. A 72-year-old woman, in whom distal weakness was first noted at the age 30, had sudden respiratory failure at age 70 that required intubation and mechanical ventilation. She has been treated with pressurecontrolled ventilation via tracheostomy since that time. DISCUSSION
In our cohort, 6 of 8 patients with MATR3 myopathy available for systematic analysis of respiratory function reported exertional dyspnea, but all showed some involvement of the respiratory muscles, including diaphragm dysfunction, weak expiratory muscles, and reduced airway clearance. Due to the small number of patients and the short follow-up period, it is not clear whether the mild and clinically non-significant changes of most lung function parameters truly represent a deterioration of lung function within 12 months. None of the patients available for follow-up became dependent on nocturnal non-invasive ventilation. However, 2 of the total cohort of 16 patients with MATR3 myopathy required mechanical ventilation, and 1 of them had experienced sudden unanticipated
respiratory failure.3 A causative relationship with the underlying muscle disease cannot be excluded. Myopathy due to MATR3 mutations involves predominantly distal limb muscles, similar to that seen in Welander distal myopathies.6 In addition, both the current and earlier studies clearly show involvement of both pharyngeal and respiratory muscles in MATR3 myopathy. This underlines the importance of regular monitoring of respiratory function in these patients. Long-term follow-up will reveal whether some of these patients will eventually require non-invasive ventilation. The authors thank Prof. Stephan Zierz (Head of the Department of Neurology, Martin-Luther University Halle-Wittenberg) for general support, Dr. Kathryn Birch for copyediting the manuscript, and the patients for their participation. REFERENCES 1. Feit H, Silbergleit A, Schneider LB, Gutierrez JA, Fitoussi RP, R eye`s C, et al. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am J Hum Genet 1998;63:1732–1742. 2. Senderek J, Garvey SM, Krieger M, Guergueltcheva V, Urtizberea A, Roos A, et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet 2009;84:511–518. 3. M€ uller TJ, Kraya T, Stoltenburg G, Hanisch F, Kornhuber M, Stoevesandt D, et al. Phenotype of Matrin 3 related distal myopathy in 16 German patients. Ann Neurol 2014;76:669–680. 4. Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 2014;17:664–666. 5. Schneider I, Hanisch F, M€ uller T, Schmidt B, Zierz S. Respiratory function in late-onset Pompe disease patients receiving long-term enzyme replacement therapy for more than 48 months. Wien Med Wochenschr 2013;163:40–44. 6. Udd B. Distal muscular dystrophies. Handb Clin Neurol 2011;101: 239–262.
LONGITUDINAL 2-POINT DIXON MUSCLE MAGNETIC RESONANCE IMAGING IN BECKER MUSCULAR DYSTROPHY ULRIKE BONATI, MD,1† MAURICE SCHMID, MSc,1 PATRICIA HAFNER, MD,2 TANJA HAAS,3 OLIVER BIERI, PhD,3 MONIKA GLOOR, PhD,3 ARNE FISCHMANN, MD,4 and DIRK FISCHER, MD1,2,5 1
Division of Neuropaediatrics, University Children’s Hospital Basel, Spitalstrasse 33, Basel 4031, Switzerland Department of Neurology, University Hospital Basel, Basel, Switzerland 3 Division of Radiological Physics, Department of Radiology, University of Basel Hospital, Basel, Switzerland 4 Division of Neuroradiology, University Hospital Basel, Basel, Switzerland 5 University Clinic of Internal Medicine, Kantonsspital Baselland, Bruderholz, Switzerland 2
Accepted 25 February 2015 ABSTRACT: Introduction: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). Methods: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1-year follow-up using a 2-point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. Results: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow-up. The severity of muscle involvement varied between various muscle groups. Conclusions: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. 918
Short Reports
Muscle Nerve 51: 918–921, 2015
Becker
muscular dystrophy (BMD) is caused by a variety of mutations in the dystrophin gene, most of which are in-frame deletions.1–3 In addition, disease severity is influenced by epigenetic and environmental factors.4 Thus, predicting progression in individual BMD patients and measuring treatment effects, particularly in clinical trials, is difficult. Recently muscle magnetic resonance imaging (MRI), in particularly quantitative MRI techniques, MUSCLE & NERVE
June 2015
such as T2 relaxation times and Dixon methods, have become valuable diagnostic tools in myopathies. They can facilitate differential diagnosis by making patterns of muscle involvement visible and pathological changes quantifiable.5 Moreover, MRI has been found to monitor disease progression in patients with muscular dystrophy more sensitively than validated motor function performance tests by detecting changes at even relatively short intervals.6 Muscle computed tomography and MRI show a distinctive involvement pattern in BMD, similar to Duchenne muscular dystrophy (DMD).7–10 Here we describe quantitative and longitudinal MRI data of the thigh muscles in 3 BMD patients using a 2point Dixon (2PD) approach. The aim of this study was to quantify the amount of fatty degeneration in the thigh and measure longitudinally the annual skeletal muscle changes in BMD. METHODS
Three patients with BMD were recruited from our outpatient clinic. Genetic analysis showed mutations in the dystrophin gene in 2 patients (splicing mutation c.3432G>A in 1 and a deletion of exons 45–47 in the other). In the third patient, multiplex ligation-dependent probe amplification could not detect a deletion. Sanger sequencing for point mutation analysis was not done. The diagnosis was made by showing reduced dystrophin expression on immunohistochemical analysis. Written informed consent was given by all patients. The study was approved by the local ethics committee. Muscle MRI and physiotherapeutic assessment were performed at baseline and at 1-year follow-up using the same protocol. Physical assessment was done by 2 physiotherapists accredited to use the motor function measurement (MFM) scale, which was chosen due to its high interrater reliability.11 This scale has 3 values: standing position and transfers (D1); axial and proximal motor function (D2); and distal motor function (D3), as well as a total (MFM total) value calculated from the D1, D2, and D3 values. MRIs of the thigh muscles (quadriceps, hamstrings, and adductors) were performed as previously described on a 3-Tesla MRI system Abbreviations: BMD, Becker muscular dystrophy; MFF, mean fat fraction; 2PD, 2-point Dixon approach; MFM, motor function measurement scale; D1-3, MFM subscales; DMD, Duchenne muscular dystrophy; MFF, mean fat fraction; OPMD, oculopharyngeal muscular dystrophy; qMRI, quantitative magnetic resonance imaging Key words: 2-point Dixon method; Becker muscular dystrophy; followup; muscle fat fraction; quantitative MRI Correspondence to: U. Bonati; [email protected] The first 2 authors (U.B. and M.S.) contributed equally to this work. C 2015 Wiley Periodicals, Inc. V
Published online 3 March 2015 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24629
Short Reports
(Magnetom Verio; Siemens Healthcare, Erlangen, Germany).12 Repeatability of positioning was similar to that done by Fischmann et al.,13 with the exception that slices were centered at 50% of the distance from the knee to the hip joint space. A 2PD14 was used to assess the mean fat fraction (MFF, in percent) due to its short acquisition time and high reproducibility.15,16 Relative fat content maps were calculated pixelwise from corresponding fat (f) and water (w) images according to f/ (f 1 w). Statistical software (SPSS; IBM SPSS, Inc., Purchase, New York) was used for data analysis. RESULTS
We studied 3 ambulatory BMD patients, aged 24.2, 28.9, and 57.4 years (mean 36.8 years), at baseline. The mean follow-up interval was 0.92 year (SD 0.13 year). The mean MFM total score declined by 1% from baseline (78.1%, SD 2.76%) to follow-up (77.1%, SD 1.45%). The mean D1 subscore declined by 2.6% from 47.9% (SD 6.45%) at baseline to 45.3% (SD 3.91%) at follow-up. The mean D2 and D3 components of the MFM showed no changes. The mean muscle MFF at baseline in all patients and in all thigh muscles increased by 3.7% from 61.6% (SD 7.6%) to 65.3% (SD 4.7%) at follow-up. With regard to the individual muscle groups, MFF increased from 65.3% to 66.4% (11.2%, SD 0.7%) in the quadriceps, from 71.8% to 75.5% (13.7%, SD 4.9%) in the hamstrings, and from 47.7% to 53.9% (16.3%, SD 8.8%) in the adductors (Fig. 1). Muscle involvement in the left and right legs was slightly asymmetric with a total mean difference in the MFF of 4.3% at baseline (SD 2.6%) and 3.4% at follow-up (SD 2.0%). The MFF was highest in the oldest patient at almost 70%, followed by the second youngest at 59.7%, and the youngest at 55.2%. Clinically, as measured by the MFM score, all patients were almost equally affected, with a MFM total score of between 76.0% and 81.2% at baseline (Fig. 1). DISCUSSION
Imaging studies using visual rating scales in BMD trials could show distinctive patterns of muscle involvement comparable to those found in DMD studies.8,9 To quantify pathological changes and to monitor disease progression in myopathies, quantitative MRI (qMRI) techniques have been shown to be more sensitive than visual rating scales.17 In this study we evaluated longitudinal qMRI data from the thigh muscles in 3 ambulatory BMD patients. When comparing our results to qMRI studies in other muscular dystrophies, the observed annual MUSCLE & NERVE
June 2015
919
FIGURE 1. Motor function measurement (MFM) total score (A), MFM D1 subscore (B), mean fat fraction (MFF) of all muscles (C), and MFF of the quadriceps muscle (D) at baseline (1) and follow-up (2). Diamonds: patient aged 25.1 years; squares: patient aged 29.8 years; triangles: patient aged 58.5 years. 2-point Dixon in-phase pictures at baseline (E) and follow-up (F) from the 25.1 year-old patient.
MFF increase of 3.7% is between that shown for DMD and that of oculopharyngeal muscular dystrophy (OPMD).17,18 This also corresponds to the rate of clinical disease progression in BMD, which is slower than that of DMD and faster than that of OPMD. In contrast, the clinical changes measured by the MFM were relatively mild, with a decrease of around 1% for the total and 2.6% for the D1 subscore. This study has limitations. First, only a small number of patients were studied. Nonetheless, the pattern of thigh muscle involvement confirms the results of 2 recent larger muscle MRI studies in BMD using a semiquantitative visual scoring system in which the hamstrings were the most severely affected followed by the quadriceps and, least severely, the adductors.8,9 Second, only the thigh muscles were analyzed. We chose the thigh because it is affected earlier and more severely in proximal myopathies. Also, proximal muscle function is closely related to impairment in standing and walking, which we measured in the MFM total and D1 subscores. Recently, Monforte et al. showed that semiquantitative analysis of fatty infiltration of calf muscles in BMD was correlated with clinical disability, confirming that regional MRI can produce clinically 920
Short Reports
meaningful results and may be used in clinical trials when scanning and analysis times must be considered.19 Third, for 2PD sequences, phase-shift artifacts have been described.20 They always occurred in our studies between legs and never in a single muscle and could therefore be compensated during data extraction. This study, as well as previous studies in other myopathies, shows that qMRI can detect disease progression in even very small sample sizes17,21,22 and has the potential to improve our understanding of myopathies.17 Results must be confirmed in a larger cohort using a longer observation period. REFERENCES 1. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509–517. 2. Kingston HM, Harper PS, Pearson PL, Davies KE, Williamson R, Page D. Localisation of gene for Becker muscular dystrophy. Lancet 1983;ii:1200. 3. Bushby KM, Gardner-Medwin D, Nicholson LV, Johnson MA, Haggerty ID, Cleghorn NJ, et al. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities. J Neurol 1993;240: 105–112. 4. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, et al. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 1991;49:54–67. 5. Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol 2010;20:2447–2460.
MUSCLE & NERVE
June 2015
6. Berard C, Payan C, Hodgkinson I, Fermanian J. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord 2005;15:463–470. 7. de Visser M, Verbeeten B Jr. Computed tomography of the skeletal musculature in Becker-type muscular dystrophy and benign infantile spinal muscular atrophy. Muscle Nerve 1985;8:435–444. 8. Tasca G, Iannaccone E, Monforte M, Masciullo M, Bianco F, Laschena F, et al. Muscle MRI in Becker muscular dystrophy. Neuromuscul Disord 2012;22(suppl 2):S100–106. 9. Faridian-Aragh N, Wagner KR, Leung DG, Carrino JA. MRI phenotyping of Becker muscular dystrophy. Muscle Nerve 2014;50:962–967. 10. Liu GC, Jong YJ, Chiang CH, Jaw TS. Duchenne muscular dystrophy: MR grading system with functional correlation. Radiology 1993;186:475–480. 11. Vuillerot C, Girardot F, Payan C, Fermanian J, Iwaz J, De Lattre C, et al. Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure. Dev Med Child Neurol 2010;52:60–65. 12. Fischmann A, Hafner P, Gloor M, Schmid M, Klein A, Pohlman U, et al. Quantitative MRI and loss of free ambulation in Duchenne muscular dystrophy. J Neurol 2013;260:969–974. 13. Fischmann A, Morrow JM, Sinclair CD, Reilly MM, Hanna MG, Yousry T, et al. Improved anatomical reproducibility in quantitative lower-limb muscle MRI. J Magn Reson Imaging 2014;39:1033–1038. 14. Dixon WT. Simple proton spectroscopic imaging. Radiology 1984; 153:189–194. 15. Gloor M, Fasler S, Fischmann A, Haas T, Bieri O, Heinimann K, et al. Quantification of fat infiltration in oculopharyngeal muscular dys-
Short Reports
16. 17.
18. 19. 20.
21.
22.
trophy: comparison of three MR imaging methods. J Magn Reson Imaging 2011;33:203–210. Hollingsworth KG, Weber MA. Advanced and quantitative MRI techniques. In: Wattjes MP, Fischer D, editors. Neuromuscular Imaging. New York: Springer; 2013. p 35–53. Fischmann A, Gloor M, Fasler S, Haas T, Rodoni Wetzel R, Bieri O, et al. Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy. J Neurol 2011;258:1333–1340. Arpan I, Willcocks RJ, Forbes SC, Finkel RS, Lott DJ, Rooney WD, et al. Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS. Neurology 2014;83:974–980. Monforte M, Mercuri E, Laschena F, Ricci E, Tasca G. Calf muscle involvement in Becker muscular dystrophy: when size does not matter. J Neurol Sci 2014;347:301–304. Hollingsworth KG, de Sousa PL, Straub V, Carlier PG. Towards harmonization of protocols for MRI outcome measures in skeletal muscle studies: consensus recommendations from two TREAT-NMD NMR workshops, 2 May 2010, Stockholm, Sweden, 1–2 October 2009, Paris, France. Neuromuscul Disord 2012;22(suppl 2):S54–67. Huang Y, Majumdar S, Genant HK, Chan WP, Sharma KR, Yu P, et al. Quantitative MR relaxometry study of muscle composition and function in Duchenne muscular dystrophy. J Magn Reson Imaging 1994;4:59–64. Fischmann A, Hafner P, Fasler S, Gloor M, Bieri O, Studler U, et al. Quantitative MRI can detect subclinical disease progression in muscular dystrophy. J Neurol 2012;259:1648–1654.
MUSCLE & NERVE
June 2015
921
In our cohort, 6 of 8 patients with MATR3 myopathy available for systematic analysis of respiratory function reported exertional dyspnea, but all showed some involvement of the respiratory muscles, including diaphragm dysfunction, weak expiratory muscles, and reduced airway clearance. Due to the small number of patients and the short follow-up period, it is not clear whether the mild and clinically non-significant changes of most lung function parameters truly represent a deterioration of lung function within 12 months. None of the patients available for follow-up became dependent on nocturnal non-invasive ventilation. However, 2 of the total cohort of 16 patients with MATR3 myopathy required mechanical ventilation, and 1 of them had experienced sudden unanticipated
respiratory failure.3 A causative relationship with the underlying muscle disease cannot be excluded. Myopathy due to MATR3 mutations involves predominantly distal limb muscles, similar to that seen in Welander distal myopathies.6 In addition, both the current and earlier studies clearly show involvement of both pharyngeal and respiratory muscles in MATR3 myopathy. This underlines the importance of regular monitoring of respiratory function in these patients. Long-term follow-up will reveal whether some of these patients will eventually require non-invasive ventilation. The authors thank Prof. Stephan Zierz (Head of the Department of Neurology, Martin-Luther University Halle-Wittenberg) for general support, Dr. Kathryn Birch for copyediting the manuscript, and the patients for their participation. REFERENCES 1. Feit H, Silbergleit A, Schneider LB, Gutierrez JA, Fitoussi RP, R eye`s C, et al. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am J Hum Genet 1998;63:1732–1742. 2. Senderek J, Garvey SM, Krieger M, Guergueltcheva V, Urtizberea A, Roos A, et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet 2009;84:511–518. 3. M€ uller TJ, Kraya T, Stoltenburg G, Hanisch F, Kornhuber M, Stoevesandt D, et al. Phenotype of Matrin 3 related distal myopathy in 16 German patients. Ann Neurol 2014;76:669–680. 4. Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 2014;17:664–666. 5. Schneider I, Hanisch F, M€ uller T, Schmidt B, Zierz S. Respiratory function in late-onset Pompe disease patients receiving long-term enzyme replacement therapy for more than 48 months. Wien Med Wochenschr 2013;163:40–44. 6. Udd B. Distal muscular dystrophies. Handb Clin Neurol 2011;101: 239–262.
LONGITUDINAL 2-POINT DIXON MUSCLE MAGNETIC RESONANCE IMAGING IN BECKER MUSCULAR DYSTROPHY ULRIKE BONATI, MD,1† MAURICE SCHMID, MSc,1 PATRICIA HAFNER, MD,2 TANJA HAAS,3 OLIVER BIERI, PhD,3 MONIKA GLOOR, PhD,3 ARNE FISCHMANN, MD,4 and DIRK FISCHER, MD1,2,5 1
Division of Neuropaediatrics, University Children’s Hospital Basel, Spitalstrasse 33, Basel 4031, Switzerland Department of Neurology, University Hospital Basel, Basel, Switzerland 3 Division of Radiological Physics, Department of Radiology, University of Basel Hospital, Basel, Switzerland 4 Division of Neuroradiology, University Hospital Basel, Basel, Switzerland 5 University Clinic of Internal Medicine, Kantonsspital Baselland, Bruderholz, Switzerland 2
Accepted 25 February 2015 ABSTRACT: Introduction: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). Methods: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1-year follow-up using a 2-point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. Results: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow-up. The severity of muscle involvement varied between various muscle groups. Conclusions: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. 918
Short Reports
Muscle Nerve 51: 918–921, 2015
Becker
muscular dystrophy (BMD) is caused by a variety of mutations in the dystrophin gene, most of which are in-frame deletions.1–3 In addition, disease severity is influenced by epigenetic and environmental factors.4 Thus, predicting progression in individual BMD patients and measuring treatment effects, particularly in clinical trials, is difficult. Recently muscle magnetic resonance imaging (MRI), in particularly quantitative MRI techniques, MUSCLE & NERVE
June 2015
such as T2 relaxation times and Dixon methods, have become valuable diagnostic tools in myopathies. They can facilitate differential diagnosis by making patterns of muscle involvement visible and pathological changes quantifiable.5 Moreover, MRI has been found to monitor disease progression in patients with muscular dystrophy more sensitively than validated motor function performance tests by detecting changes at even relatively short intervals.6 Muscle computed tomography and MRI show a distinctive involvement pattern in BMD, similar to Duchenne muscular dystrophy (DMD).7–10 Here we describe quantitative and longitudinal MRI data of the thigh muscles in 3 BMD patients using a 2point Dixon (2PD) approach. The aim of this study was to quantify the amount of fatty degeneration in the thigh and measure longitudinally the annual skeletal muscle changes in BMD. METHODS
Three patients with BMD were recruited from our outpatient clinic. Genetic analysis showed mutations in the dystrophin gene in 2 patients (splicing mutation c.3432G>A in 1 and a deletion of exons 45–47 in the other). In the third patient, multiplex ligation-dependent probe amplification could not detect a deletion. Sanger sequencing for point mutation analysis was not done. The diagnosis was made by showing reduced dystrophin expression on immunohistochemical analysis. Written informed consent was given by all patients. The study was approved by the local ethics committee. Muscle MRI and physiotherapeutic assessment were performed at baseline and at 1-year follow-up using the same protocol. Physical assessment was done by 2 physiotherapists accredited to use the motor function measurement (MFM) scale, which was chosen due to its high interrater reliability.11 This scale has 3 values: standing position and transfers (D1); axial and proximal motor function (D2); and distal motor function (D3), as well as a total (MFM total) value calculated from the D1, D2, and D3 values. MRIs of the thigh muscles (quadriceps, hamstrings, and adductors) were performed as previously described on a 3-Tesla MRI system Abbreviations: BMD, Becker muscular dystrophy; MFF, mean fat fraction; 2PD, 2-point Dixon approach; MFM, motor function measurement scale; D1-3, MFM subscales; DMD, Duchenne muscular dystrophy; MFF, mean fat fraction; OPMD, oculopharyngeal muscular dystrophy; qMRI, quantitative magnetic resonance imaging Key words: 2-point Dixon method; Becker muscular dystrophy; followup; muscle fat fraction; quantitative MRI Correspondence to: U. Bonati; [email protected] The first 2 authors (U.B. and M.S.) contributed equally to this work. C 2015 Wiley Periodicals, Inc. V
Published online 3 March 2015 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24629
Short Reports
(Magnetom Verio; Siemens Healthcare, Erlangen, Germany).12 Repeatability of positioning was similar to that done by Fischmann et al.,13 with the exception that slices were centered at 50% of the distance from the knee to the hip joint space. A 2PD14 was used to assess the mean fat fraction (MFF, in percent) due to its short acquisition time and high reproducibility.15,16 Relative fat content maps were calculated pixelwise from corresponding fat (f) and water (w) images according to f/ (f 1 w). Statistical software (SPSS; IBM SPSS, Inc., Purchase, New York) was used for data analysis. RESULTS
We studied 3 ambulatory BMD patients, aged 24.2, 28.9, and 57.4 years (mean 36.8 years), at baseline. The mean follow-up interval was 0.92 year (SD 0.13 year). The mean MFM total score declined by 1% from baseline (78.1%, SD 2.76%) to follow-up (77.1%, SD 1.45%). The mean D1 subscore declined by 2.6% from 47.9% (SD 6.45%) at baseline to 45.3% (SD 3.91%) at follow-up. The mean D2 and D3 components of the MFM showed no changes. The mean muscle MFF at baseline in all patients and in all thigh muscles increased by 3.7% from 61.6% (SD 7.6%) to 65.3% (SD 4.7%) at follow-up. With regard to the individual muscle groups, MFF increased from 65.3% to 66.4% (11.2%, SD 0.7%) in the quadriceps, from 71.8% to 75.5% (13.7%, SD 4.9%) in the hamstrings, and from 47.7% to 53.9% (16.3%, SD 8.8%) in the adductors (Fig. 1). Muscle involvement in the left and right legs was slightly asymmetric with a total mean difference in the MFF of 4.3% at baseline (SD 2.6%) and 3.4% at follow-up (SD 2.0%). The MFF was highest in the oldest patient at almost 70%, followed by the second youngest at 59.7%, and the youngest at 55.2%. Clinically, as measured by the MFM score, all patients were almost equally affected, with a MFM total score of between 76.0% and 81.2% at baseline (Fig. 1). DISCUSSION
Imaging studies using visual rating scales in BMD trials could show distinctive patterns of muscle involvement comparable to those found in DMD studies.8,9 To quantify pathological changes and to monitor disease progression in myopathies, quantitative MRI (qMRI) techniques have been shown to be more sensitive than visual rating scales.17 In this study we evaluated longitudinal qMRI data from the thigh muscles in 3 ambulatory BMD patients. When comparing our results to qMRI studies in other muscular dystrophies, the observed annual MUSCLE & NERVE
June 2015
919
FIGURE 1. Motor function measurement (MFM) total score (A), MFM D1 subscore (B), mean fat fraction (MFF) of all muscles (C), and MFF of the quadriceps muscle (D) at baseline (1) and follow-up (2). Diamonds: patient aged 25.1 years; squares: patient aged 29.8 years; triangles: patient aged 58.5 years. 2-point Dixon in-phase pictures at baseline (E) and follow-up (F) from the 25.1 year-old patient.
MFF increase of 3.7% is between that shown for DMD and that of oculopharyngeal muscular dystrophy (OPMD).17,18 This also corresponds to the rate of clinical disease progression in BMD, which is slower than that of DMD and faster than that of OPMD. In contrast, the clinical changes measured by the MFM were relatively mild, with a decrease of around 1% for the total and 2.6% for the D1 subscore. This study has limitations. First, only a small number of patients were studied. Nonetheless, the pattern of thigh muscle involvement confirms the results of 2 recent larger muscle MRI studies in BMD using a semiquantitative visual scoring system in which the hamstrings were the most severely affected followed by the quadriceps and, least severely, the adductors.8,9 Second, only the thigh muscles were analyzed. We chose the thigh because it is affected earlier and more severely in proximal myopathies. Also, proximal muscle function is closely related to impairment in standing and walking, which we measured in the MFM total and D1 subscores. Recently, Monforte et al. showed that semiquantitative analysis of fatty infiltration of calf muscles in BMD was correlated with clinical disability, confirming that regional MRI can produce clinically 920
Short Reports
meaningful results and may be used in clinical trials when scanning and analysis times must be considered.19 Third, for 2PD sequences, phase-shift artifacts have been described.20 They always occurred in our studies between legs and never in a single muscle and could therefore be compensated during data extraction. This study, as well as previous studies in other myopathies, shows that qMRI can detect disease progression in even very small sample sizes17,21,22 and has the potential to improve our understanding of myopathies.17 Results must be confirmed in a larger cohort using a longer observation period. REFERENCES 1. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509–517. 2. Kingston HM, Harper PS, Pearson PL, Davies KE, Williamson R, Page D. Localisation of gene for Becker muscular dystrophy. Lancet 1983;ii:1200. 3. Bushby KM, Gardner-Medwin D, Nicholson LV, Johnson MA, Haggerty ID, Cleghorn NJ, et al. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities. J Neurol 1993;240: 105–112. 4. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, et al. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 1991;49:54–67. 5. Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol 2010;20:2447–2460.
MUSCLE & NERVE
June 2015
6. Berard C, Payan C, Hodgkinson I, Fermanian J. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord 2005;15:463–470. 7. de Visser M, Verbeeten B Jr. Computed tomography of the skeletal musculature in Becker-type muscular dystrophy and benign infantile spinal muscular atrophy. Muscle Nerve 1985;8:435–444. 8. Tasca G, Iannaccone E, Monforte M, Masciullo M, Bianco F, Laschena F, et al. Muscle MRI in Becker muscular dystrophy. Neuromuscul Disord 2012;22(suppl 2):S100–106. 9. Faridian-Aragh N, Wagner KR, Leung DG, Carrino JA. MRI phenotyping of Becker muscular dystrophy. Muscle Nerve 2014;50:962–967. 10. Liu GC, Jong YJ, Chiang CH, Jaw TS. Duchenne muscular dystrophy: MR grading system with functional correlation. Radiology 1993;186:475–480. 11. Vuillerot C, Girardot F, Payan C, Fermanian J, Iwaz J, De Lattre C, et al. Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure. Dev Med Child Neurol 2010;52:60–65. 12. Fischmann A, Hafner P, Gloor M, Schmid M, Klein A, Pohlman U, et al. Quantitative MRI and loss of free ambulation in Duchenne muscular dystrophy. J Neurol 2013;260:969–974. 13. Fischmann A, Morrow JM, Sinclair CD, Reilly MM, Hanna MG, Yousry T, et al. Improved anatomical reproducibility in quantitative lower-limb muscle MRI. J Magn Reson Imaging 2014;39:1033–1038. 14. Dixon WT. Simple proton spectroscopic imaging. Radiology 1984; 153:189–194. 15. Gloor M, Fasler S, Fischmann A, Haas T, Bieri O, Heinimann K, et al. Quantification of fat infiltration in oculopharyngeal muscular dys-
Short Reports
16. 17.
18. 19. 20.
21.
22.
trophy: comparison of three MR imaging methods. J Magn Reson Imaging 2011;33:203–210. Hollingsworth KG, Weber MA. Advanced and quantitative MRI techniques. In: Wattjes MP, Fischer D, editors. Neuromuscular Imaging. New York: Springer; 2013. p 35–53. Fischmann A, Gloor M, Fasler S, Haas T, Rodoni Wetzel R, Bieri O, et al. Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy. J Neurol 2011;258:1333–1340. Arpan I, Willcocks RJ, Forbes SC, Finkel RS, Lott DJ, Rooney WD, et al. Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS. Neurology 2014;83:974–980. Monforte M, Mercuri E, Laschena F, Ricci E, Tasca G. Calf muscle involvement in Becker muscular dystrophy: when size does not matter. J Neurol Sci 2014;347:301–304. Hollingsworth KG, de Sousa PL, Straub V, Carlier PG. Towards harmonization of protocols for MRI outcome measures in skeletal muscle studies: consensus recommendations from two TREAT-NMD NMR workshops, 2 May 2010, Stockholm, Sweden, 1–2 October 2009, Paris, France. Neuromuscul Disord 2012;22(suppl 2):S54–67. Huang Y, Majumdar S, Genant HK, Chan WP, Sharma KR, Yu P, et al. Quantitative MR relaxometry study of muscle composition and function in Duchenne muscular dystrophy. J Magn Reson Imaging 1994;4:59–64. Fischmann A, Hafner P, Fasler S, Gloor M, Bieri O, Studler U, et al. Quantitative MRI can detect subclinical disease progression in muscular dystrophy. J Neurol 2012;259:1648–1654.
MUSCLE & NERVE
June 2015
921
