Clin Neuroradiol DOI 10.1007/s00062-015-0386-y
O r i g i n a l A rt i c l e
Clinical Muscle Testing Compared with Whole-Body Magnetic Resonance Imaging in Facio-scapulo-humeral Muscular Dystrophy J.U. Regula · L. Jestaedt · F. Jende · A. Bartsch · H.-M. Meinck · M.-A. Weber
Received: 26 November 2014 / Accepted: 13 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Objective The objective of this study was to evaluate the clinical usefulness of whole-body magnetic resonance imaging (MRI) in facio-scapulo-humeral muscular dystrophy (FSHD). Methods In 20 patients with genetically proven FSHD1, we prospectively assessed muscular involvement and correlated the results of semi-quantitative manual muscle testing and other parameters such as disease duration, creatine kinase (CK) levels and repeat length of the D4Z4 locus with whole-body MRI. Results Clinical muscle testing revealed the trapezius, pectoralis and infraspinatus as the most severely affected muscles in the shoulder, and the knee flexors and gluteus medius in the hip girdle. MRI revealed the trapezius and serratus anterior muscles in the shoulder, and the hamstrings
J.U. Regula and L. Jestaedt contributed equally to this work. J.U. Regula, MD () · F. Jende · H.-M. Meinck, MD Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] L. Jestaedt, MD · A. Bartsch, MD Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany M.-A. Weber, MD Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany M.-A. Weber, MD Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
and adductor muscles in the hip girdle, as the most severely affected muscle groups. Overall, degrees of fatty degeneration on MRI scans correlated significantly with clinical weakness. Moreover, we could detect clear affection of the trunk muscles. Corresponding to earlier reports, asymmetric involvement was frequent in both clinical examination and MRI scoring. Moreover, MRI revealed inhomogeneous muscle degeneration in a considerable proportion of both, muscles and patients. Both clinical and MRI scores significantly correlated to disease duration, but not to fragment size or CK levels. Conclusion Fatty degeneration in whole-body MRI correlates well to clinical muscle testing of the extremities but gives more information on deeper or trunk muscles. It shows structural changes in muscular disorders and may become an excellent tool for assessment of muscle involvement and follow-up studies. Keywords Muscle MRI · FSHD · Clinical muscle testing Introduction With a prevalence of approximately 1:10,000 in Europe, facio-scapulo-humeral muscular dystrophy (FSHD) is among the most common muscular dystrophies [1, 2]. Two types of FSHD have actually been distinguished: FSHD1 and FSHD2. FSHD1 is inherited autosomal dominantly with variable penetrance, but de novo mutations may occur in up to 25 % of patients [3]. In 90–95 % of cases, the disease is caused by a variable decrease of D4Z4 repeats in the telomere region of chromosome 4q35 [2, 4, 5; for detailed review, see book chapter: 6]. Chromosomal fragment size is a major factor in determining the FSHD1 phenotype. A positive correlation between
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number of repeats and age of onset, early age of onset and disease severity as well as a negative correlation between number of repeats and severity of symptoms was reported [7–9]. Symptoms usually become manifest between adolescence and middle age [3]. The key features of FSHD described by Padberg et al. [10] seem partially to be outdated because several patients with a definite FSHD1 lack at least one key feature [11, 12]. However, clinical presentation in individual patients varies widely comprising atypical or asymmetric features [13, 14]. Involvement of the abdominal or paraspinal muscles is common and sometimes pronounced [11, 15]. Besides genetic testing, imaging techniques such as ultrasonography, computed tomography (CT) or magnetic resonance imaging (MRI) have emerged to visualise structural and metabolic muscle pathologies as well in the extremities as in the deeper or trunk muscles [11, 13, 16–21]. Olsen et al. [16] reported widespread involvement of the hip girdle and leg muscles in FSHD and found a strong correlation of muscle weakness with MRI changes. Muscle imaging also demonstrates dystrophic changes in clinically normal muscles [16, 18, 22], suggesting that muscle MRI may become an important assessment tool in clinical trials involving patients with myopathies or myodystrophies [16]. This prospective study was designed to further evaluate the clinical usefulness of whole-body MRI in FSHD, with the focus on comparing detailed manual muscle testing with whole-body MRI. Our primary hypothesis was that fatty degeneration on MRI muscle imaging correlates with results of clinical muscle testing, but MRI is able to detect more affected muscles and especially those difficult to assess clinically. Patients and Methods Ethical Approval This study was approved by the institutional review board and conducted according to the Declaration of Helsinki. After full explanation of the planned examinations, 20 of a total of 27 patients eligible for this study gave their written informed consent to participate. Patients In all, 20 patients aged between 7 and 74 years (7 women, 13 men; mean age, 46 years; mean duration of clinical symptoms, 17 ± 12 years) with genetically proven FSHD1 were included prospectively into this observational study over a time period of approximately 1 year. Patients with contraindications for MRI were not included. A summary of the patients’ characteristics is given in Table 1.
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Clinical Examination and Interpretation Clinical testing of all patients was performed prior to MRI by the same neurologist (J.U. Regula) and comprised assessment of 19 muscles and muscle group functions on either side (see Table 2) according to the Medical Research Council (MRC) scale for muscle strength [23]. J.U. Regula was not involved in the MRI analysis. Trunk muscles (the abdominal and paravertebral muscles) were not evaluated with MRC grading. For this reason, those muscles were not included in the statistical analysis. No correlation between back pain and paraspinal affection was done. MRI Examination and Interpretation In all 20 patients, MRI was performed with a 3-Tesla (T) unit (Magnetom Trio, Siemens, Erlangen, Germany) using a head matrix coil, a neck matrix coil, two body matrix coils, a spine matrix coil and a peripheral angio coil. Coronal (slice thickness (ST): 10 mm, distance factor: 200 %, repetition time (TR): 650 ms, echo time (TE): 9.5 ms) and axial (ST: 6 mm, distance factor: 50 %, TR: 858 ms, TE: 11 ms) T1-weighted(w) turbo spin-echo sequences were acquired. In both coronal and axial sequences, field of view was 500 × 500 mm and image matrix was 448 × 448, resulting in an in-plane resolution of 1.12 mm. Depending on the individual height, eight to ten axial slices were positioned according to Fig. 1 (slices 9 and 10 depicting the calf muscles). Contrast agent was not applied in any patient. Due to complaints of the first patients who underwent MRI, we had to reduce the MR protocol time and decided on concentrating on the fatty degeneration of the muscles, which led to a shortening of examination time by approximately 30 min. Image interpretation was performed in consensus by two experienced readers in musculoskeletal MRI (L. Jestaedt and M.-A. Weber). Intramuscular fat—defined as areas of signal intensity equivalent to subcutaneous fat on T1-w images—was interpreted as a sign of chronic muscle degeneration [16, 24]. Assessment of fatty degeneration was scored with a four-point semi-quantitative visual scale using the signal intensity of subcutaneous fat as reference [16]— grade 1: homogeneous, hypointense signal that contrasts sharply with subcutaneous and intermuscular fat (normal muscle); grade 2: slightly hyperintense, patchy intramuscular signal changes; grade 3: markedly hyperintense, patchy, but widespread intramuscular signal changes; and grade 4: homogeneous hyperintense signal in whole muscle, similar to the signal intensity of adjacent subcutaneous fat (Fig. 2). MRI assessment comprised all muscles and muscle groups tested clinically (Table 2) and also the paravertebral and abdominal wall muscles. We defined asymmetry between homonymous muscles on both sides as difference of at least one grade either in MRC or in MRI scoring.
Clinical Muscle Testing Compared with Whole-Body Magnetic Resonance Imaging
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Table 1 Patients’ characteristics with gender, age at onset, disease duration, allele size (EcoRI and EcoRI + BlnI), CK, individual mean MRC score ± SD, individual mean MRI score ± SD, spearman’s rho and level of significance ± SD SpearSignifi± SD Mean Allele size CK (U/l) Mean Disease Allele Number Gender Age at man’s rho cance level MRI MRC (EcoRI + duration size onset score score (EcoRI) BlnI) (years) (years) a a 1 F 1 6 n.d. 4.69 0.47 1.00 0.00 n.c. n.c. 2 M 24 13 20a 20a 888 4.22 0.97 1.86 1.23 − 0.25 0.10 3 M 40 6 23 20 240 4.78 0.42 1.00 0.00 n.c. n.c. 4 M 27 2 38 38 380 4.63 0.61 1.27 0.83 − 0.56 0.001* 5 M 14 16 20 17 445 4.31 0.74 2.12 1.32 − 0.41 0.01* 6 F 40 30 33 30 352 3.84 0.68 2.68 1.42 − 0.62
O r i g i n a l A rt i c l e
Clinical Muscle Testing Compared with Whole-Body Magnetic Resonance Imaging in Facio-scapulo-humeral Muscular Dystrophy J.U. Regula · L. Jestaedt · F. Jende · A. Bartsch · H.-M. Meinck · M.-A. Weber
Received: 26 November 2014 / Accepted: 13 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Objective The objective of this study was to evaluate the clinical usefulness of whole-body magnetic resonance imaging (MRI) in facio-scapulo-humeral muscular dystrophy (FSHD). Methods In 20 patients with genetically proven FSHD1, we prospectively assessed muscular involvement and correlated the results of semi-quantitative manual muscle testing and other parameters such as disease duration, creatine kinase (CK) levels and repeat length of the D4Z4 locus with whole-body MRI. Results Clinical muscle testing revealed the trapezius, pectoralis and infraspinatus as the most severely affected muscles in the shoulder, and the knee flexors and gluteus medius in the hip girdle. MRI revealed the trapezius and serratus anterior muscles in the shoulder, and the hamstrings
J.U. Regula and L. Jestaedt contributed equally to this work. J.U. Regula, MD () · F. Jende · H.-M. Meinck, MD Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] L. Jestaedt, MD · A. Bartsch, MD Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany M.-A. Weber, MD Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany M.-A. Weber, MD Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
and adductor muscles in the hip girdle, as the most severely affected muscle groups. Overall, degrees of fatty degeneration on MRI scans correlated significantly with clinical weakness. Moreover, we could detect clear affection of the trunk muscles. Corresponding to earlier reports, asymmetric involvement was frequent in both clinical examination and MRI scoring. Moreover, MRI revealed inhomogeneous muscle degeneration in a considerable proportion of both, muscles and patients. Both clinical and MRI scores significantly correlated to disease duration, but not to fragment size or CK levels. Conclusion Fatty degeneration in whole-body MRI correlates well to clinical muscle testing of the extremities but gives more information on deeper or trunk muscles. It shows structural changes in muscular disorders and may become an excellent tool for assessment of muscle involvement and follow-up studies. Keywords Muscle MRI · FSHD · Clinical muscle testing Introduction With a prevalence of approximately 1:10,000 in Europe, facio-scapulo-humeral muscular dystrophy (FSHD) is among the most common muscular dystrophies [1, 2]. Two types of FSHD have actually been distinguished: FSHD1 and FSHD2. FSHD1 is inherited autosomal dominantly with variable penetrance, but de novo mutations may occur in up to 25 % of patients [3]. In 90–95 % of cases, the disease is caused by a variable decrease of D4Z4 repeats in the telomere region of chromosome 4q35 [2, 4, 5; for detailed review, see book chapter: 6]. Chromosomal fragment size is a major factor in determining the FSHD1 phenotype. A positive correlation between
13
2
number of repeats and age of onset, early age of onset and disease severity as well as a negative correlation between number of repeats and severity of symptoms was reported [7–9]. Symptoms usually become manifest between adolescence and middle age [3]. The key features of FSHD described by Padberg et al. [10] seem partially to be outdated because several patients with a definite FSHD1 lack at least one key feature [11, 12]. However, clinical presentation in individual patients varies widely comprising atypical or asymmetric features [13, 14]. Involvement of the abdominal or paraspinal muscles is common and sometimes pronounced [11, 15]. Besides genetic testing, imaging techniques such as ultrasonography, computed tomography (CT) or magnetic resonance imaging (MRI) have emerged to visualise structural and metabolic muscle pathologies as well in the extremities as in the deeper or trunk muscles [11, 13, 16–21]. Olsen et al. [16] reported widespread involvement of the hip girdle and leg muscles in FSHD and found a strong correlation of muscle weakness with MRI changes. Muscle imaging also demonstrates dystrophic changes in clinically normal muscles [16, 18, 22], suggesting that muscle MRI may become an important assessment tool in clinical trials involving patients with myopathies or myodystrophies [16]. This prospective study was designed to further evaluate the clinical usefulness of whole-body MRI in FSHD, with the focus on comparing detailed manual muscle testing with whole-body MRI. Our primary hypothesis was that fatty degeneration on MRI muscle imaging correlates with results of clinical muscle testing, but MRI is able to detect more affected muscles and especially those difficult to assess clinically. Patients and Methods Ethical Approval This study was approved by the institutional review board and conducted according to the Declaration of Helsinki. After full explanation of the planned examinations, 20 of a total of 27 patients eligible for this study gave their written informed consent to participate. Patients In all, 20 patients aged between 7 and 74 years (7 women, 13 men; mean age, 46 years; mean duration of clinical symptoms, 17 ± 12 years) with genetically proven FSHD1 were included prospectively into this observational study over a time period of approximately 1 year. Patients with contraindications for MRI were not included. A summary of the patients’ characteristics is given in Table 1.
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Clinical Examination and Interpretation Clinical testing of all patients was performed prior to MRI by the same neurologist (J.U. Regula) and comprised assessment of 19 muscles and muscle group functions on either side (see Table 2) according to the Medical Research Council (MRC) scale for muscle strength [23]. J.U. Regula was not involved in the MRI analysis. Trunk muscles (the abdominal and paravertebral muscles) were not evaluated with MRC grading. For this reason, those muscles were not included in the statistical analysis. No correlation between back pain and paraspinal affection was done. MRI Examination and Interpretation In all 20 patients, MRI was performed with a 3-Tesla (T) unit (Magnetom Trio, Siemens, Erlangen, Germany) using a head matrix coil, a neck matrix coil, two body matrix coils, a spine matrix coil and a peripheral angio coil. Coronal (slice thickness (ST): 10 mm, distance factor: 200 %, repetition time (TR): 650 ms, echo time (TE): 9.5 ms) and axial (ST: 6 mm, distance factor: 50 %, TR: 858 ms, TE: 11 ms) T1-weighted(w) turbo spin-echo sequences were acquired. In both coronal and axial sequences, field of view was 500 × 500 mm and image matrix was 448 × 448, resulting in an in-plane resolution of 1.12 mm. Depending on the individual height, eight to ten axial slices were positioned according to Fig. 1 (slices 9 and 10 depicting the calf muscles). Contrast agent was not applied in any patient. Due to complaints of the first patients who underwent MRI, we had to reduce the MR protocol time and decided on concentrating on the fatty degeneration of the muscles, which led to a shortening of examination time by approximately 30 min. Image interpretation was performed in consensus by two experienced readers in musculoskeletal MRI (L. Jestaedt and M.-A. Weber). Intramuscular fat—defined as areas of signal intensity equivalent to subcutaneous fat on T1-w images—was interpreted as a sign of chronic muscle degeneration [16, 24]. Assessment of fatty degeneration was scored with a four-point semi-quantitative visual scale using the signal intensity of subcutaneous fat as reference [16]— grade 1: homogeneous, hypointense signal that contrasts sharply with subcutaneous and intermuscular fat (normal muscle); grade 2: slightly hyperintense, patchy intramuscular signal changes; grade 3: markedly hyperintense, patchy, but widespread intramuscular signal changes; and grade 4: homogeneous hyperintense signal in whole muscle, similar to the signal intensity of adjacent subcutaneous fat (Fig. 2). MRI assessment comprised all muscles and muscle groups tested clinically (Table 2) and also the paravertebral and abdominal wall muscles. We defined asymmetry between homonymous muscles on both sides as difference of at least one grade either in MRC or in MRI scoring.
Clinical Muscle Testing Compared with Whole-Body Magnetic Resonance Imaging
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Table 1 Patients’ characteristics with gender, age at onset, disease duration, allele size (EcoRI and EcoRI + BlnI), CK, individual mean MRC score ± SD, individual mean MRI score ± SD, spearman’s rho and level of significance ± SD SpearSignifi± SD Mean Allele size CK (U/l) Mean Disease Allele Number Gender Age at man’s rho cance level MRI MRC (EcoRI + duration size onset score score (EcoRI) BlnI) (years) (years) a a 1 F 1 6 n.d. 4.69 0.47 1.00 0.00 n.c. n.c. 2 M 24 13 20a 20a 888 4.22 0.97 1.86 1.23 − 0.25 0.10 3 M 40 6 23 20 240 4.78 0.42 1.00 0.00 n.c. n.c. 4 M 27 2 38 38 380 4.63 0.61 1.27 0.83 − 0.56 0.001* 5 M 14 16 20 17 445 4.31 0.74 2.12 1.32 − 0.41 0.01* 6 F 40 30 33 30 352 3.84 0.68 2.68 1.42 − 0.62
