Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy Julia R. Dahlqvist, Christoffer R. Vissing, Carsten Thomsen, et al. Neurology published online August 20, 2014 DOI 10.1212/WNL.0000000000000828 This information is current as of August 20, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/08/20/WNL.0000000000000828.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Published Ahead of Print on August 20, 2014 as 10.1212/WNL.0000000000000828
Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy
Julia R. Dahlqvist, MD Christoffer R. Vissing, BSc Carsten Thomsen, MD, PhD John Vissing, MD, PhD
Correspondence to Dr. Dahlqvist: julia.rebecka.dahlqvist@regionh. dk
ABSTRACT
Objective: In this study, involvement of paraspinal muscles in 50 patients with facioscapulohumeral dystrophy (FSHD) was evaluated using MRI.
Methods: The Dixon MRI technique was used in this observational study to quantify muscle fat content of paraspinal and leg muscles. Muscle strength in the neck, back, and legs was assessed with a handheld dynamometer. All subjects completed the Low Back Pain Rating Scale questionnaire. MRI findings were compared with 31 age-matched controls and correlated to muscle strength, back pain, and MRI findings in lower extremities. Results: The fat fraction in muscles was significantly higher in patients with FSHD than in controls: paraspinal fat fraction was 38% in patients vs 20% in controls, thigh fat fraction was 36% vs 11%, and calf fat fraction was 37% vs 11%. Increased paraspinal fat fraction correlated with D4Z4 repeat size, FSHD severity score, fat fraction of the thigh, and muscle strength in the back. The prevalence of back pain was 3 times higher in patients with FSHD vs controls, but back pain did not correlate with the paraspinal fat fraction. Conclusions: This study shows a prominent involvement of paraspinal muscles in patients with FSHD, which should be considered in the management of this condition. Neurology® 2014;83:1–6 GLOSSARY DMD 5 Duchenne muscular dystrophy; FSHD 5 facioscapulohumeral dystrophy; LBPRS 5 Low Back Pain Rating Scale; TE 5 echo time.
Facioscapulohumeral dystrophy (FSHD) is the second most common autosomal dominant muscular dystrophy worldwide with a prevalence of 1:15,000 to 20,000.1 In most patients, the disease is caused by a deletion of repeats in the D4Z4 gene on chromosome 4q35.2 FSHD is a progressive disorder characterized by asymmetric muscular wasting and weakness of the face, scapular stabilizers, and proximal arms. However, the clinical presentation varies, and involvement of leg and abdominal muscles is also a common feature. Weakness of the paraspinal muscles has, however, only been reported in few patients with FSHD but has not been investigated systematically in this patient group. It is known that pain is a significant problem for many patients with FSHD, and lower back pain has been found to be the most frequent pain area of patients with FSHD.3,4 Chronic back pain in FSHD has been suggested to be exacerbated by the weakness of the abdominal and neck flexor muscles.4 However, we speculate that weakness of the paraspinal muscles could also exacerbate the lower back pain. To evaluate involvement of the paraspinal muscles in FSHD, we performed Dixon MRI of the back in 50 patients with FSHD. MRI provides a great tool to assess muscle quality in patients with muscular dystrophies whereby affected muscles often show a marked degree of fat infiltration.5 The quantitative technique is a simple spectroscopic imaging technique for water and fat separation, in which the availability of fat-only images allows for fat fraction analysis.6–8
Supplemental data at Neurology.org
METHODS Standard protocol approvals and patient consents. The Danish National Committee on Health Research Ethics approved the research protocol (approval number: H-3-2012-163) and all subjects gave written and oral consent to participate. From the Neuromuscular Research Unit, Department of Neurology (J.R.D., C.R.V., J.V.) and Department of Diagnostic Radiology (C.T.), Rigshospitalet, University of Copenhagen, Denmark. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
Subjects. Fifty subjects with FSHD were recruited among patients with a molecular diagnosis of FSHD type 1 in our clinic. The FSHD patient group consisted of 29 men and 21 women, aged 20 to 75 years. The detected allele fragment size ranged from 10 to 36 kilo base pairs (mean 24.8). Three subjects with FSHD were clinically unaffected and 3 were wheelchair users. All subjects with FSHD were able to walk at least 10 m. Thirty-one age-range–matched controls (15 men and 16 women) were recruited from the local population for comparison of findings in patients with FSHD.
Figure 1
Mapping of muscles, and MRIs of back and leg muscles
MRI. Scans were performed from March 2013 to February 2014 using a 3.0T Siemens scanner (MAGNETOM Verio Tim System; Siemens AG, Erlangen, Germany). Subjects were positioned in a supine position. A body matrix coil and a peripheral angio coil were used for signal detection. Three-planed localizers were acquired, followed by T1-weighted imaging, and Dixon scan. Axial T1-weighted slices (echo time [TE] 5 19 and repetition time 5 650) were performed from the external occipital protuberance to approximately 10 cm proximal to the medial malleolus of tibia. Slice thickness was 6.0 mm with a distance factor of 20% between slices. The number of acquisitions was 180 to 210, and field of view was 400 to 450 mm. Axial Dixon slices (TE1 5 2.45, TE2 5 3.675, and repetition time 5 5.59) were performed over the same location as the T1-weighted imaging. Slice thickness was 3.5 mm with no distance factor. The number of acquisitions was 300 to 360, and field of view was 400 to 450 mm. All scans were reviewed by the observer. Asymmetric and inhomogeneous fat infiltration along individual muscles was observed in several patients. However, the variation in fat infiltration did not show a systematic pattern. Based on these observations, 5 cross-sectional Dixon slices in which muscle volume was highest were chosen for quantitative fat fractions analysis. To verify that irregular fat infiltration along the length of muscles did not influence the results, we also measured quantitative fat fraction 10 cm proximal to the defined position on the thigh. To locate the defined cross-section positions, the localizer and the T1-weighted imaging were used. At each defined position, full cross-section of muscle groups or individual muscles was mapped and the fat fractional data were generated (figure 1, A–E). All images were analyzed by a single observer (J.D.) on a Siemens Syngo MR Workplace using Numaris/4 B17 software from January 2014 to March 2014. Details on scan positions and assessments of muscle compartments are provided in appendix e-1 on the Neurology® Web site at Neurology.org. Clinical evaluation. All subjects with FSHD were evaluated with the validated, standardized FSHD clinical score, which assesses the functional status and the muscle involvement in patients with FSHD.9 The total score can range from zero, whereby no signs of muscle weakness are present, to 15, whereby all muscle groups tested are severely impaired. The CITEC handheld dynamometer (C.I.T. Technics, Centre for Innovative Technics, the Netherlands) was used to quantify the maximum voluntary contraction in the paraspinal muscles, the pelvic girdle, and the lower extremities of all subjects. Muscle strength of the back was also examined with a static back extension endurance test. Details on how muscle strength testing was performed are provided in appendix e-1. All subjects completed the self-administered Low Back Pain Rating Scale (LBPRS) questionnaire.10 The LBPRS measures different clinical aspects of low back pain. In this study, we included the pain domain (back and legs) and the disability domain. The pain score ranges from 0 to 60 points and the disability score from 0 to 30. Asymptomatic persons score 0 and persons with extreme pain and disability score 90.11 2
Neurology 83
Muscle mapping in cervical (A), thoracic (B), and lumbar (C) regions of the back, and in the thigh (D) and calf (E) in a patient with facioscapulohumeral dystrophy (FSHD). Axial T1-weighted images of lumbar paraspinal muscles (F–I), thigh muscles (J, K), and calf muscles (L, M) in patients with FSHD (F, H, J, L) and age-matched controls (G, I, K, M).
September 23, 2014
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Figure 2
Fat fractions of muscles
Figure 3
Correlations among fat fraction, FSHD severity, and muscle strength
Fat fractions of muscles in the back, hip, thigh, and calf in 50 patients with facioscapulohumeral dystrophy (FSHD) and 31 controls. * Indicates significantly different from controls (p , 0.05). ** Indicates significantly different from controls (p , 0.0001). lat. superfic. post. 5 lateral superficial posterior; med. superfic. post. 5 medial superficial posterior.
Statistical analyses. The Student t test was used to test the 0 hypothesis. A p value ,0.05 (1-tailed when the hypothesis dictated a 1-way change, and 2-tailed testing otherwise) was considered significant. The Pearson correlation test was used to demonstrate correlation between parameters in each subject. Values are mean 6 standard error.
The Dixon images were compared with age-matched controls and correlated with age, disease severity, muscle strength, lower back pain, and MRI findings of lower extremities.
RESULTS
Subjects. All investigated subjects were included. There
were no demographic or anthropometric differences between patients with FSHD and the controls: the mean age was 44 years in patients with FSHD, and 47 in controls (p 5 0.39), and body mass index was 24.7 kg/m2 in patients and 23.8 kg/m2 in controls (p 5 0.25). MRI. Nine hundred seventy-one muscle groups for all 81
subjects were analyzed. MRI showed paraspinal fat fractions ranging from 9.7% to 80.1% in patients with FSHD compared with 8.1% to 43.2% in controls. In the legs, fat fraction ranged from 5.2% to 93.2% in patients with FSHD and from 4.7% to 30.1% in
Correlations between the paraspinal fat fraction and the thigh fat fraction (A) and facioscapulohumeral dystrophy (FSHD) severity score (B), and between the thoracic-lumbar paraspinal fat fraction and the strength in the back muscles (C) in patients with FSHD. (C) There was a ceiling effect in back strength because of the set maximum score of 400 N. The patients who reached the maximum score were not included in the correlation analysis.
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ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
3
Figure 4
Muscle strength and lower back pain in patients with FSHD and controls
with age (FSHD: R 5 0.61, p , 0.0001; controls: R 5 0.76, p , 0.0001), but not with body mass index (FSHD: p 5 0.84; controls: p 5 0.17). The paraspinal fat fraction in patients with FSHD correlated with the mean fat fraction of all thigh muscles (figure 3A), but not the calf muscles. Paraspinal fat fraction did not correlate with D4Z4 fragment size in the patients (p 5 0.67). However, when adjusted for age, there was a significant correlation between paraspinal fat fraction and D4Z4 fragment size (p 5 0.014). There was no difference in fat fraction in the thigh of patients measured 10 cm apart (data not shown). Clinical evaluation. All 50 patients with FSHD were evaluated with the FSHD clinical score. The score ranged from 0 to 12 (mean 6.1) and correlated with the mean fat fraction of cervical, thoracic, and lumbar paraspinal muscles (figure 3B). Muscle strength, investigated in 70 subjects, was lower in patients with FSHD than in controls in all examined muscle groups (figure 4A). Only 32% of the patients with FSHD reached the maximum score of 400 N in back extension compared with 77% of controls. The back muscle strength correlated inversely with thoracic-lumbar paraspinal fat fraction (figure 3C). On the static back extension endurance test, patients could maintain their upper body lifted for 69.7 seconds, which was lower than controls, who lifted for 148.3 seconds (p , 0.0001). All subjects were asked to grade their lower back pain on a scale from 0 to 10, in the LBPRS questionnaire, with 10 being the worst pain imaginable. Twenty-six percent of the patients with FSHD graded their pain from 7 to 10, 26% from 4 to 6, and 35% from 1 to 3. The last 13% had no lower back pain. The prevalence of lower back pain was higher in the patients with FSHD than in the controls (figure 4B), but it did not correlate with paraspinal fat fraction.
In this study, we investigated the involvement of the paraspinal muscles in a large cohort of patients with FSHD. Using the quantitative Dixon technique, we found significantly higher paraspinal fat fractions in patients with FSHD than in controls. Muscle strength of the back, examined with dynamometry and endurance test, was significantly lower in the patients than in the controls. In addition, the patients with FSHD reported a 3-times-higher incidence of lower back pain than the healthy controls. These results indicate that there is a prominent involvement of the paraspinal muscles in patients with FSHD, which often goes unrecognized in a clinical setting. The findings suggest that paraspinal muscle involvement should be included more actively in the clinical assessment of persons affected by FSHD. Muscle imaging has been used extensively in muscular dystrophies to evaluate muscle involvement. DISCUSSION
Muscle strength in neck, back, hip, thigh, and lower leg muscles in patients with facioscapulohumeral dystrophy (FSHD) and controls (A), and Lower Back Pain Rating Scale scores for patients with FSHD and controls (B). * Indicates significantly different from controls (p , 0.05). ** Indicates significantly different from controls (p , 0.0001). ext. 5 extension; flex. 5 flexion.
controls. The thoracic paraspinal musculature was the most severely affected back region in patients with FSHD, and 90% of the patients had fractions higher than the controls’ mean fat fraction. The fat fraction in all analyzed muscles was higher in the patients than in the controls (figures 1 and 2). The pattern of fat infiltration in the paraspinal muscles was different in the 2 groups. In patients with FSHD, fatty infiltration spread from superficial to deeper parts of the muscle, and the reverse happened in healthy controls (figure 1, F–I). In all subjects, the mean fat fraction of cervical, thoracic, and lumbar paraspinal muscles correlated 4
Neurology 83
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ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
However, involvement of the paraspinal muscles has received little attention, especially in patients with FSHD. In a study of patients with FSHD that investigated whole-body muscle involvement patterns by CT, paraspinal fat infiltration was found in 8 of the 24 patients.12 Even though CT is a fast imaging method, MRI has almost completely replaced it in the investigation of neuromuscular disorders. MRI does not require ionizing radiation, and longitudinal data can therefore be collected without risk for the patient. Furthermore, MRI provides better anatomical details and has a much higher sensitivity in identifying muscle fat infiltration than CT.13 Until now, MRI has not been utilized to systemically examine paraspinal muscle involvement in patients with FSHD and only a few cases of MRIproven paraspinal fat infiltration have been reported in this patient group. One case of paraspinal fat infiltration in FSHD was reported in a whole-body MRI study that evaluated muscle involvement in a mixed group of patients with degenerative and inflammatory myopathies, in which one patient with FSHD was included.14 Another case of paraspinal fat infiltration was found in a case study of a patient with FSHD presenting with lower back pain and bent spine syndrome.15 Another study, focusing on bent spine syndrome in 6 patients with FSHD, found severe paraspinal fat infiltration in this selected patient group.16 In the studies using CT and MRI quoted above, fat infiltration of the investigated muscles was evaluated visually on ordinal scales with 4 to 5 grades. This qualitative scoring is subjective, observer-dependent, and insensitive because of the limited number of grading possibilities. We used the Dixon MRI technique, which provides an objective measurement that quantifies the fat infiltration in mapped muscles, on a continuous and observerindependent scale.8 The technique can detect small changes in muscle fat infiltration, not detectable by T1-weighted imaging.17 Our results are in agreement with other findings of a high prevalence of lower back pain in FSHD.4 However, the pain did not correlate with the paraspinal fat fraction in patients with FSHD. The apparent disassociation between back pain and paraspinal muscle involvement parallels the disassociation between back pain and severity of osteochondrotic and degenerative disk and bone findings on spine imaging in healthy subjects.18 Another factor that has been suggested to affect muscle fat infiltration is D4Z4 fragment size.12,19 There is no clear consensus on whether muscle fat infiltration and the D4Z4 fragment size correlate. An MRI study evaluating leg involvement in 18 patients with FSHD found no correlation between leg fat infiltration and fragment size,20 while a CT study on 24 patients with FSHD found correlations between both arm and leg fat infiltration and fragment size, but not between paraspinal fat
infiltration and fragment size.12 In our study, we found a correlation between fat fraction and fragment size when adjusted for age. Paraspinal muscle involvement has been found in other muscular disorders. It has been shown that fat infiltration is present in the paraspinal muscles of patients with Duchenne muscular dystrophy (DMD), myotonic dystrophy types 1 and 2, dysferlinopathy, desminopathy, and myotilinopathy.14,21–23 In a study of 8 patients with DMD, a paraspinal fat fraction of 50% was found.22 DMD is a severe disease with development of contractures and scoliosis, and in the mentioned study, 4 of the patients had mild or severe scoliosis. It is therefore not surprising that they had a high paraspinal fat fraction. Dysferlinopathies are muscular dystrophies with great phenotypic heterogeneity. Five of 6 patients with mild to moderate muscle affection had severe paraspinal fat infiltration evaluated visually on MRI.23 Severe paraspinal fat infiltration was also found in 31% of mildly to severely affected patients with myotonic dystrophy types 1 and 221 and in 39% of a group of patients with different muscular diseases, such as desminopathy and myotilinopathy.14 These findings suggest that even in muscular dystrophies with a highly variable pattern of limb muscle involvement, axial muscles may be involved, underscoring the need for more focus on axial muscles in the management of muscular dystrophies. AUTHOR CONTRIBUTIONS J.R. Dahlqvist: design of study, analysis, acquisition and interpretation of data, drafting the manuscript. C.R. Vissing: design of study, analysis, acquisition of data, revision of manuscript. C. Thomsen: design of study, acquisition of data, revision of manuscript. J. Vissing: design of study, acquisition and interpretation of data, revision of manuscript.
ACKNOWLEDGMENT The authors thank Poul Henrik Frandsen, radiologist, Department of Diagnostic Radiology, Rigshospitalet, for his helpful advice in setting up the MRI protocol.
STUDY FUNDING The study was sponsored by grants from the Augustinus Foundation.
DISCLOSURE J. Dahlqvist, C. Vissing, and C. Thomsen report no disclosures relevant to the manuscript. J. Vissing has received research support and honoraria from Genzyme Corporation. He is a member of the Genzyme Pompe Disease Global Advisory Board. Go to Neurology.org for full disclosures.
Received March 24, 2014. Accepted in final form June 30, 2014. REFERENCES 1. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy: molecular pathological advances and future directions. Curr Opin Neurol 2011;24:423–428. 2. Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve 2006;34:1–15. 3. Abresch RT, Carter GT, Jensen MP, Kilmer DD. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care 2002;19:39–48. Neurology 83
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Jensen MP, Hoffman AJ, Stoelb BL, Abresch RT, Carter GT, McDonald CM. Chronic pain in persons with myotonic dystrophy and facioscapulohumeral dystrophy. Arch Phys Med Rehabil 2008;89:320–328. Sookhoo S, Mackinnon I, Bushby K, Chinnery PF, Birchall D. MRI for the demonstration of subclinical muscle involvement in muscular dystrophy. Clin Radiol 2007;62: 160–165. Dixon WT. Simple proton spectroscopic imaging. Radiology 1984;153:189–194. Berglund J, Johansson L, Ahlstrom H, Kullberg J. Threepoint Dixon method enables whole-body water and fat imaging of obese subjects. Magn Reson Med 2010;63: 1659–1668. Ma J. Dixon techniques for water and fat imaging. J Magn Reson Imaging 2008;28:543–558. Lamperti C, Fabbri G, Vercelli L, et al. A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: the FSHD clinical score. Muscle Nerve 2010;42:213–217. Manniche C, Asmussen K, Lauritsen B, Vinterberg H, Kreiner S, Jordan A. Low Back Pain Rating Scale: validation of a tool for assessment of low back pain. Pain 1994; 57:317–326. Smeets R, Koke A, Lin CW, Ferreira M, Demoulin C. Measures of function in low back pain/disorders: Low Back Pain Rating Scale (LBPRS), Oswestry Disability Index (ODI), Progressive Isoinertial Lifting Evaluation (PILE), Quebec Back Pain Disability Scale (QBPDS), and Roland-Morris Disability Questionnaire (RDQ). Arthritis Care Res 2011;63(suppl 11):S158–S173. Wang CH, Leung M, Liang WC, Hsieh TJ, Chen TH, Jong YJ. Correlation between muscle involvement, phenotype and D4Z4 fragment size in facioscapulohumeral muscular dystrophy. Neuromuscul Disord 2012;22:331–338. Mercuri E, Pichiecchio A, Allsop J, Messina S, Pane M, Muntoni F. Muscle MRI in inherited neuromuscular
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Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy Julia R. Dahlqvist, Christoffer R. Vissing, Carsten Thomsen, et al. Neurology published online August 20, 2014 DOI 10.1212/WNL.0000000000000828 This information is current as of August 20, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/08/20/WNL.00000 00000000828.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/20/WNL.00000 00000000828.DC1.html
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The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/08/20/WNL.0000000000000828.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Published Ahead of Print on August 20, 2014 as 10.1212/WNL.0000000000000828
Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy
Julia R. Dahlqvist, MD Christoffer R. Vissing, BSc Carsten Thomsen, MD, PhD John Vissing, MD, PhD
Correspondence to Dr. Dahlqvist: julia.rebecka.dahlqvist@regionh. dk
ABSTRACT
Objective: In this study, involvement of paraspinal muscles in 50 patients with facioscapulohumeral dystrophy (FSHD) was evaluated using MRI.
Methods: The Dixon MRI technique was used in this observational study to quantify muscle fat content of paraspinal and leg muscles. Muscle strength in the neck, back, and legs was assessed with a handheld dynamometer. All subjects completed the Low Back Pain Rating Scale questionnaire. MRI findings were compared with 31 age-matched controls and correlated to muscle strength, back pain, and MRI findings in lower extremities. Results: The fat fraction in muscles was significantly higher in patients with FSHD than in controls: paraspinal fat fraction was 38% in patients vs 20% in controls, thigh fat fraction was 36% vs 11%, and calf fat fraction was 37% vs 11%. Increased paraspinal fat fraction correlated with D4Z4 repeat size, FSHD severity score, fat fraction of the thigh, and muscle strength in the back. The prevalence of back pain was 3 times higher in patients with FSHD vs controls, but back pain did not correlate with the paraspinal fat fraction. Conclusions: This study shows a prominent involvement of paraspinal muscles in patients with FSHD, which should be considered in the management of this condition. Neurology® 2014;83:1–6 GLOSSARY DMD 5 Duchenne muscular dystrophy; FSHD 5 facioscapulohumeral dystrophy; LBPRS 5 Low Back Pain Rating Scale; TE 5 echo time.
Facioscapulohumeral dystrophy (FSHD) is the second most common autosomal dominant muscular dystrophy worldwide with a prevalence of 1:15,000 to 20,000.1 In most patients, the disease is caused by a deletion of repeats in the D4Z4 gene on chromosome 4q35.2 FSHD is a progressive disorder characterized by asymmetric muscular wasting and weakness of the face, scapular stabilizers, and proximal arms. However, the clinical presentation varies, and involvement of leg and abdominal muscles is also a common feature. Weakness of the paraspinal muscles has, however, only been reported in few patients with FSHD but has not been investigated systematically in this patient group. It is known that pain is a significant problem for many patients with FSHD, and lower back pain has been found to be the most frequent pain area of patients with FSHD.3,4 Chronic back pain in FSHD has been suggested to be exacerbated by the weakness of the abdominal and neck flexor muscles.4 However, we speculate that weakness of the paraspinal muscles could also exacerbate the lower back pain. To evaluate involvement of the paraspinal muscles in FSHD, we performed Dixon MRI of the back in 50 patients with FSHD. MRI provides a great tool to assess muscle quality in patients with muscular dystrophies whereby affected muscles often show a marked degree of fat infiltration.5 The quantitative technique is a simple spectroscopic imaging technique for water and fat separation, in which the availability of fat-only images allows for fat fraction analysis.6–8
Supplemental data at Neurology.org
METHODS Standard protocol approvals and patient consents. The Danish National Committee on Health Research Ethics approved the research protocol (approval number: H-3-2012-163) and all subjects gave written and oral consent to participate. From the Neuromuscular Research Unit, Department of Neurology (J.R.D., C.R.V., J.V.) and Department of Diagnostic Radiology (C.T.), Rigshospitalet, University of Copenhagen, Denmark. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
Subjects. Fifty subjects with FSHD were recruited among patients with a molecular diagnosis of FSHD type 1 in our clinic. The FSHD patient group consisted of 29 men and 21 women, aged 20 to 75 years. The detected allele fragment size ranged from 10 to 36 kilo base pairs (mean 24.8). Three subjects with FSHD were clinically unaffected and 3 were wheelchair users. All subjects with FSHD were able to walk at least 10 m. Thirty-one age-range–matched controls (15 men and 16 women) were recruited from the local population for comparison of findings in patients with FSHD.
Figure 1
Mapping of muscles, and MRIs of back and leg muscles
MRI. Scans were performed from March 2013 to February 2014 using a 3.0T Siemens scanner (MAGNETOM Verio Tim System; Siemens AG, Erlangen, Germany). Subjects were positioned in a supine position. A body matrix coil and a peripheral angio coil were used for signal detection. Three-planed localizers were acquired, followed by T1-weighted imaging, and Dixon scan. Axial T1-weighted slices (echo time [TE] 5 19 and repetition time 5 650) were performed from the external occipital protuberance to approximately 10 cm proximal to the medial malleolus of tibia. Slice thickness was 6.0 mm with a distance factor of 20% between slices. The number of acquisitions was 180 to 210, and field of view was 400 to 450 mm. Axial Dixon slices (TE1 5 2.45, TE2 5 3.675, and repetition time 5 5.59) were performed over the same location as the T1-weighted imaging. Slice thickness was 3.5 mm with no distance factor. The number of acquisitions was 300 to 360, and field of view was 400 to 450 mm. All scans were reviewed by the observer. Asymmetric and inhomogeneous fat infiltration along individual muscles was observed in several patients. However, the variation in fat infiltration did not show a systematic pattern. Based on these observations, 5 cross-sectional Dixon slices in which muscle volume was highest were chosen for quantitative fat fractions analysis. To verify that irregular fat infiltration along the length of muscles did not influence the results, we also measured quantitative fat fraction 10 cm proximal to the defined position on the thigh. To locate the defined cross-section positions, the localizer and the T1-weighted imaging were used. At each defined position, full cross-section of muscle groups or individual muscles was mapped and the fat fractional data were generated (figure 1, A–E). All images were analyzed by a single observer (J.D.) on a Siemens Syngo MR Workplace using Numaris/4 B17 software from January 2014 to March 2014. Details on scan positions and assessments of muscle compartments are provided in appendix e-1 on the Neurology® Web site at Neurology.org. Clinical evaluation. All subjects with FSHD were evaluated with the validated, standardized FSHD clinical score, which assesses the functional status and the muscle involvement in patients with FSHD.9 The total score can range from zero, whereby no signs of muscle weakness are present, to 15, whereby all muscle groups tested are severely impaired. The CITEC handheld dynamometer (C.I.T. Technics, Centre for Innovative Technics, the Netherlands) was used to quantify the maximum voluntary contraction in the paraspinal muscles, the pelvic girdle, and the lower extremities of all subjects. Muscle strength of the back was also examined with a static back extension endurance test. Details on how muscle strength testing was performed are provided in appendix e-1. All subjects completed the self-administered Low Back Pain Rating Scale (LBPRS) questionnaire.10 The LBPRS measures different clinical aspects of low back pain. In this study, we included the pain domain (back and legs) and the disability domain. The pain score ranges from 0 to 60 points and the disability score from 0 to 30. Asymptomatic persons score 0 and persons with extreme pain and disability score 90.11 2
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Muscle mapping in cervical (A), thoracic (B), and lumbar (C) regions of the back, and in the thigh (D) and calf (E) in a patient with facioscapulohumeral dystrophy (FSHD). Axial T1-weighted images of lumbar paraspinal muscles (F–I), thigh muscles (J, K), and calf muscles (L, M) in patients with FSHD (F, H, J, L) and age-matched controls (G, I, K, M).
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Figure 2
Fat fractions of muscles
Figure 3
Correlations among fat fraction, FSHD severity, and muscle strength
Fat fractions of muscles in the back, hip, thigh, and calf in 50 patients with facioscapulohumeral dystrophy (FSHD) and 31 controls. * Indicates significantly different from controls (p , 0.05). ** Indicates significantly different from controls (p , 0.0001). lat. superfic. post. 5 lateral superficial posterior; med. superfic. post. 5 medial superficial posterior.
Statistical analyses. The Student t test was used to test the 0 hypothesis. A p value ,0.05 (1-tailed when the hypothesis dictated a 1-way change, and 2-tailed testing otherwise) was considered significant. The Pearson correlation test was used to demonstrate correlation between parameters in each subject. Values are mean 6 standard error.
The Dixon images were compared with age-matched controls and correlated with age, disease severity, muscle strength, lower back pain, and MRI findings of lower extremities.
RESULTS
Subjects. All investigated subjects were included. There
were no demographic or anthropometric differences between patients with FSHD and the controls: the mean age was 44 years in patients with FSHD, and 47 in controls (p 5 0.39), and body mass index was 24.7 kg/m2 in patients and 23.8 kg/m2 in controls (p 5 0.25). MRI. Nine hundred seventy-one muscle groups for all 81
subjects were analyzed. MRI showed paraspinal fat fractions ranging from 9.7% to 80.1% in patients with FSHD compared with 8.1% to 43.2% in controls. In the legs, fat fraction ranged from 5.2% to 93.2% in patients with FSHD and from 4.7% to 30.1% in
Correlations between the paraspinal fat fraction and the thigh fat fraction (A) and facioscapulohumeral dystrophy (FSHD) severity score (B), and between the thoracic-lumbar paraspinal fat fraction and the strength in the back muscles (C) in patients with FSHD. (C) There was a ceiling effect in back strength because of the set maximum score of 400 N. The patients who reached the maximum score were not included in the correlation analysis.
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Figure 4
Muscle strength and lower back pain in patients with FSHD and controls
with age (FSHD: R 5 0.61, p , 0.0001; controls: R 5 0.76, p , 0.0001), but not with body mass index (FSHD: p 5 0.84; controls: p 5 0.17). The paraspinal fat fraction in patients with FSHD correlated with the mean fat fraction of all thigh muscles (figure 3A), but not the calf muscles. Paraspinal fat fraction did not correlate with D4Z4 fragment size in the patients (p 5 0.67). However, when adjusted for age, there was a significant correlation between paraspinal fat fraction and D4Z4 fragment size (p 5 0.014). There was no difference in fat fraction in the thigh of patients measured 10 cm apart (data not shown). Clinical evaluation. All 50 patients with FSHD were evaluated with the FSHD clinical score. The score ranged from 0 to 12 (mean 6.1) and correlated with the mean fat fraction of cervical, thoracic, and lumbar paraspinal muscles (figure 3B). Muscle strength, investigated in 70 subjects, was lower in patients with FSHD than in controls in all examined muscle groups (figure 4A). Only 32% of the patients with FSHD reached the maximum score of 400 N in back extension compared with 77% of controls. The back muscle strength correlated inversely with thoracic-lumbar paraspinal fat fraction (figure 3C). On the static back extension endurance test, patients could maintain their upper body lifted for 69.7 seconds, which was lower than controls, who lifted for 148.3 seconds (p , 0.0001). All subjects were asked to grade their lower back pain on a scale from 0 to 10, in the LBPRS questionnaire, with 10 being the worst pain imaginable. Twenty-six percent of the patients with FSHD graded their pain from 7 to 10, 26% from 4 to 6, and 35% from 1 to 3. The last 13% had no lower back pain. The prevalence of lower back pain was higher in the patients with FSHD than in the controls (figure 4B), but it did not correlate with paraspinal fat fraction.
In this study, we investigated the involvement of the paraspinal muscles in a large cohort of patients with FSHD. Using the quantitative Dixon technique, we found significantly higher paraspinal fat fractions in patients with FSHD than in controls. Muscle strength of the back, examined with dynamometry and endurance test, was significantly lower in the patients than in the controls. In addition, the patients with FSHD reported a 3-times-higher incidence of lower back pain than the healthy controls. These results indicate that there is a prominent involvement of the paraspinal muscles in patients with FSHD, which often goes unrecognized in a clinical setting. The findings suggest that paraspinal muscle involvement should be included more actively in the clinical assessment of persons affected by FSHD. Muscle imaging has been used extensively in muscular dystrophies to evaluate muscle involvement. DISCUSSION
Muscle strength in neck, back, hip, thigh, and lower leg muscles in patients with facioscapulohumeral dystrophy (FSHD) and controls (A), and Lower Back Pain Rating Scale scores for patients with FSHD and controls (B). * Indicates significantly different from controls (p , 0.05). ** Indicates significantly different from controls (p , 0.0001). ext. 5 extension; flex. 5 flexion.
controls. The thoracic paraspinal musculature was the most severely affected back region in patients with FSHD, and 90% of the patients had fractions higher than the controls’ mean fat fraction. The fat fraction in all analyzed muscles was higher in the patients than in the controls (figures 1 and 2). The pattern of fat infiltration in the paraspinal muscles was different in the 2 groups. In patients with FSHD, fatty infiltration spread from superficial to deeper parts of the muscle, and the reverse happened in healthy controls (figure 1, F–I). In all subjects, the mean fat fraction of cervical, thoracic, and lumbar paraspinal muscles correlated 4
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However, involvement of the paraspinal muscles has received little attention, especially in patients with FSHD. In a study of patients with FSHD that investigated whole-body muscle involvement patterns by CT, paraspinal fat infiltration was found in 8 of the 24 patients.12 Even though CT is a fast imaging method, MRI has almost completely replaced it in the investigation of neuromuscular disorders. MRI does not require ionizing radiation, and longitudinal data can therefore be collected without risk for the patient. Furthermore, MRI provides better anatomical details and has a much higher sensitivity in identifying muscle fat infiltration than CT.13 Until now, MRI has not been utilized to systemically examine paraspinal muscle involvement in patients with FSHD and only a few cases of MRIproven paraspinal fat infiltration have been reported in this patient group. One case of paraspinal fat infiltration in FSHD was reported in a whole-body MRI study that evaluated muscle involvement in a mixed group of patients with degenerative and inflammatory myopathies, in which one patient with FSHD was included.14 Another case of paraspinal fat infiltration was found in a case study of a patient with FSHD presenting with lower back pain and bent spine syndrome.15 Another study, focusing on bent spine syndrome in 6 patients with FSHD, found severe paraspinal fat infiltration in this selected patient group.16 In the studies using CT and MRI quoted above, fat infiltration of the investigated muscles was evaluated visually on ordinal scales with 4 to 5 grades. This qualitative scoring is subjective, observer-dependent, and insensitive because of the limited number of grading possibilities. We used the Dixon MRI technique, which provides an objective measurement that quantifies the fat infiltration in mapped muscles, on a continuous and observerindependent scale.8 The technique can detect small changes in muscle fat infiltration, not detectable by T1-weighted imaging.17 Our results are in agreement with other findings of a high prevalence of lower back pain in FSHD.4 However, the pain did not correlate with the paraspinal fat fraction in patients with FSHD. The apparent disassociation between back pain and paraspinal muscle involvement parallels the disassociation between back pain and severity of osteochondrotic and degenerative disk and bone findings on spine imaging in healthy subjects.18 Another factor that has been suggested to affect muscle fat infiltration is D4Z4 fragment size.12,19 There is no clear consensus on whether muscle fat infiltration and the D4Z4 fragment size correlate. An MRI study evaluating leg involvement in 18 patients with FSHD found no correlation between leg fat infiltration and fragment size,20 while a CT study on 24 patients with FSHD found correlations between both arm and leg fat infiltration and fragment size, but not between paraspinal fat
infiltration and fragment size.12 In our study, we found a correlation between fat fraction and fragment size when adjusted for age. Paraspinal muscle involvement has been found in other muscular disorders. It has been shown that fat infiltration is present in the paraspinal muscles of patients with Duchenne muscular dystrophy (DMD), myotonic dystrophy types 1 and 2, dysferlinopathy, desminopathy, and myotilinopathy.14,21–23 In a study of 8 patients with DMD, a paraspinal fat fraction of 50% was found.22 DMD is a severe disease with development of contractures and scoliosis, and in the mentioned study, 4 of the patients had mild or severe scoliosis. It is therefore not surprising that they had a high paraspinal fat fraction. Dysferlinopathies are muscular dystrophies with great phenotypic heterogeneity. Five of 6 patients with mild to moderate muscle affection had severe paraspinal fat infiltration evaluated visually on MRI.23 Severe paraspinal fat infiltration was also found in 31% of mildly to severely affected patients with myotonic dystrophy types 1 and 221 and in 39% of a group of patients with different muscular diseases, such as desminopathy and myotilinopathy.14 These findings suggest that even in muscular dystrophies with a highly variable pattern of limb muscle involvement, axial muscles may be involved, underscoring the need for more focus on axial muscles in the management of muscular dystrophies. AUTHOR CONTRIBUTIONS J.R. Dahlqvist: design of study, analysis, acquisition and interpretation of data, drafting the manuscript. C.R. Vissing: design of study, analysis, acquisition of data, revision of manuscript. C. Thomsen: design of study, acquisition of data, revision of manuscript. J. Vissing: design of study, acquisition and interpretation of data, revision of manuscript.
ACKNOWLEDGMENT The authors thank Poul Henrik Frandsen, radiologist, Department of Diagnostic Radiology, Rigshospitalet, for his helpful advice in setting up the MRI protocol.
STUDY FUNDING The study was sponsored by grants from the Augustinus Foundation.
DISCLOSURE J. Dahlqvist, C. Vissing, and C. Thomsen report no disclosures relevant to the manuscript. J. Vissing has received research support and honoraria from Genzyme Corporation. He is a member of the Genzyme Pompe Disease Global Advisory Board. Go to Neurology.org for full disclosures.
Received March 24, 2014. Accepted in final form June 30, 2014. REFERENCES 1. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy: molecular pathological advances and future directions. Curr Opin Neurol 2011;24:423–428. 2. Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve 2006;34:1–15. 3. Abresch RT, Carter GT, Jensen MP, Kilmer DD. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care 2002;19:39–48. Neurology 83
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Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy Julia R. Dahlqvist, Christoffer R. Vissing, Carsten Thomsen, et al. Neurology published online August 20, 2014 DOI 10.1212/WNL.0000000000000828 This information is current as of August 20, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/08/20/WNL.00000 00000000828.full.html
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Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/20/WNL.00000 00000000828.DC1.html
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