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Limb girdle muscular dystrophies ten Dam, L.

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Download date:29 Sep 2021 Eur J Neurol. 2016;23:688-703Eur J Visser de Marianne Mike P. Wattjes VerhammeCamiel Anneke J. van Kooi der Leroy Dam ten diseases acquired muscle in inherited and Muscle imaging

CHAPTER 2 Chapter 2

ABSTRACT

In this review we discuss the use of conventional (computed tomography, magnetic resonance imaging, ultrasound) and advanced muscle imaging modalities (diffusion tensor imaging, magnetic resonance spectroscopy) in hereditary and acquired . We summarize the data on specific patterns of muscle involvement in the major categories of muscle disease and provide recommendations on how to use muscle imaging in this field of neuromuscular disorders.

20 Muscle imaging in inherited and acquired muscle diseases

INTRODUCTION

In the last decades, neuromuscular imaging has become an important tool in diagnosis, and monitoring of disease progression and treatment of both hereditary and acquired myopathies.1, 2 Muscle imaging in addition to clinical examination and electromyography may support the clinical diagnosis, although muscle biopsy and genetic testing are often 2 Chapter required to establish a definitive diagnosis of hereditary muscle diseases. Muscle imaging can also serve as an aid in distinguishing between different diseases and thus guide genetic testing.3 More practically, by identifying affected muscles, muscle imaging is useful for targeted muscle biopsy.4, 5 The aim of this review is to give a comprehensive overview on the use of magnetic resonance imaging (MRI), ultrasound (US), and advanced muscle imaging techniques [diffusion tensor imaging (DTI), MR-spectroscopy (MRS)] in hereditary and acquired myopathies. Computed tomography (CT) which was for long the only available imaging tool is currently less often used because of its deleterious ionizing radiation effects, and therefore a limited number of publications are included in this review. We shall also summarize the data on specific patterns of muscle involvement in the major categories of muscle disease and provide recommendations on how to use muscle imaging in this field of neuromuscular disorders.

METHODS

A literature search was performed in PubMed using the terms muscular imaging, magnetic resonance imaging (MeSH), ultrasonography (MeSH) or tomography, X-Ray computed (MeSH) in combination with the different muscle disorders studied. No specific exclusion criteria were formulated. The PubMed search was followed by a manual search in the reference lists of the publications found.

ASSESSMENT OF MUSCLE CHANGES

In most myopathies, muscle tissue undergoes morphological changes giving rise to replacement of muscle by connective tissue and/or fat. Furthermore, there can be either loss of muscle bulk (atrophy) or enlargement of muscle either by true hypertrophy or by so-called pseudohypertrophy in which enlargement is due to fat deposition. These changes have to be differentiated from physiological changes of muscle tissue during lifetime (e.g. sarcopenia) and are not specific for primary muscle disease as chronically denervated muscles can also show muscle tissue loss and fatty infiltration (e.g. postpolio syndrome).6 In general there is a good correlation between fatty degeneration of muscle tissue and muscle strength (Figure 1, 2).7-11 However, muscle imaging may reveal more abnormalities

21 Chapter 2 as compared to the clinical examination, e.g. in myopathies with a limb girdle distribution of muscle weakness, lumbar paraspinal muscles and to a lesser extent muscles of the lower leg can also show changes on MRI whereas muscle strength is considered to be normal. Sometimes, as in distal myopathies, muscle imaging reveals fewer abnormalities.7 There is great variety as regards the distribution pattern of muscle involvement in hereditary muscle disorders. Pattern recognition on muscle imaging might be helpful in distinguishing between different disease entities.

FIGURE 1 | Muscle MRI of ANO5 related

Axial T1-weighted images of a patient with Miyoshi-like distal (MMD3) due to a mutation in the ANO5 gene. There is fatty degeneration of the gluteal muscles at the level of the pelvis, in particular the gluteal minimus (GMi) muscles are completely replaced by fat (A), involvement of the posterior and anterior muscles at the level of the thigh (B) and fatty degeneration of the calf muscles (C).

22 Muscle imaging in inherited and acquired muscle diseases

MUSCLE IMAGING MODALITIES Computed tomography Computed tomography of skeletal muscles shows the distribution and severity of replacement of muscle tissue by fat and assesses the size of muscle.12, 13 However, compared to other imaging modalities such as MRI and US, muscle CT scan has a number of disadvantages 2 Chapter such as the use of ionizing radiation and lower soft tissue contrast. CT should thus only be performed if there are contraindications to performing MRI, such as cardiac pacemaker, automatic cardioverter defibrillator, ferromagnetic haemostatic clips in the central nervous system, metallic splinter in the eye and other magnetically activated implants.14 Muscle CT scan can serve as an alternative in claustrophobic patients and those unable to lie still for longer periods of time. CT should not be performed in children.

Conventional muscle resonance imaging Recently MRI has become the preferred modality for muscle imaging as it has the advantage of achieving a higher soft tissue contrast compared to CT and shows more accurately the distribution of replacement of muscle tissue by fat (Figure 1, 3).

FIGURE 3 | Muscle MRI in dystrophinopathy

Axial T1-weighted image of the thigh of a patient with Becker muscular dystrophy (BMD). There is predominant fatty degeneration of the posterior compartment, i.e., adductor magnus (AM) and biceps femoris (BF) muscles, with relative sparing of the semitendinosus (ST), gracilis (G) and sartorius (S) muscles. The anterior compartment shows involvement of the lateral (VL) and medial vastus (VM) muscles with relative sparing of the intermedius vastus (VI) and rectus femoris (RF) muscle. This patient was asymptomatic and referred because of hyperCKemia.

Another advantage is that specific information can be obtained based on the MRI sequences used. On non-enhanced T1-weighted MRI sequences fatty degeneration of muscle tissue can be assessed. Using fat suppressed T2-weighted or short-tau inversion

23 Chapter 2 recovery (STIR) sequences oedema (focal or diffuse hyperintensity) of skeletal muscles can be detected. However, intramuscular edema is rather non-specific and can be a precursor of muscle damage or inflammation in muscle disease. It may also be found after trauma or overuse of the muscle, in infection, neoplasm, rhabdomyolysis, recent vascular event and even denervation.15-18 Several visual rating scales have been developed allowing a semi- quantitative assessment of the degree and the pattern of fatty muscle degeneration and muscle oedema. However no standardization has taken place. For fatty degeneration the most established rating scale is the five-point rating scale, ranging from stage 0 (normal appearance) to stage 4 (total replacement of muscle tissue by fat and/or connective tissue).19 For assessment of muscle oedema a three-point rating scale is used, with 0 meaning absent, 1 mild and 2 definite muscle oedema.20

Quantification of muscle oedema is possible on T2-weighted images and quantification of fatty degeneration can be achieved in multiple ways, e.g. on T1-weighted images or using Dixon MRI.21 For the latter images fat and water components are separated allowing for calculation of fat fraction. Quantifying fatty degeneration has attained a higher reliability, being less dependent on the observer compared to visual rating scales and easier to reproduce.10 Furthermore, quantification of fatty degeneration can detect traces of fatty degeneration which do not yet result in loss of muscle strength or decrease in functional status making it a useful method to provide longitudinal outcome measures in therapeutic trials. For optimal reproducibility of quantitative MRI in longitudinal studies it is important to use consistent positioning of limbs and to select a site for imaging at a fixed distance from a landmark visible on a scout-image (i.e. knee joint in lower limb muscle imaging).2, 22, 23 Quantitative MRI allows for assessing all muscles in one plane including the deep seated muscles and is able to cover a larger area of interest compared to quantitative US.24

Most studies focus on the muscle involvement solely of the lower limb, although more recently whole body MRI (WBMRI) has been advocated because of its higher diagnostic impact.25

A standardized protocol for the evaluation of patients who are suspected of a muscle disorder is lacking.26 We suggest that protocols should be customized, although all muscle imaging studies should include axial T1-weighted images of the paraspinal muscles, pelvic girdle, thigh and lower leg muscles to properly evaluate fatty degeneration of muscle and muscle size.27 When there is a clinical suspicion of an inflammatory myopathy axial and coronal STIR or T2-weighted images with fat suppression to evaluate muscle oedema should be added.5 The T1-weighted images should be evaluated for characteristic patterns of fatty degeneration, as is seen in some of the diseases described below (Figure 2).

24 Muscle imaging in inherited and acquired muscle diseases

FIGURE 2 | Schematic representation of specific patterns of muscle involvement Chapter 2 Chapter

Schematic representation of specific patterns of muscle involvement in in LGMDD5 collagen 6-related/ (A), FSHD (B), RYR1 (C), SEPN1 (D), alpha-B-crystallinopathy (E), non-dystrophic (F), GSDII (G), dystrophinopathy (H), LGMDR1 calpain3-related/LGMD2A (I), LGMDR9 FKRP-related/LGMD2I (J), anoctaminopathy (K), dysferlinopathy (L). (1, 7, 20, 25, 58, 67, 78) The replacement of muscle tissue by fat is reflected by the grey color of (part of) the muscle. Darker grey represents more replacement of muscle tissue by fat. The first column shows a cross-section at the level of the thigh, the second shows cross-sections through the lower leg.

In the absence of a specific pattern of muscle involvement systematic evaluation of the MRI images is recommended as, for example, predominant involvement of lower leg muscles, anterior muscles of the thigh or the medial head of the gastrocnemius compared to the lateral head can indicate specific types of muscle disease (Figure 5).

25 Chapter 2

FIGURE 5 | Flow chart for diagnosis of muscle disorders based on MR muscle imaging

However, in end stages of muscle disease muscle imaging is less useful since virtually all muscles will be replaced by fat. The protocol could be expanded to include axial images of the shoulder girdle, trunk, arms, neck and tongue if necessary (WBMRI protocol) (Table 1).25

26 Muscle imaging in inherited and acquired muscle diseases

TABLE 1 | Muscle imaging protocol

Muscle MRI protocol

Differential MRI Inspection Type of scan Muscles to evaluate diagnosis sequences

Hereditary T1-WI Hyperintensity: Standard Axial images of paraspinal, 2 Chapter and acquired representing replacement pelvic girdle, thigh and calf myopathy of muscle tissue by fat muscles Pattern of fatty Whole body Additional axial images through degeneration (on indication) shoulder girdle, trunk, arms, Changes in muscle size neck and tongue. Additional coronal images Acquired STIR/T2-WI with Hyperintensity: Standard Axial images of paraspinal, myopathy fat suppression representing muscle pelvic girdle, thigh and calf In addition to oedema muscles. T1-WI Coronal images of lower extremity Whole body Additional axial images through (on indication) shoulder girdle, trunk, arms, neck and tongue Additional coronal images Muscle US screening protocol (28)

Transducer choice Inspection Muscles to evaluate Superficial muscles Visual assessment for focal changes Proximal and distal muscles of 7.5 MHz in children and in adults. Homogeneity of distribution of echo upper and lower extremities: Deeper muscles intensities within the muscle biceps brachii, forearm flexors, 5 MHz in adults or broadband Screening for calcifications with clinical quadriceps and tibial anterior transducer with a range of at least 7 suspicion of inflammatory myopathy muscles. to 12 Hz. Quantitative analysis Other muscles may be added Muscle thickness. Quantitative gray scale depending on the differential analysis and/or quantitative backscatter diagnosis, or to direct muscle analysis biopsy

Dynamic muscle ultrasound Detection of physiologic and pathologic muscle movements such as fasciculations with clinical suspicion of spinal muscular atrophy and fibrillations with clinical suspicion of inflammatory myopathy

Pattern of muscle involvement throughout the body

MRI, magnetic resonance imaging; STIR, short-tau inversion recovery; T1-WI, T1-weighted imaging; T2-WI, T2-weighted imaging; US, ultrasound

Muscle ultrasound Muscle US can assess atrophy and changes in muscle architecture, and may visualize patterns of muscle involvement. Increased echogenicity is correlated with replacement

27 Chapter 2 of muscle tissue by fat and fibrous tissue. Advantages of muscle US include its real-time assessment and lack of ionizing radiation, which renders the technique extremely suitable for pediatric patients and patients who cannot lie still without sedation. US can also be used to evaluate fasciculations and movement of the diaphragm. However, muscle US cannot visualize muscle oedema, and it is cumbersome to visualize deeply located muscles.12 It is important to note that US settings and different transducers affect the appearance of muscle.28 Taking this into account, muscle echogenicity can be quantified using quantitative gray scale analysis and quantitative backscatter analysis.29 Quantification of fatty degeneration on US is superior to visual assessment and can accurately discriminate between children with and without a neuromuscular disorder and between myopathies and neurogenic disorders.12, 30, 31 (Figure 4) Practical advice for a standardized US protocol for the evaluation of patients who are suspected of a muscle disorder have been published (Table 1) and currently an international guideline is developed.28

FIGURE 4 | Muscle ultrasound of a patient with Emery Dreifuss Muscular Dystrophy

Ultrasound images of a 12 year-old child with Emery-Dreifuss muscular dystrophy caused by a lamin A/C mutation (A biceps brachii muscle; B tibial anterior muscle) as compared to an age-matched healthy control (C biceps brachii muscle; D tibial anterior muscle). Proximal more than distal muscles in arms and legs showed increased echogenicity. Muscles in the arms (arrowhead) and legs (arrow) show increased echogenicity. Biceps brachii muscle measured at two thirds of distance from the acromion the antecubital crease of the left arm. Tibial anterior muscle measured at one fourth of distance from lower border of patella to lateral malleolus of the left leg. B brachialis muscle, BB biceps brachii muscle, EDL extensor digitorum longus muscle, H humerus, IM interosseous membrane, M median nerve, SC subcutaneous tissue, S skin, TA tibialis anterior muscle.

28 Muscle imaging in inherited and acquired muscle diseases

MUSCLE IMAGING IN HEREDITARY MYOPATHIES Pattern recognition The hereditary myopathies consist of a large and heterogeneous spectrum of diseases (Table 2). There is no consensus on the reliability and accuracy of pattern recognition in the diagnosis of different subgroups of muscular dystrophies. Pattern recognition on 2 Chapter muscle imaging was found to have a high sensitivity (90%) in the diagnosis of muscular dystrophies that present with rigidity of the spine (selenoprotein N,1 (SEPN1), lamin A/C (LMNA), collagen 6 (COLVI), calpain-3 (CAPN3) related muscular dystrophies).3 With the exception of LGMDD5 collagen 6-related/Bethlem myopathy (COLVI), pattern recognition to differentiate between muscular dystrophies presenting with limb girdle muscle weakness (dystrophinopathy (DYS), sarcoglycanopathies and fukutin-related protein (FKRP), anoctamin 5 (ANO5), LMNA, CAPN3 related muscular dystrophies) was found to be less accurate given the poor overall sensitivity (40%) accompanied by a poor interobserver rating (κ:0,27).1 Seemingly distinctive patterns of muscle involvement have been described in congenital muscular dystrophies (CMD) and myofibrillar myopathies. However no studies have been performed to assess the characteristics of muscle imaging in these particular groups.32, 33

TABLE 2 | Characteristics of the major groups of muscle disorders

Gene Age of onset Muscle Early Cardiac (years) weakness contractures involvement

Muscular dystrophies Dystrophinopathy Duchenne muscular dystrophy DYS 3-5 Proximal + Becker muscular dystrophy DYS > 7 Proximal Limb girdle muscular dystrophy LGMDR1 calpain3-related/ CAPN3 2-45 Proximal + LGMD2A LGMDR2 dysferlin-related/ DYSF 10-39 Proximal LGMD2B LGMDR9 FKRP-related/ FKRP 0.5-27 Proximal + LGMD2I LGMDR12 anoctamin5- ANO5 11- 51 Proximal + related/LGMD2L Nucleopathies Emerinopathies EMD 0-40 + + Laminopathies LMNA 10-20 Proximal or + + distal Distal myopathies Welander distal myopathy TIA1 20-77 Distal Udd myopathy TTN 40-80 Distal +

29 Chapter 2

TABLE 2 | Characteristics of the major groups of muscle disorders (continued)

Gene Age of onset Muscle Early Cardiac (years) weakness contractures involvement Vocal cord and pharyngeal MATR3 30-57 Distal distal myopathy VCP mutated distal myopathy VCP > 35 Distal Distal nebulin myopathy NEB Child or adult Distal Miyoshi distal myopathy 1 DYSF Teens to 38 Distal Miyoshi distal myopathy 3 ANO5 20-40 Distal + Congenital muscular dystrophies UCMD/Bethlem myopathy/ COLVI Congenital + LGMDD5 collagen 6-related Dystroglycanopathies POMT1 Congenital POMT2 Congenital ISPD Congenital Oculopharyngeal muscular dystrophy OPMD PABPN1 20-60 Proximal Facioscapulohumeral dystrophy FSHD DUX4 Congenital Proximal, distal, - 40 face DMI DMPK Neonatal Proximal, distal, + -adults face DMII ZNF9 Teens, adults Proximal, distal, + face Glycogen storage disease (GSD) Pompe’s disease (GSDII) GAA Variable Proximal + Congenital myopathies Ryanodine receptor 1 related RYR1 Congenital - Proximal, face, myopathy childhood respiratory Selenoprotein N,1 related SEPN1 Congenital - 1 Proximal, distal, + myopathy face Beta-tropomyosin related TPM2 Congenital - Proximal, distal, childhood face, respiratory Dynamin 2 related myopathy DNM2 Variable Distal, face, + respiratory X-linked myotubular myopathy MTM1 Infancy Proximal, distal, respiratory Alpha-actin rod myopathy ACTA1 Congenital Proximal Lipid storage myopathies MTPD HADHA/ Variable Proximal, distal + HADHB LCHADD HADHA Variable Proximal, distal + VLCADD ACADVL Child or adult Myalgia, + rhabdomyolysis Myofibrillar myopathies Desminopathy DES 20-40 Proximal, distal +

30 Muscle imaging in inherited and acquired muscle diseases

TABLE 2 | Characteristics of the major groups of muscle disorders (continued)

Gene Age of onset Muscle Early Cardiac (years) weakness contractures involvement Alpha-B-crystallinopathy CRYAB Early to middle Distal + adulthood

ZASPopathy LDB3 Childhood - 73 Proximal or + 2 Chapter distal Myotilinopathy TTID 42-77 Distal + + Filaminopathy FLNC 0-30 Distal + Non-dystrophic myotonia CLCN1 Infancy to adult Proximal (Becker and Thomsen disease) SCN4A Infancy to early Proximal childhood Hypokalemic SCN4A Infancy to early Proximal childhood

Dystrophinopathy Magnetic resonance muscle imaging in dystrophinopathies (DYS gene) has been extensively studied and a similar pattern of muscle involvement is found in Duchenne (DMD) and Becker muscular dystrophy (BMD), with medio-posterior fatty infiltration of the thigh and gastrocnemius muscles and hypertrophy of the sartorius, gracilis, semitendinosus, gastrocnemius and rectus femoris muscles.1, 34 (Figure 3) The pattern observed in a manifesting female carrier of DMD bears resemblance to those found in DMD and BMD patients.35 Fat quantification on muscle MRI has been found to be more precise compared to visual rating of fatty degeneration in DMD. It can detect subtle changes in fat fraction and thus might be useful on a longitudinal basis to track disease progression in these patients.36-38 Quantitative MRI shows a decrease in muscle oedema and fat fraction in DMD patients treated with corticosteroids compared to corticosteroid-naïve patients.21 Muscle US shows atrophy of the gastrocnemius in adults with DMD.39 Quantitative US is a precise tool for the longitudinal follow up of fatty infiltration in young DMD patients, which can show disease progression despite functional improvement.30, 40

Emerinopathies/laminopathies The group of emerinopathies/laminopathies comprise multiple muscular dystrophies that typically present with weakness in a scapuloperoneal or limb girdle distribution, contractures and defects in cardiac conduction and/or cardiomyopathy. These Emery-Dreifuss muscular dystrophies (EDMD) are categorised by inheritance pattern and gene mutation. Mutations in lamin A/C (LMNA) can cause, amongst other things, autosomal dominant EDMD2 and autosomal recessive EDMD3. Mutations in the emerin gene (EMD) give rise to the X-linked

31 Chapter 2 variant of EDMD. Both LMNA and EMD patients show predominantly fatty degeneration of the posterior compartment of the thigh and calf muscles with selective involvement of the medial head of the gastrocnemius.41-43

Limb girdle muscular dystrophies Using muscle imaging to differentiate between muscular dystrophies in the group of limb girdle muscular dystrophies (LGMD) remains cumbersome. MRI patterns of muscle involvement have been described in almost all LGMD. However these are based on small case series and often show a non-specific pattern of fatty degeneration. The most common LGMD are LGMDR1 calpain3-related/LGMD2A (CAPN3 gene), LGMDR2 dysferlin-related/LGMD2B (DYSF), LGMDR9 FKRP-related/LGMD2I (FKRP) and LGMDR12 anoctamin5-related/LGMD2L (ANO5) which all show predominantly posterior muscle degeneration at the level of the thigh, selective involvement of the medial head of the gastrocnemius and relative sparing of the gracilis muscle. In these LGMD types both gracilis and sartorius muscles are most likely to show signs of hypertrophy. Selective involvement of the adductor magnus muscle in LGMDR1 calpain3-related/LGMD2A and LGMDR2 dysferlin-related/LGMD2B, involvement of the peroneal and tibial anterior muscles in LGMDR2 dysferlin-related/LGMD2B and LGMDR9 FKRP-related/LGMD2I and patchy involvement of the quadriceps muscles in LGMDR2 dysferlin-related/LGMD2B and LGMDR12 anoctamin5-related/LGMD2L can possibly be used to differentiate between these disorders (Figure 1).1, 7, 44

Recent studies in larger groups of LGMDR9 FKRP-related/LGMD2I, LGMDR12 anoctamin5- related/LGMD2L and LGMDD1 DNAJB6-related/LGMD1D (DNAJB6) show more specific patterns of muscle involvement which may yield a higher diagnostic accuracy for muscle imaging in LGMD in the future.7, 10, 45

Distal myopathies There are more than 20 distal myopathies. They can be categorised clinically by age of onset and pattern of inheritance. Further distinction can be made using muscle MRI which differentiates between diseases based mainly on involvement of the anterior lower leg muscles which is a characteristic feature in some distal myopathies and markedly absent in others. Tibial muscular dystrophy (Udd myopathy TMD TTN gene), VCP-mutated distal myopathy (VCP), distal nebulin myopathy (NEB) and Welander distal myopathy (WMD TIA1) show fatty degeneration of the anterior lower leg muscles, desminopathy (DES) and alpha-B-crystallinopathy (CRYAB) often show early involvement of the peroneal muscles whereas in ZASPopathy (LDB3), distal myotilinopathy (TTID), vocal cord and pharyngeal distal myopathy (MATR3 ) and distal actin binding domain filaminopathy FLNC( )

32 Muscle imaging in inherited and acquired muscle diseases predominantly the posterior lower leg muscles are affected.46, 47 The distal myopathies were considered a separate group of muscular dystrophies. However, mutations in DYSF give rise to Miyoshi distal myopathy (MMD1) and also LGMDR2 dysferlin-related/LGMD2B with proximal muscle involvement.48 Furthermore, mutations in ANO5 can cause both Miyoshi- like distal myopathy 3 (MMD3) and LGMDR12 anoctamin5-related/LGMD2L (Figure 3).49 These diseases are now considered to be part of a spectrum of dysferlinopathies and 2 Chapter anoctaminopathies, mainly on the basis of similar muscle imaging findings in MMD1 and LGMDR2 dysferlin-related/LGMD2B and in MMD3 and LGMDR12 anoctamin5-related/ LGMD2L, respectively.44 The dysferlinopathies often show involvement of the anterior compartment of the lower leg muscles which is not found in the anoctaminopathies.7 In the distal myopathies the lower leg muscles are preferentially involved, but proximal muscles may also show alterations at an early stage of the disease.50, 51

Congenital muscular dystrophies The CMD comprise different disorders often associated with congenital contractures. Not all have a strictly congenital onset and some have been shown to be a part of a broader phenotype. Autosomal dominant EDMD2 is part of the spectrum of LMNA related muscular dystrophies, including amongst others familial lipodystrophy. Likewise, Ullrich congenital muscular dystrophy (UCMD) is part of the COLVI related muscular dystrophies. Interestingly the pattern of muscle involvement on MRI is similar in the congenital and late- onset variants of these diseases.1, 52 COLVI related muscular dystrophies, e.g. LGMDD5 collagen 6-related/Bethlem myopathy, show specific fatty degeneration of the central part of the rectus femoris and involvement of the rim between soleus and gastrocnemius muscles, a unique feature that may be helpful in establishing the diagnosis.52

LMNA related muscular dystrophies show predominant involvement of the posterior compartment of the thigh and calf muscles.1, 53 Whole body MRI showed abnormalities in a specific pattern in particular in patients studied due to rigid spine syndrome and hyperlaxity syndrome. WBMRI also has additional value in showing selective sparing of the muscles of the forearm, masticatory and tong muscles.25 There is insufficient data on the use of muscle imaging in merosin deficient CMD.54 The dystroglycanopathies are a genetically heterogeneous group with a large possible number of clinical phenotypes, publications on muscle imaging comprise of small case reports. The dystroglycanopathies with mutations in the protein O-mannosyltransferase genes (POMT1 and POMT2) may show a similar pattern of fatty infiltration as LGMDR9 FKRP-related/LGMD2I.55 Isoprenoid synthase domain containing (ISPD) related dystroglycanopathy does not have a specific pattern of fatty infiltration.56 The use of muscle US in CMD must be investigated further. A clear

33 Chapter 2 correlation between MR and US pattern has been shown in a single case report in COLVI related muscular dystrophy.57

Facioscapulohumeral dystrophy Facioscapulohumeral dystrophy (FSHD) often shows a characteristic pattern of muscle weakness on clinical examination resulting in a minor role for muscle imaging in the diagnostic process. However, as is found on clinical examination, a specific asymmetric pattern of muscle involvement on muscle imaging has been described in FSHD (DUX4 gene) starting with prominent degeneration of paraspinal and tibialis anterior muscles followed by the gastrocnemius muscle. At the level of the thigh the posterior compartment is selectively involved with relative sparing of the vastus muscles.58, 59 Involvement of the shoulder girdle shows early fatty infiltration of the trapezius and serratus anterior muscles, followed by latissimus dorsi and pectoralis major muscles. The spinati and subscapular muscles are almost always spared.60, 61 A comparison of quantitative muscle US and quantitative MRI in FSHD shows a good correlation for quantifying fatty degeneration.24

Myotonic dystrophy As with FSHD there is a characteristic pattern of muscle involvement in myotonic dystrophy type 1 (DM1 DMPK gene) and DM2 (ZNF9). The most frequently affected muscles in DM1 are the medial head of gastrocnemius, soleus and vastus medialis muscles. In DM2, however, the erector spinae and gluteus maximus muscles are most vulnerable to degeneration.62 WBMRI of these patients shows dilatation of the oesophagus.32 Muscle MRI of the masticatory muscles show a decrease of the size of these muscles in DM1 but not in DM2 compared to healthy volunteers.63

Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy (OPMD, PAPBN1 gene) can often be diagnosed clinically (ptosis and dysphagia are the clinical hallmarks) and the reports on muscle imaging show a non-specific pattern of muscle involvement of the posterior compartment of the thigh and calf.64, 65 It is possible to monitor subclinical disease progression using quantitative evaluation of muscle fat fraction in these patients.2

Metabolic myopathies In the group of metabolic myopathies the most widely studied myopathy is Pompe’s disease (glycogenosis type II, GAA gene) which in adults shows a spreading pattern of fatty degeneration starting with the paraspinal muscles and the posterior thigh muscles. Subsequently, the quadriceps femoris with selective sparing of the biceps femoris, the rectus femoris, sartorius and lateral portion of the vastus lateralis muscle are involved.66

34 Muscle imaging in inherited and acquired muscle diseases

WBMRI shows marked involvement of the tongue and subscapular muscles.25, 67 Muscle US shows relative sparing of the triceps brachii and rectus femoris muscles.68 The limited data on muscle imaging in juvenile onset Pompe’s disease suggests early involvement of the adductor magnus muscle.69 Quantitative muscle MRI was used to assess disease progression in patients with Pompe’s disease treated with enzyme replacement therapy.70 Muscle MRI after 6 months of therapy showed an increase of muscle bulk of muscles that were relatively 2 Chapter spared prior to therapy.71 Other diseases of glycogen storage such as Cori-Forbes disease (GSD III, AGL gene), McArdle disease (GSD V, PYGM), Tarui’s disease (GSD VII, PFKM) and the large group of mitochondrial myopathies do not show specific patterns on muscle imaging.72 This may be due to the episodic or exercise-related nature of symptoms in these disorders. Exercise induced muscle weakness may not result in morphological changes in the skeletal muscle which can be detected by muscle imaging.

In the long-chain fatty acid oxidation disorder, a lipid storage myopathy, abnormalities on muscle imaging can be found. In mitochondrial trifunctional protein deficiency (MTPD, HADHA/HADHB), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD, HADHA) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD,ACADVL ) there is generalized muscle oedema on muscle imaging of the lower leg. Additionally there is fatty degeneration of the muscles of the thigh in VLCADD of the calf muscles in LCHADD and of the whole lower limb in MTPD.73 In carnitine palmitoyltransferase 2 deficiency (CP2D, CPT2) structural muscle changes are rare.

Congenital myopathies Congenital myopathies are characterized by specific structural abnormalities in muscle tissue. Ryanodine receptor 1 (RYR1) related myopathies show a characteristic pattern of involvement of the vasti, adductor magnus and sartorius muscles at the level of the thigh and involvement of the calf and peroneal muscles. There is selective sparing of the rectus femoris, adductor longus and gracilis muscles at thigh level and of the tibialis anterior muscle at lower leg level.54, 74 Muscle imaging in patients with SEPN1 mutations shows specific fatty degeneration of the sartorius and semimembranosus muscle. As the disease progresses the pattern of muscle involvement at the level of the thigh resembles that of RYR1.3 WBMRI can help differentiate between the two, because SEPN1 myopathy shows severe atrophy of the sternocleidomastoideus and preservation of the masticatory muscles in contrast to RYR1 .25, 75 In beta-tropomyosin (TPM2) related nemaline myopathy there is a predominantly distal involvement, with selective sparing of the gastrocnemius and peroneal muscles. At thigh level there is involvement of the rectus femoris, vastus lateralis and semimembranosus muscles. WBMRI in TPM2 myopathy reveals involvement of the

35 Chapter 2 temporal and lateral pterygoid muscle at the level of the head and relative sparing of the shoulder girdle muscles.76

Dynamin 2-related (DNM2) also shows initially distal fatty degeneration, save for relative sparing of the gastrocnemius muscle. At the level of the thigh there is involvement of the posterior compartment, most notably the semimembranosus and biceps femoris muscles. WBMRI can show specific muscle involvement of the lateral pterygoid muscles in the head, neck extensors, paraspinal and deep forearm muscles.77

X-linked myotubular myopathy and alpha-actin rod myopathy (ACTA1) show diffuse involvement of muscle in the lower limb.54

Myofibrillar myopathies The myofibrillar myopathies are grouped together because of similar findings on histological examination, where there is degradation of and accumulation of degradation products in intracellular inclusions. Early cardiac involvement which can result in respiratory failure is seen in combination with proximal or distal muscle weakness in desminopathy (DES gene) and with distal muscle weakness in alpha-B-crystallinopathy (CRYAB).78 Muscle imaging shows early involvement of the semitendinosus, gracilis, sartorius and peroneal muscles. This should make these diseases easily distinguishable from most muscular dystrophies where there is often selective sparing of the gracilis and sartorius muscles.1 In ZASPopathy (LDB3) and myotilinopathy (TTID) there is a similar pattern of fatty degeneration of the lower limb with early involvement of the soleus and medial gastrocnemius and at thigh level early involvement of the semimembranosus and adductor magnus muscles. Later in the course of the disease there is involvement of all calf muscles. However, ZASPopathy manifests clinically with prominent distal muscle weakness, whereas myotilinopathy (LGMD1A) shows proximal muscle weakness.79

Filaminopathy (FLNC) also presents with proximal muscle weakness reflected by diffuse involvement of the thigh muscles with relative sparing of the lateral vastus, sartorius, gracilis and semitendinosus muscles on muscle imaging. Fatty degeneration of the soleus and medial gastrocnemius muscles occur at an early stage.33 There are no studies of muscle imaging in BAG3 related myofibrillar myopathy.

Skeletal muscle channelopathies The skeletal muscle channelopathies present clinically with myotonia and can be associated with muscle weakness. Muscle imaging in non-dystrophic myotonia, i.e., myotonia congenita (CLCN1 gene) and paramyotonia congenita (SCNA4) can show fatty infiltration or oedema

36 Muscle imaging in inherited and acquired muscle diseases of all muscles of the thigh, but at the level of the lower leg shows sparing of the tibialis posterior muscle and a distinctive central stripe in the medial gastrocnemius muscle.20 No differences were found between the pattern of muscle involvement of autosomal dominant (Thomsen disease) and autosomal recessive myotonia congenita (Becker disease), or between CLCN1 and SCNA4 related non-dystrophic myotonias. Young patients with CLCN1 related non-dystrophic myotonia often have no abnormalities on MRI.20, 80 In older 2 Chapter patients hypokalemic periodic paralysis (hyperPP) can result in fatty degeneration of muscle without a specific pattern.81

MUSCLE IMAGING IN ACQUIRED MYOPATHIES Idiopathic inflammatory myopathies The idiopathic inflammatory myopathies (IIM) include dermatomyositis, subclassified in classic adult-onset dermatomyositis (DM) and juvenile DM, polymyositis (PM) subclassified as PM sensu strictu, necrotizing auto-immune myopathy, non-specific myositis or overlap myositis which is often associated with connective tissue disease82, and sporadic inclusion body myositis (sIBM). DM and PM show diffuse symmetrical muscle oedema of most often the quadriceps and hamstrings muscles and in some cases of the triceps brachii and deltoid muscles. In DM oedema can be located either focally or diffusely in the muscle, along the fascia, subcutaneously or cutaneously (Figure 6).83

FIGURE 6 | Muscle MRI in inflammatory myopathy

Axial T2-weighted image with fat suppression of the thigh in a dermatomyositis patient. The hyperintensities in the lateral and intermedial vastus muscles represent muscle edema. Hyperintensity can also be observed subcutaneously (arrow) and in the skin (arrowhead).

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Fasciitis is common and can be seen on muscle US as a significant increase in thickness of the fascia in the majority of patients with PM and DM.84 In juvenile IIM (whole body) muscle MRI often shows no abnormalities, but if present there is diffuse muscle oedema in both the upper and lower extremity which can also involve distal muscles that are normal on clinical examination.11, 85 MRI T2 relaxation time is a reliable and valid measure of inflammation and disease activity within muscle in children with juvenile DM.86, 87 Quantitative US can be used in the follow up of juvenile DM to assess muscle size and echo intensity of muscle, which represents either fatty degeneration (residual muscle damage) or active inflammation of muscle.88 In most patients with autoimmune necrotizing myopathy related to anti signal recognition particle antibodies (anti-SRP myopathy) muscle MRI of the thigh shows muscle oedema of both the anterior and posterior compartment with predominant involvement of the vastus lateralis compared to the vastus intermedius muscle. Fatty infiltration was prominent in a third of anti-SRP myopathy patients, predominantly of the posterior thigh muscles. Patients with fatty degeneration were refractory to steroid therapy.89 Fatty degeneration can also be found in PM but is less pronounced than in anti-SRP myopathy.90 Muscle oedema can disappear with the use of immunosupressants.91 MRI can be a useful adjunct to muscle biopsy. Using skeletal muscle MRI prior to a muscle biopsy results in a higher diagnostic accuracy of the biopsy, as there is often focal inflammation. Furthermore using MRI as an add-on test when muscle biopsy is negative reduces the false negative rate.5 In sIBM there is prominent asymmetrical fatty infiltration of skeletal muscles, muscle oedema is less prominent in sIBM. There is early involvement of the deep finger flexor muscle which can be found on muscle MRI prior to clinical muscle weakness. The legs are more often and more severely affected than the arms. Fatty degeneration is most striking in the anterior muscles of the thigh and the medial gastrocnemius muscle. There is often relative sparing of the rectus femoris.92

There is more often and more severe fatty degeneration of the quadriceps muscles compared to the iliopsoas muscle, reflecting the clinical symptoms where there is also more weakness of knee extension compared to hip flexion.93 A recent study of quantitative assessment of muscle size on MRI 8 weeks after treatment with bimagrumab showed increased thigh muscle volume in patients with sIBM, after 24 weeks this increase was still found but did not differ significantly with patients who received placebo treatment.94

Toxic myopathies The most common toxic myopathies are caused by steroids, statins and alcohol. On muscle imaging they all show muscle oedema of the thigh muscles in a non-specific pattern reflecting either rhabdomyolysis in the acute form or a less well understood pathophysiology in the chronic form.95 Muscle imaging cannot be used to differentiate between different toxins.96

38 Muscle imaging in inherited and acquired muscle diseases

Rhabdomyolysis In rhabdomyolysis affected muscles may show oedema, necrosis or infarction on MRI (hyperintensity on T2-weighted and STIR images) or deposits of methaemoglobin or proteinaceous material after haemorrhage (hyperintensity on T1-weigthed images) with rim enhancement and stipple sign on contrast enhanced images in the acute phase of the disease.97 2 Chapter

FUTURE PROSPECTS Diffusion tensor imaging A recent development has been the use of DTI in muscle disease. DTI assesses the biological structure of muscle and can show changes in the structure of tissues which have not yet resulted in morphological changes. MR tractography, a three dimensional depiction of structures assessed by DTI, can be especially useful to detect changes in normally well organised tissue, such as muscle fibers. Preliminary studies using DTI have proven that it can be applied to detect muscle ischemia, muscle trauma and decrease of muscle fibers in myositis patients.98, 99

Functional magnetic resonance imaging Functional imaging using MRS allows visualisation of muscle metabolism. Numerous studies have been performed using phosphorus 31 (³¹P) MRS in mitochondrial myopathies. ³¹P MRS has the potential to visualize the kinetics of the muscle metabolism, phosphocreatine (PCr), adenosine triphosphate (ATP), pH, and inorganic phosphate, which is disturbed in the mitochondrial myopathies. The diagnostic accuracy of ³¹P MRS of the flexor digitorum superficialis and tibialis anterior muscle in mitochondrial myopathies is variable showing a high specificity but a low sensitivity. Recent reports on ³¹P MRS show elevated phosphodiester/ATP ratios in skeletal muscle of patients with BMD and elevated PCr/ATP ratios in skeletal muscle of patients with FSDH skeletal before fatty infiltration becomes apparent on conventional muscle imaging.100, 101 Quantifying fat fraction using ¹H MRS shows less intramuscular fat deposition in patients with DMD on corticosteroids. Given the combination of the technical difficulty and cost of MRS it cannot yet be used in clinical practice.102

Intracellular sodium can be visualized using ²³Na MRI. In patients with skeletal muscle channelopathies, structural muscle imaging does not always show abnormalities but MRI can be used to show intracellular sodium accumulation during cold-induced weakness in these patients.103 Higher intracellular sodium is also seen in patients with hyperPP with permanent weakness compared to those without permanent weakness and in patients with

39 Chapter 2

DMD, which suggests a role of elevated intracellular sodium in the pathogenesis of these diseases.104, 105

Disease and treatment monitoring Inflammation of skeletal muscle, measured as T2 relaxation time on MRI, can be used as a reliable measure of disease activity in juvenile dermatomyositis86, and quantitative measurement of fatty degeneration on MRI and US has achieved a high reliability which will be useful in the follow up of progression of muscle disease (e.g. DMD) and as an important (secondary) outcome in the growing number of therapeutic trials in patients with both inherited and acquired muscle disease (e.g. sIBM and Pompe’s disease).2, 10, 21, 71, 88, 94 For MRI and US to be useful as monitoring tools it is important to standardize image acquisition protocols. An effort has been made recently to harmonize the MRI scanning protocols and to collaborate on defining specific patterns of muscle involvement to improve the diagnostic process in muscle disease.26, 106

40 Muscle imaging in inherited and acquired muscle diseases

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