P4.25 Functional outcome measures in limb girdle muscular dystrophy 2I: Correlations with MRI

Abstracts / Neuromuscular Disorders 20 (2010) 596–680

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Hospital, Yokohama, Japan, d Higashisaitama National Hospital, Hasuda, Japan

infiltrated by fat than proximal parts. On average 5% more fatty infiltration was shown over a distance of 15 mm along the muscle.

Recently the therapies for muscular disorders are being developed. However, the method to measure muscle volume has not been established in determining the effect of therapeutic intervention. We have developed a new method for evaluating muscle volume using CT. We defined estimated muscle volume at a given CT slice level of the thigh as muscle volume index (MVI), and the ratio of MVI to total volume within the range of interest as % muscle volume index (%MVI). The purpose of this study is to confirm the validity of this method by investigating the relationship between functional stage and the new indices, and describing muscle damage progression by the indices. We calculated MVI and %MVI by means of making the histogram of CT value and applying the formula for correcting partial volume effect. A study in 21 patients with Duchenne muscular dystrophy (DMD) showed that MVI and %MVI at the maximum circumference level of the thigh were significantly correlated with functional stage (Ueda). The transitional change in MVI and %MVI was significantly regressed to an exponential function Y = Ae-rX. This result is accord with those of previous study as to change in serum CK in DMD. This implies that the rate of DMD muscle degradation might depend on the amount of existing muscle. This method is useful in assessing natural clinical course of disease and the efficacy of therapeutic interventions.

doi:10.1016/j.nmd.2010.07.219

doi:10.1016/j.nmd.2010.07.218

P4.23 Non uniform fatty infiltration distribution of skeletal muscle tissue in facioscapulohumeral dystrophy B.H. Janssen a, R.J.W. Arts b, N.B.M. Voet c, C.I.H. Nabuurs a, B.G.M. Engelen b, A. Heerschap a a

Radboud University Nijmegen Medical Centre, Radiology, Nijmegen, Netherlands, b Radboud University Nijmegen Medical Centre, Neurology, Nijmegen, Netherlands, c Radboud University Nijmegen Medical Centre, Rehabilitation, Nijmegen, Netherlands Introduction: Facioscapulohumeral dystrophy (FSHD) is the third most common genetic muscular dystrophy. It is characterized by an uneven distribution of affected and unaffected muscles. We questioned if a similar heterogeneity exists within muscles. We used MRI techniques to quantify fatty infiltration over the length of thigh muscles of FSHD patients. Methods: 22 genetically proven FSHD patients were examined on a Siemens Trio 3T system. During the experiment multiple slices of multi-echo MR images were acquired covering between 59 and 83 mm of the upper leg. Signal decay by T2 relaxation in these images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue (Kan et al, 2009). From the fit a degree of fatty infiltration was determined for each muscle and for each slice, which made it possible to study the degree of fatty infiltration over the length of the muscle. Results: A total of 272 thigh muscles were investigated of which 35 qualified as intermediately and showed progression of the disease over the length of the muscle. These muscles were selected for further analysis. For every muscle linear regression analysis was performed on the level of fatty infiltration over the length. The median slope over the investigated muscles was 0.05, indicating a 5% increase of fatty infiltration over a muscle length of 15 mm distal. The median R on the fatty infiltration over the length of these muscles was 0.93, signifying the linear fit to be a accurate representation of the actual data. Conclusion: We objectively proved that intermediate diseased muscle in FSHD patients are not homogeneously affected, as distal parts are more severely

References Kan et al, 2009 Kan, H.E., et al., 2009. Neuromuscular Disorders.

P4.24 Asymmetry of skeletal muscle involvement in facioscapulohumeral muscular dystrophy: a neuroimaging study K. Sugie 1, Y.K. Hayashi 2, K. Goto 2, I. Nishino 2, S. Ueno 1 1 Nara Medical University, Neurology, Nara, Japan, 2 National Center of Neurology and Psychiatry, Neuromuscular Research, Tokyo, Japan

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant inherited disorder characterized by early involvement of facial and scapular muscles, with eventual spread to the pelvic and lower limb muscles. To evaluate the presence and distribution of skeletal muscle involvement, we studied five right-handed male patients with FSHD (19–74 years old) by whole-body neuroimaging. All patients showed truncation of 3.3-kb D4Z4 repeat sizes less than 35 kb on 4q35. Three patients had right-predominant upper limb muscle atrophy. Another 68-year-old patient had right-predominant atrophy of not only the upper limbs, but also the lower leg muscles. However, the degree of asymmetry was minimal in these four patients. Interestingly, the other 63-year-old patient showed hemiatrophy (atrophy only on the right side of the body). Muscle CT image at the shoulder level revealed atrophy of the right shouldergirdle and greater pectoral muscles. On MRI, adipose tissue replacement of muscle was asymmetrically pronounced in the biceps and the triceps brachii, forearm, femoral, tibialis anterior, and calf muscles only on the right side. Neurological examinations including electromyography showed right-sided muscle weakness/atrophy. No central nervous system involvement was apparent. Although asymmetric muscle involvement is considered one of the characteristic clinical features of FSHD, hemiatrophy without contralateral involvement has not been reported previously in elderly patients with FSHD. The degree of asymmetry did not correlate with the number of D4Z4, disease duration, or age at onset. Asymmetry in FSHD might depend not only on the genetic predisposition of specific muscles to be more or less affected, but also on epigenetic factors, including mechanical handedness. Our findings suggest that FSHD is more clinically variable than previously thought. doi:10.1016/j.nmd.2010.07.220

P4.25 Functional outcome measures in limb girdle muscular dystrophy 2I: Correlations with MRI M. Eagle, A. Mayhew, T.A. Willis, H. Lochmuller, K. Bushby, V. Straub Institute of Genetics, Newcastle Muscle Centre, Newcastle, United Kingdom Introduction: MRI is useful for diagnosis in muscular dystrophies and more recently has been considered as a potential outcome measure in clinical trials. Functional outcome measures have not been validated for use in LGMD 2I. We developed a series of functional outcome measures including timed tests, myometry, Adapted North

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Abstracts / Neuromuscular Disorders 20 (2010) 596–680

Star Ambulatory Assessment and FVC as part of a wider study which used magnetic resonance imaging and magnetic resonance spectroscopy to evaluate muscle damage in LGMD 2I. Methods and patients: Thirteen ambulant patients were recruited via Newcastle Muscle Centre (Age range, 21–64; male:female, 9:3). Respiratory function walking ability measured by the 6 MWD and 10 m walk were correlated with each other and with a quantitative measure of fat infiltration (3-point Dixon technique). Assessment of muscle strength by myometry was also correlated with 6 MWD. Results: FVC did not correlate with functional evaluations or total % fat. The 6 MWD and 10 m walk correlated well with each other ( 0.88, p = 0.01) and with total % fat (0.926, p = 0.01; 0.872, p = 0.01). Assessment of fat infiltration in individual muscles was correlated with the 6 MWD. The highest correlation was with vastus lateralis and vastus medialis ( 0.909, p = 0.01; 0.838, p = 0.01). Semitendinosus, semimembranosus, rectus femoris, and lateral gastrocnemius also all correlated at p = 0.01. Medial gastrocnemius, soleus, sartorius, long and short heads of biceps femoris correlated less significantly, p = 0.05. The % fat infiltration in tibialis anterior,peroneus longus and gracilis did not correlate with the 6 MWD. 6 MWD correlated at the p = 0.01 level (0.556–0.624) with myometry of hip flexion, abduction and adduction, knee extension and flexion. Conclusions: 6 MWT and 10 m walk correlate well with quantitative assessment of fat infiltration. Functional measures and myometry correlate well with each other. These results open up the possibility of using these measures in a clinical trial. doi:10.1016/j.nmd.2010.07.221

P4.26 Assessing muscle pathology by MRI in LGMD2I T.A. Willis 1, K.G. Hollingsworth 2, M.L. Sveen 3, J. Morrow 4, J. Vandenheede 5, A. Mayhew 1, M. Eagle 1, K. Bushby 1, H. Lochmüller 1, M. Hanna 6, J. Vissing 3, P. Carlier 5, V. Straub 1 1 Newcastle University, Institute of Human Genetics, Newcastle, United Kingdom, 2 Newcastle University, Newcastle Magnetic Resonance Centre, Newcastle, United Kingdom, 3 University of Copenhagen, Neuromuscular Research Unit, Copenhagen, Denmark, 4 University College London, Institute of Neurology, London, United Kingdom, 5 Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France, 6 University College London, Neurology Department, London, United Kingdom

Limb Girdle Muscular Dystrophy 2I (LGMD2I) is caused by mutations in the fukutin related protein gene (FKRP) and associated with abnormal glycosylation of a-dystroglycan. Although MRI is useful for diagnostic purposes in muscular dystrophies, it has become of interest more recently as a possible outcome measure and potentially useful in clinical trials. The aim of this ongoing multi-centre study is to (i) assess the pattern of fat infiltration in a large cohort of LGMD2I patients using a qualitative radiological score and (ii) to implement a quantitative 3-point Dixon technique, developing a non-invasive tool to track the progression of fat infiltration longitudinally. The study involves 40 ambulant LGMD2I, homozygous for the common mutation, patients from Newcastle, London, Paris and Copenhagen. The age range is 21–64 years and disease duration, 4–49 years. We have compared the infiltration with matched adult controls. From the qualitative T1w data, 717 muscles have been assessed: 47% are rated in the top two qualitative grades. There is widespread involvement of all muscle groups, however some are better preserved until late stage. The pattern of fat infiltration is consistent throughout subjects with a typical whorled pattern of involvement in the posterior thigh muscles, particularly semimembranosus and a striated/variegated appearance in the soleus.

From the quantitative Dixon data so far, there is overall correlation between qualitative and quantitative assessments (j = 0.79, p < 0.0005), and more importantly the quantitative data has correlated well with myometry and functional outcome measures, such as timed tests. Fat infiltration in the vastus lateralis correlated strongly with knee extensor strength (j = 0.825, p < 0.001), the ‘timed up and go’ test (j = 0.901) and the 6-min walk test (j = 0.801, p < 0.01). This study illustrates the usefulness of quantitative MRI as a potential outcome measure for muscular dystrophy trials. doi:10.1016/j.nmd.2010.07.222

P4.27 Muscle MRI findings in anoctaminopathy A. Sarkozy 1, D. Hicks 1, J. Miller 2, M.C. Walter 3, P. Reilich 3, H. Lochmuller 1, K. Bushby 1, V. Straub 1 1 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 2 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom, 3 Friedrich Baur Institute, Ludwig-Maximilians University, Munich, Germany

Recessive mutations in the ANO5 gene have recently been identified in patients with either limb girdle muscular dystrophy type 2L (LGMD2L) or Miyoshi-like Myopathy (MMD3), collectively called anoctaminopathies. Our cohort of patients with anoctaminopathy shows a predominantly proximal pattern of weakness affecting the pelvic girdle and the lower limbs. Variable distal involvement is also observed, and sometimes presents as the first or predominant feature, similar to Miyoshi Myopathy. The upper extremities are affected only late in the disease process, usually with selective M. biceps brachii weakness and wasting. We have carried out MRI imaging of the lower limbs in our cohort of patients with anoctaminopathy. A prevalent selective involvement of the posterior compartment muscles is observed in all patients, with asymmetric wasting of the hamstring and medial gastrocnemius muscles. All patients were either homozygous or compound heterozygous for the recurrent c.191dupA mutation detected in exon 5. The majority of patients showed a prevalent proximal distribution of weakness, while a few presented more distal involvement. Muscle MRI was performed at diagnosis or during follow-up, with duration of disease of 10–15 years on average. Muscle pathology was evaluated on T1 weighted images. The pattern of pathology on MRI is different from the pattern observed in other LGMDs, but showed similarities to patients with LGMD2B. doi:10.1016/j.nmd.2010.07.223

P4.28 Comparative analysis of clinic status, pathology and muscle MRI: 16 cases of distal myopathies/muscular dystrophies J. Hu, Z. Zhao The Third Hospital of Hebei Medical University, China, Neuromuscular Department, Shijiazhuang, Hebei, China Objective: To investigate diagnostic value of clinic, pathology and muscle MRI value for distal myopathy/muscular dystrophy. Methods: Clinical data analysis, skeletal muscle MRI, muscle biopsis, histochemical stain, anti-dysferlin monoclone antibody immunohistochemical stain were executed for 16 patients. Results: Comprehensive analysis of clinical, EMG, skeletal muscle MRI, muscle pathology data: 10 cases of Miyoshi distal muscular dystrophy, three cases of distal myopathy with rimmed vacuoles, two cases