Vol. 4, Issue 9 : Muscular Dystrophy: Medical Imaging in Clinical Trials

San Antonio (TX), Bolton (MA)

The imaging of muscle diseases has undergone significant expansion and evolution over recent decades.  Magnetic resonance imaging (MRI), in particular, has been increasingly utilized to provide clinically useful information on the extent, severity, and activity of muscle involvement in such varied muscle diseases as muscular dystrophies, congenital and metabolic myopathies, motor neuron diseases, and inflammatory and infectious conditions of muscle.  MRI is ideally suited to evaluate large regions of muscles, and may assist in targeting sites for biopsy and electromyography, as well as evaluating disease progression and response to therapy.

Muscular dystrophies are a group of muscular disorders characterized by muscular weakness and hypotonia, with Duchenne muscular dystrophy and Becker’s muscular dystrophy being two of the more common of these conditions.   Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition with an incidence of approximately one in 3,500 boys and an age of onset of 4-6 years.  The fundamental abnormality is a mutation or absence of dystrophin, resulting in muscle injury during eccentric contraction.  Clinically, there is progressive relatively symmetric muscle weakness beginning in the proximal pelvic girdle and progressing distally over time into the extremities—particularly the calves and shoulder girdle.  Asymmetric involvement of thigh musculature may be seen, with fatty atrophy most prominent in the gluteus and adductor magnus musculature, and active inflammatory change most prominent in the adductor, quadriceps, and biceps femoris muscle bellies.   The gracilis is generally the most resistant muscle, followed by the sartorius, semitendinosus, and semimembranosus muscles.

Becker’s muscular dystrophy is also an X-linked recessive disorder, with an age of onset of approximately 11 years.  Again, dystrophin is affected, however in general Becker’s muscular dystrophy is less severe than DMD.   Symptoms begin in the lower extremities, preceding upper extremity involvement by 5-10 years.  Again present is calf pseudohypertrophy with enlargement of soleus and gastrocnemius musculature, with thigh musculature is relatively spared—including the gracilis, Sartorius, adductor longus, rectus femoris, semitendinosus, and semimembranosus musculature.

Clinical evaluation in muscular dystrophies includes a clinical functional score (CFS) utilized to assess muscular strength, although this is understandably subject to inherent variability and bias, particularly in a young child.  More invasive evaluation includes muscle biopsy, which is painful, and limited due to sampling error.  Finally, there is monitoring of the serum level of creatine kinase (CK).

Although a biochemical marker utilized in monitoring disease activity in both DMD and Becker’s muscular dystrophy, this is not a highly reliable marker.  Therefore, the noninvasive use of magnetic resonance imaging to evaluate disease progression and response to therapy is highly useful.

A medical imaging protocol for evaluation of muscular dystrophies includes basic non-quantitative anatomic imaging with a fluid sensitive sequence such as fat saturated fast spin-echo T2 or STIR (fast spin-echo inversion recovery) images, in at least one plane.  The axial plane is generally the most useful when evaluating exact muscle groups affected and assessing the degree of inflammation versus fatty replacement.   Axial and coronal conventional T1 non fat suppressed images are also essential for evaluation of fatty replacement within the musculature.

Ideally, a non-invasive but quantitative or semi-quantitative method to assess disease progression in muscular dystrophy would be available.  This has been accomplished both by use of MR grading systems, and more recently, by methods such as utilization of T2 mapping and even proton spectroscopy.  In 1993, Liu et al. published an MR grading system with functional correlation, for use in Duchenne muscular dystrophy.  The grading system was based on the number of preserved muscle groups in the pelvic girdle and thigh, as well as the severity of fatty infiltration in the pseudohypertrophied calf, and the increase in subcutaneous fat.  Thirteen total muscle groups in the pelvic girdle were evaluated, as were 11 muscle groups in the thigh, with the score based on number of muscle groups involved.  Total MR grading score was correlated clinically with the Clinical Functional Score, serum creatine kinase measurements, patient age, and disease duration.

Recently, Kim et al. analyzed T2 maps in pelvic and thigh musculature in patients with Duchenne muscular dystrophy, with increased T2 values thought to result from presence of fatty infiltration in muscle.  The authors then correlated these T2 values with grade of fatty infiltration obtained on nonquantitative MR imaging, as well as clinical outcome tests.   The color coded T2 maps were generated by placement of regions of interest (ROIs) in three sections of muscle—at the level of the sciatic foramen, the greater trochanter-ischial tuberosity, and at the very proximal portion of the femoral diaphysis.  Eighteen total muscles in the right side of the pelvic girdle and thigh were evaluated. Predictably, the muscle with the longest T2 value was the gluteus maximus, with this muscle also demonstrating the greatest cumulative score for fatty infiltration on the anatomic MR imaging.

Future directions and imaging frontiers for muscular dystrophy assessment will probably involve investigation of the use of hydrogen 1 (¹H) magnetic resonance spectroscopy.  MR proton spectroscopy, in concert with apparent diffusion coefficient (ADC) maps, is already being used in the evaluation of brain white matter in children with congenital muscular dystrophies.  Phosphorus-31 MR spectroscopy has been performed in cardiac muscle in those with muscular dystrophy, to assess cardiac phosphocreatine to adenosine triphosphate ratios noninvasively in these patients, as altered expression of dystrophin results in a reduction in this ratio.

Conclusion

In summary, noninvasive monitoring of disease state, progression, and therapy response in the case of muscular dystrophy is not only feasible, but provides both nonquantitative anatomic data as well as quantitative information in the form of MR grading scales of fatty infiltration of muscle groups, T2 mapping of the musculature of the pelvic girdle and thighs, and now MR proton spectroscopy.  These data can be correlated with clinical outcome measurements and assessments as well as serum creatine kinase levels, histopathologic analysis obtained from muscle biopsy, and genetic testing.

About the Author

Dr. Swart is a board-certified radiologist at Intrinsic Imaging and has specialized training in orthopedic radiology. She is a graduate of Harvard University in Cambridge, Massachusetts, where she graduated summa cum laude in Cognitive Neuroscience. She earned her M.D. from Columbia College of Physicians and Surgeons in New York, NY, where she earned the Janeway Prize, awarded to the person graduating at the top of their medical school class. She conducted research in the Neurology Department as part of an American Academy of Neurology Research Scholarship, with publication in the journal Stroke. After completion of her medical training, Dr. Swart then completed a diagnostic radiology residency at Johns Hopkins Hospital, in Baltimore, MD, where she was elected to serve as chief resident of diagnostic radiology. She then further sub-specialized in musculoskeletal radiology at National Orthopedic Imaging Associates in San Francisco, California with Dr. David Stoller.

About Intrinsic Imaging LLC

Located in Bolton, Massachusetts and San Antonio, Texas, Intrinsic Imaging is an FDA audited, ISO 9001:2008 and ISO 13485:2003 certified, GAMP® 5 compliant medical imaging core lab specializing in providing imaging core lab services for clinical trials. Its comprehensive medical imaging core lab services include, but are not limited to, expert radiologist consultation, protocol and charter development, site qualification, training and management, as well as image acquisition, processing and detailed radiologic analysis.

Intrinsic Imaging has more than sixty full-time, board-certified diagnostic radiologists on staff that have sub-specialization in all therapeutic areas including, but not limited to, Cardiovascular, Central Nervous System, Gastrointestinal & Genitourinary, Medical Device, Musculoskeletal and Oncology.