Jasper M Morrow, Matthew RB Evans and Mary M Reilly
MRC Centre for Neuromuscular Diseases
Department of Molecular Neurosciences, UCL.
Institute of Neurology, London, UK
One of the major challenges in developing new treatments in Charcot-Marie-Tooth is accurately measuring how much worse the disease gets over time. Although this is readily apparent to both patients with CMT and their doctors, to be able to perform a trial of a new treatment, disease severity needs to be recorded as a numerical value. Of utmost importance in slowly progressive conditions such as CMT, this value must change over a couple of years so that it can be determined if the new treatment stops disease progression. Currently used measurements of severity in CMT, such as the CMT Neuropathy Score used in the Vitamin C treatment studies, showed only very small changes over two years. Recent research at the MRC Centre for Neuromuscular Diseases has been looking at whether MRI can rise to the challenge to provide sensitive and accurate severity measurements in CMT.
MRI is well established in other areas of neurology with the advantages of being painless, non-invasive and not involving exposure to radiation. Although MRI is a relative newcomer on the neuromuscular scene, it already has an established role in assisting in diagnosis of a wide range of nerve and muscle diseases. It is a unique form of medical imaging which harnesses the innate magnetic properties of hydrogen atoms found in all tissues in the human body. These hydrogen atoms line up with the magnetic field when the person goes into the machine, and give off signals when the magnetic field changes during the scan. These signals are recorded by the MRI and reconstructed to create a picture of the part of the body of interest, in this case the legs. The hydrogen atoms generate different signals depending on what kind of tissue they are in (fat, muscle, nerve, skin) which creates contrast between these tissues, but also differentiates normal from abnormal tissue.
In CMT, although the nerve is the site of initial damage and changes in the nerves have been demonstrated on MRI of patients with CMT; there are also secondary changes in muscles as they lose connection with their nerve supply. As these muscles become involved, they slowly reduce in size and become infiltrated with fatty tissue. With advances in medical physics, novel MRI techniques have been developed which allow precise quantification of the percentage of fat in any tissue. Measurement of fat in leg muscles is therefore potentially a good marker of disease severity in patients with CMT.
With this in mind, the MRC Centre for Neuromuscular Diseases at Queen Square has been developing quantitative MRI as a potential severity measure to be used in CMT treatment trials for patients. In 2011, 20 patients with CMT and 20 volunteers were enrolled in a longitudinal study to measure progression of the disease using MRI. To date, patients and volunteers have been examined clinically and by MRI at two time points separated by 12 months. The preliminary results from this study are very encouraging, showing that there was an abnormally increased amount of fat in leg muscles of CMT patients and that this measurement correlated with other markers of disease severity including muscle strength. Most importantly MRI was accurate enough to show change in this measurement over 12 months follow-up in some patients, whereas the volunteer measurements didn’t change at all. MRI therefore appears able to detect disease progression in CMT over a 12 month period in some patients, where other measurements cannot, and therefore has the potential of being an excellent outcome measure for treatment trials involving CMT.
We aim to continue this study for several years to obtain as much information as possible regarding the use of MRI in CMT, and specifically to determine the minimum number of years needed to detect change in all patients with CMT, so that MRI can be used in clinical trials. This is a very exciting development in CMT research, and may revolutionise the way in which CMT patients are monitored both clinically, as well as in future trials involving new treatments.