Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life Standards, a Target Identification Collaboration

Background DM1 is a rare, inherited, progressive disease as well as an autosomal dominant multisystemic disorder. It is the most common adult form of muscular dystrophy, with a prevalence of approximately 10 per 100,000 people affected. With 733 million people in Europe, we estimate that 75,000 people are DM1 patients in Europe. Typical symptoms of the disease include progressive muscle weakness and wasting from distal to proximal, ptosis, weakness of facial, jaw and anterior neck muscles, myotonia, daytime sleepiness, fatigue and cataract. Other symptoms of adult DM1 include cardiac conduction defects, as well as endocrine, gastrointestinal and cognitive dysfunction. DM1 is one of the most variable human diseases, has complex, multisystemic and progressively worsening clinical manifestations and leads to severe physical impairment, restricted social participation and premature death.

There is no pharmaceutical treatment for causal or symptomatic relief of DM1 core symptoms (with the exception of Modafinil for excessive daytime sleepiness). Thus the aim of treatment is to relieve impairments, reduce limitations and optimise participation. Physical activity has been acknowledged as an important factor for health in general. For patients with a slowly progressive neuromuscular disease, such as DM1, there is accumulating evidence for prescribing low-to-moderate-intensity strength and aerobic exercise training, and an active lifestyle. Nevertheless, recent reviews conclude that existing studies are limited in number and quality, and that there is a need for disease-specific, randomised, controlled trials investigating the effect on quality of life.

RATIONALE FOR THE STUDY It was demonstrated recently by an OPTIMISTIC research partner that severe fatigue, defined as a score equal to or higher than 35 on the subscale fatigue of the Checklist Individual Strength (CIS-fatigue), was reported by around 70% of patients with DM1. These severely fatigued patients had more problems with physical and social functioning as well as with their mental and general health than similar patients without severe fatigue. They also had more problems with concentration and planning. As such, experienced fatigue should be clearly distinguished from muscle weakness, which is probably the most common and characteristic symptom of DM1 and also of a lack of initiative (apathy) that is known to occur often in DM1.

In a longitudinal study, we built a model of perpetuating factors for fatigue in patients with DM1. It appeared that lack of physical activity, sleep disturbances and pain all contributed to experienced fatigue. In addition, loss of muscle strength and pain contributed to fatigue through a lower level of physical activity. Ultimately, experienced fatigue and physical activity both contributed to the level of societal participation. A lack of initiative further increased fatigue but also had a direct negative effect on societal participation. Thus, theoretically, in order to improve societal participation one should compensate for a reduced initiative, optimise physical activity and alleviate experienced fatigue. To alleviate fatigue one should address the fatigue maintaining factors identified by the model, e.g. experience of pain or sleep disorders.

The main rationale for the combination of CBT and physical activity is based on our DM1-specific model. The DM1-specific model shows that physical activity, experienced fatigue and lack of initiative are the main determinants of DM1 health status. OPTIMISTIC is the first model-based clinical trial in DM1. It evaluates the effect, and the maintenance of effects, of CBT combined with exercise training on the reduction of chronic fatigue in patients with DM1.