CBT Improves Function, Reduces Fatigue in Muscular Dystrophy

Pauline Anderson

June 28, 2018

LISBON, Portugal — A new multicenter study shows that cognitive-behavioral therapy (CBT) decreases fatigue and improves physical activity and social participation in adults with myotonic muscular dystrophy type 1 (DM1) but was associated with an increased risk for falls.

"With no curative treatment and few symptomatic treatments, cognitive-behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1," the researchers, with lead author Kees Okkersen, MD, Department of Neurology, Radboud University Medical Centre, Nijmegen,  the Netherlands, conclude in their report.

Further, the results illustrate that European centers can collaborate, for a rare neuromuscular condition, on a randomized trial of CBT that mimics a drug trial, said senior study author Baziel van Engelen, MD, professor of Neuromuscular Disorders, Radboud University Medical Center.

The results were presented at the Congress of the European Academy of Neurology (EAN) 2018 and published online June 19 in Lancet Neurology.

European Collaboration

DM1 is the most common form of a dominantly transmitted muscular dystrophy. It leads to severe fatigue, impaired physical functioning, restricted social involvement, and early death, van Engelen told meeting delegates.

There's no cure for DM1 and symptomatic treatment options are limited, although studies have suggested that exercise may have some benefit, he said.

In addition to improving the health status of patients with DM1, the OPTIMISTIC (Observational Prolonged Trial In Myotonic dystrophy type 1 to Improve quality of life Standards, a Targeted Identification Collaboration) trial aimed to create a clinical infrastructure for European DM1 trials.

The trial was a collaboration among investigators at four neuromuscular referral centers in Paris, France; Munich, Germany; Nijmegen, the Netherlands; and Newcastle, United Kingdom.

Creating a European DM1 network requires databases or registries of potential participants and investigators who have worked together, said van Engelen.

"We also translated all the outcome parameters and CBT materials into the four languages, so we can really harmonize the CBT network in these four countries," he said.

The trial was similar in design to a clinical drug trial. "The time frame was comparable," as were outcome measures that were patient-oriented, said van Engelen. He added that the new study also involved monitoring side effects and was based on pilot studies, also akin to a clinical trial.  

One of the aims of the study was to prepare a DM1 "trial toolbox" to facilitate future drug trials, said van Engelen.

The main determinants of health status for patients with DM1 are fatigue, lack of initiative, sleep issues, and physical inactivity. It was these determinants that investigators hoped to address by using CBT, Okkersen told Medscape Medical News in a separate interview.

The study included patients with DM1 and their caregivers. The patients were able to walk independently and scored 35 or greater on the fatigue subscale of the Checklist Individualized Strength (CIS), and  so were "highly fatigued," said van Engelen.

Patients were randomly assigned to standard care plus CBT or to standard care alone.

Compensatory Goals

In the intervention group, patients received 10 to 14 sessions of patient-tailored CBT over 10 months. CBT involved establishing goals to compensate for reduced initiative and optimizing interactions with others. Such goals involved regulating sleep-wake patterns, physical activity, and changing pain behavior and beliefs as well as beliefs surrounding fatigue and the disease itself, said van Engelen.

All patients in the intervention group were provided with activity programs, and some opted to participate in additional training to further increase exercise capacity.

What "standard care" includes for patients with DM1 depends on the healthcare system in individual countries, said Okkersen.

"Usually, it means that one care provider — typically a rehabilitation specialist or neurologist — has regular follow-up with a patient and coordinates care by referring to other relevant specialties, for example, cardiology, pulmonology, physical therapy, and speech therapy."

Guidelines for DM1 management may differ between counties and may be nonexistent in some places, added Okkersen.

The 10-month outcome analysis included 120 in the intervention group and 122 in the standard care group. Van Engelen noted that the dropout rate was about 8%, which is similar to that in a clinical trial.

The primary outcome was the 10-month change from baseline in the patient-reported DM1-Activ-c scale. The score for this 25-item scale, which rates capacity for social participation and activity measures, ranges from 0 to 100.

This score in the CBT group increased from 61.22 at baseline to 63.92 after 10 months, while the score in the control group decreased from 63.00 to 60.79. The mean between-group difference was 3.27 points (95% confidence interval [CI], 0.93 - 5.62; P = .007).

This statistically significant finding was prolonged over 16 months. The analysis at 16 months included 114 patients in the CBT group and 111 in the standard care group.

A secondary endpoint was activity as measured by the 6-minute walk test (6MWT). On this test, the CBT group went from an average of 389.29 meters to 420.65 meters (an 8% change) while the increase in the control group was much smaller: 400.69 meters to 401.10 meters.

Here again, the results were prolonged to 16 months, said van Engelen. "So this was very supportive for our primary outcome."

Other secondary outcomes included measures of fatigue, daytime sleepiness, and number of hours of being active. These, too, were all positive for the intervention group.

Subgroup analyses showed that effects of CBT were "definitely not dependent on clinical site, on sex, on age, on additional graded exercise module, and not on muscular impairment status," said van Engelen. He added that even the involvement of caregivers did not affect the impact of CBT, which he found surprising.

Although exercise did not provide additional benefit, "we should be careful in interpreting this result, as a relatively small group of patients received graded exercise, so the statistical power was limited," commented Okkersen.

Just how CBT might improve fatigue and activity levels in these patients is unclear, but Okkersen said he and his colleagues are "working to gain insights" into such mechanisms. "This may be relevant to optimizing CBT in future studies and/or in clinical practice."

As for adverse events (AEs), there were more falls in the CBT group (5 vs 1 in the standard care group). "They are more active so they tend to fall, and that's something we have to keep in mind for the next study," commented van Engelen.

About 19% of patients in the CBT group and 15% in the standard care group had a serious AE, including falls. The most common were gastrointestinal and cardiac problems.

These effects were disease-related and expected, said Okkersen. "DM1 is a severe, multisystem disease, in which cardiac and gastrointestinal involvement is well-established."

However, he added, "the fact that serious adverse events were roughly similarly divided between the intervention and control groups is reassuring with regard to the safety of CBT."

Okkersen said this new study is important for many reasons.  "It's the first large, randomized trial in a rare genetic disease and it shows a beneficial effect."

It also validated outcome measures in DM1, established a European infrastructure for DM1 trials, and "targets a group of patients who could be considered relatively neglected," he said.

The researchers obtained blood samples from study patients and are investigating pathways possibly important to CBT-related improvements, said Okkersen. "We are in search of druggable targets."

CBT is widely available in most major European centers, said Okkersen. "It could be integrated into existing rehabilitation programs for myotonic dystrophy type 1, if combined with appropriate measures to prevent falls."

"Pivotal" Study

In a comment accompanying the publication in Lancet Neurology, Cynthia Gagnon, MD, Université de Sherbrooke, Sherbrooke, Quebec, Canada, and colleagues call this a "pivotal" study "because it provides new information about a potential treatment to enhance perceived capability for activity and participation in this patient population."

A "key question" that needs to be addressed if CBT is to be implemented for these patients in clinical practice, they write, would be to determine the mechanism of its effects, "given the pattern of cognitive impairments typical of myotonic dystrophy type 1 that might impede the therapeutic process (eg, absence of awareness, memory deficits, and dysexecutive syndrome, including poor planning skills)."

They point out that the study design didn't include formal assessment of whether CBT counseling was "duly implemented" in patients' daily routines, which could help substantiate behavioural changes.

"Additionally, the effect of cognitive behavioural therapy was not proven beyond any reasonable doubt, because minimal detectable changes and minimal clinically important differences in primary and secondary endpoints that could help to further justify the implementation of this intervention were not estimated," they write. "However, the decrease in fatigue and increase in accelerometry based activity are supportive of the positive effects of cognitive behavioural therapy."

They say that "additional well done research studies are needed because there are no curative treatments and few symptomatic treatments available for myotonic dystrophy type 1."

"Notwithstanding some methodological shortcomings, including the absence of pulmonary function testing that would help to gauge the ability of participants to be active, this study sets an example for future trials to implement cognitive behavioural therapy for patients with myotonic dystrophy type 1," Gagnon and colleagues conclude.

"Importantly, this research endeavor clearly supports trial readiness among the European community with regards to patients' engagement toward clinical trials, recruitment and retention capacities, and proven collaboration between four major clinical and research centres."

The study received funding from the European Union Seventh Framework Programme. van Engelen, Okkersen and the editorialists have disclosed no relevant financial relationships.

Congress of the European Academy of Neurology (EAN) 2018. Presented at the Plenary Symposium: Highlights and Breaking News session, June 19, 2018.

Lancet Neurol. Published online June 19, 2018. Abstract, Comment

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