206th ENMC International Workshop: Care for a novel group of patients – adults with Duchenne muscular dystrophy Naarden, The Netherlands, 23–25 May 2014

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Workshop report

206th ENMC International Workshop: Care for a novel group of patients – adults with Duchenne muscular dystrophy Naarden, The Netherlands, 23–25 May 2014 Jes Rahbek a,*, Birgit F. Steffensen a, Kate Bushby b, Imelda J.M. de Groot c a

The National Rehabilitation Centre for Neuromuscular Diseases, Aarhus, Denmark b Newcastle University, Newcastle upon Tyne, UK c Radboud University Medical Centre, Nijmegen, The Netherlands Received 6 May 2015

1. Introduction The 206th ENMC International Workshop, “Care for a novel group of patients – adults with Duchenne muscular dystrophy (DMD)” [1] was held in Naarden on May 23–25, 2014 and was attended by 28 representatives from Belgium, Canada, Denmark, France, Germany, The Netherlands, the UK and the USA. The overall aim of the workshop was to evaluate existing knowledge, and determine the gaps in knowledge on observed clinical aspects for adults with DMD. This would allow the creation of care standards for adults with DMD, following on from the international guidelines on best practice care for DMD, The Diagnosis and Management of Duchenne Muscular Dystrophy [2]. The objectives were to 1) list existing knowledge of physical and psychological aspects and their management as presented by experienced clinicians; 2) discuss organizational solutions to care in the transitional and advanced stages of the disease; 3) establish a task force group with representatives from different medical and care specialities to continue the work on developing care standards. 2. Description of problems and personal solutions Kate Bushby (Newcastle University, UK) began the workshop with an update on the work in progress in the United States and Europe on revising and defining standards of care for DMD.

* Corresponding author. The National Centre for Neuromuscular Diseases, Kongsvang Allé 23, 8000 Aarhus C, Denmark. Tel.: +45 22 65 24 44; fax: +45 8948 2212. E-mail address: [email protected] (J. Rahbek).

The existing care standards [2] focus on the child and young adult with DMD in the ambulatory and non-ambulatory stages of the condition, and contain very little information on transition to adult care and management of complications in adult life. 2.1. Living with DMD as an adult Peter Mikkelsen is 32 years old and lives in his own apartment in Copenhagen, Denmark. He has a BA in Danish literature and media studies and is a certified systemic coach at senior practitioner level. Since 2005, he has worked as a lecturer and taught Sexology and Disability to medical students at the University of Copenhagen. He uses invasive ventilation via a tracheostomy. Peter Mikkelsen talked about the types of problems he had encountered during adulthood: the physical and bodily issues which have made it difficult for him to carry out normal but significant activities such as writing, drawing, singing and steering his wheelchair; impairment effects such as lacking time because daily activities are extremely time-consuming; how his social life sometimes suffers leading to isolation and loneliness; about the prejudice that because you have DMD, you have a low IQ, or you are treated as the eternal child who has no sexual desires. He talked about the need for a sex and love life, about how it is possible to satisfy oneself with sex toys, and the importance of feeling cared for by friends and family. In his experience, local and regional differences too often set the standard for social welfare and treatment options, and access to education and cultural events. Peter Mikkelsen described two coping strategies that he uses: inward personal work with mental and social challenges, and outward political activism directed towards material and cultural boundaries.

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He said that the prerequisite for a good life is that one’s basic needs are met. To him, this means having the right invasive respiratory equipment, personal assistance around the clock, an adapted powered wheelchair, being able to use a computer, tablet and smart phone, having access to sex toys and general assistive devices, being able to get around in a customized van and living independently in his own apartment. Jon Hastie is 33 years old and lives in West Sussex in the UK. He holds a PhD in Government and is a documentary filmmaker having raised money and made a film about six men living with DMD. He is also co-founder of DMD Pathfinders, a user-led charity and network for teenagers and adults with DMD in the UK. He is involved with the British patient organizations MDUK and Action Duchenne, and works as a consultancy officer on how to make homes more accessible for disabled people. He uses mask ventilation 23 hours a day. Jon Hastie talked about the barriers and opportunities he had experienced in his extended transition to independent living. He now lives in his own flat and has a multi-agency care package with eight personal assistants which he manages on his own, but in order to get this far he has had to engage in a protracted fight with the system. To get the help he needs, he has been forced to apply for funding in several different places and there has been very little information or help with the process. He has also experienced a lack of information concerning specific medical options such as invasive ventilation. In 2014, Jon co-founded a new charity, DMD Pathfinders, with seven other adults with the condition. His wish list for this charity includes better advice and advocacy services; an employment and volunteering service; more R&D in assistive technology; and a campaign and awareness-raising team. He would like to see more peer advocacy groups across the world and, finally, a cultural shift in the medical world where providers start recognizing that adults with DMD are the experts. To challenge care inequalities in the different parts of the UK, he would like to see increased awareness of best practice and standards of care as many patients still have poor access to specialist care; people who live close to a centre are much better off than those who live further away. Care should be integrated and streamlined at centralized care units instead of being spread across many different hospitals, and it should be available for everybody. In conclusion, he said that if support for people living with DMD is to be improved, it must start with a cultural shift towards seeing those living with DMD as experts by experience, and a move towards greater patient involvement and collaboration in the provision of advice and support. 2.2. Transition from young to adult care Jan Verschuuren (Leiden University Medical Centre, The Netherlands) began his presentation by asking the question ‘Why do we need transition? Child neurologists have so much experience!’ Although it is clear that a continuation of care by the same group of professionals would be ideal and solve many of the

current problems involved with transfer of care from one group of professionals to another, this does not seem realistic at the moment. Several hurdles may stand in the way of successful transition. These include parents who, due to their child’s chronic condition, tend to be overprotective thus preventing the development of independent behaviour in the child, and the young man who finds it difficult to voice his own needs when transferred to adult care. Another complicating factor is that this adult group of men living with DMD is new to most medical specialists, and knowledge about the disease in adults is not routinely available. Finally, the adult healthcare system struggles to coordinate DMD care in line with multidisciplinary best practice as it involves a number of specialists in different areas: neurologist, pulmonologist, cardiologist and preferably a rehabilitation specialist. Successful transition calls for coordination and communication between the patient and his family, the various specialists, and, if possible, a multidisciplinary team at the hospital, and specialists outside the medical centre. To ensure successful transition the following should be available: an organizing and communications coordinator; adequate rooms and facilities to welcome the patient; a multidisciplinary team with physicians and paramedical personnel; preparation of patient and parents for differences in healthcare settings and new roles and responsibilities; transfer of information from paediatric team to adult team; a protocol for communication with the GP and other providers outside the multidisciplinary team and outside the hospital; a standardized letter to inform other medical personnel; social support for education, daily activities, accommodation, and support for the parents in their new role; tools and personnel for standardized follow-up, and regular meetings and workshops to secure the training of medical personnel and enable exchange of ideas and expertise. 2.3. Training and education of adult providers to care for adults with DMD Kathi Kinnett (Parent Project Muscular Dystrophy, USA) pointed out that one of the barriers to finding adult providers for DMD is a paucity of training programmes for adult primary care providers. Adults with DMD are difficult patients for providers to care for; they are a new population that only few providers know about and they require complicated multisystem management. They deal with the same issues as younger boys with DMD plus a number of adult issues that are unknown or not yet described. A major issue for patients and providers alike is that appropriate local providers are hard to find and patients must either stay with the paediatric provider or deal with fragmented care. The questions are: who needs to be educated and where is the medical home? Is it with the primary carer or the specialist? Criteria for successful adult care are: that providers are specialists in DMD; that they are able to help patients plan for the future early on; that they are aware that managed care

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demands time and dedication to coordinating primary care; that they acknowledge that the patient is the expert in his own care. Patients, on the other hand, must feel confident about the care provided, must have had the right care during adolescence if care in adulthood is going to be satisfactory, and must be willing to make their own care decisions. Ideally, adult care for DMD should be a multidisciplinary approach with coordinated appointments and care ensuring communication with patient, primary care provider and other specialists. 2.3.1. Discussion and focus areas Is transition to adult care really necessary? Should patients remain with paediatricians or should the paediatrician’s care overlap to make a “soft” transition? It was agreed that • Some form of transition must take place, as it is not only about going from child to adult care but also becoming an adult with social implications; • A facility where patients are followed from childhood to adulthood could be a solution; • Support for parents to allow their children to partake in decisions and support for boys in making independent decisions are important aspects of transition. The health system could act as a role model in this by allowing young patients to be alone with their providers; • Best practice experiences from other diseases (e.g. congenital heart disease and ALS) should be collected and applied in educating adult neurologists/rehabilitation specialists and setting up teams for DMD; • Expectations of the individual patient to manage his own care and life with DMD must be raised, and during adolescence parents should be supported to accept “letting go”. • National initiatives could include lobbying to raise the importance of this care. The two men with DMD said that an all-round coordinator who would not only help coordinate medical care but also help with other aspects of life would be preferred. 3. Epidemiology: the natural history of DMD above the age of 18

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less likely to receive care according to care recommendations due to differences in healthcare systems and financial resources in the participating countries. 3.2. Causes of death and ages of survival in DMD. What is the care status? Shree Pandya (University of Rochester, USA) reported data from a multicentre study (MD STARnet) on the sociodemographic profile and health related outcomes for adults with Duchenne or Becker muscular dystrophy [4]. Among 384 patients born from January 1982 to December 1992, 32% have died (mean age 17.6 y) and 20% were lost to follow-up. Causes of death were not available for all individuals. Mean age for remaining patients were 21.5 y (17–28.6). 158 patients received or had received non-invasive ventilation (NIV), 46 patients were on invasive ventilation. 188 patients had developed cardiomyopathy and 58 had received percutaneous gastrostomy for feeding. Steroids were started in 188 patients and discontinued in 134 patients, mostly at the time of loss of ambulation (mean 11.6 years). 98% lived with their parents or family and only 24% had completed post high school education. The data helped to identify needs, e.g. to prepare patients for employment and independent living, and to provide funding for care and assistance so the burden on families is reduced. Birgit Steffensen (Danish Rehabilitation Centre for Neuromuscular Diseases) presented data from a longitudinal study on 53 steroid-naïve patients with DMD born in the period 1983–1992 [5]. 35 patients from the cohort are still alive (aged 22–31 years); 18 died (aged 15–30). Patients were ventilated by NIV (29/53) or IV (33/53). Causes of death were mainly cardiac failure, either as the only cause (n = 8), or as combined with an infection (n = 6), constipation (n = 2), a bleeding gastric ulcer (n = 1) or a ruptured stomach (n = 1). All but two patients received cardiac treatment. The study indicates that – after assisted ventilation has been implemented as standard treatment – death caused by respiratory problems is seldom but death caused by cardiac failure, often in connection with infections or abdominal problems, has become frequent.

3.1. Age distribution and care of adult patients with DMD in Europe

3.3. The natural histories of respiratory, cardiac and motor abilities of adults with DMD who grew up during different decades: with and without steroid treatment

Jan Kirschner (University Medical Center Freiburg, Germany) described the findings from the CARE-NMD project, a questionnaire survey on care and quality of life carried out among 1062 patients within seven European countries in 2011–13 [3]. 17% of the patients were ≥18 years old; 45% of the patients were in the late non-ambulatory stage. Most patients attended a neuromuscular centre; the majority of those who did not attend a centre were adults, and nonattendance was mostly due to distance. A large proportion of adults with DMD did not receive physiotherapy. Not all countries could provide ventilation support. There was a significant correlation between distance and level of care and between level of care and quality of life. Adults with DMD were

Ros Quinlivan (National Hospital for Neurology and Neurosurgery, United Kingdom) discussed the changing natural history of DMD and a growing population of adults living with the condition. Survival has increased as a consequence of improved management of cardiac and pulmonary complications. There are now different populations of DMD adults with different medical treatments (steroid naïve, daily/intermittent treatment, type and onset of treatment). Cohort studies have shown that corticosteroids preserve respiratory and cardiac functions and reduce incidence of scoliosis requiring surgery [6–10]. Audit data from the NHNN population of 57 adult DMD patients seen between 2010 and 2014 show that three steroid-naïve

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patients had died at the mean age 19.5 years (cardiac; respiratory failure; thyrotoxic crisis). Among the remaining 54 patients (aged 17–37), 36 were treated with steroids, with duration of treatment between 6 months and more than 10 years. 16 were still on steroid treatment at the time of the audit, two of whom were still ambulant (aged 18 and 21 years) and upper limb function was preserved in the steroid treated group. Limb fractures had occurred in 15 patients, 13 of whom were on steroids. 3/54 steroid-naïve patients had painful hip subluxation. 19/54 patients had required spinal surgery. Respiratory function was preserved in the steroid treated patients with a mean FVC of 2.11 litres and of the 22/54 who were on NIV only one had received steroid treatment and that was for 6 months only. One patient who had a tracheostomy was steroid naïve as were the 2/54 patients on full-time non-invasive ventilation. 46/54 were on ACE inhibitors and beta blockers for cardiomyopathy, but left ventricular ejection fraction was greater in the steroid treated cohort. Bladder and bowel problems were present only in the steroid-naïve patients and included: constipation, abdominal pain, bloating and episodes of pseudo-obstruction (n = 16), anal fissure (n = 2), sigmoid volvulus requiring bowel resection (n = 1), urinary frequency and/or incontinence (n = 2), and renal calculi (n = 2). Awareness of dehydration and renal failure is important in this group. 3/54 patients had type 2 diabetes (2 of whom were steroid naïve), and 3/54 patients had epilepsy. One patient with severe cardiomyopathy had an embolic cerebrovascular accident and another died from a cardiac arrhythmia caused by thyrotoxic crisis. Other challenges for the adult DMD patients were social isolation, depression and anxiety requiring psychological input. The various sequelae represent a major challenge for the adult DMD patient, and inappropriate handling of secondary symptoms may be fatal. Furthermore, many patients complained of fragmentation of care across multiple specialist services with no clear first point of access, and had great difficulty attending outpatient clinics due to fatigue and transportation difficulties. To overcome this, NHNN has recently opened a neuromuscular complex care centre (NMCCC), which aims to ‘wrap care’ around the patient. Adults with DMD are admitted electively for 2–3 nights into a purpose-built adapted unit where they can see all of the relevant specialists and therapists necessary to provide the full complement of multi-disciplinary care as outlined in the DMD care standards [2,11]. An advantage of this approach is that not only is it more convenient for the patient but it also provides opportunities for socializing. 3.3.1. Discussion and focus areas Neuromuscular centres with coordinated, patient-centred care would be preferred. Patients are partners for care decisions. In places where distances to such centres are long, engaging the general practitioner (GP) might be a solution as distance is often a barrier to getting the right care. GPs should also be involved in emergency care, and guidelines on emergency care should be integrated in the standard of care document. • A shift is needed from seeing DMD as a childhood disease to seeing it as a childhood onset chronic disease.

• The guidelines should contain a clear statement that planning for adulthood must start from the time of diagnosis. • Adult care must be addressed systematically with a multidisciplinary attitude. • Examples of best practice could be collected and disseminated. 4. Medical treatment (corticosteroids and heart medicine) 4.1. Effect of treatment with steroids, including their side effects Douglas Biggar (University of Toronto, Canada) talked about corticosteroids (CS) as a standard treatment for boys with DMD. Most clinicians would agree that daily CS have the greatest benefits if the side effects can be managed and/or tolerated, but more than 30 different protocols for administering CS make it almost impossible to compare studies. The longterm benefits include prolonged ambulation, preserved cardiac and pulmonary function, reduced need for scoliosis surgery and preserved independence for self-feeding. With preserved pulmonary function and a stronger cough, night time hypoventilation and the need for BiPAP are delayed, and there are fewer admissions to hospital for treatment of pneumonia. Steroid-related long-term side effects such as weight gain, growth suppression and delayed puberty, osteoporosis, hypertension and cataract should be monitored and addressed. Despite these side effects, benefits of chronic steroid treatment generally outweigh the risks [7]. Corticosteroid treatment should be continued after loss of ambulation. Nathalie Goemans (University Hospital Leuven Gasthuisberg, Belgium) stressed that most studies are carried out on cohorts under the age of 18, which means there is a lack of studies on side effects in adult patients. Contrary to benefits, side effects seem smaller in intermittent corticosteroids compared to daily corticosteroids. Side effects range from hypertension, hyperactivity, decreased height, weight gain and cataracts to vertebral fractures. Fractures of long leg bones are 25% whether or not steroid-treated. Data [12] from her group of 30 adult patients showed that five were steroid naïve, six had less than 3 years of steroid treatment and 19 patients more than 3 years. 14/19 patients (aged 18–26) had been on steroids (Deflazacort) for 12.8 years (9–16), mean dosage was 24.5 mg/d. Side effects were steroid aspects (78%), symptomatic vertebral fractures (21%), cataract surgery (14%), and scoliosis surgery (7%). There were no reports on behavioural issues, major GI symptoms, hypertension (all were on ACE inhibitors) or severe medical events related to steroid use. Interruption of steroid treatment in early adolescence was mostly due to the effects steroids had on appearance. Areas of concern in adults are endocrine status, bone lipid and glucose metabolism, cataract and gastrointestinal problems. 4.1.1. Discussion and focus areas Several benefits have been reported with continued use of corticosteroids after cessation of ambulation. Preservation of arm and hand function, FVC, and cardiac function are some of the long-term benefits, as are the prevention of scoliosis and delay in NIV. The participants discussed whether CS treatment

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could benefit adult steroid-naïve non-ambulant patients. Kate Bushby pointed out that there is very limited evidence for benefits in starting steroids in older patients; furthermore, the side effects profile may be different in older patients such as vulnerability of the stomach and GI tract. There is a need for cohort studies and assessment methods that are adequately sensitive to measure adult patients with limited strength and physical function. • The profile of steroids in the care considerations for adults must be increased. Doses in adults are not based on scientific evidence. • The use of steroids should not stop at loss of ambulation: this recommendation should be strengthened. • Natural history studies in older patients should be systematic to highlight new areas of concern. • Guidelines for adult patients must stress the need for continued and comprehensive monitoring. 4.2. Cardiomyopathy in the adult person with DMD, cardiac treatment including management of side effects John Bourke (Freeman Hospital & Newcastle University, UK) talked about cardiac dystrophinopathy, typically beginning with regional left ventricular systolic dysfunction in the postero-basal or lateral-basal segments of the left ventricle. Natural history studies have shown that, once detectable, heart involvement progresses relentlessly if untreated. Heart failure symptoms do not occur, however, until LV-ejection fraction is 10–15%. The course of cardiac dystrophinopathy can crudely be divided into three phases: 1. Phase of damage and excessive repair, during which cardiac myocytes are lost, repair mechanisms are overwhelmed and fibrosis begins (‘molecular biological’ phase); 2. Surveillance and intervention phase, when left ventricular impairment becomes evident objectively in the absence of symptoms (asymptomatic phase); 3. End-stage with the onset of symptoms or risk of ventricular arrhythmias. Sudden death is still seen even in patients receiving appropriate follow-ups and is thought to be mainly cardiac. The possibility of coagulation abnormalities (deep venous thrombosis and pulmonary emboli) is possibly under-recognized. Although many therapies are already available that may modify the course of cardiomyopathy in DMD, the evidence for individual drugs is more anecdotal than definitive. The goals of treatment can roughly be divided according to the three phases outlined. Disease modifying interventions, if effective, are likely to play the greatest role in reducing the degree/rate of cardiac myocyte loss and so preserve heart pump function long-term. However, it cannot be assumed that approaches which preserve skeletal muscle function will also invariably benefit the heart. Steroids have a positive effect despite of all the reservations and cause fewer heart failure related deaths. At the end-stage, the addition of loop-diuretics to other therapies improves

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symptoms. This is also the phase when left ventricular assist devices or cardiac transplantation may have a role in DMD. Patients with severely reduced left ventricular function (LVEF ≤ 35%) are at risk of ventricular tachyarrhythmias. Implantable cardioverter-defibrillators are increasingly discussed with adult DMD patients, whose quality-of-life is good. However, the effect ICDs or LV-assist devices on qualityof-life in adult DMD patients has yet to be determined and few are eligible for cardiac transplantation. Best management of DMD-cardiomyopathy is likely to require the use of various drugs deployed sequentially or in combinations in relation to what is happening at a cellular/ molecular biological tissue level. Achieving this is unlikely to simply mean that ‘more is always better’ and maximizing benefits without incurring adverse effects or increasing treatment burden remains a major challenge [8,9]. 4.2.1. Discussion and focus areas Too many patients are not being treated according to the care standards, and therapy initiated in adults cannot make up for treatments that should have been started at an earlier age. Adherence to current guidelines would be an achievement in the adult population based on registry and natural history studies, and would be expected to be advantageous as a first step. The participants agreed that patients should be given information early on, and therapy options should be openly discussed with the patients, including uncertainties. Experiences from treatment with left ventricular assist devices and transplantation are starting to accumulate, and implantable defibrillator treatment should be discussed including its impact on quality of life in DMD. • Guidelines for adult patients with DMD must stress continuation of comprehensive monitoring. • Cardiac treatment should also be reinforced in the guidelines. • A registry of DMD patient experiences, ICD and sudden cardiac death should be promoted. 5. Respiratory treatment 5.1. Non-invasive and invasive assisted ventilation Ole Nørregaard (Danish Respiratory Centre West, AUH, Denmark) and Michel Toussaint (Rehabilitation Hospital Inkendaal, Belgium) talked about the restrictive respiratory insufficiency that systematically occurs in adolescents and young adults with DMD. The guidelines on DMD recommend annual measurements of awake end-tidal CO2 levels by capnography in non-ambulant patients who have suspected hypoventilation, FVC < 50%, and predicted and/or current use of assisted ventilation. Advanced respiratory insufficiency is often associated with weight loss. Since respiration is most vulnerable during sleep, the first signs of respiratory insufficiency will often be sleep related symptoms, and Ole Nørregaard recommended that cardiopulmonary monitoring or polysomnography (PSG) be used for standard assessment when respiratory insufficiency occurs. PSG provides data on sleep quality which is often compromised during hypercapnic respiratory insufficiency.

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When nocturnal hypercapnia occurs, non-invasive ventilation (NIV) via positive air pressure on a nasal or full face mask at night is recommended. At night, NIV increases nocturnal gas exchange, and during the day, it may improve ventilatory function as a result of increased pulmonary compliance and the resetting of sensitivity in respiratory centres. There is increasing evidence for the benefits of ventilation/ventilator support, including reduction in pulmonary death [13–17]. There are no clear indications of when to switch to daytime ventilation or of the benefits of switching from non-invasive ventilation to ventilation via a tracheostomy (IV). However, signs of respiratory fatigue such as dyspnoea and excessive weight loss may be sufficient reasons to initiate daytime ventilation, although it is recommended to document daytime hypoventilation using pulse oximetry and CO2-measurements (typically end-tidal or transcutaneous techniques). Pulse oximetry and capnography are normally used for patients with elevated diurnal laboured breathing suffering from dyspnoea who need additional ventilator support during daytime. In Denmark, IV is suggested when the patient requires respiratory support for more than typically 12–16 hours per day, when non-invasive ventilation can no longer sustain acceptable oxygenation, and when secretions in the airways become a problem. Invasive ventilation may be administered via pressuretargeted ventilators; however, volume-targeted devices are used most frequently, usually via an uncuffed or fenestrated tube in order to preserve the ability to speak. In Denmark, laymen helpers are trained as assistants so that the adult ventilator user can live an independent life. Michel Toussaint recommended the use of full time volume cycled NIV in combination with a nasal mask during the night and a mouthpiece during the day; however, tracheostomy may be provided when mechanical cough-assistance techniques are ineffective in treating chronic cough insufficiency. Central and peripheral airway clearance techniques are recommended as treatment for infections and swallowing troubles. A simple kind of inspiratory aid such as breath-stacking via either Ambu-bag or ventilator improves the coughing ability in all DMD patients; simple manual chest compression (MAC) may be ineffective as an expiratory aid in patients with maximal expiratory pressure (MEP) > 34 cmH2O [18]. In very weak patients (vital capacity < 500 ml, MEP < 15 cmH2O), the use of a mechanical insufflation– exsufflation device is recommended [19]. Peripheral airway clearance may be achieved by intrapulmonary percussive ventilation in patients who have difficulty in mobilizing secretions or have persistent atelectasis.

5.1.1. Discussion and focus areas The experience of initiation of ventilation is still not uniform in different patient groups, and it is unclear whether progression of respiratory problems and sleep apnoea is the same in steroidnaïve and steroid treated patients. Choice of mode of ventilation and interface is not fully described across increasing need for ventilation, and clinics may not always be flexible in interfaces

offered. The patients report that it is difficult to get unbiased information and that more ongoing support during the period of transition from night-time to fulltime ventilation is needed. Guidance on risks and benefits of NIV and IV, use of Cough Assist, etc. should be improved, and type of ventilation should be tailored to each patient. Cardiac and respiratory treatment should be seen together to optimize survival and Quality of Life. • Requirement for nocturnal monitoring should be considered in the guidelines. • Guidelines should list the various options for NIV and IV, not recommend one or the other. • Patient information on respiratory therapy options must be improved. • Requirements should include recommendations for minimum monitoring and guidelines should be reinforced for better adherence. • Need for studies on Natural History to collect and compare patient experiences and outcomes

5.2. Oro-facial problems 5.2.1. Mouth and upper airway problems: macroglossia, difficulties in chewing and speaking, mal-occlusion of teeth Imelda de Groot (Radboud University Medical Centre, Nijmegen, The Netherlands) presented a study on changes in craniofacial morphology during the course of the disease [20,21]. Craniofacial growth is influenced by age and stage of the disease as is the growth of the mandible: in controls, mandibular growth is straight downward and forward; in boys with DMD, growth was downward until 16 years and after that a forward growth factor was noticed, as was an increase in the width of the maxillary and mandibular arches, especially posterior, and a significant decrease of bite force compared with healthy controls, and a reduction of active mouth opening with a significant reduction in late non ambulatory stage. Malocclusions were frequent, and the boys reported problems with swallowing thick liquids, hard and dry food, choking while swallowing, delayed start of swallowing, sticking food, and increased time to eat a meal. Ultrasound studies of the masseter muscle in DMD (6–20 years) showed no significant difference in thickness compared to controls, but showed that the masseter had a poorer structure quality in the elder non-ambulant controls [22]. Another study of 24 patients with DMD described a relation between maximum tongue pressure and the range of the hyoid bone excursion on VFSS. Also, negative correlation with the width and depth of the palate with tongue pressure in 11 patients with DMD was described [23]. A study by means of quantitative ultrasound of the oral muscles, sEMG, anterior tongue pressure, and videofluoroscopic swallowing (VFSS) showed progressive involvement of the muscles and swallowing problems with the first sign in the geniohyoid muscle during the ambulatory phase (ultrasound), tongue hypertrophy during the early and late non-ambulatory phase (ultrasound), increasing problems with solid food (VFSS), progressive decrease in tongue

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pressure, and lowest sEMG measurements in late nonambulatory phase [24]. A study on the feasibility of training masticatory function by means of chewing gum showed positive results [25]. Elizabeth Vroom (United Parent Project Muscular Dystrophy, The Netherlands) described how malocclusion of teeth can contribute to poor nutrition and how it can be prevented by avoiding mouth breathing and keeping the tongue in. Exercising with chewing gum has shown positive results. Partial glossectomy, where part of the tongue is removed, is not recommended. It is still possible to treat unrelated orthodontic problems, but treatment of overjet and overbite should be given careful consideration. As for the benefit/risk of third molar extraction, indications have changed a lot over the years; 9 out of 10 times it is not really needed. Ventilation is recommended during dental interventions but more studies on different interfaces are needed. 5.2.2. Orofacial impairment Birgit Steffensen (The Danish Rehabilitation Centre for Neuromuscular Diseases) presented the results of a Danish survey on self-reported orofacial problems among patients with DMD [unpublished data]. A questionnaire on problems with eating, speaking, facial and tongue movements, changes of tongue and teeth was sent to patients with DMD above 10 years (n = 139). The response rate was 73% and the responders were 11–49 years old. On the question: “For how long can you speak before you get tired or less clear?” approximately 50% aged 20–40 years said they could speak for less than 30 minutes. On the question: “Do people understand you when you speak to them on the phone?” 15% responded “not always”, “seldom” or “never”; 83% of the responders had never had any speech training. When asked to rate their speech problems on a scale from 0 to 10 it became clear that speech problems increased with age and that 10% of those indicating it was a problem were below 20 years of age. 5.2.2.1. Discussion and focus areas. Jon Hastie pointed out that being unable to open the mouth widely enough is a frequently reported problem on Pathfinders. The guidelines should include speech issues and their effect on social life and quality of life, and should emphasize the importance of being referred to a speech therapist. Speech therapy is already in the existing guidelines but many patients are not referred. Guidelines should also include recommendations on food adjustment from solid to semi liquid and flushing with liquid. Studies and data are needed in the following areas: • Stretching to improve mouth opening • Chewing and swallowing. A swallowing questionnaire (reference) has recently been validated in DMD that could be used. • Dental problems/malocclusion • Steroids and their impact on tongue size • Ventilator use during dental procedures and use of different interfaces

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6. Endocrine aspects and nutrition in the adult with DMD 6.1. Gastrointestinal problems in DMD Jes Rahbek (The Danish Rehabilitation Centre for Neuromuscular Diseases) described what seems to be a much overlooked problem in adult men with DMD: almost all adult DMD patients above 25–30 years of age registered with the Danish Rehabilitation Centre for Neuromuscular Diseases report bowel and bladder problems, notably problems with constipation. Several studies show that dystrophin can be found in the smooth muscles and there is evidence for functional smooth muscular impairment in boys and men with DMD [26]. With the increase in age, many of them experience gastrointestinal symptoms which several studies have confirmed [12,27–30]. The reason for this can be ascribed to functional dysfunction such as delayed gastric emptying, intestinal paresis, oropharyngeal weakness and dysphagia. The condition calls for preventive measures and pharmacological interventions to avoid gastroesophageal reflux and constipation. In addition to the functional smooth muscle impairment, a number of competitive factors add to the increase of gastrointestinal symptoms such as immobilization, lack of exercise, lack of time to eat and drink, reluctance to drink to avoid frequent visits to the toilet, lack of help for everyday routines, treatment of constipation and diarrhoea and lack of knowledge of possible treatments [31]. 6.1.1. Discussion and focus areas Peter Mikkelsen and Jon Hastie had both experienced gastrointestinal problems and said that to their knowledge, this is common among men with DMD. Colon massage can relieve the problem somewhat but they both have to take additional medication as well. Studies show that the problem is not agerelated and that smooth muscle involvement in early age is important. • More information and evidence of the size of the problem is needed: not many patients talk about it. • GI specialists should be urged to take an interest in the area. GPs and Home health nurses should be taught to take responsibility for the problem. • A natural history study of gastrointestinal problems in adults is needed along with a study of the younger population. • The guidelines should emphasize the need for drinking plenty of liquid. 6.2. Bone health issues Nathalie Goemans (University Hospitals Leuven, Belgium) talked about skin and bone problems and osteoporosis. Bone mineral density is typically reduced in boys with DMD even before steroid use, and is associated with an increased risk of limb fractures. Maintenance of optimal bone health is of vital importance to patients with DMD, and Nathalie Goemans suggested that the revised guidelines contain information on

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prevention and treatment based on general knowledge. We know that calcium supplements are effective as are Vitamin D supplements, and that bisphosphonates increase bone mineral density; whether they can reduce vertebral fractures has yet to be proven. Intravenous bisphosphonate therapy has been associated with improvements. Teriparatide has proven effective in increasing bone mineral density and reducing fractures. 6.2.1. Discussion and focus areas Guidelines should emphasize the use of calcium and vitamin D supplements to keep vitamin D levels high. The current recommendations of following steroid treated patients with DXA scanning annually were questioned by more clinicians present who said they do not use them. More evidence is needed for regular DXA. Skin problems such as pressure sores from sitting and lying, and from using NIV with a mask, are common in adults with DMD and should be highlighted in the guidelines. The problem can be relieved by regular positional change, provision of the right type of mattress, etc. and often depends on the level of care received. Pressure sores from a ventilator mask can be avoided by changing or adapting the interface. There is a lack of clear guidance on bone health in long-term steroid treated adults. More data are needed on: • Bone mineral density in adults with DMD • The effect of bisphosphonates • The effect of testosterone and growth hormone on BMD 6.3. Nutrition and tube feeding Kathi Kinnett (Parent Project Muscular Dystrophy, USA) pointed out that evaluation and maintenance of a healthy nutritional state is of paramount importance to the overall health of boys and men living with Duchenne. Bioelectrical impedance analysis (BIA) is possibly a good method to assess nutritional status, as it is non-invasive, cheap and easy to use, and could be discussed in the adult guidelines. We know that a gastric tube is a potential intervention for managing undernutrition, swallowing disorders, dysphagia, and aspiration. The possibility of placing of a gastric tube should be discussed early on with parents, rather than in an emergency situation when swallowing problems have developed and when respiratory, body weight loss or under-nutrition have become issues. 6.3.1. Discussion and focus areas The true caloric need in DMD is not really understood but we know that nutrition is closely linked with respiratory and cardiac function and needs to be evaluated holistically. Patients report that gastric tubes are well tolerated, but we need evidence identifying appropriate indications for tube placement. The adult guidelines should emphasize: • Eating a healthy diet and the potential benefits of high calorie or protein supplements. • Access to a specialist dietician.

• Surveillance and management of both weight (overweight/ obesity and underweight) and nutrition. 7. Motor function and activity in the adult with DMD Muscle weakness in the upper limbs starts in the ambulant child and follows a progressive proximal to distal pattern leaving the adult patient with very little muscle strength – if any – in his fingers and minimal upper limb function. Adults with DMD have very impaired upper limb function and it is thus very difficult to measure. Laurent Servais presented data on his work in developing and validating a new tool for evaluation of distal arm and hand function in nonambulant patients with DMD [32,33]. The MyoPinch, MyoGrip and MOVIPLATE are capable of measuring strength in extremely weak patients and can be used in adult patients. The tools made it possible to notice a significant one-year change in a population of 34 non-ambulant patients. In his clinic, Laurent Servais uses the tools before and after onset of steroid treatment. Ulla Werlauff (The Danish Rehabilitation Centre for Neuromuscular Diseases) presented data on upper limb function and sitting ability in a Danish cohort of 77 steroidnaïve men with DMD (18–46 years) [34]. 68 patients had sufficient hand function to drive their power wheelchair. The steering technique was age dependent and ranged from normal joystick to lightweight joystick to scanner driving. All patients could maintain a supported sitting position in their power wheelchair and nine patients could also maintain a sitting balance outside their wheelchair; 69 patients needed a permanent or intermittent headrest when sitting in their wheelchair. Pain due to sitting position was common. 7.1. Discussion and focus areas Upper limb function including hand function is critical for QoL and social life since the patient relies on this function in many daily activities, such as the ability to operate his wheelchair, computer and smart home technologies. Cold extremities may affect the upper limb function, and patients report significantly poorer hand function in cold weather. Optimal seating and power wheelchair controls are essential prerequisites for maximizing the use of residual muscle strength in the adult man with DMD. Sitting balance and contractures are important to address, but the CARE-NMD study found that access to professional physiotherapy among adults is highly variable and severely constrained in some countries [3]. It was agreed that the guidelines for children should apply for adults as well, and it should be emphasized that physiotherapy is not the same as home stretching. • Guidelines on sitting posture as well as guidelines on arm function should be highlighted. • A workshop on seating posture for more specific guidelines in adult patients is needed to prepare better evidence for guidance. • The importance of physiotherapy should be stressed along with the need to empower patients to demand physiotherapy.

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8. Other impacts on adult life

8.2. Psychological issues in adulthood

8.1. Pain and fatigue

Jos Hendriksen (Kempenhaeghe Centre of Neurological Learning Disorders, The Netherlands) presented studies showing that there is now substantial evidence on possible psychological deficits in boys and men with DMD, especially with regard to neuropsychological and neurobehavioral functioning [40–42]. Among the most common reported problems are: verbal deficits, reading problems, attention deficit disorders (ADHD), and autism spectrum disorders (ASD). The mechanism responsible for this psychological comorbidity is believed to be cerebral in origin, as dystrophin is also present in many brain areas. Research on the exact nature of this brainbehaviour mechanism is still in progress. It can be argued that DMD should be regarded as a disorder of brain and muscle as opposed to one that is primarily muscular in origin [43]. However, it should be remembered that the majority of men with DMD function normally and without deficits. Until now, research on psychological issues has mainly focused on childhood and early adolescence, but given the medical therapies and prolonged survival, there is an urgent need for further research in these psychological issues in (early) adulthood. Above all, diagnostic procedures should be developed to specifically identify strengths and weaknesses in the neuropsychological and neurobehavioral functioning of men with DMD and those at risk of serious psychological deficits. The PARS-III questionnaire was suggested to be a reliable and valid instrument in assessing psychosocial adjustment [43]. Standardized procedures to assess neurobehavioral disorders in men with DMD should also be developed, and longitudinal research on the developmental profile of these psychological deficits is needed. Finally, therapeutic interventions (e.g. psychotherapy, psychopharmacology) should be developed and evaluated for their effectiveness in these young men.

Imelda de Groot presented a range of studies on pain and fatigue. In one study [35], approximately half of the 43 boys aged 8–18 years reported pain whereas 70% of their parents said their boys had pain. Parents also said pain caused more participation restrictions than their boys did. Another study on youth with NMD [36] showed that the most frequent location of pain in DMD was in the legs followed by the back and that the pain interfered with sleep, general activity, mood, mobility, school/work and recreational activities. In a study on adults [37] in which 132 respondents had DMD/BMD, 19% reported severe usual pain, and 21% moderate usual pain. The pain interfered with movement, leisure and general activities, mood, and sleep. A recent study of arm function in [38] 213 (1–35 y) boys and men with DMD showed that pain was progressive depending on the stage of the disease and that it differed in intensity depending on the location of the arms. The highest intensity of pain was felt in the shoulders and the intensity was higher in the preferred arm. Fatigue is not frequently described in human studies. The mechanism of fatigue is attributed to the loss of the binding of the Nitro Oxide Synthase due to the disruption of dystrophin [39]. In mdx mice, low intensity aerobic training seems to improve muscle functioning. Birgit Steffensen presented an unpublished Danish study of Pain and Fatigue in DMD in a cohort of 18–40+ year-olds. The study showed that pain increased by age, but not to severe pain. Very few took painkillers as it upset their stomachs. Patients who had undergone scoliosis surgery reported lower limb pain. The study also showed that fatigue was a problem in 43% and in 25% on a daily basis. 8.1.1. Discussion and focus areas Data on frequency and site of pain in older patients are limited, also the relationship to prior interventions such as surgery. The distinction between pain and stiffness may be difficult, and evidence on how to measure and treat pain is lacking. Pain must not be ignored, and it is important to identify the cause of the pain so appropriate treatment can be supplied in a timely manner. Suggestions for treatment include dynamic exercise and hydrotherapy. Adjustment of the wheelchair also plays a role in supporting the posture and preventing pain. Experience from Pathfinders shows that fatigue is a daily problem and more data is needed in order to understand the scale of this issue. A strict definition of fatigue is needed so as not to confuse it with sleepiness. The relationship between fatigue and ventilation is important and should be borne in mind. • Pain must be addressed, acknowledged and managed. • Pain and stiffness can be correlated. • Tools are needed to evaluate fatigue without reliance on physical function and to follow up on adjustment.

8.3. Sexual problems in DMD Laurent Servais (Institut de Myologie, Hôpital de la PitiéSalpêtrière, France) is the coordinator of a clinic he has set up at the hospital in Paris offering sexual advice to youths and adults with neuromuscular disorders from Paris and the rest of France. Its interdisciplinary team consists of doctors (gynaecologists, urologists, rehabilitation physicians) and psychologists. The clinic has become a success, but not for DMD. The question is why no men with DMD have consulted the clinic when problems with sexuality are often reported by youths and adults with DMD. A possible reason could be that teenage men are uncomfortable addressing sexual issues and asking their parents to be taken to the clinic. Indeed, it must be noted that when time is specifically devoted during the consultation for a private talk between the child neurologist and the patient, in the absence of the parents, sexuality is a very frequently reported concern. Cultural differences could play a role as well. In Belgium, it is possible for clinicians to advice patients to consult a prostitute whereas in France it is only legal to offer medical advice. The need for an affective and/or sexual

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relationship may lead to patient vulnerability, especially during virtual relationships on the internet. 8.3.1. Focus points and discussion Love and sexuality are a frequently discussed topic on Pathfinders’ Facebook group. Using peers as mentors or role models might solve the problem of overcoming shyness to address the issue. In Denmark, an organization called Handicap Sexology offers counselling and instruction in the use of sex toys such as vibrators. Another coping mechanism could be not to ‘oversexualize’ relationships but instead focus on the importance of ‘romantic love’ and friendship. Love and sexuality are not addressed in the current guidelines but guidelines for adults need to recognize that they play an important role in wellbeing and QoL. Countries vary very much in attitudes and possibilities, and good practice should be shared. The psychological side to these issues should also be addressed. • The issue of love and sex needs to be addressed early on, and parents should be ‘warned’ ahead of time that this is something they will eventually have to deal with. • Clinicians and patients alike must be given the right tools to bring up the issue during consultations. 8.4. End-of-life care Kathi Kinnett (Parent Project Muscular Dystrophy, USA) introduced the topic by wondering why end-of-life care should be different for people living with DMD than for everybody else, and whether this is an appropriate term. The issue is not described in the current guidelines and there is no clear definition of the term. It is important to make a distinction between end-of-life care, palliative care and hospice care and use the terms appropriately. A problem with addressing end-of-life care is when to have the conversation about a topic no one wants to talk about: not during adolescence, not during crises when it’s going to do more damage than good, not when the person is not coping well. There is a lack of studies and patient reports on the subject. It was suggested that all people living with DMD develop an “emergency care plan.” This plan would include all interventions that a person wishes, and does not wish, to be employed during an emergency, or acute care, situation. It was also suggested that everyone in the family participates in this exercise, and that the plans be developed before crises occur. 8.4.1. Focus points and discussion Jon Hastie and Peter Mikkelsen said they would not have wanted to have a conversation about end-of-life care, and neither of them could think of any reason for having it. It might be appropriate to discuss end-of-life care or forward planning in connection with intervention or transition decisions on e.g. ventilation and gastrostomy and with patients with weak hearts: what should be done if anything goes wrong? The subject

can be reversed to become a positive issue relating to control of life, self-determination, autonomy and empowerment. It should, however, be emphasized that having the discussion in an emergency with personnel who are not familiar with the patient is not a good idea. The issue of euthanasia was raised; what if patients ask for it? In The Netherlands and Belgium where euthanasia is organized, patients with DMD are informed about it but no one has asked for it so far. The issue of risk taking behaviour in youths was addressed. Should boys with DMD be informed of the specific risks of using drugs/smoking/alcohol? These are behaviours which are part of normal adolescence and adulthood; however, there are cautions specific to DMD and there is a lack of knowledge about interactions with prescribed medications. It was suggested that the issues could be addressed in connection with evaluations during adolescence. As for the issue of marijuana, it might be useful to look into experiences from other chronic conditions where the drug is used for pain relief. 9. The need for clinical trials in adult DMD Table 1 summarizes the discussions from the workshop sessions on the need for clinical trials in adult DMD. 10. Summary The workshop addressed the issues of a group of men with DMD whose life expectancy has increased due to interventions such as ventilation, cardiac treatment and increasingly the longterm beneficial effects of steroids. This is a very heterogeneous group who had had different care modalities over their lifetime – long-term steroid users, people with previous exposure to steroids for different periods and steroid naïve people. There is still a real lack of knowledge outside specialized centres on the basic areas of care. People with DMD wish to be partners in addressing these issues. Advocacy both for and from DMD – helping people with DMD to become advocates for each other – can really help, for example at transition. Some of the social challenges people with DMD currently face may be less for the next generations of adults, but to achieve this there needs to be a paradigm shift from the time of diagnosis, involving education and families in preparation for adulthood. Key factors from the perspective of the current generation of adults with DMD are frequently around social issues more than medical worries, and these should ideally be addressed in a holistic manner alongside medical care. Nonetheless, in order to maintain good health and facilitate participation in society, we need to deal with the medical issues as well, and we should be defining the care team with the principle that a neuromuscular centre co-ordinating care is key, with the use of healthcare pathways to define care in an emergency, and a contact point with centres available 24/7. The ongoing CDC-led update of the care considerations for DMD should include specific advice as to how the guidelines

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Table 1 Issues to be addressed in the future Subject/area

Issue discussed

Type of information needed

Medical treatment

Cohort studies and assessment methods that are adequately sensitive to measure strength and physical function in adult DMD. Data on dose use. Cost/benefit study of drugs. A proper natural history study to have something to compare with when drugs come along. Make registries attractive to older patients. Natural history studies needed Systematic collection of patient experience and outcomes needed. Natural history studies on risks/benefits of NIV and tracheostomy ventilation. Studies and data needed on: stretching to improve mouth opening, chewing and swallowing, steroids’ impact on tongue size. Natural history study of dental problems/malocclusion. Studies on different interfaces for ventilation during dental interventions. Patients report problems with constipation. Few have full Information and evidence of the size of the problem are needed along faecal incontinence, some leaking. Urinary problems have with a natural history study of gastrointestinal problems in adults and also been reported. the younger population. Lack of clear guidance on bone health in long term steroid More data on bone mineral density in adults with DMD; the effect of treated adults. bisphosphonates; the effect of testosterone and growth hormone on BMD. Natural history study needed. Current guidelines limited. Many patients report pain and More data needed on pain and info of the scale of fatigue and fatigue. possible solutions. Relationship with ventilation. Tools for evaluation needed. Sitting balance and proactive contracture control. Workshop on sitting posture.

Will adult steroid naïve patients benefit from corticosteroids and what is the side effect profile in older patients? New medications Because of limited funding, we must be certain that available drugs bring something to the patient. Patients will not accept side effects if the drug does not help. Ensure that all patients have access to new drugs. Cardiac function People are not treated according to guidelines. Respiratory Is the well-understood progression of respiratory problems function/ventilation seen the same way in steroid treated patients? What about the occurrence of sleep apnoea? Chewing/swallowing/dental High levels of problems with chewing and swallowing reported Ventilation is recommended during dental interventions

Gastrointestinal

Bone health issues

Pain and fatigue

Sitting posture

apply to adults with DMD as well as a supplement on primary and emergency care. Information should accommodate the changing natural history of DMD, with increasing use of steroids at the time of transition to adult care. Rewriting the textbooks and getting the new perspective of DMD as a childhood onset chronic disease are an important message. E-health could be really important in future models of care and should be explored, as distance is cited as a real barrier to access to care. A small group will be set up to develop a protocol for investigation for a natural history study in adult DMD, to include an in depth medical review, and seek funding for this. Acknowledgements This workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Deutsche Gesellschaft für Muskelkranke (Germany), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Spierfonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Telethon Foundation (Italy), and Spierziekten Nederland (The Netherlands), and associated members: Association Française contre les Myopathies (France) and Muscular Dystrophy Association of Slovenia (Slovenia). With special thanks to Sanquin Pasmaprodukten for their support. The workshop received supplementary funding from Parent Project Muscular Dystrophy (US) and Muskelsvindfonden (Denmark).

Participants Doug Biggar John Bourke Kate Bushby Teresa Gidaro Nathalie Goemans Imelda de Groot Jos Hendriksen Kathi Kinnett Jan Kirschner Annette Mahoney Angela Montesanti Ole Norregaard Shree Pandya Ros Quinlivan Jes Rahbek Sunil Rodger Laurent Servais Birgit Steffensen Michel Toussaint Jan Verschuuren Elizabeth Vroom Ulla Werlauff Jodi Wolff Ulrike Schara

Canada United Kingdom United Kingdom France Belgium The Netherlands The Netherlands USA Germany Denmark USA Denmark USA United Kingdom Denmark United Kingdom France Denmark Belgium The Netherlands The Netherlands Denmark USA Germany

Patient representatives John Hastie Peter Mikkelsen

United Kingdom Denmark

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ENMC representatives Alexandra Breukel Annelies Zittersteijn Denise Dute Georg Padberg

The Netherlands The Netherlands The Netherlands The Netherlands

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Please cite this article in press as: Jes Rahbek, Birgit F. Steffensen, Kate Bushby, Imelda J.M. de Groot, 206th ENMC International Workshop: Care for a novel group of patients – adults with Duchenne muscular dystrophy, Naarden, The Netherlands, 23–25 May 2014, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2015.05.005