123rd ENMC International Workshop: Management and Therapy in Myotonic Dystrophy, 6–8 February 2004, Naarden, The Netherlands
Article Outline
- 1. Introduction
- 2. General aspects, evidence base and outcome measures for myotonic dystrophy
- 3. Symptomatic management
- 4. Trials, patient cohorts and management
- 5. Future trial development
- 6. Conclusions
- 7. List of participants
- Acknowledgements
- References
- Copyright
1. Introduction
This was the second Workshop on the management of myotonic dystrophy (DM1). The first (99th ENMC International Workshop) led to the publication of the book: Myotonic dystrophy, present management, future therapy [1]. The main aim of the present Workshop was to discuss outcome measures, and symptomatic treatment in myotonic dystrophy to enable international collaboration on management and treatment.
The Workshop was attended by 22 participants form 11 countries (Belgium, Canada, Finland, France, Italy, Japan, the Netherlands, Russia, Sweden, UK and USA). Participants included geneticists, neurologists, occupational therapists, a clinical trial coordinator, and a patient representative.
Agreement was reached on a core set of outcome measures to be gathered in outpatient clinics, to be developed as a computerised database. Quality of life aspects of myotonic dystrophy were presented. Symptomatic management was discussed for somnolence, gastrointestinal features, cardiac symptoms, and behavioural problems in childhood. Results from various centres demonstrated that most patients were frequently not being seen once a year. A study showed a patient-held care card improved their care. Encouraging results from Japanese and American pharmacological trials were presented. The Workshop decided to create a website (www.myotonic.org) and discussion board to facilitate communication, and to propose a systematic Cochrane review on muscle wasting and weakness in DM1.
2. General aspects, evidence base and outcome measures for myotonic dystrophy
Testsuo Ashizawa discussed recent scientific advances in the field and their relevance to therapy. Potential treatment approaches were based on molecular mechanisms of disease, which were all subsequent to the mutation at the DNA, mRNA, and protein levels. Muscleblind was the major protein that interacts with expanded CUG repeats of the DMPK RNA transcript [2]. In addition, Muscleblind knockout mice showed a DM1-like phenotype with cataracts, myopathy and myotonia [3]. Expanded CUG repeats in DM1 selectively bind and sequester nuclear transcription factors, causing reduced mRNA levels of selected genes in DM1-affected cells [4].
Potential new treatment strategies based on these novel insights were: deletion of expanded (CTG)n by radiation or drugs (replication inhibitors, cyclophosphamide, Mitomycin C) [5], [6], [7]. In addition to this strategy acting on the DNA CTG repeat, other therapeutic approaches involve: DMPK mRNA, proteins involved in the pathogenic mechanisms, transcription factors, haploinsufficiency of DMPK and Six5, correction of tissue-specific abnormalities, treatments based on tissue-specific disease process, symptomatic treatments, DHEA-S and IGF1, and empirical or serendipitous approaches.
The phenotypic differences between DM1 and DM2 are now clearly recognised. Bjarne Udd reviewed the DM2 phenotype compared to that of DM1 and identified the following potentially distinguishing features: later onset, prominence of pain, proximal distribution of weakness with exceptions such as the deep finger flexors, and characteristic differences in histopathology. Age of onset in DM2 was usually between 30 and 60 years, there was no congenital form, no childhood onset and only exceptionally a juvenile onset. Anticipation was not usually seen. Muscle weakness was proximal and typically mild until 60–70 years of age. Facial weakness, ptosis, bulbar symptoms and respiratory defects were minimal or absent. Most DM2 patients had no muscle atrophy and calf hypertrophy was present. Clinical myotonia on activation was found in less than 50% and is variable from day to day. Myotonia is found using EMG in 90%. Myalgia was prominent, radiculopathy-like or diffuse and was not exercise-related. Cataracts in DM2 were of the DM1-type, occurring in approximately 50% before age 60, and 20% required extraction. DM2 patients showed normal performance or mild abnormalities in cognition and behaviour [8]. There was no hypersomnia, tremor was present in 20–30% and leg muscle cramps occurred. In DM2, no post-anaesthetic problems were reported and no specific measures were required. In conclusion, the worst cases of DM2 were as severely disabled as adult onset DM1 cases, on the other hand, in the mildest form, patients had very late onset, over the age 70, with proximal muscle weakness and hardly any EMG myotonia.
The clinical spectrum observed gave rise to a prospective study for checking DM2 in undetermined myopathies; of 52 myopathy patients with unknown cause 16 had a DM2 mutation. Three of these patients had a PROMM phenotype but no family history. The diagnosis was especially likely in those patients with EMG myotonia or increased insertional activity, muscle pains or unexpected nuclear clump fibers on biopsy. DM2 remains a diagnostic challenge, but the availability of DNA testing is a great help.
Douglas Wilcox gave a general review on evidence based medicine and the methodology of Cochrane reviews and the Scottish Intercollegiate Guidelines Network (SIGN) Guidelines. Both organisations were formed in 1993. Their aims were to monitor the effect of healthcare and influence clinical practice by generating recommendations for effective practice based on review of current evidence.
Baziel van Engelen discussed the various published outcome measures for DM, the advantages of computerised tools for data input, storage and analysis of trends were shown. Availability of DNA analysis for DM1 and DM2 necessitated redefining the natural history of myotonic dystrophies. Objectives for outcome measures were: to identify patient's problems and natural history, to quantify certain parameters and to allow research into possible therapies. Various disease-specific methods of assessment had been developed and included the muscular impairment rating scale (MIRS), Cardiff myotonic dystrophy muscle clinic record, Glasgow myotonic dystrophy clinical milestone record and the French ‘Steinert’ protocol. [1] In addition, general neuromuscular disease profiles like INQoL (Michael Rose), and non-specific tools like the Sickness Impact Profile (SIP), Rand-36, Epworth Sleepiness Scale, McGill pain questionnaire, and EuroQol exists. Agreement was reached on a core set of outcome measures achievable in the outpatient clinical setting, to be developed as a computerised facility and aiming at selecting patient cohorts for future trials (Table 1).
Table 1. Consensus of core clinical data of DM1 proven patients for electronic storage, aiming at selecting patient cohorts for future trials
| Questionnaire |
 Educational attainment |
| Occupation |
| Muscular Impairment Rating Scale |
| Age-related milestones (in years) |
| Age of loss of employment |
| Age of onset of myotonia |
| Age of onset of weakness in |
| Neck |
| Face |
| Hands |
| Feet |
| Age of loss of activities |
| Climb stairs |
| Get out of chair |
| Get out of bed |
| Walk without aid |
| Prepare a meal |
| Get dressed |
| Attend to own toilet |
| Ambulation: (loss of ability to walk, with or without aids) |
| Age of onset of cardiac symptoms |
Absence or presence (if present, age of onset in years) |
| Effects on sleep |
| Respiratory features |
| Response to general anaesthesia |
| Cataracts |
| Visual acuity decreased |
| Reproduction—subfertility or complications |
| Diabetes |
| Baldness |
| Learning difficulties |
Present history (yes/no) |
| Swallowing symptoms |
| Chest infections |
| Cardiac symptoms |
| Weakness |
| Stiffness=myotonia |
| Assistance devices/falling |
| Gastrointestinal symptoms |
| Cataract/vision problems/eye operations |
| Somnolence change |
Questionnaires |
| Epworth Sleepiness Scale |
| Rivermead Mobility Index |
Examination |
| Forced vital capacity (standing or sitting) |
| Forced vital capacity (supine) |
| Time to swallow 100ml water |
| Handgrip strength (right, left) |
| Visual acuity |
| Rise from chair without arms (functional score) |
| Two functional tests (lying to standing and sitting to standing time, in seconds) |
| Myotonia (hands action and percussion myotonia, eyes action myotonia) |
Additional investigation |
| ECG (PR inverval, QRS width, branch block, rate) |
3. Symptomatic management
Bruno Eymard and Denis Duboc reported a group of DM1 patients with severe cardiac involvement beginning before age of 18 years [9]. This topic was poorly documented [10]. Eleven patients were identified: four were presented with congenital and infantile type of DM1, six were teenagers with no cognitive dysfunction, mild clinical signs and onset after 10 years of age, and a last 13-year-old girl had a completely normal clinical examination. The main results were as follows: age at onset of the severe heart involvement was between age of 10 and 18 years; sudden death occurred in two patients and a cardiac arrest was resuscitated in one case; arrhythmia was found in nine cases (atrial flutter, ventricular tachycardia, and atrial fibrillation in four, four, and one cases, respectively); conduction defect required pace-maker in five patients; a triggering effect of exercise was suggested in 6 out of 11 patients; cardiac problems were the presenting symptom of DM1 in five cases. Various DM1 phenotype were associated with heart involvement: congenital, infantile, mild adolescence without mental retardation, pure cardiac (one case); no correlation was found with CTG expansion. These data were too preliminary to propose systematically genetic testing in young asymptomatic patients from DM1 families: further prospective studies were warranted to refine the management and genetic counselling of these young patients at risk of major adverse cardiac events. Since, physical activity precipitated arrhythmias, exercise testing with ECG was recommended in young patients with DM1 before sports practice.
David Hilton Jones, Maxwell Damian and Giovanni Meola presented the topic of somnolence and its management. Excessive daytime sleepiness (EDS) was a very common, but under-recognised feature of myotonic dystrophy. The potential causes were hypoventilation inducing hypercapnia, sleep-disordered breathing and ‘central’ mechanisms. Chronic hypercapnia, due to central dysfunction (reduced drive) and/or muscle weakness were common in DM1, but it was not severe enough to cause CO2 narcosis and no correlation was observed between EDS and muscular disability [11]. DM1 sleep-disordered breathing was associated with obstructive and central apnoeas. However, there was a poor correlation with these parameters and EDS [12]. The evidence was strongly in favour of EDS mainly due to a specific central mechanism. Three pieces of evidence support this hypothesis of a ‘primary’ CNS involvement: occurrence of sleep-onset REM in several patients [13], pathological demonstration of neuronal loss in the dorsal raphe nucleus and superior central nucleus in DM1 with hypersomnia [14], and finally, decreased secretion of hypocretin.
Measurement of EDS was obtained by subjective and objective methods, respectively: Epworth sleepiness scale (ESS), Stanford sleepiness scale (SSS), and multiple sleep latency test (MSLT) and maintenance of wakefulness tests (MWT).
Two specific approaches of treating EDS have been reported: firstly, assisted ventilation for sleep-disordered breathing (CPAP if obstructive apnoeas, BiPAP if nocturnal hypoventilation and or central sleep apnoea) and secondly, CNS stimulant drugs (Modafinil, Dexamphetamine, Methylphenidate). Several studies have looked at the use of Modafinil in myotonic dystrophy. An open study by Damian et al. [15], including 11 DM1 patients, showed increased sleep latency, and a major improvement in average ESS scores. In 2002, MacDonald et al. [16] performed a double blind crossover trial of Modafinil. Forty patients were enrolled. ESS and SSS scores improved, but no objective measures were performed [16]. The Oxford group undertook a double-blind cross over trial based on 20 patients receiving 200mg of Modafinil or placebo [17]. The main findings were improved MWT, reduced ESS, improved SSS and absence of cardiac complications. The practical management of EDS was presented with different successive steps: identification of EDS, exclusion of negative factors compromising sleep hygiene (alcohol, caffeine, bed time, inappropriate medications) sleep studies with pulse oximetry and (if possible) a formal study in a sleep laboratory. If sleep-disordered breathing was identified, the patient should be offered assisted ventilation: CPAP if there was evidence of obstructive sleep apnoea and Bi PAP for nocturnal hypoventilation or central apnoeas. If there was no evidence of sleep-disordered breathing, and the degree of EDS significantly disrupts the patient's lifestyle, a trial of Modafinil was indicated. The starting dose was 100mg in the morning, switching to 200mg after a week. If after 2 weeks, the response was insufficient, the dose was increased: 200mg in the morning and at midday (before 1 pm). Maximal dose was 600mg daily. If no benefit was obtained after one month, the drug should be discontinued.
Hakan Forsberg presented data concerning gastrointestinal involvement in DM1. Experience of this Swedish group in this field was large [18], [19], [20], [21]. Their series includes 40 DM1 patients (six congenitally affected), all of them interviewed on symptoms. Eleven complained of slow gastric emptying, 20 from diarrhoea. Twenty-eight percent of patients had gastrointestinal (GI) problems before the diagnosis of DM and 25% considered GI problems to be the most disabling consequence of DM1. Gastric emptying was studied using a 99Tc-labelled test meal, in comparison with a group of healthy controls. Patients with DM1 had a significantly slower gastric emptying [22]. Moreover, plasma concentration of motilin was significantly decreased in patients. Electrogastrography was significantly altered. Combined impairment of gastric pacing and hormone response might be responsible for most retarded emptying in patients. Episodic diarrhoea was found in 13 out of 40 patients, and 12 were at least occasionally incontinent. Malabsorption of bile acids in 12 out of 20 patients and small bowel bacterial overgrowth in 2 out of 8 patients were the most frequently occurring mechanisms of diarrhoea [19]. Endocrine cell area in the DM1 rectum was significantly decreased for chromogranin A. Current practice of the Norbotten group are as follows: cholestyramine improves diarrhoea, incontinence and pain in most patients; norfloxacin may be effective when cholestyramine fails. Erythromycin or metoclopramide are worth trying for symptoms of slow gastric emptying.
Christine De Die-Smulders and Jean Steyaert presented the behavioural problems in childhood onset myotonic dystrophy. Diagnosis of childhood DM1 was often missed in affected adolescents or children due to lack of neurological problems or due to aspecific neurological problems, and apparently negative family history [23]. Signs included dysarthria, which was very frequent, early and progressive facial weakness, and a retarded motor development might also be found. These were eventually accompanied by myotonia in later childhood. Cognitive defects may be combined with psychological problems (emotional and behavioural problems, attention deficit, delusion disorders), somnolence, chronic fatigue and somatic complaints [24], [25]. Social isolation was frequent. The main recommendations in these patients were the following: (1) early diagnosis by DNA testing, suggested in a child with cognitive difficulties; (2) regular follow up by a paediatrician or paediatric neurologist (a multidisciplinary approach being very suitable); (3) if cognitive, behavioural and emotional problems were suspected, IQ testing and referral to a psychologist or child psychiatrist should not be delayed; (4) organ complications required special attention. A yearly ECG was necessary.
4. Trials, patient cohorts and management
Experience of two groups from The Netherlands and Quebec concerning quality of life and social factors in DM1 was presented. Three groups of neuromuscular disorders were analysed comparatively in the Dutch population (Baziel van Engelen): DM1, FSH dystrophy, and Hereditary Sensory and Motor Neuropathies type I (including 322, 139 and 137 patients, respectively). Screening concerned education level, checklist of individual strength, sickness impact profile, Euroquol, Epworth sleepiness scale, McGill pain questionnaire, and actometer measurements. The following characteristics were found in DM1 patients: lower education level, reduced professional activity, abnormal sickness impact profile, low actometer values, presence of pain in 44% and excessive sleepiness in one third of patients. In a second current transverse study in the DM1 population of Saguenay (Quebec), determinants of disabilities, social participation and quality of life indexes will be analysed by Mathieu's group. The interactions between personal factors (involving organic systems and capabilities), environmental factors and accomplishment of life habits (social participation) (all of them influencing quality of life) will be assessed. This involved assessment at the patient's home and the clinic. Two hundred DM1 patients over 18 years were randomly selected. A better understanding and awareness of these data will hopefully lead to improvements in their quality of life by more effective management.
A current collaborative 6 month pilot study of falls in myotonic dystrophy was presented by the Cardiff team. The main assessed parameters were the incidence of falls, the impact on confidence and the relationship to the following clinical factors: muscle strength, balance, functional movement and ambulatory mobility. Fifteen DM1 patients were initially assessed at the Research Centre for Clinical Kinesiology and were being followed by weekly postcards for 13 weeks with a final postcard at 6 months. Several assessment tools were used (hospital activity and depression scale, activities-specific balance confidence scale, Tinetti scales, medical checklist).
Margaret Bowler of the UK Myotonic Dystrophy Support Group (MDSG) presented the ways in which their support network supported patients, family, carers and professionals. She described the key elements of how the Support Group delivered help to these groups of individuals. Central to their activity was a telephone help line, manned by volunteers. This was supported by 22 volunteer regional contacts, who served the UK population of 60 million. Local, regional and national meetings were organised for affected families and volunteers from the Support Group and become involved with professional groups who might have patients with DM1. The Support Group had also created a range of information leaflets and cards that were posted to families and professionals on request. The Support Group's website http://www.mdsguk.org/ was becoming an increasingly important tool for the distribution of information and communication between geographically isolated members through its active discussion board. Many European countries do not appear to have a similar group and the MDSG has offered to help others to create a similar support network.
Douglas Wilcox presented data from three UK centres, which showed the majority of DM1 patients were not under annual review at a specialist clinic. The MDSG have campaigned for better services, asking professional groups ‘What are you doing for our members who do not attend specialist clinics?’ A patient held myotonic dystrophy care card was developed and distributed in partnership with the MDSG and gave patients information about complications and recommended health screening in DM1. An audit showed that two thirds of West of Scotland patients already had the card and that cardholders felt better informed and more in control of their management than non-cardholders. Seventy-nine percent of cardholders had a recommended ECG within the last year compared with 3.5% of non-cardholders.
Cynthia Gagnon reported a population study of DM1 in an area of high prevalence (1/525) in Quebec. This was postulated to be due to a founder effect with a previously high birth rate in an isolated population. Over the last 15 years the proportion of classic adult phenotype in the population has reduced while the proportion of milder cases has increased. This was attributed to the effects of population ageing, low birth rate, genetic counselling and predictive testing.
Leila Akhmadeeva reported data from Bashkortostan Republic (Russia). It was the region with the highest prevalence of DM1 in the countries of the former Soviet Union. The recent joint study with Veytsman (USA) predicts rising of prevalence if no predictive DNA testing will become available on a regular basis. Now the prevalence in the Bashkirian subpopulation was 2.7 times higher than in the Russian subpopulation, but this situation was predicted to shift because of interethnic marriages. Bashkortostan is the only region in Russia where there is a regularly updated database on DM1. In addition, various studies, including those about quality of life in DM1 families were performed.
Hakan Forsberg reported another region with high prevalence, the Norrbotten area of Sweden. In this population the mean age of death in adult cases was 54.8 years.
Nakaaki Ohsawa and Richard Moxley presented encouraging results from Japanese and American trials of DHEA-S (androgen), Troglitazone, and Mexiletine. Even if some other results were debated (DHEA) they showed that effective protocols and tools to measure myotonia, muscle strength and effects on activities of daily living (ADL) existed for further therapeutic trials. Trials with an Igf-1 derivative, somatokine, were planned.
5. Future trial development
Wide ranging discussion raised the need for a means of effective communication to be set up to link existing delegates, encourage new members to join and to distribute documentation. A web site and discussion board will be set up at www.myotonic.org and will be linked to the ENMC website. It was agreed that a Cochrane review of ‘Interventions for muscle wasting and weakness in myotonic dystrophy’ should be undertaken. Several areas were identified that require further work, e.g. falls in DM1 and abdominal pain in DM1. After fruitful discussion, a core set of outcome measures was agreed. These should help standardise assessment in different centres.
6. Conclusions
Animated discussions during this workshop clarified different points of view, and constructively resulted in a proposal for outcome measures for DM1. These outcome measures will allow assessing natural history and may facilitate selecting patient cohorts for future trials.
This was an enjoyable and fruitful workshop that will lead to new collaborations and will contribute significantly to the improvement of future therapeutic RCTs for DM1 in both Europe and North America.
7. List of participants
Leila Akhmadeeva (Ufa, Russia)Tetsuo Ashizawa (Galveston, Texas USA)Margaret Bowler (Nottingham, UK)Kate Bushby (Leicester, UK)Christine de Die-Smulders (Maastricht, The Netherlands)Denis Duboc (Paris, France)Baziel van Engelen (Nijmegen, The Netherlands)Bruno Eymard (Paris, France)Hakan Forsberg (Lulea, Sweden)Cynthia Gagnon (Jonquière, Canada)Peter Harper (Cardiff, UK)David Hilton-Jones (Oxford, UK)Giovanni Meola (Milan, Italy)Richard Moxley III (New York, USA)Nakaaki Ohsawa (Osaka-Fu, Japan)Mark Rogers (Cardiff, UK)Catherine Sampson (Cardiff, UK)Jean Steyaert (Leuven, Belgium)Bjarne Udd (Vaasa, Finland)Douglas Wilcox (Glasgow, UK)Andoni Urtizberea (ENMC Research Director, Paris, France)Michael Rose (ENMC Clinical Trial Network mediator, London, UK)
Acknowledgements
This workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and the ENMC main sponsors: Association Française contre les Myopathies (France); Deutsche Gesellschaft für Muskelkranke (Germany); Telethon Foundation (Italy); Muscular Dystrophy Campaign (UK); Muskelvindfonden (Denmark); Prinses Beatrix Fonds (The Netherlands); Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland); Österreichische Muskelforschung (Austria); Vereniging Spierziekten Nederland (Netherlands).
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PII: S0960-8966(05)00055-6
doi:10.1016/j.nmd.2005.02.001
© 2005 Elsevier B.V. All rights reserved.
