1. Treatment and Management here and Now DMD Katie Bushby, Michelle Eagle, Robert Bullock, Mike Gibson, John Bourke Newcastle upon Tyne Muscle Centre

2. Reappraisal of natural history in Duchenne muscular dystrophy DMD is a treatable disease –Predictable complications in different systems Respiratory support is proven to improve life expectancy with maintenance of a good quality of life Cardiac surveillance and treatment is likely to have similar benefits Steroid treatment prolongs ambulation, reduces scoliosis and improves cardiac and respiratory function The evidence base is improving but collaborative studies and evidence to maximise benefits, establish and apply best practise to all patients are still urgently needed

3. What has made the difference? DMD and survival (M Eagle) Studied the notes of 197 boys with DMD looked after in Newcastle since 1967 Mean age at death in 1960s was 14 years 1970s, 80s and 90s it was 19 years SPECIALIST CARE +5 YEARS

4. Better co-ordinated care probably led to improved survival across decades, but without treatment of respiratory failure survival beyond 25 is unlikely

5. Natural history: drop in FVC was mirrored by increasing symptoms

6. Patients were frequently symptomatic for many months before their death

7. Low FVC and the presence of symptoms predicted time to death

8. Respiratory management: prevention surveillance and treatment Prevention: flu immunisation, chest physio, assisted insufflation Surveillance: forced vital capacity, overnight home oximetry Treatment: prompt treatment of infections, nocturnal ventilation

9. Changing the natural history: Non-invasive ventilation normalises overnight oxymetry

10. Impact of ventilation on symptoms and FVC Most patients reported complete resolution of symptoms Weight stabilised Less chest infections Able to continue with school/ college

11. The provision of home nocturnal ventilation has improved the chance of surviving to 25 to at least 53% HOME NIV +7 YEARS

12. HOME NIV AND SS + 9 YEARS

13. Monitoring FVC, symptoms, pulse oxymetry allows prediction of respiratory failure and elective treatment preventing severe symptoms and giving patients and families control of the process

14. MDC consensus meeting on scoliosis surgery in DMD Multidisciplinary approach needed from early age Surgery performed in specialist centres is safe and effective Best to plan to operate when there is progression of Cobb angle but still correctable Maximise cardiac and respiratory function

15. What about the heart?

16. Cardiac involvement in DMD is almost invariable, but rarely symptomatic until late stages Short PR: Q waves: Tall R in V1-2: Twaves abnormal Reduced ejection fraction and wall motion abnormalities

17. Heart failure management LV dysfunction and heart failure reflect loss of contractile function and secondary changes (signalling, regulation of contraction) Traditional management concentrated on symptom relief Current emphasis is on prevention of deterioration and prolongation of survival (ENMC guidelines) Duboc et al 2005: indications that early treatment is protective John Bourke- UK heart protection trial to start late 2005

18. What if you could delay cardiac/ respiratory failure? First long term cohort studies of steroids in DMD are reporting –Lower incidence of cardiomyopathy –Massively preserved forced vital capacity –Reduced/ abolished need for scoliosis surgery –With prolongation of ambulation to 12+, possibly mid-teens

19. Steroid use in DMD (Cochrane review April 2004, AAN 2005) Corticosteroids improve strength outcomes in DMD The most widely used regimes are prednisolone 0.75mg/kg/day and deflazacort 0.9mg/kg/day These are probably equivalent in effect Deflazacort- ? More cataracts/ less weight gain A variety of alternative regimes have been suggested to reduce side effects

20. Polarisation of practise Of 15 centres questioned ahead of potential trial –No steroids –Daily prednisolone (0.75mg/kg/day) –Daily deflazacort (0.9mg/kg/day) –Intermittent prednisolone –Intermittent deflazacort –Low dose steroids (0.35mg/kg/day) –Weekend high dose prednisolone……….

21. Major issue Efficacy against side effects No alternative regime is proven to be as effective as daily- long term gains? But the side effect profile is likely to be better –Weight gain, behaviour changes, osteoporosis, cataracts (more rarely: GI disturbance, diabetes, infection etc)

22. Few boys with DMD have a BMD >50 th centile pre steroids and our early data confirms reduction in LS BMD with 1 year of continuous steroids

23. Osteoporosis People with DMD have low bone density without steroids Steroids increase this tendency (especially in the back) The best way to keep bones healthy is by maintaining a good diet, getting sunshine and maintaining mobility DEXA scores should not be used to dictate treatment plans (steroids or bisphosphonates)

24. The UK consensus on the use of steroids in DMD Steroids should be discussed with all parents early Information about the various options should be provided An informed choice between intermittent and continuous dosage made Results should be collected in a standardised manner (North Star project) –With respect to efficacy and side effects Pending the definitive trial

25. Our results Over the last 3 years over 40 children have been started on one or other of these regimes Increase in energy, function and power has been marked With the most positive results in the younger boys Weight gain has been the most common side effect Functional testing illustrates clear improvement as well as strength Gains in quality of movement, energy levels, inclusion

26. ENMC consensus The use of steroids does alter strength and function in DMD Long term trials (ENMC/EU) are planned to test different treatment regimes Routine treatment should be according to best practise to minimise and treat potential side effects www.enmc.org

27. Treatment modalities in a complex disorder are additive Specialist care + 5 years Home nocturnal ventilation + 7 years(+) HNV plus spinal surgery + 9 years Long term steroid treatment with preservation of respiratory and cardiac function (Biggar et al) Management of cardiac failure

28. Future treatments area also likely to be additive Other pharmacological treatments Gene therapy Upregulation of utrophin Antisense oligonucleotide therapies Stem cell based treatments –All still have major barrier of systemic delivery

29. Adult patients with DMD Medical care –Ventilation- may use GPB/ some increasing requirement with age –Cardiac support –Nutrition- ng tube/ gastrostomy? –GI tract- constipation Smooth muscle? Bladder? –Weakness/ contractures End of life issues –Cause of death?

30. Quality of life- young people

31. Danish research (Rahbek et al 2005) 65 adults with DMD aged 18-42 Quality of life excellent No worries about disease or about the future Positive assessment of income, participation, housing Areas for improvement –Further education, adult relationships, pain in sitting

32. Adults with DMD Major period of readjustment for todays parents –the goalposts have moved –Schools and social services not geared towards adult life –Uniform agreement in QOL studies that patients are positive –Family and technology are major determinants of wellbeing –Families may be dissatisfied with lack of social opportunities

33. Quality of life- parents

34. Treatment for the here and now There is a major role for proactive management in patients with muscular dystrophy –This can follow simple rules and should be applicable to every patient Evidence of efficacy is accumulating and should continue to develop Participation in trials is essential to develop new gold standards Major social adjustments may be needed to support increased longevity and allow opportunities to be properly developed

35. Thanks to the Newcastle team