Treatment and Management here and Now DMD

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Treatment and Managementhere and Now DMD

• Katie Bushby, Michelle Eagle, Robert Bullock,
  Mike Gibson, John Bourke
• Newcastle upon Tyne Muscle Centre

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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

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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

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Better co-ordinated care probably led to improved
survival across decades, but without treatment
of respiratory failure survival beyond 25 is
unlikely
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Natural history drop in FVC was mirrored by
increasing symptoms
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Patients were frequently symptomatic for many
months before their death
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Low FVC and the presence of symptoms predicted
time to death
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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

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Changing the natural history Non-invasive
ventilation normalises overnight oxymetry
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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

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The provision of home nocturnal ventilation has
improved the chance of surviving to 25 to at
least 53
HOME NIV 7 YEARS
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HOME NIV AND SS 9 YEARS
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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
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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

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

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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

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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

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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.

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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)

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Few boys with DMD have a BMD gt50th centile pre
steroids and our early data confirms reduction in
LS BMD with 1 year of continuous steroids
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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)

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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

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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

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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

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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

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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

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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?

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Quality of life- young people
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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

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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

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Quality of life- parents
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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

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Thanks to the Newcastle team