Treatment and Managementhere and Now

DMD

Katie Bushby, Michelle Eagle, Robert Bullock, Mike Gibson, John

BourkeNewcastle upon Tyne Muscle

Centre

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

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 yearsSPECIALIST CARE +5 YEARS

Better co-ordinated care probably ledto improved survival across decades, but without treatment of respiratory failuresurvival beyond 25 is unlikely

149 173 197 2210.00

0.25

0.50

0.75

1.00

1.25

1.50chest infectiondied in hospital

fatigue, needsto lie downduring day,difficulty gettinggo to sleep

weightloss

afraid ofgoing tosleep

age in months

FV

C

Natural history: drop in FVC was mirrored by increasing symptoms

0

10

20

symptoms

% fr

eque

ncy

Patients were frequently symptomaticfor many months before their death

0 10 20 30 40 50 600.0

0.5

1.0

1.5

months to death

FV

C

Low FVC and the presence of symptomspredicted time to death

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

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

0.00

0.25

0.50

0.75

1.00

FVC atventilation

one yearpostventilation

two years postventilation

FV

C

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

The provision of home nocturnal ventilationhas improved the chance of surviving to 25to at least 53%

HOME NIV +7 YEARS

Analysis of the impact of spinalsurgery and ventilation inpatients born since 1970

0 5 10 15 20 25 300

20

40

60

80

100

spinal surgery no ventilation

Spinal surgery + ventilation

ventilated no spinal surgery

No ventilation no spinal surgery

current age/age at death

perc

enta

ge s

urvi

val

HOME NIV AND SS + 9 YEARS

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 20020

1

2

3 emergency ventilation

elective ventilation followingchest infectionelective ventilation

year of ventilation

freq

uen

cy

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

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

What about the heart?Mean age of death

vent + SS vent 1990s 1980s 1970s 1960s CM10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28 ventilated in 1990s

Died in 1990s

Died in 1980s

Died in 1970s

Died in 1960s

Cardiomyopathy

vent + SS

age

at d

eath

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 fractionand wall motion abnormalities

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

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

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

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……….

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)

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

BMD L1-4 against age (Male)

0.2

0.4

0.6

0.8

1.0

5 6 7 8 9 10 11

age

BM

D L

1-4

Baseline Male Normal M-2SD M+2SD Baseline +1year

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)

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

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

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

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

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

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?

Quality of life- young people

Family

Health

finan

cial in

depe

nde

socia

l life

leisu

re ti

me

achie

vem

ent a

nd le

a

indep

ende

nce

work

0

1

2

3

4

cues

freq

uen

cy

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

Adults with DMD

• Major period of readjustment for today’s 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

Quality of life- parents

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1

2

3

4

5

cues

freq

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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

Thanks to the Newcastle team