Upload
lizeth-henwood
View
216
Download
0
Tags:
Embed Size (px)
Citation preview
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
0
1
2
3
4
5
cues
freq
uen
cy
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