Transcript Treatment for the here and now

Treatment and Management
here and Now
DMD
Katie Bushby, Michelle Eagle, Robert
Bullock, Mike Gibson, John Bourke
Newcastle 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 years
SPECIALIST CARE +5 YEARS
Better co-ordinated care probably led
to improved survival across decades, but
without treatment of respiratory failure
survival beyond 25 is unlikely
fatigue, needs
to lie down
during day,
difficulty getting
go to sleep
weight
loss
1.50
1.25
chest infection
afraid of died in hospital
going to
sleep
FVC
1.00
0.75
0.50
0.25
0.00
149
173
197
221
age in months
Natural history: drop in FVC was mirrored
by increasing symptoms
sh ch
or es
tn t i
es nf
s o ec
t
we f br ion
ig ea
he ht l th
p a d os
un oor ach s
ab ap es
le pe
to tite
fre
s
qu fa lee
en tig p
di
ffi
t w ue
cu
ak d
lty
i
n
sw au ng
di
s
a
e
l
ffi
cu a low a
l
n in
ab ty c ore g
do ou xi
in
m gh a
in in
ac crea
ce se cy al p g
ss d an ain
or se os
irr
y m cr e
ita
e d
a
bl fr usc tion
e o ai le s
r l d o us
et f s e
ha le
di
ffi
n
ig rgic ep
cu
ht
lty
a
ge tac swe m
tti hy at
ng ca s
to rdi
sle a
ep
% frequency
20
10
0
symptoms
Patients were frequently symptomatic
for many months before their death
1.5
FVC
1.0
0.5
0.0
0
10
20
30
40
50
60
months to death
Low FVC and the presence of symptoms
predicted 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
Impact of ventilation on
symptoms and FVC
1.00
0.75
FVC
• Most patients
reported complete
resolution of
symptoms
• Weight stabilised
• Less chest infections
• Able to continue with
school/ college
0.50
0.25
0.00
FVC at
ventilation
one year
post
ventilation
two years
post
ventilation
The provision of home nocturnal ventilation
has improved the chance of surviving to 25
to at least 53%
HOME NIV +7 YEARS
Analysis of the impact of spinal
surgery and ventilation in
patients born since 1970
percentage survival
100
Spinal surgery + ventilation
80
spinal surgery no ventilation
ventilated no spinal surgery
60
No ventilation no spinal surgery
40
20
0
0
5
10
15
20
25
30
current age/age at death
HOME NIV AND SS + 9 YEARS
emergency ventilation
frequency
3
elective ventilation following
chest infection
elective ventilation
2
1
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
year of ventilation
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
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
ventilated in 1990s
28
26
Died in 1990s
Died in 1980s
25
Died in 1970s
24
Died in 1960s
Cardiomyopathy
27
age at death
23
22
21
20
19
18
17
16
15
14
13
12
11
10
v ent + SS
v ent
1990s
1980s
1970s
1960s
CM
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
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)
BMD L1-4 against age (Male)
Baseline
Male Normal
M-2SD
M+2SD
Baseline +1year
1.0
BMD L1-4
0.8
0.6
0.4
0.2
5
6
7
8
9
10
11
age
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
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?
ia
l
in
ea
lth
H
ily
m
de
pe
n
so de
ci
al
ac
l
lif
e
hi
e
ev isur
e
em
en tim
e
ta
n
in
d
de
pe lea
nd
en
ce
w
or
k
an
c
fin
Fa
frequency
Quality of life- young people
4
3
2
1
0
cues
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
su
r
fa
m
il
in e/s y
d
o
re epe cia
l
lig
n
io de
n
n
+ s ce
pi
rit
ua
fin
l
an
he
ci
a
su al s lth
pp ec
or ur
t n ity
et
w
o
ho rk
lid
ay
in
te
s
le
fri
c
pr
e
of tua nd
es l s s
t
si
on imu
al
la
gr
c ow
liv om th
m
in
g
u
co nit
nd y
iti
on
s
le
i
frequency
Quality of life- parents
5
4
3
2
1
0
cues
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