Transcript Duchenne Muscular Dystrophy: Neuromuscular Management

Duchenne Muscular Dystrophy:
Neuromuscular Management
Introduction
• Muscles weaken due to lack of dystrophin
• Regular checkups with specialists are required
• Steroids are the only drugs which alter the
natural history of DMD
– Should only be prescribed by doctors with
appropriate expertise
– Proactive side-effect management is crucial
– No current evidence that other supplements work
Regular Checkups
• Neuromuscular specialist every 6 months
– Monitor disease progression
– Make decisions about new treatments at
appropriate times
– Anticipate and prevent any problems including
side effect prevention and management
• Specialist physiotherapist and/or occupational
therapist every 4 months
What to measure?
• Specific tests vary between clinics
– Consistency, experience and regular review important
• Areas of assessment include
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Strength (force generated at joints)
Range of joint motion (monitor contractures)
Timed tests (e.g. 6MWT, rise from floor, steps)
Motor function scales (e.g. North Star) – different scales
may be needed at different times
– Activities of daily living (assess whether additional help
required to assist independence)
• Further information in TREAT-NMD Registry of
Outcome Measures www.treat-nmd.eu/rom
Assessments: Strength Testing
• Method
– Manual muscle testing (MRC scale)
– Quantitative myometry (if MRC scale 3-5)
• Aims
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Serial assessment to identify outliers from expected clinical course
Monitor disease progression, predict functional losses
Assess response to treatment
Monitor muscle imbalance
• Ambulatory
– Test lower extremity strength by manual muscle testing every 6
months
• Non-Ambulatory
– Early stages: test upper and lower extremity strength every 6 months
– Later stages: value of testing is less certain
Assessments: Range of motion
• Method
– Goniometry
• Aims
– Baseline: identify emerging muscle hypoextensibility and joint
contractures that might contribute/lead to functional deterioration or
musculoskeletal or integumentary problems
– To identify need for additional/altered therapeutic/surgical intervetion
(i.e. orthoses, splinting, use of standers, iliotibial band lengthening)
• Ambulatory
– Lower extremities: hip, knee, ankle joints, iliotibial band, hamstrings,
gastrocnemius
• Non-Ambulatory
– Lower extremities: hip, knee, ankle joints, iliotibial band, hamstrings,
gastrocnemius
– Upper extremities: elbow, wrist, long finger flexors
Assessments: Timed Testing
• Method
– Standardised use of timed function tests
• Aims
– Easy and relevant measure of daily functional status and
responsiveness to change
• Ambulatory
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Timed 10m walk
Timed Gowers’ manouvre
Time to climb 4 stairs
Time to rise from chair
Time to put on a shirt may be relevant in late ambulatory stage
• Non-Ambulatory
– Time to put on a shirt may be relevant in early non-ambulatory stage
– Timed testing not applicable in late non-ambulatory stage
Assessments: Motor function scales
• Method
– Assessment of motor function in specific domains to give a composite
score
• Aims
– Allows monitoring of progression and response to therapy
• Ambulatory
– Vignos lower extremity scale
– North Star Ambulatory Assessment
– Motor function measure
• Non-Ambulatory
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Brooke upper extremity scale
Egen Klassifikation functional assessment
Hammersmith motor scales
Motor function measure
Assessments: Activities of daily living
• Method
– Assessment of impairment in daily activities in the home, school and
community settings
• Aims
– Highly relevant to targeted input with aids, adaptation, and access to
environmental controls
• Ambulatory
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Frequency of falls, step activity monitoring
Self-care skills
Writing, computer use
Functioning in school and community settings
• Non-Ambulatory
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Self-care skills
Writing, computer use
Control of manual and electric wheelchair
Functioning in school and community settings
Drug Treatments
• Steroids are only evidence-based drug
treatment for musculoskeletal DMD symptoms
• Effective and safe use is based on regular
assessment of function and side-effects
• As new evidence is available, these guidelines
will be revised
Steroid Treatment: Introduction
• Significant experience in steroid use for many
conditions
• Benefits should be balanced with proactive
management of possible side-effects
• Use of steroids very important: should be
discussed with all families early
Steroids: The Basics
• Steroids are the only drugs known to slow decline
in muscle strength and motor function in DMD
• Goals
– Help child walk independently for longer
– Minimise later breathing, heart and orthopaedic
problems
– Can also reduce risk of scoliosis
• Prevention/management of side-effects should
be proactive and anticipatory.
• Early intervention to prevent problems.
Steroids: Starting treatment
• Optimal time for starting treatment is when
motor skills have reached a plateau (4-6yrs)
• Not recommended to start steroids in children
who are still gaining motor skills (esp <2 yrs)
• Recommended national vaccination schedule
should be completed prior to beginning
steroid treatment
• Varicella (chicken pox) immunity should be
established
Steroids: Starting treatment (2)
• Decision to initiate treatment should be based on
a serial assessment and parental report: care is
required if initiating steroid treatment at an initial
visit, or as a second-opinion consultation
• Starting treatment in non-ambulant boys is an
individual decision, which should take into
consideration individual risk factors
• Many experts recommend continuation of steroid
treatment after the loss of ambulation, to
preserve upper limb strength, slow scoliosis, and
delay decline in respiratory and cardiac function
Steroid Regimes 1
• Two steroids recommended for DMD
– Prednisone (also known as prednisolone)
– Deflazacort
• Believed to work similarly: neither known to be better
• Planned trials will provide more knowledge
• Choice of steroid depends on
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Availability
Cost to family
The way the drug is taken
Perceived side effects
Steroids: Prednisone
• Inexpensive, both tablet/liquid fomulations
• Recommended starting dose: 0.75mg/kg/day
• In ambulatory individuals dosage commonly
increased as child grows, to ~40kg in weight
• Max dose capped at ~30mg/kg/day
• Non-ambulatory teenagers above 40kg:
– Dosage often allowed to drift down to 0.3-0.6mg/kg/day
range: below cap, but still shows substantial benefits
Steroids: Deflazacort
• May have slightly lower risk of weight gain
• More expensive than prednisone, available in
fewer tablet sizes, and liquid formulation not
widely available.
• Recommended starting dose: 0.9mg/kg/day
• In ambulatory individuals dosage commonly
increased as child grows, to ~40kg in weight
• Max dose capped at ~36mg/kg/day
• Non-ambulatory teenagers above 40kg:
– Dosage often allowed to drift down to 0.5-0.7mg/kg/day range:
below cap, but still shows substantial benefits
Steroid Regimes 2
• Daily dose of steroids better understood than alternate
regimes (trial data may modify this)
• Maintenance steroid dose
– Balance between growth, individual response, and burden of
side-effects
– Should be reviewed at every clinic visit, based on test results
and tolerability/manageability of side effects
• For boys on relatively low dosage (less than starting dose
per kg of body weight) who begin to show functional
decline, it may be necessary to consider a “functional
rescue” adjustment.
– The dosage is increased to target, and the individual reevaluated for any benefit in 2-3 months.
Initiation of steroids in nonambulatory individuals
• No consensus on optimal steroid dosage if
initiated in a non-ambulatory individual
• Not known how effective this treatment is in
preventing scoliosis or stabilising
cardiac/respiratory function
• This area warrants further study
Steroid management and side effects
• Some patients may experience short-lived side-effects
(hyperactivity, mood swings) for a few hours after
medication is given. Administration in the afternoon
may alleviate these difficulties
• Before starting/stopping medication, the doctor should
be consulted
• Doctors should always be informed that a patient is on
steroids – especially if considering surgery, or during
infection/injury, as steroids can suppress the immune
system.
• Patients should never stop taking steroids suddenly
Management of steroid medication
• Dose reduction suggested if intolerable/nonmanageable side-effects occur, with
reassessment by phone/clinical visit one
month later to assess control of side effects
• If daily dosing schedule leads to
unmanageable and/or intolerable side effects
that do not improve when the dose is
reduced, it is appropriate to change to an
alternative regime
Management of steroid medication (2)
• Steroid therapy should not be abandoned until at
least one dosage reduction and change to an
alternative regime have been pursued, for both
ambulatory and non-ambulatory patients
• Should adjustments prove ineffective in making
any significant side-effects sufficiently
manageable/tolerable, it is necessary to
discontinue steroid therapy.
– Decision should be made in partnership with the
patient and family
– Steroids should never be stopped suddenly
Other drugs and supplements
• Oxandrolone, an anabolic steroid, is not recommended
• Safety in the use of botulinum toxin A (Botox) has not been studied in
treatment/prevention of contractures for DMD and is not
recommended
• No support for systemic use of creatine; if a patient is taking creatine
and has evidence of kidney problems it is necessary to discontinue this
supplement
• Due to a paucity of evidence in published literature, no
recommendations can be made about other drugs/supplements,
including:
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Co-enzyme Q10
Carnitine
Amino acids (glutamine, arginine)
Anti-inflammatories/antioxidants (fish oil, vitamin E, green tea extract,
pentoxifylline)
– Herbal/botanical extracts
• Additional research is needed in this area
Steroid side effects: recommended
monitoring and intervention
• Different people will have very different
responses to steroids. Some of the more
common side-effects are listed below.
• Key to successful management is an
awareness of potential side-effects,
preventing/reducing them where possible.
Side effects: general & cosmetic
Steroid side effect
Recommended monitoring
Weight gain, obesity Particular vigilance needed if
and Cushingoid
patient, parents, or siblings
features
are obese
Intervention
Implement proactive dietary
management for the entire
family, not just the patient
Dietary advice to be
reinforced before starting
steroids; warn about
increased appetite
Consider change from
prednisone to deflazacort
Hirsutism
Forewarn parents
Does not usually occur to an
extent that warrants a change
in medication
Acne, tinea, warts
More noticeable in teenagers
Use ancillary treatment
measures (topical prescription)
and do not rush to change the
GC regimen unless the boy is
emotionally distressed
Select an alternative regimen
Side effects: general & cosmetic (2),
behavioural
Steroid side effect
Recommended monitoring
Intervention
Growth retardation
Monitor height at least every
6 months as part of general
care (stature often small in
DMD even without steroids)
Consider endocrine evaluation
if growth plateaus
Delayed puberty
Monitor Tanner stage
Consider endocrine
assessment if notably delayed
or patient is upset by the delay
Identify any family history of
delayed sexual maturation
Adverse behavioural Identify any baseline mood,
changes
temperament, ADHD issues,
and advise parents that these
often transiently worsen in
the initial 6 weeks on GC
therapy
Decide whether baseline issues
should be treated before
starting GC therapy (e.g. ADHD
counselling or prescription)
Consider changing timing of GC
medication to later in the day
Consider behavioural health
referral
Side effects: immune/adrenal
suppression
Steroid side effect
Recommended monitoring
Intervention
Immune/adrenal
suppression
Advise parents of risk of
serious infection and need to
promptly address minor
infection
Obtain varicella immunisation before
starting GC therapy; confirm with
protective serum titre
Advise parents to inform all
medical personnel that their
child is on steroids and carry
steroid alert card
Ensure that the GC is not
stopped abruptly
Engage in tuberculosis surveillance
Obtain infectious diseases
consultation if serious infection
occurs
Substitute prednisone equivalent if
deflazacort is temporarily unavailable
Implement intravenous stress-dose
hydrocortisone or
methylprednisolone coverage for
surgery or major illness (no accepted
treatment strategy; anaesthesia or
endocrine consultation
recommended)
Give intravenous coverage if nothing
by mouth
Side effects: hypertension, glucose
intolerance, gastric complications (1)
Steroid side effect
Recommended monitoring
Intervention
Hypertension
Monitor blood pressure as
percentile for height and sex
at each clinic visit
If blood pressure >99%, reduce
salt intake, weight reduction
Urine dipstick for glucose at
clinic visits
If urine is glucose-positive,
then try fasting or postprandial blood glucose, and if
abnormal, then seek an
endocrine consultation
Glucose intolerance
Enquire about polyuria,
polydipsia
Gastritis /
Gastroesophagal
Reflux Disease
(GERD)
Enquire about GERD
symptoms (heartburn)
Advise parents to report
symptoms
If ineffective, refer for possible
ACE inhibitor or β blocker
medication
Avoid NSAIDs
Prescribe ranitidine or protonpump inhibitor and antacid if
symptomatic
Side effects: gastric complications (2),
cataracts
Steroid side effect
Recommended monitoring
Intervention
Peptic ulcer disease
Advise parents of risk and to
report symptoms
Avoid NSAIDs
History of gastritis, GERD,
abdominal pain, or faecal
blood
Test stool for blood if anaemic
or suggestive history
Cataracts
Annual ophthalmological
examination
Prescribe ranitidine or protonpump inhibitor and antacid if
symptomatic
Seek gastrointestinal
consultation
Consider switching from
deflazacort to prednisone if
cataracts evolve that affect
vision
Seek ophthalmology
consultation
Side effects: bone demineralisation
Steroid side effect
Recommended monitoring
Intervention
Bone
demineralisation
and increased
fracture risk
Take careful fracture history
For 25-hydroxy vitamin D
concentration 20–31 nmol/L,
give 1000 IU orally twice daily,
for <20 nmol/L, give 2000 IU
orally twice daily
Annual DEXA to monitor bone
density
Annual monitoring of 25hydroxy vitamin D blood
concentration (ideally late
winter in seasonal climates)
and supplement with vitamin
D3 if level is <32 nmol/L
Dietitian should assess
calcium and vitamin D intake
Recheck serum 25-hydroxy
vitamin D concentration again
after 3 months on therapy
Encourage weight-bearing
activities
Take multivitamin supplements
with vitamin D3
Consider bisphosphonates,
such as pamidronate
Side effects: myoglobinuria
Steroid side effect
Recommended monitoring
Intervention
Myoglobinuria
Enquire about abnormal
coloration of urine after
exercise, urine testing
Advise avoidance of excessive
eccentric (eg, descending
stairs, squatting down,
trampolining) and
resistive exercise
Commence renal investigations
if persistent
Schema for initiation of GC medication
Prednisone
Deflazacort
0.75mg/kg/day
0.9mg/kg/day
First line unless pre-existing weight
and/or behavioural issues favour
deflazacort
Consider as first line when pre-existing
weight and/or behavioural issues
Age <2 years
Improving (typical): GC
initiation not
recommended
Plateau (uncommon):
monitor closely
Decline (atypical): consider
alternative
diagnoses/concomitant
pathology
Age 2-5 years
Age ≥ 6 years
Improving: GC initiation not
recommended
Improving (uncommon):
consider BMD
Plateau: GC initiation
recommended
Plateau: GC initiation highly
recommended
Decline: GC initiation highly
recommended
Decline: GC initiation highly
recommended
Non-ambulatory: refer to
text
Schema for management of GC
medication
If any side effects are manageable and tolerable
Incremental increase in dose for growth to maximum weight of 40kg (prednisone 30mg/day or
deflazacort 36mg/day)
If in functional decline and on subtarget dose, increase to target dose
Continue even when non-ambulatory for retarding of scoliosis, decline in pulmonary function
tests, and possible heart failure.
If side-effects unmanageable/intolerable : change in GC regimen necessary
Reduce daily dosage by 25-33% and reassess in 1 month
If side-effects are still unmanageable and intolerable
Consider lowering additional 25% on daily schedule; minimum effective daily dose of
prednisone is approximately 0.3mg/kg/day
If weight gain/behaviour are main issues, consider change to deflazacort or high-dose
weekend
If patient/parents about to abandon treatment entirely, consider 10/10 or 10/20
intermittent dose
Alternative GC dosing strategies
Prednisone
dose
Deflazacort
dose
Comments
In case of sideeffects
Alternate
day
0.75-1.25mg/kg
every other day
2mg/kg every
other day
Less effective but consider
when daily schedule has
side-effects that are not
effectively managed or
tolerated
Must reduce
dose if sideeffects are not
manageable or
tolerable
High-dose
weekend
5mg/kg given
each Friday and
Saturday
Not yet tested Less data on effectiveness
as compared to a daily
schedule, especially if
weight gain/behavioural
issues are problematic
Must reduce
dose if sideeffects are not
manageable or
tolerable
Intermittent
0.75mg/kg for
10 days
alternating with
10-20 days off
medication
0.6mg/kg on
days 1-20 and
none for the
remainder of
the month
Must reduce
dose if sideeffects are not
manageable or
tolerable
Less effective, but has
fewer side effects.
Considered the least
effective, but possibly best
tolerated regimen before
abandoning steroid
treatment altogether
References & Resources
• The Diagnosis and Management of Duchenne
Muscular Dystrophy, Bushby K et al, Lancet
Neurology 2010 9 (1) 77-93 & Lancet
Neurology 2010 9 (2) 177-189
– Particularly references, p186-188
• The Diagnosis and Management of Duchenne
Muscular Dystrophy: A Guide for Families
• TREAT-NMD website: www.treat-nmd.eu
• CARE-NMD website: www.care-nmd.eu