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Neuromuscular disorders in children;
making sense of the muscle, lung and brain
Sleep Course-Bristol
Anirban Majumdar
Consultant Paediatric Neurologist
Neuromuscular conditions
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Overview
Diagnosis
Pathophysiology
Surveillance and Treatments for NMD
Trends and Survival in NM disorders
Who goes into respiratory failure ?
The future
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2.
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What we can do now
What we will try to do in the future
Clinical vignettes
Neuromuscular / respiratory- the interface
Brain
Brain stem
Spinal cord
Anterior horn cell
Nerve
Neuromuscular junction
Muscle
Multisystem disorders
Ataxias
Metabolic/ Mitochondrial
Chanelopathies/ storage disorders
SMA
Demylinating/
Axonal
Neuropathy
Myesthenias
Dystrophy
Myopathy
Tone
Hypotonia is a common diagnostic problem
Hypotonia = floppiness
Weakness
MRC evaluation of muscle power
0 – no contraction
1- flicker
2- Active movement with gravity eliminated
3- Active movement against gravity
4 - Active movement against gravity and resistance
5- Normal power
+ and – denotes through what range of normal
movement
Recognizable patterns
Hypotonia + weakness = neuromuscular disease
Hypotonia without weakness may be
•CNS
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birth asphyxia
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CNS malformations
•Metabolic
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lipidoses/MPS
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amino-organic acidurias
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peroxisomal
•Connective tissue
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Ehlers-Danlos/Marfan
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OI
•Chromosomal
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PWS
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Downs
Neuromuscular disorders
• Presents with
– floppiness
– weakness
– delayed motor milestones,
– abnormal gait, clumsiness,
– speech and swallowing difficulties
– Respiratory, cardiac failure
• Age : from newborn to adult life
• Very wide range of severity and disability
• Intelligence : very wide range
History
Clinical examination
Genetic analysis
Biochemistry
Immunology
Muscle imaging
EMG/NCV
Muscle Biopsy
Nerve biopsy
Immunohistochemistry
Historical Notes
1851:
Edward Merynon describes 10 cases in England
1861:
Duchenne de Boulogne fils. De la paralysie
atrophique graisseuse de l’enfance.
Archives Generales de Medicine 1861
Autographed copy of: De la Paralysie
Musculaire Pseudo-hypertrophique
1868
Clinical presentation
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Delayed walking
Waddling gait
Gower sign
Pelvic muscle weakness and lumbar
lordosis
Global developmental delay
Pseudo hypertrophy of muscles
Learning difficulties
Raised CK levels
Duchenne (Xp21) MD
• The most common muscle disorder in childhood
• X-linked, 30 per 100 000 liveborn males (neonatal
screening)
• Symptoms appear in first 5 years
Genetics
• X linked with recessive inheritance
• 1/3 spontaneous mutations
• Affects 1 in 3500 live male births
• Absence or deficiency of dystrophin in
muscle membrane, smooth muscle and
brain
Normal
Dystrophin Gene
dystrophin pre-mRNA
dystrophin mRNA
DystrophiN protein
Duchenne MD
DysXrophin Gene
dysxrophin pre-mRNA
dysxrophin mRNA
DysX protein
Becker MD
Dys-rophin Gene
dys-rophin pre-mRNA
dys-rophin mRNA
DysrophiN protein
Surveillance and Treatments in DMD
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Heart
Respiratory
Scoliosis
Maintaining ambulation
Respiratory - Problems
• Respiratory problems are predictable
• Correlation with overall muscle strength and
ambulation – rarely problems in ambulant boys
• Progressive fall in FVC predicts respiratory
failure
• Nocturnal hypercapnia – subtle symptoms ie
headaches, tiredness, poor performance at
school, restless sleep
Respiratory -Problems
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Increased amount of chest infections
FVC <40 % indicates sleep studies
Consider flu and pneumococcal vaccination
Early antibiotic treatment
Physio: Postural drainage / assisted cough
What are the symptoms of progressive respiratory failure ?
• Subtle
– weight loss
– reduction in energy levels
– poor performance at school.
• Sleep disturbance
– increased requirement for turning overnight.
• Chest infections
– frequent and difficult to treat.
• Established hypercapnia and not treated
– Headaches
– general malaise, poor eating
– high risk of death from respiratory failure during intercurrent infection.
Evolution of respiratory failure in NMD
FVC 100% pred
Surveillance
Normal breathing
Monitor
REM related sleep
disordered breathing
FVC < 40% pred
NREM and REM sleep
disordered breathing
FVC < 20% pred
Daytime ventilatory failure
Simonds A.
Chest infection
FVC < 60% pred
Chest
physio
NIV
Cough
assist
Respiratory Surveillance:
• Forced Vital Capacity (FVC)
– absolute values and %
predicted for height or arm
span
– easy way to document the
progression of respiratory
muscle weakness.
• FVC drops to 1.25 l or <40%
predicted value
– serial measurement of
overnight oxymetry and CO2
– allows the recognition of the
development of nocturnal
respiratory failure.
Respiratory- Non-invasive ventilation
• Early discussion
• Indication: FVC <40 %, nocturnal
hypoventilation
• Mean age 17 years (Newcastle)
• Improvement of daytime symptoms
• Less infections
• Daytime ventilation later
• ? Tolerance
Ventilation- the benefits
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Patients notice
– frequency of chest infections falls
– infections that do occur may be effectively managed with the ventilator to assist
coughing.
– may develop a need to use the ventilator for increasing periods during the day
– a portable ventilator may need to be provided that can be transported on the
wheelchair.
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Nocturnal ventilation
– Long-term follow up studies - very effective as a treatment for respiratory failure
– often nocturnal use alone provides very good stabilisation for many years.
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Ventilation
– mean age of death (Newcastle) 19 years to at least 25 years
– survival into the fourth decade is now possible !
Current Respiratory guidelines
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ATS Consensus Statement: Respiratory Care of the patient with Duchenne Muscular
Dystrophy AJRCCM;2004:456-65
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Recommendation for Respiratory care of children with Spinal Muscular Atrophy Type II &
III Neuromusc Disord 2003;13:184-89
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Ventilatory support in Congenital Neuromuscular Disorders – congenital myopathies,
congenital muscular dystrophies and SMA II Neuromusc Disord 2004;14:56-69
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MDC Recommendations for the Respiratory care of adults with Muscle Disorders (2005-in
preparation)
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Consensus Conference: Clin indications for NIV in CRF. Chest 1999;116: 521-4
Are we getting it right ?
Incidence and mortality rate for DMD (Denmark)
Jeppesen J et al Neuromusc Dis 2003; 13:804-2
Management trends in DMD
Jeppesen J Neuromusc Dis 2003;13:804-12
When to initiate NIV in NMD
• Background:
– NIV can be lifesaving in hypercapnic patients.
– Mean survival 9.7 months in hypercapnic DMD patients if
ventilatory support not provided (Vianello et al, 1997).
– Survival extended in other cohorts (Bach, Eagle,
Simonds).
– Clinical course in other NMD not so predictable
• BUT
Preventative / prophylactic NIV
in asymptomatic normocapnic
DMD patients is not beneficial
Prophylactic NIPPV in DMD
Raphael et al Lancet 1994
Control
NIV
When to initiate NIV
• Initiation of NIV at time of nocturnal hypoventilation
before development of daytime hypercapnia will prevent
ventilatory decompensation and improve QOL
• Initiation of NIV in asymptomatic patients before the
onset of sleep disordered breathing or daytime
hypercapnia is NOT recommended
How do we compare to others ?
100%
80%
60%
40%
20%
0%
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Lung/airways
Thoracic Cage
Neuromuscular
European use of ventilation by disease categories Lloyd Owen ERJ 2005
Cardiovascular
Cardiac- Surveillance
• ECG and ECHO at diagnosis, 2-yearly until 10, yearly
thereafter (European Neuromuscular Centre, Netherland)
• 10% of female carriers develop overt cardiac failure:
ECG and ECHO at diagnosis and 5-yearly
Cardiac -Treatment
• Single study suggests ACE inhibitor use before cardiac
abnormalities are detectable as protective in the long term
• Currently treatment with ACE inhibitors +/- β-blockers is
initiated when echo findings of LV dysfunction
• Diuretics etc as required for complications
Special case of Emery Dreyfus
Muscular Dystrophy
• X linked EDMD- arrythmias- pacemaker
• AD EDMD- VF-implantable defibrillator
Scoliosis surveillance
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Factors causing loss of ambulation in Duchenne
 weakness
 contractures
progressive scoliosis
rapid growth spurt
falls/injury /fractures
 fear
 motivation
Marion Main
Ways of maintaining ambulation in NM
disorders
• maintain power
– Steroids in DMD
– Beta agonists in SMA
• control contractures/deformity
• prevent injury
• Orthoses
• maintain motivation
– child and parents/carers
Marion Main
Trends in survival in DMD- secular trends
Eagle et al Neuromusc Dis 2002
SS= scoliosis surgery
Eagle et al Neuromusc Dis 2002
Duchenne muscular dystrophy - survival in Wales by
decade of birth 1955-1995
120
100
percentage alive
80
55-64
60
65-74
75-84
85-94
40
20
0
4
6
8
10
12
14
16
18
20
age / years
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24
26
28
30
32
34
Duchenne mean survival by 5 year cohort of birth
25
20
age
15
10
5
0
55-59
60-64
65-69
70-74
year of birth
75-79
80-84
Joint neuro respiratory clinics- doing
the right thing ?
YES
When is the right time to refer to the
respiratory team ?
EARLY
Advantages of Joint Clinics
• Don’t send patient to …x, y, z
• Invite …x, y, z, to be part of your team
Who is involved with the care of NM patients?
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GP,
community paediatrician at district general hospital
hospital paediatrician at district general hospital,
paediatric neurologist at tertiary hospital,
neuromuscular specialist national centre,
paediatric respiratory consultant and nurse
paediatric cariologist
physiotherapist,
occupational therapist,
speech and language therapist,
dietician,
social worker,
geneticist,
orthotist,
wheelchair services,
orthopaedic surgeon,
spinal surgeon,
neurophysiologist,
Histopathologist,
anaesthetist,
intensivist,
special educational needs teacher.
Neuromuscular nurse specialist
palliative care team
Transitional care team to take over care on reaching adulthood
Parents
The future
1.
2.
What we can do .
What we are trying to do.
What we can do : Role of steroids
• Prednisolone / Deflazacort
• Regimes:
– Prednisolone 0.75 mg/kg/day
– Deflazacort 0.9 mg/kg/day
• consider alternate day dose or steroid breaks
• How long to give it?
• Increase in muscle strength
• Prolonged ambulation for up to 2 years
• ? Improvement in cardiac function
• ? Lessen scoliosis
• ? Improves respiratory function
Cochrane 2004: Improvement in muscle strength and function for 6 months to 2 years
What we can do in 2008 : in the UK
Scoliosis surgery
Management of nocturnal hypoventilation
Maintain ambulation
Treatment of cardiomyopathy and arrhythmias
Effective transition of care
Excellence in palliative care
What they can do in 2008 : in Europe
All the above AND
Provide social opportunities and education
Prevent social isolation
Have a job
Drive a car
Have sex / have a relationship
PTC124
PTC 124
nonsense mutation
allows the cellular
machinery to read
through premature
stop codons in
mRNA
The future:
Nonsense mutation correction
The future:
Exon skipping
Gene therapy progress and prospects: Duchenne muscular dystrophy
K Foster, H Foster and J G Dickson
http://www.nature.com/gt/journal/v13/n24/full/3302877a.html
The future:
Use of ACE-I Losartan
• angiotensin II receptor antagonist drug used to treat high blood
pressure.
• positive results in mouse model of Marfan syndrome,
• studied in mdx-mice
• TGF-β inflammatory pathway is also activated in the muscle of
DMD boys and in the mdx mouse.
• DMD already use ACE-I for treatment of cardiomyopathy
• Why not use Losartan to reduce the inflammation?