Neuromuscular disorders in children; making sense of the muscle, lung and brain

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Neuromuscular disorders in children making
sense of the muscle, lung and brain

• Sleep Course-Bristol
• Anirban Majumdar
• Consultant Paediatric Neurologist

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Neuromuscular conditions

1. Overview
2. Diagnosis
3. Pathophysiology
4. Surveillance and Treatments for NMD
5. Trends and Survival in NM disorders
6. Who goes into respiratory failure ?
7. The future
8. What we can do now
9. What we will try to do in the future
10. Clinical vignettes
11. Neuromuscular / respiratory- the interface

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• Brain
• Brain stem
• Spinal cord
• Anterior horn cell
• Nerve
• Neuromuscular junction

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• Multisystem disorders
• Ataxias
• Metabolic/ Mitochondrial
• Chanelopathies/ storage disorders
• SMA
• Demylinating/
• Axonal
• Neuropathy

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Tone

• Hypotonia is a common diagnostic problem
• Hypotonia floppiness

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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

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Recognizable patterns

• Hypotonia weakness neuromuscular disease
• Hypotonia without weakness may be
• CNS
• birth asphyxia
• CNS malformations
• Metabolic
• lipidoses/MPS
• amino-organic acidurias
• peroxisomal
• Connective tissue
• Ehlers-Danlos/Marfan
• OI
• Chromosomal
• PWS
• Downs

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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

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History Clinical examination Genetic
analysis Biochemistry Immunology Muscle
imaging EMG/NCV Muscle Biopsy Nerve
biopsy Immunohistochemistry
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Historical Notes

• 1851 Edward Merynon describes 10 cases in
  England
• 1861 Duchenne de Boulogne fils. De la paralysie
  atrophique graisseuse de lenfance.
• Archives Generales de Medicine 1861

Autographed copy of De la Paralysie Musculaire
Pseudo-hypertrophique1868
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Clinical presentation

• Delayed walking
• Waddling gait
• Gower sign
• Pelvic muscle weakness and lumbar lordosis
• Global developmental delay
• Pseudo hypertrophy of muscles
• Learning difficulties
• Raised CK levels

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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

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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

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Normal
DystrophiN
Dystrophin Gene dystrophin pre-mRNA dystrophin
mRNA DystrophiN protein
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Duchenne MD
DysX
DysXrophin Gene dysxrophin pre-mRNA dysxrophin
mRNA DysX protein
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Becker MD
DysrophiN
Dys-rophin Gene dys-rophin pre-mRNA dys-rophin
mRNA DysrophiN protein
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Surveillance and Treatments in DMD

• Heart
• Respiratory
• Scoliosis
• Maintaining ambulation

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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

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Respiratory -Problems

• Increased amount of chest infections
• FVC lt40 indicates sleep studies
• Consider flu and pneumococcal vaccination
• Early antibiotic treatment
• Physio Postural drainage / assisted cough

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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.

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Evolution of respiratory failure in NMD
Surveillance
Normal breathing
FVC 100 pred
Monitor
FVC lt 60 pred
REM related sleep disordered breathing
Chest physio
FVC lt 40 pred
NIV
Chest infection
Cough assist
NREM and REM sleep disordered breathing
FVC lt 20 pred
Daytime ventilatory failure
Simonds A.
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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 lt40 predicted value
• serial measurement of overnight oxymetry and CO2
• allows the recognition of the development of
  nocturnal respiratory failure.

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Respiratory- Non-invasive ventilation

• Early discussion
• Indication FVC lt40 , nocturnal hypoventilation
• Mean age 17 years (Newcastle)
• Improvement of daytime symptoms
• Less infections
• Daytime ventilation later
• ? Tolerance

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Ventilation- the benefits

• 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.
• 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.
• Ventilation
• mean age of death (Newcastle) 19 years to at
  least 25 years
• survival into the fourth decade is now possible !

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Current Respiratory guidelines

• ATS Consensus Statement Respiratory Care of the
  patient with Duchenne Muscular Dystrophy
  AJRCCM2004456-65
• Recommendation for Respiratory care of children
  with Spinal Muscular Atrophy Type II III
  Neuromusc Disord 200313184-89
• Ventilatory support in Congenital Neuromuscular
  Disorders congenital myopathies, congenital
  muscular dystrophies and SMA II Neuromusc Disord
  20041456-69
• MDC Recommendations for the Respiratory care of
  adults with Muscle Disorders (2005-in
  preparation)
• Consensus Conference Clin indications for NIV in
  CRF. Chest 1999116 521-4

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Are we getting it right ?Incidence and
mortality rate for DMD (Denmark)
Jeppesen J et al Neuromusc Dis 2003
13804-2
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Management trends in DMD

Jeppesen J Neuromusc Dis 200313804-12
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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

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Prophylactic NIPPV in DMD

Preventative / prophylactic NIV in asymptomatic
normocapnic DMD patients is not beneficial
Raphael et al Lancet 1994
Control
NIV
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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

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How do we compare to others ?
European use of ventilation by disease categories
Lloyd Owen ERJ 2005
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Cardiovascular
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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

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Cardiac -Treatment

• Single study suggests ACE inhibitor use before
  cardiac abnormalities are detectable as
  protective in the long term
• Currently treatment with ACE inhibitors /-
  ß-blockers is initiated when echo findings of LV
  dysfunction
• Diuretics etc as required for complications

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Special case of Emery Dreyfus Muscular Dystrophy

• X linked EDMD- arrythmias- pacemaker
• AD EDMD- VF-implantable defibrillator

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Scoliosis surveillance

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Ways of treating scoliosis



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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
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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
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Trends in survival in DMD- secular trends

Eagle et al Neuromusc Dis 2002
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SS scoliosis surgery
Eagle et al Neuromusc Dis 2002
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Joint neuro respiratory clinics- doing the right
thing ? YES When is the right time to refer to
the respiratory team ? EARLY
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Advantages of Joint Clinics

• Dont send patient to x, y, z
• Invite x, y, z, to be part of your team

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Who is involved with the care of NM patients?

• 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,

MULTIDISCIPLINARY
Parents
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The future

• What we can do .
• What we are trying to do.

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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

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• 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

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PTC124
PTC 124 nonsense mutation allows the cellular
machinery to read through premature stop codons
in mRNA
The future Nonsense mutation correction
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Gene therapy progress and prospects Duchenne
muscular dystrophyK Foster, H Foster and J
G Dickson http//www.nature.com/gt/journal/v13/n2
4/full/3302877a.html
The future Exon skipping
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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-ß 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?