Introduction to Pediatric Neuromuscular Disorders

 

 

Neuromuscular diseases by location:

  • Motor neuron – upper and lower motor neuron
    • Guillain-Barrι Syndrome
      • Acute inflammatory demyelinating polyneuropathy
      • AMAN – acute motor axonal neuropathy (campylobacter)
      • AMSAN – acute motor/sensory axonal neuropathy
      • Miller-Fischer – ataxia, areflexia, ophthalmoplegia
      • acute panautonomic neuropathy – rare
    • Spinal muscular atrophy
      • progressive muscle weakness caused by anterior horn cell loss
      • patient is weak and hypotonic, but bright and normal cognitive ability
      • mutation in the SMA locus (chromosome 5q11.12-q13.3)
      • type I – Werdnig-Hoffman disease, onset <6 months, survival <2 years
      • type II – chronic SMA, onset 6-18 months, survival to adolescence
      • type III – Kugelburg-Welander disease, onset >18 months, survival to 6th decade
  • Neuromuscular junction
    • Myasthenia gravis
      • Autoimmune antibodies against acetylcholine nicotinic postsynaptic receptors
      • Prominent bulbar involvement (extraocular movements, ptosis)
      • Weakness worse with continued activity
    • Botulism
      • Botulinum toxin binds proteins involved in synaptic vesicle release into NMJ
  • Muscle
    • Duchenne/Becker muscular dystrophy
      • Progressive proximal muscle weakness caused by mutation in dystrophin (Xp21.2)
      • Duchenne MD
        • Presentation before age 5. calf hypertrophy, wheelchair bound by age 10
      • Becker MD – continues to be ambulatory into teens

 

Neuromuscular diseases by cause:

  • Muscular dystrophies
    • Disorders of structural proteins of the muscle sarcolemma
    • Progressive muscle weakness and atrophy of specific distribution
    • Genetic disorders:
      • Autosomal recessive, e.g., LGMD type 2A-H
      • Autosomal dominant, e.g., LGMD type 1A-C, fascioscapulohumeral dystrophy, myotonic dystrophy
      • X-linked, e.g., Duchenne MD, Becker MD (dystrophin), Emery-Dreifuss MD (emerin)
    • Congenital muscular dystrophies
      • Combined muscle, eye, and brain abnormalities
      • E.g. Fukuyama MD, muscle-eye-brain disease, Walker-Warburg syndrome
  • Structural myopathies
    • Disorders of structural proteins from within the muscle fibre
    • Congenital hypotonia and weakness, non-progressive (except for growth spurts)
    • Nemaline myopathy
      • Named for the nemaline rods seen on muscle histology
      • Proximal, bulbar, trunk/respiratory muscle weakness
      • Disorder of the alpha-actin, nebulin, tropomyosin 2, tropomyosin 3, or troponin T
    • Central core myopathy (ryanodine receptor 1 (RYR1))
    • Multiminicore myopathy (selenoprotein N (SEPN1), ryanodine receptor 1 (RYR1))
    • Centronuclear myopathy (X-linked myotubularin (MTM1))
  • Inflammatory myopathies
    • Dermatomyositis
      • Perivascular inflammation causing muscle fibre ischemia
      • Muscle pain, weakness, violaceous discolouration of eyelids, erythematous skin lesions over extensor surfaces of joints, malar rash, percutaneous calcium deposits, mildly elevated CK
    • Polymyositis
      • Inflammation of muscle fibres, rare in children
  • Metabolic myopathies
    • Episodic worsening of muscle weakness and CK elevation
    • Impaired metabolism of glycogen, lipids, or mitochondrial function
    • Due to medications, toxins, nutritional deficiencies
  • Infectious myopathies
    • Viral, parasitic myositis

 

Patient history

  • Clinical history
    • Age of onset of symptoms and rate of progression
    • Antenatal history – reduced fetal movements, breech presentation, polyhydramnios
    • Neonatal history – poor feeding, weak cry, frequent aspiration pneumonia
    • Developmental history – delayed motor milestones, loss of milestones
  • Genetic history
    • Detailed family pedigree, consanguinity, sex of affected relatives (inheritance)
    • Examine parents and siblings if possible
    • Reactions to anaesthetics (malignant hyperthermia)
  • Symptoms
    • Distribution of muscle weakness – localized, diffuse, proximal/distal, bulbar, respiratory
    • Exercise tolerance, fatigue – myasthenia gravis, glycolytic enzyme deficiency, vascular ischemia
    • Muscle pain – pain at rest  in inflammatory myopathies, vasculitis, viral or parasitic myositis
    • Abnormal muscle activity
      • Fasciculations – spontaneous activation of motor units (Normal if stress, also dehydration, renal failure, electrophyte imbalance.)
      • Cramps – involuntary, painful contractions (Normal after strenuous exertion, caffeine.
      • Myotonia – tetanic activation of muscle fibers, e.g., myotonic dystrophy, myotonia congenita
      • Tetany – sustained muscle contraction, e.g., hypocalcemia, hypomagnesemia, metabolic alkalosis, Clostridium tetani.

 

Physical examination

  • Inspection
    • Symmetry, atrophy, hypertrophy, pseudohypertrophy
    • Pseudohypertrophy (dystrophinopathy, childhood acid maltase deficiency)
    • Fasciculations, myokymia, clinical and percussion myotonia
    • Scapular winging, kyphoscoliosis
    • Contractures
    • Gait abnormalities, e.g, waddling gait (pelvic weakness), foot drop
    • Face – ptosis, extraocular movement palsies
    • Elongated facies (facial muscle weakness)
    • High arched palate (facial muscle weakness in utero)
  • Palpation
    • Tendernous, nodules, fibrosis (Duchenne MD)
    • Hypotonia, head control, truncal tone, limb tone
  • Manual muscle strength testing
    • Formal muscle strength grading
    • Observation of strength, e.g., Gower’s manuevre
  • Percussion
    • Deep tendon reflexes
    • Percussion of tongue, finger extensors, thenar eminence to elicit myotonia
    • Percussion of injured peripheral nerves to elicit pain (e.g., Tinel sign)
  • General examination
    • Skin, hair
    • ECG and echocardiogram – heart muscle

 

Investigations

  • Laboratory tests
    • Creatine kinase (CK)
      • >20000 IU – acute myoglobinuria, e.g., toxic, traumatic, malignant hyperthermia
      • 5000-10000 IU – DMD, polymyositis, BMD w/ exertion
      • 1000-2000 – BMD, mild myositis
      • 500 – exercise, idiopathic hyperCKemia, can be increased after EMG testing
      • 250 – normal in structural myopathies and myotonia
    • Lactate – elevated in mitochondrial myopathies
    • Electrolytes
    • Molecular genetic studies
  • Electromyography and nerve conduction studies (EMG/NCS)
  • Muscle imaging (ultrasound, CT, MRI)
  • Muscle biopsy (histopathology, electron microscopy, immunohistochemistry)

 

Management

  • Specfiic management depends on disorder, e.g., steroids in DMD and dermatomyositis, Mestinon (pyridostigmine) for myasthenia gravis, IVIG for Guillain-Barrι syndrome
  • Supportive care – physiotherapy, occupational therapy, feeding, respiratory
  • Ensure screening for associated manifestations – cardiac, ophthalmologic, skeletal
  • Avoid malignant hyperthermia (inhaled anaesthetics, muscle blockers), e.g., in DMD, BMD, nemaline myopathy, central core myopathy, multiminicore myopathy
  • Genetic screening and counselling of family members