NMJ conditions Flashcards
Symptoms of muscle/NMJ disorders
- Muscle pain
- Weakness
- Cramp
- Fatigue
- Wasting
- Family History
- Note: Importance of absence of sensory Sx
Discuss diagnostic approach
- weakness constant (myopathies) or fluctuating (NMJ)?
- lifelong or acquired?
- progressive (congenital, mitochondrial….) or not(congenital)?
List some considerations
- Is it a pure muscle/NMJ disease? i.e. no bowel involvement etc
- How long has it been coming on? – chronicity
- Pattern of weakness – distal vs proximal vs ocular/facial vs fluctuating
- Provoking factors –heat/cold/fatigue/drugs
- Associated disease – rash, mitochondrial, autoimmune diseases, thyroid,
- Family History
- Medications – corticosteroids, lipid lowering agents
List some investigations for muscular disease
- Blood Tests
- CK ^[no strenuous exercise in week], Antibodies e.g. for autoimmune etiologies, TFTs e.g. for thyroid associated myopathies
- Genetic Studies - but limit of e.g. WGS is expecting certain variant to be useful
- Neurophysiology - EMG, NCS
- Muscle Biopsy - ‘forgiving’, but painful and not patient-friendly. Only useful if muscle is diseased and not dead. Can be open or core
- Imaging i.e. MRI of muscle, esp. to guide biopsy
In general limited.
europhysiological Ix of Weakness
- Repetitive Stimulation
- Decrement for MG
- Exclude neuropathy
- EMG – differentiate between neuropathic and myopathic features: observe wavelength and amplitude
- Myopathic EMG – small polyphasic potentials, may have spontaneous activity
Describe MG
- Autoimmune disease
- Antibodies to Acetylcholine Receptor (AChR)
- 2 age incidences
- Young= female dominated
- Older= less sex difference
- Prevalence 20 per 100,000, incidence 3-4 per million
Describe MG pathogenesis
- Anti-AChR Abs
- Associated autoimmune diseases
- Infants of MG mothers have transient disease
- Response to immune mediated treatments
- B-cell mediated disease
- T-cells important as thymic abnormalities well recognized= probably primary T cell disease that evokes B response
- Abs are polyclonal IgG
- MUSK Abs in 10-20% of generalized disease
Myasthenia and Antibodies
- AChR Abs in 80-85% of generalized and 55% of ocular
- AChR –ve generalized disease, 70% are MUSK +ve
- AChR Abs
- Block Ach binding site
- Cross-linking of AChR on postsynaptic receptor
- C’ activation with destruction of postsynaptic receptor
- Muscle-specific tyrosine kinase (MUSK) reduces AChR clustering
Desribe MG clinical features
- Ocular or generalised forms
- Ocular weakness- either ptosis or diplopia (high number of NMJs in the eye– greater eloquence of movement)
- Initial symptom in 2/3
- Limb weakness – generalised weakness
- Most often proximal muscles
- Can include bulbar muscles
- Exacerbating factors – intercurrent illnesses, esp. infection and drugs (A/Bs and anaesthetics)
- Myasthenic crisis – sudden respiratory failure
- Fluctuating weakness exacerbated by exercise and improved with rest – ‘fatigue’
Describe MG investigations
- Antibodies
- +ve in 85% if generalised disease or 50% of ocular
- Neurophysiology
- Repetitive stimulation
- Single fibre study
- Pharmacology Testing
- edrophonium challenge - other agents used these days. Inhibit AChase to reverse presenting symptoms
- Imaging
- chest CT for thymoma or hyperplasia - identify a red flag
Describe MG treatment
- No good RCT’s available
- Broad symptom management approach
- Cholinesterase Inhibitors – pyridostigmine
- Corticosteroids but long-term side effects
- Azathioprine
- Plasmapheresis – esp. if myasthenic crisis (resp weakness)
- IVIG – useful in acute setting
- Thymectomy – esp. if thymic hyperplasia
- Other immunosuppressants, eg mycophenylate, rituximab (CD20)
Cholinesterase Inhibitors
- Reduce breakdown of acetylcholine at NMJ
- Pyridostigmine main agent available in Aus
- 10mg and 60mg tabs
- Main problem is that they do not modify the disease
- With time progressive loss of AChRAbs
Generalised MG
- Corticosteroids effective – can get initial paradoxical worsening. Need high dose for remission
- IVIG or aphaeresis helpful in acute setting
- Azathioprine as steroid sparing agent – 6/12 to work
- Thymectomy if young, thymoma, hyperplasia and early in the disease.
Describe LEMS
- Antibodies against presynaptic voltage calcium gated channel
- SCLC in 50-60% i.e. paraneoplastic
- Generalised weakness
- Ocular involvement less common
- Reflexes depressed but increase with reinforcement
- Augmentation on repetitive stimulation esp. at high frequency or post-contraction
- Rx 3,4 diaminopyridine
Describe botulism
- Types:
- Foodborne
- Wound
- Overdosage for treatment
- Infantile botulism
- Clinical Features:
- Pupillary involvement
- Autonomic involvement
- Reflexes may be depressed
- Dx:
- wound culture
- serum Ab
- toxin in food
Describe DMD
- X linked
- In-frame deletion – severe = Duchene’s (DMD)
- Out of frame deletion – milder = Becker’s (BMD)
- DMD is 1 per 3500 male births, BMD 1/10th
- Although X linked, 1/3rd sporadic
- Dystrophin a binding protein
Dystrophins - DMD
- Normal at birth
- Clumsy in first year
- Arise using Gower’s procedure
- Child does not run or jump
- By 6-7 start to fall
- Wheelchair usually by 12
- Scoliosis and cardiac involvement
- Death in early adulthood or late teens, improving
Describe Becker’s MD
- Weakness usually appears in the first decade
- May not present till 30’s
- Walk beyond 15
- Calf hypertrophy, contractures like DMD
- Leg/muscle cramps common
- Cardiac disease, though later
- Corticosteroids less effective
Describe FSHD
- Autosomal dominant
- Prevalence 1-2 per 100,000, likely slightly higher
- Chr. 4q35
- Severity may vary within the same family
FSHD – Clinical Features
- Facial weakness
- Scapula weakness and winging
- Biceps, triceps affected, Deltoid spared
- Ankle dorsiflexors and abdominal muscles may be affected
- Asymmetry common
Describe myotonic dystrophy
- 2 types – distal and proximal
- DM 1 more common
- AD inheritance
- 1 per 8000 births
- Chr. 19q13.3
- Trinucleotide repeat of CTG = Gene testing now diagnostic tool of choice
- Correlation with repeat size and anticipation
Myotonic Dystrophy
- Hand weakness
- Foot drop
- Ptosis and facial weakness
- Neck weakness
- Myotonia
DM – Other features
- Frontal balding
- Cardiac involvement
- Daytime somnolence
- Diabetes
- Cataracts
- Other endocrine involvement
