Myasthenia gravis Flashcards
Examination findings and signs of myasthenia gravis
- Variable ptosis (unilateral/bilateral asymmetrical)
- Accentuated by sustained upgaze
- Improves following eye closure
1A. Cogan lid twitch sign - upon looking down (rested), upper eyelid overshoot before saccade back to ptotic position - Furrowing of forehead with frontalis muscle (to compensate weakness)
- Weakness of oculomotor muscles (not limited to any CN) with variable strabismus and diplopia
- Caution for pseudo-INO - Bilateral facial muscle weakness
- Lack of facial expression
- On closing eyes, eyelashes not buried
- Easily overcome eye closure with finger and thumb
- Peek sign - eye drift open to reveal sclera during eye closure
- Inflate cheek easily overcome and air readily escape through lips when cheeks squeezed
- Lips cannot easily opposed - Myasthenia snarl - upper mouth corner fails to contract
- Jaw weakness, jaw hangs open, easily closed with force
- Weakness of neck muscles, flexors > extensors
- Jaw supporting sign - hands under chin to support weak jaw and neck
- Voice weak with nasal twang
- Nasal speech with prolonged vocalisation - count 1 to 25
- Proximal weakness with fatiguability, UL > LL
- Repeated abduct and adduct shoulder 10-15 times - No wasting, DTR normal, sensation normal
Look for:
1. Thymectomy scar
2. IST - steroid side effect - purpura, cushingoid
3. Associated autoimmune disease
- Hyperthyroidism, hypothyroidism
- Diabetes
- SLE
- RA
- Pernicious anaemia
- Pemphigus
- Drug history
How would you differentiate pseudo-INO in MG to actual INO?
- Sustained lateral gaze causes medial rectus of adducting eyes fatigue, thus nystagmus coarser in abducting eye
(INO - adduction becomes normal when abducting eye is covered) - Fluttering of ptotic eyelid (lid hopping)
- Intrasaccadic fatigue:
- Saccadic slowing with repeated eye movement due to fatiguability
- Saccades increasing duration
Pathophysiology of myasthenia gravis
Autoimmune antibodies against nicotinic acetylcholine receptor (nAChR) on post-synaptic membranes of neuromuscular junction causing impaired NMJ transmission
- Complement-mediated destruction
- Complement-mediated damage and loss of normal folds of post-synaptic membrane (reduced area for insertion)
- Functional blockage of receptor
- Accelerated endocytosis and breakdown of nAChR
- Cross-linking 2 adjacent nAChRs by anti-AChR
Clinical classification of myasthenia gravis
- Ocular MG (15%) - weakness confined to eyelids and extraocular muscles
- Generalised MG (85%) - generalised weakness
What are the autoantibodies causing MG?
- Anti-AChR (80-90%)
- Anti-MuSK (10%) - previously thought seronegative
Patients with anti-MuSK are usually female with prominent neck, bulbar and respiratory weakness
What drugs may exacerbate MG?
- Penicillamine
- Aminoglycosides
- Fluoroquinolones
- Macrolides
- Beta blockers
- Calcium antagonist
- Quinine and quinidine
- Procainamide
- Lithium and magnesium
- Phenytoin
- Lignocaine
What is the potential link between rheumatoid arthritis and MG?
- Autoimmune disease association
- Penicillamine-induced MG (treatment for RA)
What other conditions present similarly to MG?
- Botulism
- Lambert-Eaton Myasthenia Syndrome (LEMS)
- Mitochondrial myopathy (CPEO)
- Miller-Fisher syndrome
- Snake bites (cobra, kraits, coral snakes)
What are the differences between MG and LEMS?
What may cause false positive tensilon test?
- Motor neuron disease
- Poliomyelitis
- LEMS
- GBS
- Myositis
- Botulism
What are the causes of false positive nAChR antibodies?
- First degree relatives of patient with MG
- Motor neuron disease
- LEMS
- Thyroid ophthalmopathy
- Autoimmune hepatitis
- Primary biliary cirrhosis
- SLE
- Rheumatoid arthritis
- Penicillamine therapy
Ice pack test
Ice pack applied to ptotic eyelid for 2-5 minutes with improvement of ptosis.
High sensitivity and specificity
However difficult to tolerate
What is Hering’s law?
When a ptotic eye lifted manually, there is no longer a requirement for excessive eyelid intervention, resulting in other eyelid becoming ptotic
Treatment of MG
- Acetylcholinesterase inhibitor - symptomatic
Side effects: muscarinic - nausea, vomiting, diarrhoea, cramps, diaphoresis, lacrimation, salivation, bronchial secretions - Immunosuppressives
- Steroids - may cause transient increase in weakness up to 15%
- Steroid sparing: azathioprine, cyclosporin, MMF - Plasma exchange - acute severe exacerbation
- Lasts 6-8 weeks - IVIG - acute severe exacerbation
- Useful in poor vascular access or septicaemia - Thymectomy - 75% experience benefit like reduced immunomodulatory requirement, successful taper, permanent symptomatic control
Why do we offer thymectomy to MG patients?
- T lymphocyte tolerance to auto-antigen develops in thymus
- Thymic abnormalities - hyperplasia 65%, thymoma 15%
- More severe, generalised weakness, higher autoAb titres
Thymectomy increased medication free remission
Higher probability if there is thymus hyperplasia, high AChR Ab titre and short duration of disease
Investigations for Myasthenia Gravis
- AchR antibody, Anti-MusK
- CT thorax - thymoma
- Repetitive nerve stimulation (RNS)
- Single fibre electromyography (SFEMG) - 90-95% sensitivity
- Nerve conduction study TRO neuropathy
- Previously Tensilon test, ice pack test (superceded by RNS)
Physiology of neuromuscular junction
Action potential travels down motor nerve and reaches presynaptic nerve terminal
VGCC open with influx of Ca2+ irons triggering fusion of ACh-filled vesicles with membrane and releasing ACh into synaptic cleft
2 ACh molecules bind to each AChR in posynaptic membrane opens Na+ channel with influx on Na+ generating miniature endplate potentials (MEPPs)
Multiple receptors activate simultaneously and produce suffieient MEPPs summation to form EPP large enough to trigger action potential
Action potential propagates and trigger Ca2+ release from sarcoplasmic reticulum to cause musclec ontraction
ACh molecule then unbinds and released back into synaptic cleft, where AChE decomposes Ach into choline and acetitc acid and reuptake by pre-synaptic terminal for new synthesis of ACh.
Epidemiology of MG
Slight women > men (3:2)
Bimodal age distribution (women 3rd decade, men 5th decade)
Prognosis of MG
Natural without treatment:
20-30% death due to respiratory failure
20% persistent symptoms
25% spontaneous improvement
25% spontaneous remission
Thymoma in pathogenesis of MG
15% MG has thymoma - epithelial instead of lymphocytic in origin
90% benign and treated with resection
10% malignant survival 5-10 years
50% benign thymic hyperplasia??
Thymus hyperplasia or thymoma
Thymic myoid cells express AChRs proximate to site of T-lymphocyte maturation
Targets for antibody sensitisation
Thymic B lymphocytes produce anti-AChR antibodies
Thymic cells selectively increase production of anti-AChR
How would you counsel pregnant women with MG?
12% neonates born are floppy with difficulty breathing and sucking - transient neonatal myasthesia
- Transfer of maternal AChR antibodies to infant through placenta
- Lasts several weeks up to 12 weeks and resolves spontaneously
- Severity of disease or antibody titres DO NOT corelate with neonatal myasthenia
RNS involves repeat transcutaneous electrical stimulation of all motor fibres within a peripheral nerve which generates successive impulses. Consecutive electrical responses are recorded.
Progressive failure of transmission across increasing number of NMJs with repeated stimulation
Fewer activation of muscle fibres and progressively smaller and lower frequency CMAPs (2-3Hz).
Decrement may be improved with:
1. Brief voluntary exercise of tested muscle
2. Anticholinesterase inhibitor administration
SFMEG records single muscle fibre discharges during volitional contraction or electrical stimulation of axon branch to muscle fibre.
Jitter is increased with intermittent failure of transmission across certain NMJs.
(Myopathic and neuropathic diseases may also have increased jitter)
Jitter is the quantitation of variability in transmission time across NMJ from discharge to discharge
Mary Walker phenomenon
Fatigue and weakness of forearm in MG when exercised with cuff around upper arm inflated above SBP to occlude circulation.
When cuff is deflated, myasthenia symptoms in the rest of the body worsens within minutes.
This is due to lactic acidosis binding to calcium and reducing available ionised and serum calcium
Drug induced autoimmune MG
Occurs in 1% patients taking D-penicillamine for RA or Wilson’s disease
6 times more common in women
Autoantibodies disappear with discontinuation of drug
Trimethadione (anticonvulsant) may induce MG
Steroid induced exacerbation of MG
Acute weakness 1-3 weeks after initiation of prednisolone
To prevent occurrence:
1. Pretreatment with PE and/or IVIG, or
2. Gradual increasing prednisolone dose
Myasthenia crisis is acute exacerbation of MG with severe weakness, bulbar or respiratory dysfunction.
___
Temporising therapy with plasmapheresis or IVIG followed by chronic immunosuppressive.
Lambert Eaton Myasthenia Syndrome (LEMS) presents with weakness and fatigabiltiy of prximal muscles - thighs, pelvic girdle, with depressed or absent tendon reflexes
Minimal extraocular and bulbar muscle involvement
Mild autonomic dysfunction - dry mouth
Muscle strength and reflexes may incerase transiently post-exercise
LEMS antibodies cross react with VGCC reducing its number and activation cascade leading to fever ACh vesicles release.
Associated with small cell carcinoma of lung
Botulism develops within 2-48 hours after ingestion of clostridium botulinum contaminated food.
Ocular and bulbar paralysis, difficult eye convergence, diplopia, ptosis, jaw weakness, dysphagia, dysarhtria
Nausea, vomiting , diarrhoea precedes symptoms
Constipation, urinary retention, non-reactive dilation of pupils from autonomic dysfunction
Respiratory failure and limb paralysis without sensory loss or mental status changes
Death within 48 days without respiratory support
Botulinum toxin interfere with ACh release
Other NMJ toxins
1. Black widow spider veom - rapid release of ACh depleting storage and inhbiits choline reuptake, causing painful muscle spasms, GI symptoms, then weakness
- Atracirium - nicotinin AChR antagonist for general anaesthesia
- Snake venom - alpha-bungarotoxin binds to AChR and blocking similar to MG
