Myasthenia Gravis

• Autoimmune disorder against post-synaptic nicotinic acetylcholine receptors of the neuromuscular junction
• Characterized by fatigable weakness
• May present with
  • Ptosis, diplopia
  • Dysphagia, dysarthria
  • Proximal weakness
• Course
  • Ocular (20%)
  • Oropharyngeal or generalized (80%)
• Age of onset
  • Third / fourth decade, female predominance
  • Sixth decade, male predominance

Relevant physical signs

• Inspection
  • Ptosis (may be unilateral, asymmetrical or bilateral)
  • Frontalis overactivity to compensate for ptosis
  • Feeding aids (nasogastric tube, percutaneous gastrostomy tube)
  • Walking aids
  • Thymectomy scar (midline sternotomy)
  • Scars from previous central line placement
  • Cushingoid appearance (complication of treatment)
  • Tremor (immunosuppression)
• Eyes
  • Ptosis, exacerbated by exertion
    • “Look upwards at my finger and count to 20”
    • Ask the patient to relax their forehead, to negate the effect of frontalis
    • May be more evident by holding the more affected eyelid (curtain sign)
      • Hering’s law: when a ptosed eyelid is manually lifted, there is no longer a requirement for excessive eyelid innervation, causing a reduction in innervation to the contralateral eyelid and ptosis.
    • Voice may soften with sustained activity
  • Complex ophthalmoplegia with binocular diplopia
  • Pupils are always spared in myasthenia (should be equal and reactive to light)
• Muscles of facial expression usually intact, but may be weak
• Bulbar weakness
  • Speech: slurred, nasal
  • Swallowing dysfunction
  • Weakness of palatal elevation
  • Coughing after being asked to swallow (aspiration)
• Upper and lower limbs
  • Normal reflexes (reduced in Lambert-Eaton myasthenic syndrome, absent in Miller-Fisher)
  • Neck flexion (correlates with respiratory muscle weakness)
  • Proximal weakness
    • Fatigability of proximal muscles – test shoulder abduction in both arms initially. Then, get the patient to relax the left arm, while keeping the right arm abducted against resistance. After 20 seconds, test both shoulder abduction in both arms again – if the right arm is now weaker, there is fatigability
• Associated autoimmune diseases
  • Graves’ disease – proptosis, lid retraction, complex ophthalmoplegia
  • Hashimoto’s thyroiditis – bradycardia, proximal myopathy, goitre
  • Diabetes – diabetic dermopathy, finger prick marks for blood sugar monitoring
  • Systemic lupus erythematosus – malar rash, alopecia, mouth ulcers, arthropathy
  • Rheumatoid arthritis – symmetrical deforming polyarthropathy

Differential diagnosis

• Lambert-Eaton myasthenic syndrome (LEMS)
• Miller-Fisher syndrome
• Botulism
• Mitochondrial myopathy

Precipitants of acute myasthenia exacerbation

• Intercurrent infections
• Non-compliance to treatment
• Stress
• Drugs
  • Antibiotics: fluoroquinolones, macrolides, aminoglycosides, tetracyclines
  • Anti-hypertensives: calcium channel blockers (especially verapamil), β-blockers
  • Penicilliamine
  • Lithium
  • Phenytoin
  • Lignocaine

Investigations

• Full blood count (anaemia of chronic disease, macrocytic anaemia of pernicious anaemia)
• Renal function, liver function (prior to starting immunosuppressive therapy)
• Serology
  • Nicotinic acetylcholine receptor Ab (positive in 50% of ocular, 85% of generalized myasthenia)
  • Muscle-specific kinase Ab (middle-aged women with bulbar and respiratory muscle weakness)
  • Voltage-gated calcium channel Ab (LEMS)
• Tenilson test – improvement in weakness following administration of edrophonium (only for patients with obvious weakness or ptosis)
• Electrophysiology
  • Repetitive nerve stimulation – place a recording electrode over the end-plate region of a muscle, then stimulate the motor nerve to that muscle at 3Hz. In MG, there will be a reduction in amplitude in the compound muscle action potential with RNS (decrement > 10%).
    • LEMS results in an increment of CMAP at 20Hz
  • Single-fiber electromyography looking for abnormally-increased jitter (more sensitive and specific than RNS, but more technically difficult and less widely-available)
• Computed tomography of the thorax, especially in nAChR patients (>75%) for thymic abnormalities
  • 85% thymic hyperplasia
  • 15% thymoma
• Negative inspiratory force to screen for respiratory muscle weakness

Management

• Multidisciplinary team approach
• Patient education, physiotherapy and occupational therapy to preserve and maximize function
• Acetylcholinesterase inhibitors (pyridostigmine, Mestinon) for symptomatic relief
  • Side-effects: nausea, vomiting, increased secretions, abdominal cramps, diarrhoea
  • Cholinergic crisis from too much ACh at the NMJ: flaccid paresis, meiosis, SLUDGE (salivation, lacrimation, urinary incontinence, diarrhoea, gastrointestinal hyper-motility, emesis)
• Acute myasthenic crises
  • Consider intubation for airway protection
  • Intravenous immunoglobulin or
  • Plasma exchange
• Long-term immunosuppression
  • Corticosteroids
    • If starting at high doses, start concurrently with IVIG/PLEX due to risk of transient worsening of myasthenic symptoms
    • Leads to remission in 30% and improvement in 50% of patients
    • Slowly taper to maintain control of disease with addition of pyridostigmine
  • Azathioprine
  • Mycophenolate
  • Cyclosporine
• Surgical referral for thymectomy: can result in medication-free remission

Summary

Sir, this patient has a fatigable ptosis and a complex ophthalmoplegia. There is no evidence of bulbar weakness on clinical examination – there are no feeding aids such as a nasogastric tube, and the speech is normal. There is mild fatigability of the proximal muscles, and the deep tendon reflexes are all present. This is most consistent with a diagnosis of myasthenia gravis. There is a midline sternotomy scar, suggesting previous thymectomy. The patient appears Cushingoid, and this may be related to chronic steroid therapy to maintain disease control. There are no other signs to suggest a related autoimmune disorder such as Graves’ disease, Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis or pernicious anaemia. Other differential diagnoses would include the Lambert-Eaton myasthenic syndrome and Miller-Fisher syndrome, but I would expect the reflexes to be diminished or absent in these conditions.