Physiology · Year 1 · from Physiology

Case 1: Myasthenia Gravis - Postsynaptic Receptor Dysfunction

Clinical Image

Source: Wikimedia Commons - Myasthenia Gravis - CC BY-SA 3.0

Patient Presentation

A 32-year-old female presents to the neurology clinic with a 4-month history of progressive fatigue, double vision (diplopia), and drooping eyelids (ptosis) that worsen throughout the day and improve with rest. She first noticed symptoms in the evening after long days at work. Recently, she has developed difficulty swallowing (dysphagia), particularly with solid foods, and her voice becomes nasal and weak after prolonged speaking. She denies muscle pain, sensory changes, or bowel/bladder dysfunction.

Demographics

  • Age: 32 years
  • Sex: Female
  • Onset: Insidious over 4 months with fluctuating course

Chief Complaint

Fluctuating weakness, ptosis, diplopia, dysphagia, and dysarthria that worsen with activity

Physical Examination

  • General: Alert, comfortable at rest
  • Cranial nerves:
  • Ptosis: Bilateral, worse on right, increases with sustained upgaze (fatigability test positive)
  • Eye movements: Limited abduction and elevation bilaterally, diplopia in multiple directions
  • Facial weakness: Mild bilateral facial weakness with "snarling" smile
  • Speech: Becomes increasingly nasal with counting to 100
  • Palate: Weak palatal elevation bilaterally
  • Motor: 4+/5 strength in proximal upper extremities after repetitive testing (demonstrating fatigability)
  • Reflexes: Normal 2+ throughout
  • Sensory: Intact to all modalities

Workup

  • Acetylcholine receptor (AChR) antibodies: Positive (highly specific for MG)
  • Anti-MuSK antibodies: Negative
  • Repetitive nerve stimulation (RNS): Decremental response >10% at 3 Hz stimulation of facial nerve (positive for NMJ disorder)
  • Single-fiber EMG: Increased jitter and blocking
  • CT chest: 3 cm anterior mediastinal mass consistent with thymoma
  • Pulmonary function tests: FVC 78% predicted (monitor for myasthenic crisis)
  • Tensilon (edrophonium) test: Rapid improvement in ptosis (positive, though rarely performed now)

Diagnosis

Myasthenia Gravis (seropositive, generalized) with thymoma

Treatment

  1. Pyridostigmine (acetylcholinesterase inhibitor) 60 mg TID for symptomatic relief
  2. Prednisone taper for immunosuppression (start low, go slow to avoid initial worsening)
  3. Steroid-sparing agent: Azathioprine or mycophenolate for long-term immunosuppression
  4. Thymectomy for thymoma (mandatory) and potential disease modification
  5. IVIg or plasmapheresis reserved for myasthenic crisis or pre-operative preparation
  6. Avoid medications that worsen MG: aminoglycosides, beta-blockers, magnesium, certain antibiotics
  7. MedicAlert bracelet and emergency action plan
  8. Monitor for myasthenic crisis (FVC < 1L or NIF < -25 requires ICU admission)

Physiological Principles Demonstrated

  • Neuromuscular junction physiology: Acetylcholine (ACh) is released from motor nerve terminals, crosses the synaptic cleft, and binds nicotinic ACh receptors (nAChR) on the motor end plate, causing depolarization (end-plate potential) that triggers muscle action potentials.
  • Safety factor: Normally, far more ACh is released than needed to reach threshold (safety factor). In MG, antibody-mediated destruction of nAChRs reduces receptor density, narrowing the safety factor.
  • Fatigability mechanism: With repeated stimulation, presynaptic ACh stores transiently deplete. In normal muscle, the safety factor compensates. In MG, reduced receptor numbers mean successive stimuli produce progressively smaller EPPs that fail to reach threshold.
  • Decremental response: Repetitive nerve stimulation at 2-3 Hz causes progressive amplitude decline of the compound muscle action potential (CMAP) because fewer muscle fibers are activated with each stimulus.
  • Acetylcholinesterase inhibitors: Pyridostigmine inhibits acetylcholinesterase, prolonging ACh availability in the synaptic cleft and increasing the probability of receptor binding despite reduced receptor numbers.
  • Autoimmune pathophysiology: Anti-AChR antibodies cause receptor loss through complement-mediated destruction, accelerated receptor internalization, and direct functional blockade.

All cases for this lecture as Markdown