What is the likely diagnosis for a patient with no chronic conditions, taking no medications, and presenting with worsening fatigue, arm weakness with repeated use, double vision, voice changes, and ptosis (drooping of the left upper eyelid) relieved by cold stimulation, with normal vital signs, including a body mass index (BMI) within normal limits, normal heart rate, normal respirations, normal blood pressure, and normal oxygen saturation, and deep tendon reflexes of 2/4?

Myasthenia Gravis: Autoimmune Neuromuscular Junction Disorder

This patient has myasthenia gravis, an autoimmune disorder where antibodies attack acetylcholine receptors at the neuromuscular junction, preventing normal nerve signal transmission to muscles and causing the characteristic fatigable weakness that worsens with repetitive activity and improves with rest. 1

Pathophysiologic Mechanism

The underlying mechanism involves a B-cell mediated autoimmune attack on the neuromuscular junction 1:

• Acetylcholine receptor antibodies bind to and block acetylcholine receptors on the postsynaptic muscle membrane, preventing acetylcholine released from the presynaptic nerve terminal from effectively binding and triggering muscle contraction 1

• This antibody-mediated receptor blockade reduces the number of available receptors for stimulation, resulting in lower amplitude muscle fiber activation and progressive weakness with repeated use 2

• Extraocular muscles are particularly vulnerable due to their unique twitch fiber composition and fewer acetylcholine receptors compared to other muscle groups, explaining why ocular symptoms (ptosis, diplopia) are often the presenting features 1

Clinical Features Supporting This Diagnosis

This patient demonstrates the classic triad of myasthenia gravis 3:

• Fatigable weakness that worsens with sustained activity (arm weakness with repeated brush strokes, jaw fatigue with chewing) and improves dramatically with rest (symptoms resolve after sleep) 4, 1

• Fluctuating ocular symptoms including ptosis that worsens by evening and diplopia, with the pathognomonic finding of ptosis relief with ice pack application 3, 5, 1

• Bulbar involvement manifested by voice changes (dysarthria) and difficulty chewing, indicating progression beyond purely ocular disease 4, 1

• Preserved deep tendon reflexes (2/4) with no muscle wasting or sensory deficits, distinguishing this from muscular dystrophy or neuropathy 3

Why This Mechanism Explains the Clinical Pattern

The autoimmune attack on acetylcholine receptors specifically explains 1, 2:

• Worsening with repetitive use: Each muscle contraction depletes available acetylcholine, and with fewer functional receptors, the neuromuscular junction cannot maintain adequate transmission during sustained activity

• Improvement with rest: Allows time for acetylcholine stores to replenish and receptors to recover from desensitization

• Diurnal variation: Symptoms worsen throughout the day as cumulative muscle use exhausts the compromised neuromuscular transmission capacity

• Ice pack test positivity: Cooling improves acetylcholinesterase function and prolongs acetylcholine availability at the synapse, temporarily compensating for reduced receptor numbers 3, 5

Diagnostic Confirmation Required

Acetylcholine receptor antibody testing is the gold standard serological test with 80-88% sensitivity for generalized myasthenia gravis and 98-100% specificity 3:

• If seronegative, test for muscle-specific kinase (MuSK) antibodies (positive in one-third of seronegative patients) and lipoprotein-related protein 4 (LRP4) antibodies 4, 3

• Repetitive nerve stimulation showing decremental response or single-fiber EMG demonstrating increased jitter confirms neuromuscular junction pathology 4, 3

• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) is mandatory to assess for respiratory muscle involvement, as this can progress to life-threatening myasthenic crisis 4, 5

Critical Management Considerations

All grades of myasthenia gravis warrant immediate work-up and intervention given the potential for rapid progression to respiratory compromise 4:

• This patient has generalized myasthenia gravis (MGFA Class II) with ocular, bulbar, and limb involvement, requiring neurology consultation 4

• Chest CT is essential to screen for thymoma, present in 10-15% of myasthenia patients and requiring different management 3

• Certain medications can precipitate myasthenic crisis and must be avoided: beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics 1

• Monitor for concurrent myositis or myocarditis with CPK, troponin, ECG, and echocardiography if indicated, as these can co-occur with myasthenia gravis 4