Summary Table

01Pathophysiology

Myasthenia gravis is a type II hypersensitivity reaction in which IgG autoantibodies target the nicotinic acetylcholine receptors (AChR) on the postsynaptic membrane of the neuromuscular junction. These antibodies cause damage through three mechanisms: complement-mediated destruction of the postsynaptic membrane, accelerated internalization and degradation of AChR (antigenic modulation), and direct blockade of the acetylcholine binding site.

The net result is a reduced density of functional AChR at the motor end plate. Under normal physiology, acetylcholine is released in excess relative to the number of receptors needed to generate an action potential. This surplus is called the safety factor of neuromuscular transmission. In MG, the safety factor is lost. During the first few contractions, enough ACh still binds to trigger a response, but with repeated stimulation, the presynaptic ACh vesicle pool becomes transiently depleted. In a healthy NMJ this depletion is inconsequential because receptors are abundant. In MG, even a small drop in ACh release pushes the end-plate potential below the threshold, and the muscle fiber fails to fire. This explains the hallmark pattern: weakness that worsens with repeated activity and improves after rest, because rest allows ACh stores to replenish.

The thymus gland plays a central role. In younger patients, thymic hyperplasia (particularly germinal center formation) serves as the site where autoreactive T-cells are primed and B-cells are activated to produce anti-AChR antibodies. In older patients, a thymoma may be present, which is a neoplasm of thymic epithelial cells that disrupts normal immune tolerance. This is why every patient with confirmed MG must have chest imaging to evaluate the thymus.

Ocular muscles are affected earliest and most frequently because they have a lower safety factor than limb muscles (fewer AChR per junction, higher firing frequency, and different fiber composition), making them the first to fail when receptor density drops.

In the anti-MuSK subtype (~5 to 8% of MG), antibodies target muscle-specific kinase, a receptor tyrosine kinase critical for AChR clustering during synapse formation. These patients tend to present with prominent bulbar and facial weakness (dysarthria, dysphagia, facial atrophy) with relative sparing of the limbs, and they respond poorly to acetylcholinesterase inhibitors.

02Classification and Clinical Manifestation

Myasthenia Gravis Foundation of America (MGFA) Classification

Serological Subtypes

Age of Onset Pattern

03Diagnostic Workup

The best initial test when MG is suspected is serum anti-AChR antibody testing. This test is highly diagnostic when positive (specificity approaches 99%), meaning a positive result essentially confirms the diagnosis. However, it is not perfectly sensitive: approximately 85% of patients with generalized MG and only about 50% of patients with purely ocular MG will test positive.

If anti-AChR antibodies are negative but clinical suspicion remains high, the next step is to test for anti-MuSK antibodies, which are found in roughly 40% of "seronegative" patients. If both are negative and suspicion is still strong, anti-LRP4 antibodies or cell-based AChR assays can be considered.

Repetitive nerve stimulation at low frequency (2 to 3 Hz) is the standard electrodiagnostic test. In MG, successive stimuli produce progressively smaller compound muscle action potentials, resulting in a decremental response of greater than 10% between the first and fourth or fifth stimulus. This reflects the progressively failing neuromuscular transmission as ACh depletion meets reduced receptor density. RNS is more sensitive in proximal muscles (facial nerve, spinal accessory nerve) than in distal ones.

The most sensitive test for MG is single-fiber EMG (SFEMG), which measures the variability in time interval ("jitter") between two muscle fibers in the same motor unit. In MG, the impaired NMJ transmission causes increased jitter and intermittent blocking (failure of one fiber to fire). SFEMG sensitivity approaches 92 to 100% even in ocular MG, but it is not very discriminating between different NMJ disorders, so it is sensitive but not highly disease-defining on its own.

The edrophonium (Tensilon) test involves injecting a short-acting acetylcholinesterase inhibitor intravenously and observing for rapid, transient improvement in an objectively measurable deficit (usually ptosis or extraocular movement). The test has largely fallen out of routine practice due to risk of bradycardia and the availability of serologic testing, but it remains a classic exam topic. Atropine should be available at bedside in case of cholinergic side effects.

The ice pack test is a safe, simple bedside test for ocular MG. Applying an ice pack to a closed ptotic eyelid for 2 minutes improves ptosis because cooling slows acetylcholinesterase activity at the NMJ, allowing more ACh to accumulate and bind. It requires no medications and has no cardiac risk.

Every patient with confirmed MG requires CT of the chest (or MRI) to evaluate the anterior mediastinum for thymoma. About 10 to 15% of MG patients will have a thymoma, and up to 30 to 50% of thymoma patients will eventually develop MG.

In patients with bulbar or respiratory symptoms, pulmonary function testing with serial forced vital capacity (FVC) and negative inspiratory force (NIF) monitoring is essential. The "20/30/40 rule" signals impending myasthenic crisis and need for intubation:

• FVC < 20 mL/kg

• NIF weaker than -30 cmH${}_2\_2$O

• More than 40% decline from baseline FVC

04Management and Treatment

Acute symptomatic control begins with pyridostigmine (Mestinon), an acetylcholinesterase inhibitor that increases the amount of ACh available at the NMJ. It does not alter the disease course but provides symptomatic relief. Typical starting dose is 60 mg orally every 4 to 6 hours, titrated based on symptom control. It is important to recognize that overdosing pyridostigmine can cause a cholinergic crisis (excessive ACh leading to paradoxical weakness, plus muscarinic symptoms like salivation, lacrimation, urination, diarrhea, miosis, and bradycardia). This is a classic exam trap: distinguishing cholinergic crisis from myasthenic crisis (see Traps section below). Note that in MuSK-positive MG, pyridostigmine is often poorly tolerated or ineffective, and these patients typically require earlier and more aggressive immunosuppression.

Immunosuppressive therapy is the backbone of long-term management. Prednisone is the first-line immunosuppressant. A key clinical pearl is that corticosteroids can transiently worsen weakness during the first 1 to 3 weeks of high-dose initiation, which can precipitate crisis in patients with bulbar or respiratory involvement. Therefore, prednisone should be started at a low dose and escalated gradually in moderate-to-severe disease, or initiated in a monitored inpatient setting. Once remission is achieved, the dose is slowly tapered to the minimum effective level.

Steroid-sparing agents such as azathioprine (2 to 3 mg/kg/day) or mycophenolate mofetil (1 to 1.5 g twice daily) are added when long-term corticosteroid side effects become a concern, or when disease control is insufficient with steroids alone. Azathioprine requires checking thiopurine methyltransferase (TPMT) levels before initiation to avoid severe myelosuppression in patients with TPMT deficiency. These agents take 6 to 12 months to reach full effect, so they must be started alongside steroids, not instead of them.

Thymectomy is recommended for all patients with thymoma regardless of MG severity. The MGTX trial demonstrated benefit of thymectomy even in non-thymomatous, AChR-positive, generalized MG patients between ages 18 and 65, showing improved clinical outcomes and reduced need for immunosuppressants over 3 years. Thymectomy is generally not beneficial in MuSK-positive MG (thymic pathology is rarely present in this subtype).

Myasthenic crisis is a life-threatening exacerbation involving respiratory failure requiring intubation. The two acute treatments are IVIG (2 g/kg divided over 2 to 5 days) and plasmapheresis (5 to 6 exchanges over 10 to 14 days). Both work rapidly (days to 1 to 2 weeks) and are considered equally effective. The choice depends on institutional preference and patient factors: plasmapheresis is preferred when a faster onset is needed and venous access is available; IVIG is preferred when central line access is problematic or in patients with hemodynamic instability. During crisis, pyridostigmine should be temporarily held to eliminate any contribution from cholinergic excess and to reduce secretion burden during mechanical ventilation.

Drugs that exacerbate MG are a commonly tested topic. Key offenders include:

• Aminoglycosides and fluoroquinolones

• Beta-blockers

• Magnesium sulfate (avoid in pregnant MG patients with preeclampsia)

• D-penicillamine (can actually induce MG)

• Botulinum toxin

• Neuromuscular blocking agents (succinylcholine, curare)

• Telithromycin and macrolides

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most tested trap in MG questions is the distinction between myasthenic crisis and cholinergic crisis. Both present as acute worsening of weakness in a patient with known MG, and both can lead to respiratory failure. The vignette will distinguish them by the clinical context: a myasthenic crisis occurs when disease is undertreated (infection trigger, missed medications, recent surgery), while a cholinergic crisis follows a recent increase in pyridostigmine dose and is accompanied by prominent muscarinic signs (SLUDGE: salivation, lacrimation, urination, defecation, GI cramping, emesis). The next best step for both is securing the airway, but subsequent management diverges: myasthenic crisis requires IVIG or plasmapheresis, while cholinergic crisis requires stopping pyridostigmine and administering atropine if needed.

The second major trap is confusing MG with Lambert-Eaton syndrome. Both cause proximal weakness, but the direction of fatigability is opposite. A vignette describing weakness that gets better with use (patient is weak when standing from a chair but gains strength after walking a few steps) points to Lambert-Eaton. A vignette where weakness gets worse with use (patient is fine in the morning but drops things by evening, or develops ptosis after sustained upward gaze) points to MG. Additionally, Lambert-Eaton is associated with small cell lung carcinoma, so a concurrent smoking history or lung mass should redirect your thinking.

A third commonly tested point is the transient worsening of weakness when initiating high-dose corticosteroids. Students often select "start high-dose prednisone" as the answer in a patient with moderate-to-severe or bulbar-predominant MG, not realizing this can precipitate crisis. The tested principle is that corticosteroids should be initiated cautiously with slow dose escalation, or the patient should be in a monitored setting.

Finally, do not forget that every patient with newly diagnosed MG needs a CT chest. This is tested both as a "next best step" after serologic confirmation and as a screening question. Missing a thymoma has therapeutic consequences because thymoma-associated MG requires surgical resection regardless of disease severity, and unresected thymoma carries malignant potential.

The core competency being tested across MG questions is pattern recognition of fluctuating, fatigable weakness (especially ocular onset), correct sequencing of the diagnostic workup (serology first, electrophysiology if seronegative, imaging of the chest in all confirmed cases), and understanding the hierarchy of treatment from symptomatic control through immunosuppression to crisis management.