What are the signs and symptoms, diagnostic evaluation, and management of myasthenia gravis?

Myasthenia Gravis: Clinical Presentation, Diagnosis, and Management

Signs and Symptoms

Myasthenia gravis presents with fluctuating, fatigable muscle weakness that worsens with repeated use and improves with rest, most commonly affecting ocular, bulbar, and limb muscles in variable patterns. 1

Ocular Manifestations (Most Common Initial Presentation)

• Ptosis (eyelid drooping) that worsens with sustained upgaze and improves with rest—often the first symptom, appearing unilateral or bilateral 1, 2
• Diplopia (double vision) from extraocular muscle weakness, characteristically asymmetric and variable throughout the day 1, 2
• Variable strabismus (eye misalignment) that changes during examination 2
• Pupils are NEVER affected—this is a critical distinguishing feature; pupillary involvement should immediately redirect you toward third nerve palsy or other diagnoses 1, 3
• Approximately 50% of patients present with purely ocular symptoms initially, but 50-80% will progress to generalized disease within a few years (most commonly within 2 years) 1, 3, 2

Bulbar Manifestations

• Dysarthria (slurred speech) that worsens with prolonged talking 1, 2
• Dysphagia (difficulty swallowing)—a particularly concerning sign requiring immediate evaluation, as it is present in >50% of cases preceding myasthenic crisis 1, 3
• Facial weakness causing reduced facial expression 2
• Hoarseness indicating bulbar involvement 1

Limb and Trunk Weakness

• Proximal > distal muscle weakness pattern 1, 2
• Difficulty climbing stairs (lower limb weakness) 1
• Neck weakness with difficulty holding up the head 1, 2

Respiratory Manifestations (Life-Threatening)

• Respiratory muscle weakness can rapidly progress to respiratory failure (myasthenic crisis) 1, 3, 2
• Shortness of breath with light activity is an urgent red flag 1, 3

Characteristic Clinical Features

• Fluctuation: symptoms vary throughout the day, typically worse in evening and with fatigue 1, 2
• Fatigability: weakness worsens with repetitive muscle use 1, 2
• Variability: examination findings can change completely during a single visit 1
• Symptoms are mild or undetectable upon awakening and worsen throughout the day 4

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Diagnostic Evaluation

Bedside Clinical Tests (Perform Immediately)

The ice pack test is highly specific for myasthenia gravis and should be performed at the bedside in any patient with variable ptosis or diplopia. 3

Ice Pack Test Procedure

• Apply ice pack over closed eyelids for 2 minutes for ptosis or 5 minutes for strabismus/ophthalmoplegia 3
• Measure baseline ptosis using marginal reflex distance (MRD) and quantify ocular deviation in prism diopters before ice application 3
• Positive test: improvement of ptosis by ≥2 mm OR reduction in ocular deviation by ≥50% (or ≥10 prism diopters if baseline >20 PD) 3
• Cooling slows acetylcholine breakdown, allowing limited acetylcholine to remain longer in the synaptic cleft and partially overcome receptor blockade 3

Rest Test

• Have patient close eyes for several minutes; improvement in ptosis or strabismus supports diagnosis (less standardized than ice test) 3

Edrophonium (Tensilon) Test

• Sensitivity 86% for ocular myasthenia 3
• Must be performed in monitored setting with atropine (0.4-0.5 mg IV) immediately available for muscarinic side effects (bradycardia, bronchospasm, hypotension) 3

Serologic Testing (First-Line Confirmatory)

• Acetylcholine receptor (AChR) antibodies: present in nearly all generalized MG but only 40-77% of ocular MG 3, 2
• Muscle-specific kinase (MuSK) antibodies: approximately one-third of seronegative cases are MuSK-positive 3, 2
• Lipoprotein-related protein 4 (LRP4) antibodies: additional assay to improve diagnostic yield in seronegative cases 3, 2
• About 50% of purely ocular MG patients are seronegative for AChR antibodies; negative result does NOT exclude diagnosis 3

Electrodiagnostic Studies

• Single-fiber electromyography (SFEMG): >90% sensitivity for ocular MG, considered gold standard 3, 5
• Repetitive nerve stimulation: recommended by American Academy of Neurology alongside antibody testing 3
• Standard EMG and nerve conduction studies may be normal early in disease 3

Imaging Studies

• Chest CT: mandatory to screen for thymoma (present in 10-15% of MG patients; 30-50% of thymoma patients have MG) 3, 2
• Brain MRI: if needed to exclude brainstem stroke or other central etiologies mimicking MG 3, 4

Additional Workup

• Pulmonary function tests (negative inspiratory force [NIF] and vital capacity [VC]): crucial for monitoring respiratory compromise in generalized MG 3, 2
• CPK, aldolase, troponin T: evaluate for concurrent myositis/myocarditis (can co-occur, especially with immune checkpoint inhibitors) 3, 2
• ECG and echocardiography: if cardiac involvement suspected 3, 2
• CSF examination: typically normal in MG (helps distinguish from Guillain-Barré syndrome where protein is elevated by week 2) 3

Critical Differential Diagnoses to Exclude

Diagnosis	Key Distinguishing Features
Third nerve palsy	Pupillary involvement present; requires immediate neuroimaging for aneurysm/ischemia [3]
Thyroid eye disease	Proptosis, eyelid retraction, mechanical restriction on forced duction testing; orbital imaging shows tendon-sparing muscle enlargement [3]
Botulism	Symmetric cranial nerve palsies, pupillary involvement, early GI symptoms, descending paralysis [3,2]
Guillain-Barré syndrome	Ascending weakness, sensory involvement, elevated CSF protein [3,2]
Lambert-Eaton syndrome	Autonomic dysfunction, strength improves with repeated contraction (opposite of MG) [3]

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Management

MGFA Classification System (Guides Treatment Decisions)

• Class I: Ocular symptoms only 3
• Class II: Mild generalized weakness 3
• Class III: Moderate generalized weakness 3
• Class IV: Severe generalized weakness 3
• Class V: Myasthenic crisis requiring intubation 3

Treatment Algorithm by Disease Severity

MGFA Class I-II (Ocular or Mild Generalized)

First-line: Pyridostigmine

• Start 30 mg orally three times daily, gradually increase to maximum 120 mg orally four times daily as tolerated 3, 2
• Approximately 50% of ocular MG patients show minimal response to pyridostigmine alone 3, 6
• Acetylcholinesterase inhibitor works by increasing acetylcholine concentration in synaptic cleft to overcome receptor blockade 2

Second-line: Corticosteroids (if inadequate response to pyridostigmine)

• Prednisone 1-1.5 mg/kg orally daily 3
• Must increase dose slowly due to risk of precipitating myasthenic crisis 6
• After achieving target dose, taper slowly to lowest effective dose 6
• 66-85% of patients show positive response 3, 2

Third-line: Steroid-sparing agents

• Azathioprine or mycophenolate for patients requiring long-term immunosuppression 3, 6

MGFA Class III-V (Moderate to Severe or Crisis)

Immediate actions:

• Admit with ICU-level monitoring capability 3
• Obtain urgent neurology consultation 3
• Permanently discontinue any immune checkpoint inhibitors if present 3

Acute treatment:

• Combination therapy: pyridostigmine + prednisone 1-1.5 mg/kg orally daily 3
• IVIG (2 g/kg over 5 days) or plasmapheresis for moderate to severe symptoms 3
• Intubation and ventilatory support for Class V (myasthenic crisis) 3

Surgical Management

• Thymectomy: indicated when thymoma identified on imaging; can lead to substantial symptom reduction 3, 2, 6
• Ocular MG without thymoma is NOT usually treated with thymectomy 6

Non-Pharmacologic Options for Ocular Symptoms

• Ptosis crutches for spectacles 6, 7
• Prism spectacles for diplopia 6, 7
• Occlusive devices or patches 6
• Eyelid supports or contact lenses 6
• Strabismus surgery or eyelid elevation surgery only in long-standing, stable cases 6

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Critical Pitfalls and Medications to Avoid

Medications That Precipitate or Worsen Myasthenic Crisis

Avoid the following medications in all MG patients: 3, 2

• β-blockers
• IV magnesium
• Fluoroquinolones
• Aminoglycosides
• Macrolide antibiotics
• Statins (can cause myopathy that obscures myasthenic weakness) 2

Clinical Pitfalls

• Failure to recognize early respiratory involvement can be fatal—all grades of MG warrant thorough evaluation given potential for rapid progression 3, 2
• Dysphagia is a critical warning sign: present in >50% of cases preceding myasthenic crisis; requires immediate evaluation for aspiration risk 3
• Do not delay treatment while awaiting confirmatory testing: approximately 50% of ocular MG patients are seronegative for AChR antibodies 3
• Unilateral ptosis without fluctuation does NOT exclude MG: atypical presentations occur, and diagnosis should still be considered after excluding stroke 4
• Regular pulmonary function monitoring is mandatory in generalized MG to prevent respiratory failure 3, 2

High-Risk Populations Requiring Urgent Evaluation

• Patients with concurrent myocarditis or myositis (especially with immune checkpoint inhibitors)—significantly raises mortality risk 2
• Any patient with MG requiring surgery must have preoperative AChR antibody levels measured to avoid respiratory failure during anesthesia 3
• Approximately 20% of thymoma patient mortality is related to MG complications 3

Referral and Ongoing Management

• All suspected MG cases require neurology referral—primary care should not initiate disease-specific therapy 2
• Collaboration between experienced ophthalmologist and neurologist is necessary for ocular MG 3
• Monitor for associated autoimmune conditions (thyroid disease, SLE, rheumatoid arthritis) 2