Myasthenia gravis

Epidemiology

• Most common disorder of neuromuscular transmission; prevalence ~20 per 100,000
• Bimodal age distribution: women peak in 2nd–3rd decade; men peak in 6th–7th decade
• 15–20% of patients with MG will experience myasthenic crisis, most commonly within the first 2 years
• ~20% of myasthenic crises are the initial presentation of MG

Background

• Autoantibody degradation, dysfunction, and blockade of acetylcholine receptor (AChR) at the neuromuscular junction (NMJ)
• Thymus is abnormal in ~75% of patients (85% hyperplasia, 15% thymoma)
  • Thymectomy resolves or improves symptoms in most patients, especially those with a thymoma
• No sensory, reflex, pupillary, or cerebellar deficits
• Key distinguishing feature from other NMJ disorders: normal reflexes, normal sensation, no autonomic symptoms, no fasciculations, worsening weakness with repetitive motion

Drugs Associated with Exacerbations

Critical

Review the medication list of every MG patient presenting to the ED, regardless of chief complaint

May Unmask or Worsen

• Antimicrobials (Aminoglycosides, clindamycin, erythromycin, tetracycline, doxycycline, azithromycin, fluoroquinolones, vancomycin, chloroquine, hydroxychloroquine)
• Cardiovascular drugs (beta blockers, procainamide, quinidine)
• Neuro/psych meds (chlorpromazine, lithium, prochlorperazine, phenytoin, risperidone)
• Other (Botox, quinines, magnesium, iodinated contrast agents)

Usually Well-tolerated, but Occasionally Associated

• Local anesthetics
• Antibiotics (Tetracycline/doxycycline, macrolides, metronidazole, nitrofurantoin)
• Anticonvulsants (carbamazepine, ethosuximide, gabapentin, phenobarbital, phenytoin)
• Butyrophenones (haloperidol)
• Phenothiazines (chlorpromazine/prochlorperazine)
• Calcium channel blockers
• Steroids (may transiently worsen symptoms upon initiation; see Management)
• Ophthalmic drugs (betaxolol/timolol/proparacaine)

Precipitants of Myasthenic Crisis

Identify and treat the trigger in every crisis presentation:

• Infection (most common cause, >30–40% of crises; respiratory infections #1, aspiration pneumonitis #2)
• Medication changes (see above; also includes tapering or abrupt discontinuation of immunosuppressants)
• Non-adherence with pyridostigmine or immunosuppressants
• Surgery/anesthesia
• Initiation or discontinuation of corticosteroids
• Emotional or physical stress, heat
• Electrolyte abnormalities (Ca, Phos, Mg)
• Thyroid disease (hyper- or hypothyroid; associated with autoimmune thyroid disease)
• Pregnancy/postpartum
• No identifiable trigger found in ~50% of patients

Clinical Features

Cranial nerve palsy and ptosis in a patient with myasthenia gravis

• Muscle weakness
  • Proximal extremities
  • Neck extensors ("dropped head")
  • Facial/bulbar muscles (dysphagia, dysarthria, dysphonia)
• Ocular weakness (presenting symptom in ~50% of patients; eventually involved in >80%)
  • Ptosis (often asymmetric)
  • Diplopia
  • CN III, IV, or VI weakness
• Symptoms worsen with repetitive use and as the day progresses
• Respiratory weakness: dyspnea (especially supine/orthopnea), weak cough, inability to clear secretions, pausing mid-sentence to breathe, tachypnea with shallow breathing

MGFA Clinical Classification

Class	Description
I	Ocular MG only
II	Mild generalized (IIa = predominantly limb/axial; IIb = predominantly bulbar)
III	Moderate generalized (IIIa = predominantly limb/axial; IIIb = predominantly bulbar)
IV	Severe generalized (IVa = predominantly limb/axial; IVb = predominantly bulbar)
V	Requiring intubation (myasthenic crisis)

Differential Diagnosis

Weakness

• Neuromuscular weakness
  • Upper motor neuron:
    • CVA
    • Hemorrhagic stroke
    • Multiple sclerosis
    • Amyotrophic Lateral Sclerosis (ALS) (upper and lower motor neuron)
  • Lower motor neuron:
    • Spinal and bulbar muscular atrophy (Kennedy's syndrome)
  • Spinal cord disease:
    • Infection (Epidural abscess)
    • Infarction/ischemia
    • Trauma (Spinal Cord Syndromes)
    • Inflammation (Transverse Myelitis)
      • Acute flaccid myelitis
    • Degenerative (Spinal muscular atrophy)
    • Tumor
  • Peripheral nerve disease:
    • Guillain-Barre syndrome
    • Toxins (Ciguatera)
    • Tick paralysis
    • Diabetic peripheral neuropathy
  • Neuromuscular junction disease:
    • Myasthenia gravis crisis
    • Botulism
    • Organophosphate toxicity
    • Lambert-Eaton myasthenic syndrome
  • Muscle disease:
    • Rhabdomyolysis
    • Dermatomyositis
    • Polymyositis
    • Alcoholic myopathy
• Non-neuromuscular weakness
  • Can't miss diagnoses:
    • ACS
    • Arrhythmia/Syncope
    • Severe infection/Sepsis
    • Hypoglycemia
    • Periodic paralysis (electrolyte disturbance, K, Mg, Ca)
      • Hypokalemic periodic paralysis
      • Thyrotoxic periodic paralysis
    • Respiratory failure
  • Emergent Diagnoses:
    • Symptomatic Anemia
    • Severe dehydration
    • Hypothyroidism
    • Polypharmacy
    • Malignancy
    • Aortic disease - occlusion, stenosis, dissection
  • Other causes of weakness and paralysis
    • Acute intermittent porphyria (ascending weakness)

Myasthenia Gravis vs Lambert-Eaton Myasthenic Syndrome

Feature	Myasthenia Gravis	Lambert-Eaton (LEMS)
Mechanism	Postsynaptic AChR antibodies	Presynaptic P/Q-type VGCC antibodies
Initial symptoms	Ocular (ptosis/diplopia) in ~60%	Proximal leg weakness in ~95%
Pattern of weakness	Craniocaudal (eyes → bulbar → limbs)	Caudocranial (legs → arms → cranial)
Effect of repetition	Weakness worsens	Weakness initially improves (Lambert's sign)
Deep tendon reflexes	Normal	Depressed (may improve post-exercise)
Autonomic dysfunction	Absent	Common (dry mouth, constipation, impotence)
Cancer association	Thymoma (10–15%)	Small cell lung cancer (~60%)
Respiratory crisis	Common	Rare
RNS pattern	Decremental response	Initial decrement then incremental post-exercise

Evaluation

Right partial ptosis (left picture) with left lid showing compensatory pseudo lid retraction (Hering's law): Right picture: after edrophonium test, note improvement in ptosis.

A chest CT showing a thymoma (red circle).

ED Workup

Always evaluate respiratory function serially (q2hr or more frequently if deteriorating):

• Forced Vital Capacity (FVC): normal ≥60 mL/kg; <20 mL/kg indicates impending respiratory failure
• Negative Inspiratory Force (NIF): normal is −80 to −100 cmH₂O; values closer to 0 indicate weaker effort
• Tidal volume
• Ability to handle secretions
• Continuous capnography (best early indicator of ventilatory deterioration)

Intubation Triggers (Consider when ANY of the following present):

FVC < 20 mL/kg (or < 1 L, or rapidly declining)	NIF weaker than −30 cmH₂O (i.e., closer to 0)
Significant bulbar dysfunction with aspiration risk	Hypercapnia (pCO₂ > 45 mmHg)
Inability to handle secretions	Orthopnea with rapid shallow breathing
Serial decline in respiratory parameters	Clinical respiratory distress

Do NOT rely on SpO₂ alone—MG causes hypercarbic respiratory failure; hypoxemia is a late finding that may suggest atelectasis or aspiration

Bedside Tests

• Prolonged upward gaze test
  • Have the patient gaze upward at examiner's finger for 30–60 seconds
  • Diplopia or ptosis that develops is suggestive of MG
• Ice Pack Test (high specificity for MG)
  • Place ice-pack on closed eyes for 2 mins; positive if ptosis decreases by ≥2 mm
• Single breath count test
  • Have patient take a deep breath and count aloud as high as possible; <20 suggests respiratory compromise

Neuro Workup

The following may be considered for neurologic workup, but are not typically indicated in the ED:

• ACh-R antibody testing: first-line investigation. Positive in 80–90% of generalized MG and 40–55% in ocular MG. (Results take days—do not delay treatment while awaiting)
  • MuSK antibody testing: for patients negative for ACh-R antibodies
• Thyroid function
• Neurophysiology: Repetitive nerve stimulation (RNS) is the initial test; if negative, consider single-fibre electromyography
• MR scan of brain: Patients with negative serology and neurophysiology, and symptoms compatible with ocular myasthenia may have structural brain disease
• Thymus imaging (CT or MRI): All patients with suspected myasthenia, regardless of distribution or serology
• Edrophonium/Tensilon test (sensitivity ~50% overall, ~80% in crisis; generally not used in ED due to risk of bradycardia/bronchospasm)

Myasthenic Crisis vs Cholinergic Crisis

Feature	Myasthenic Crisis	Cholinergic Crisis
Cause	Exacerbation of MG (infection, medication, stress)	Excessive acetylcholinesterase inhibitor use
Pupils	Normal	Miotic (constricted)
Secretions	Normal or mildly increased	Markedly increased (SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis)
Fasciculations	Absent	Present
Bradycardia	Absent	May be present
Diaphoresis	Absent	Present
Response to edrophonium	Improvement	Worsening
Modern relevance	Common	Exceedingly rare with modern dosing (pyridostigmine < 120 mg q3hr)

Management

Avoid medications that can cause/worsen exacerbations (see Background), including magnesium (which can precipitate respiratory failure)

Myasthenic Crisis

Priorities

(1) Secure the airway, (2) Identify/treat the precipitant, (3) Immunomodulatory therapy, (4) Neurology consultation early

Respiratory Support

• Noninvasive ventilation (BiPAP) may be used as initial support or bridge to intubation
  • Can be successful even in patients with bulbar weakness
  • Predictors of NIV failure: hypercapnia (pCO₂ >45 mmHg), APACHE II ≥6, serum bicarb ≥30
  • Monitor closely—these patients often need definitive airway management
• Intubation (if needed)—favor elective intubation over emergent
  • If possible, intubate without paralytic agents (use adequate sedation alone)
  • If paralysis is required, use a nondepolarizing agent at reduced dose (preferred):
    • Rocuronium 0.5–0.6 mg/kg (roughly half the standard dose)
    • MG patients are extremely sensitive to nondepolarizing agents—standard doses can cause prolonged paralysis (case reports of >4 hours)
    • Sugammadex can reverse rocuronium/vecuronium (dose 2–4 mg/kg, or 16 mg/kg for immediate reversal); have available
  • If depolarizing agents must be used:
    • Succinylcholine 1.5–2.0 mg/kg (roughly double the standard dose)
    • MG patients are resistant to succinylcholine (fewer functional AChRs); may require up to 2.6× normal dose
    • Not contraindicated in MG (unlike other neuromuscular diseases, no risk of hyperkalemia from receptor upregulation)
    • Response may be unpredictable; avoid defasciculating dose of nondepolarizer
  • Avoid benzodiazepines and opioids pre-intubation if possible (respiratory depressant effects exaggerated in MG patients)

Pharmacologic Management in Crisis

• Discontinue acetylcholinesterase inhibitors (pyridostigmine/neostigmine) to reduce bronchial secretions
  • Exception: if patient is NOT intubated, continue home pyridostigmine—abrupt cessation can worsen crisis
  • Restart pyridostigmine as patient approaches extubation
• Plasmapheresis (PLEX) — generally preferred in crisis for faster onset
  • Usually improvement by 2nd–3rd session
  • Effect lasts 15–20 days
  • Contraindicated in sepsis, hemodynamic instability
  • Requires central venous access
• IVIG
  • 0.4 g/kg/day for 5 days (total 2 g/kg)
  • Effect lasts 30–45 days
  • May take days to weeks for full effect
  • Contraindicated in renal failure, hypercoagulability, IgA deficiency
• PLEX and IVIG are considered equivalent for exacerbations overall, but PLEX may have faster onset; choice depends on patient factors and local availability

Corticosteroids in Crisis

• Use with caution in the acute setting
  • Steroid initiation can cause transient worsening (in ~50% of patients), typically 5–10 days after initiation
  • Generally defer initiation until after PLEX/IVIG has been started and patient is stabilized
  • If patient was previously on steroids, continue the same dose

Outpatient / Non-Crisis Management

Pyridostigmine and neostigmine provide symptomatic relief but do not alter the course of crisis. Consider avoiding in ICU ventilated patients due to increased secretions.

• Pyridostigmine: Titrate up to find the lowest effective dose
  • Initially 30 mg four times daily for 2–4 days
  • Then 60 mg (1 tablet) four times daily for 5 days and experiment with timing
  • Then increase to 90 mg four times daily over 1 week if required
  • If patient's usual dose has been missed the next dose is usually doubled
  • IV route: 1/30th of the PO dose (2–3 mg) by slow IV infusion
• Neostigmine
  • 0.5 mg IV
• Prednisolone: If symptomatic despite pyridostigmine. Monitor for diabetes mellitus.
  • Ocular myasthenia gravis
    • Start 5 mg on alternate days for three doses, increase by 5 mg every three doses until symptoms improve
    • Maximum dose: 50 mg on alternate days (or 0.75 mg/kg/alternate day)
  • Generalized myasthenia gravis
    • Start 10 mg on alternate days for three doses, increase by 10 mg every three doses until symptoms improve
    • Maximum dose: 100 mg alternate days (or 1.5 mg/kg)

Disposition

Admit (ICU/Neuro ICU)

• Any myasthenic crisis (respiratory failure or impending)
• FVC < 20 mL/kg or NIF weaker than −30 cmH₂O
• Rapidly declining serial respiratory parameters
• New-onset or worsening bulbar symptoms with aspiration risk
• Consideration for thymectomy if not previously done

Admit (Floor/Stepdown)

• MG exacerbation without respiratory failure but requiring IV medications, monitoring, or initiation of PLEX/IVIG
• New diagnosis of MG with significant symptoms

Consider Discharge with Close Follow-up

• Known MG with mild exacerbation, stable respiratory parameters, adequate oral intake, and reliable follow-up with neurology
• Ensure medication list has been reviewed and offending agents discontinued
• Patient education on signs of respiratory compromise and when to return

Key Consult Points for Neurology

• Current medication regimen (pyridostigmine dose, immunosuppressants)
• FVC, NIF, and trend over ED visit
• Suspected precipitant (infection, medication change, non-adherence)
• Prior crisis history and treatments (PLEX vs IVIG preference, thymectomy status)

Medication Dosing

Myasthenic Crisis

• IVIG 0.4 g/kg/day x5 days (or 1 g/kg/day x2 days) IV — Alternative to plasmapheresis; preferred if sepsis or hemodynamic instability

Outpatient/Symptomatic

• Pyridostigmine 60 mg QID (titrate to effect) PO — Provides symptomatic relief; does not alter disease course

See Also

• Weakness
• Guillain-Barré syndrome
• Botulism
• Lambert-Eaton myasthenic syndrome
• Organophosphate toxicity