Myasthenic Crisis (Adult)

Quick Reference Card

Critical Definition

Myasthenic crisis is defined as respiratory failure requiring mechanical ventilation or airway protection in a patient with myasthenia gravis (MG), representing the most severe, life-threatening manifestation of the disease. [1,2]

Red Flags - Immediate Action Required

Emergency Management Algorithm

MYASTHENIC CRISIS INITIAL MANAGEMENT
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1. AIRWAY: Early intubation if FVC less than 15-20 mL/kg
   - Avoid succinylcholine (resistance)
   - Reduced dose rocuronium (0.3-0.5 mg/kg)
   - Sugammadex available for reversal

2. ICU ADMISSION: Mandatory for all crisis patients

3. IMMUNOTHERAPY (Choose one):
   A) Plasmapheresis (PLEX)
      - 5 exchanges over 10-14 days
      - 1-1.5 plasma volumes per session
      - Preferred for MuSK-positive MG
   
   B) IVIG
      - 2 g/kg total over 2-5 days
      - Preferred if no central access

4. MANAGE ANTICHOLINESTERASES:
   - Hold pyridostigmine during crisis
   - Resume when stable, off ventilator

5. STEROIDS: Use cautiously
   - May worsen weakness first 1-2 weeks
   - Start after PLEX/IVIG initiated

6. IDENTIFY AND TREAT PRECIPITANT

Medications to Avoid in Myasthenia Gravis

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1. Definition and Epidemiology

Formal Definition

Myasthenic crisis is defined by the Myasthenia Gravis Foundation of America (MGFA) Task Force as respiratory failure requiring mechanical ventilation or endotracheal intubation to protect the airway from aspiration due to bulbar dysfunction in the setting of myasthenia gravis. [1] This definition emphasizes the critical respiratory compromise that distinguishes crisis from exacerbation.

Epidemiology

Risk Factors for Crisis

Patient Factors:

• MuSK-antibody positive MG (higher bulbar involvement) [7]
• Late-onset MG (> 50 years)
• Thymoma-associated MG
• Previous crisis (recurrence rate 30-40%)
• Comorbid respiratory disease
• Male sex (some studies)

Disease Factors:

• Generalized MG (vs ocular)
• Short disease duration before treatment
• Inadequate immunosuppression
• Seronegative MG with aggressive phenotype

Exam Detail: MGFA Classification: The MGFA Clinical Classification is used to grade MG severity:

• Class I: Ocular weakness only
• Class II: Mild generalized weakness
• Class III: Moderate generalized weakness
• Class IV: Severe generalized weakness
• Class V: Myasthenic crisis - intubation required

Understanding this classification is essential for documenting disease progression and predicting crisis risk. Patients in Class III-IV are at highest risk of progressing to Class V (crisis). [1]

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2. Pathophysiology

Normal Neuromuscular Junction

The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle fibers:

1. Presynaptic terminal: Contains acetylcholine (ACh) vesicles
2. Synaptic cleft: Contains acetylcholinesterase (AChE)
3. Postsynaptic membrane: Contains nicotinic ACh receptors (AChRs) concentrated at junctional folds

Normal Transmission:

• Action potential triggers Ca2+ influx at nerve terminal
• ACh vesicles fuse with membrane, release ACh
• ACh binds AChRs, triggering endplate potential
• If threshold reached, muscle action potential generated
• AChE rapidly hydrolyzes ACh, terminating signal

Myasthenia Gravis Pathophysiology

MG is an autoimmune disorder targeting the postsynaptic NMJ:

Antibody Types and Mechanisms: [7,8]

Consequences at NMJ:

• Reduced functional AChR density (up to 80% reduction)
• Simplified postsynaptic folds
• Widened synaptic cleft
• Decreased "safety factor" for neuromuscular transmission
• Fatigable weakness: initial impulses succeed, repeated stimulation fails

Crisis Pathophysiology

Myasthenic crisis represents catastrophic failure of the respiratory pump:

Respiratory Muscle Involvement:

1. Diaphragm weakness: Primary driver of hypoventilation
2. Intercostal weakness: Reduced chest wall expansion
3. Accessory muscle fatigue: Compensatory mechanisms fail
4. Bulbar weakness: Aspiration risk, impaired cough

Physiological Cascade:

Reduced NMJ transmission efficiency
            ↓
Diaphragmatic and intercostal weakness
            ↓
Decreased tidal volume and vital capacity
            ↓
Hypoventilation (rising PaCO2)
            ↓
Hypoxemia (falling PaO2)
            ↓
Respiratory muscle fatigue (acidosis worsens weakness)
            ↓
Respiratory arrest

Exam Detail: Molecular Pathophysiology of AChR-MG:

The pathogenic antibodies in AChR-positive MG are predominantly IgG1 and IgG3 subclasses, which activate complement. The mechanisms of receptor loss include:

1. Complement-mediated lysis: C5b-9 membrane attack complex damages postsynaptic membrane
2. Antigenic modulation: Antibody cross-linking of AChRs accelerates internalization and degradation
3. Functional blockade: Some antibodies directly block ACh binding site

The thymus plays a central role in AChR-MG pathogenesis. Thymic hyperplasia (65%) or thymoma (10-15%) provides the immunological environment for autoreactive T and B cell development. Germinal centers within the thymus can produce anti-AChR antibodies. [8,9]

MuSK-MG Distinctions: MuSK antibodies are predominantly IgG4 (non-complement fixing), acting through:

• Disruption of AChR clustering at endplates
• Interference with agrin-MuSK signaling pathway
• These patients have more severe bulbar and respiratory involvement with higher crisis risk [7,10]

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3. Precipitating Factors

Identifying and treating the precipitant is crucial for crisis resolution. In approximately 30-40% of cases, a clear precipitant can be identified. [4,5]

Infection (Most Common - 30-40% of Cases)

Key Point: Respiratory infections are both a precipitant AND a consequence of myasthenic weakness, creating a vicious cycle. [5]

Medications (25-30% of Cases)

Antibiotics: [11,12]

Cardiovascular Drugs:

Neuromuscular Blocking Agents:

• Succinylcholine: Resistance (may need 2x normal dose) but prolonged recovery
• Non-depolarizing agents: Marked sensitivity - reduce dose by 50-75%
• Sugammadex: Safe reversal agent for rocuronium in MG

Other Medications:

• D-penicillamine (induces MG-like syndrome)
• Immune checkpoint inhibitors (pembrolizumab, nivolumab)
• Interferon-alpha
• Botulinum toxin (focal worsening possible)
• Statins (case reports, controversial)
• Iodinated contrast agents (rare)

Surgical Procedures

Perioperative Management Principles:

• Optimize MG control preoperatively (PLEX/IVIG if unstable)
• Avoid long-acting neuromuscular blockers
• Extubate only when fully awake with strong cough
• Continue anticholinesterases until surgery (hold morning of)
• Close monitoring 48-72 hours postoperatively

Medication Changes

Other Precipitants

• Pregnancy/postpartum: Exacerbation in first trimester, postpartum crisis
• Emotional stress: Poorly quantified but recognized
• Extreme temperatures: Heat particularly
• Trauma: Major injury
• Thyroid dysfunction: Both hyper- and hypothyroidism
• Contrast agents: Rare reports with gadolinium, iodinated contrast

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4. Clinical Presentation

Symptoms of Impending Crisis

Respiratory Symptoms (Most Critical):

Bulbar Symptoms:

General Symptoms:

• Progressive weakness (proximal > distal)
• Neck flexor weakness ("dropped head")
• Fatigue worsening through day
• Diplopia and ptosis (may be absent in crisis)

Physical Examination Findings

General Inspection:

• Anxious, distressed appearance
• Tripod positioning (leaning forward)
• Speaking in short phrases
• Visible accessory muscle use
• Diaphoresis (hypercapnia)

Vital Signs:

• Tachypnea (RR > 25/min)
• Tachycardia (compensatory)
• Possible hypertension (stress response, hypercapnia)
• May see hypotension in late/cholinergic crisis

Respiratory Examination:

Neurological Examination:

Bedside Assessment Tools

Single Breath Count Test:

• Ask patient to count out loud after deep breath
• Normal: > 25-30
• Moderate impairment: 15-25
• Severe (less than 15): FVC likely less than 1L - crisis imminent

Head Lift Duration:

• Sustained head lift off pillow while supine
• Normal: > 2 minutes
• less than 5 seconds: Severe weakness, high crisis risk

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5. Differentiation: Myasthenic vs Cholinergic Crisis

This distinction is critical as management differs completely. [2,13]

Comparative Features

SLUDGE/BBB Mnemonic for Cholinergic Excess

SLUDGE:

• Salivation (excessive)
• Lacrimation (tearing)
• Urination (increased)
• Defecation (diarrhea)
• GI cramping
• Emesis

BBB:

• Bradycardia
• Bronchorrhea
• Bronchospasm

Diagnostic Approach

1. Medication Review:

• Calculate recent pyridostigmine dose
• Doses > 450-600 mg/day increase cholinergic risk
• Time relationship of symptoms to medication

2. Clinical Assessment:

• Cholinergic signs (SLUDGE) point to excess medication
• Pure weakness without cholinergic features suggests myasthenic crisis

3. Edrophonium (Tensilon) Test:

• Rarely performed in crisis (high risk)
• IV edrophonium (2-10mg)
• Improvement → myasthenic crisis
• Worsening → cholinergic crisis
• Requires atropine at bedside, continuous monitoring
• Sensitivity limited in crisis setting

4. Drug Holiday Approach:

• Most reliable modern approach
• Hold all anticholinesterases
• Support ventilation
• Observe over 48-72 hours
• Both myasthenic and cholinergic crisis improve with drug holiday
• Restart pyridostigmine at low dose once stable

Clinical Pearl: Practical Approach: In modern practice, the "drug holiday" is preferred over Tensilon testing in crisis. All anticholinesterases are held, mechanical ventilation is provided, and the patient is treated with PLEX or IVIG. Anticholinesterases are gradually reintroduced once the patient is improving and ready for weaning. Anticholinesterases can interfere with PLEX efficacy and may increase secretions, complicating airway management. [2,5]

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6. Investigations

Respiratory Monitoring (Most Critical)

The "20/30/40 Rule" for Intubation: [4,6]

• FVC less than 20 mL/kg
• NIF < -30 cmH2O (or -20 to -25 in some protocols)
• Decline of >30% from baseline FVC

Laboratory Studies

Diagnostic Studies

Antibody Testing (Usually Known at Crisis):

• AChR antibodies (binding, blocking, modulating)
• MuSK antibodies (if AChR negative)
• LRP4 antibodies (research settings)

Imaging:

Electrophysiology (Usually Deferred in Crisis):

• Repetitive nerve stimulation (decremental response)
• Single-fiber EMG (increased jitter) - most sensitive
• Not typically performed during crisis

Monitoring Trends

Graphing FVC and NIF:

• More important than single values
• Decline > 30% over 24-48 hours concerning
• Stabilization suggests treatment response
• Plot on bedside chart for visual trend assessment

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7. Management

Airway Management

Indications for Intubation: [4,5,6]

Do not wait for respiratory arrest - intubate early while patient is stable

Intubation Technique in MG:

NIV (BiPAP) Considerations:

• May temporize in early/mild crisis
• Settings: IPAP 10-15, EPAP 5, titrate to comfort
• Close monitoring essential - low threshold to intubate
• Contraindicated if unable to protect airway, excessive secretions, or rapid decline
• Success rate ~50% in avoiding intubation in mild cases

Immunotherapy

Two equally effective rapid-acting immunotherapies are available. [14,15,16]

Plasma Exchange (PLEX):

PLEX Advantages:

• Slightly faster onset
• Preferred for MuSK-positive MG (better response) [7]
• More predictable response

PLEX Complications:

• Hypotension (most common)
• Catheter-related (infection, thrombosis, bleeding)
• Electrolyte disturbances (hypocalcemia, hypokalemia)
• Coagulopathy (depletion of clotting factors)
• Citrate toxicity (if FFP used)
• Allergic reactions

Intravenous Immunoglobulin (IVIG):

IVIG Advantages:

• No central line required
• No hemodynamic instability
• No coagulopathy

IVIG Complications:

• Headache (most common, 25-50%)
• Aseptic meningitis (rare but severe)
• Acute kidney injury (especially sucrose-containing formulations)
• Thromboembolism (arterial and venous)
• Hemolytic anemia (anti-A/B antibodies in product)
• Anaphylaxis (especially IgA-deficient patients)
• Fluid overload (large volume infusion)

PLEX vs IVIG Comparison: [14,15]

Evidence Debate: PLEX vs IVIG Evidence:

The landmark randomized trial by Barth et al. (Neurology 2011) compared PLEX and IVIG in 84 patients with MG exacerbation, including some requiring ventilation. At 14 days, there was no significant difference in improvement on the Quantitative MG Score (QMGS). Both treatments were equally effective with similar safety profiles. [14]

A Cochrane review confirms there is insufficient evidence to determine superiority of either treatment, and choice should be based on availability, patient factors, and clinician expertise. [16]

For MuSK-positive MG, observational data suggest PLEX may be more effective, as IVIG response is often incomplete. This is thought to be due to the IgG4 predominance of MuSK antibodies. [7,10]

Corticosteroids

Critical Consideration: High-dose corticosteroids can cause transient worsening of MG in 30-50% of patients during the first 1-2 weeks. This is thought to be due to a direct effect on neuromuscular transmission or transient immunological changes. [1,17]

Steroid Use in Crisis:

Anticholinesterase Management

Pyridostigmine in Crisis:

Supportive Care

Weaning from Mechanical Ventilation

Criteria for Extubation: [5,6]

Weaning Approach:

• Daily spontaneous breathing trials (SBT)
• Tracheostomy consideration if no progress by 10-14 days
• Pyridostigmine resumed at low dose before extubation attempt
• Close monitoring post-extubation (25-30% reintubation rate)

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8. Special Populations

MuSK-Positive Myasthenia Gravis

Management Implications:

• Lower threshold for airway protection
• PLEX preferred for crisis
• Rituximab considered earlier in refractory cases
• Thymectomy less beneficial (no thymic pathology)

Thymoma-Associated MG

Pregnancy

Management in Pregnancy:

• Continue pyridostigmine (safe)
• Prednisone acceptable (avoid high-dose dexamethasone - crosses placenta)
• IVIG preferred over PLEX (but both safe)
• Azathioprine may be continued (category D but extensive safety data)
• Avoid: Mycophenolate, methotrexate (teratogenic)
• Monitor for neonatal MG (10-20% of infants, transient)
• Magnesium sulfate for preeclampsia: EXTREME CAUTION - may precipitate crisis

Elderly Patients

• Higher risk of crisis
• More comorbidities complicating management
• Slower recovery
• Higher complication rates (pneumonia, delirium)
• Thymectomy benefit less clear > 65 years

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9. Prognosis and Outcomes

Modern Era Outcomes [5,6]

Prognostic Factors

Poor Prognostic Factors:

• Age > 50 years at crisis
• Thymoma-associated MG
• Delayed initiation of treatment
• Aspiration pneumonia
• Sepsis
• Multiple organ failure
• Previous crisis
• MuSK-positive MG (more difficult to treat)
• Prolonged intubation (> 2 weeks)

Favorable Factors:

• Young age
• First crisis
• Clear precipitant (removable)
• Rapid response to PLEX/IVIG
• AChR-positive subtype
• No thymoma

Long-Term Management After Crisis

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10. Common Viva Questions and Model Answers

Question 1: "A 45-year-old woman with known myasthenia gravis is admitted with increasing dyspnea. How do you assess her?"

Model Answer: "This patient with known MG presenting with dyspnea is concerning for impending myasthenic crisis.

My assessment would focus on:

Immediate ABC approach with supplemental oxygen and continuous monitoring.

Respiratory assessment is the priority:

• Serial FVC and NIF measurements - FVC less than 15-20 mL/kg or NIF less than -20 cmH2O would indicate need for intubation
• Single breath count - less than 15 is concerning
• Look for paradoxical abdominal breathing indicating diaphragmatic failure
• ABG for hypercapnia, which is a late sign

Differentiate myasthenic from cholinergic crisis by examining for SLUDGE signs - excessive secretions, miosis, bradycardia, and fasciculations would suggest excess pyridostigmine.

Identify precipitants:

• Any recent infection - respiratory tract most common
• Medication changes - new aminoglycosides, fluoroquinolones, beta-blockers
• Recent surgery
• Medication non-adherence

I would prepare for intubation if respiratory parameters are declining, using reduced-dose rocuronium and avoiding succinylcholine. All patients in crisis require ICU admission."

Question 2: "What medications should be avoided in myasthenia gravis and why?"

Model Answer: "Multiple medication classes can worsen myasthenia gravis through effects on neuromuscular transmission.

Antibiotics are the most clinically relevant group:

• Aminoglycosides like gentamicin are contraindicated as they block presynaptic calcium channels and have postsynaptic effects
• Fluoroquinolones have been associated with crisis in case reports
• Macrolides and tetracyclines have weaker associations but warrant caution

Cardiovascular drugs:

• Magnesium sulfate is highly problematic as it blocks presynaptic calcium channels - critical to remember in obstetric patients with preeclampsia
• Beta-blockers, particularly propranolol, can worsen weakness
• Quinidine and procainamide have direct neuromuscular blocking effects

Neuromuscular blocking agents:

• Succinylcholine causes resistance initially, requiring higher doses, but then prolonged paralysis
• Non-depolarizing agents show marked sensitivity - use at 50% or less of normal dose

Other agents:

• D-penicillamine can induce an MG-like syndrome
• Immune checkpoint inhibitors are increasingly recognized as triggers
• Iodinated contrast agents have rare associations

All MG patients should carry a card listing contraindicated medications, and any prescriber should verify safety before administering new drugs."

Question 3: "Compare plasma exchange and IVIG for myasthenic crisis."

Model Answer: "PLEX and IVIG are equally effective for myasthenic crisis based on randomized trial evidence, with the choice depending on patient factors and availability.

Plasma exchange:

• Mechanism: Removes circulating antibodies, complement, and immune complexes
• Protocol: 5-6 exchanges over 10-14 days, exchanging 1-1.5 plasma volumes
• Onset: Slightly faster, improvement often within 1-2 days
• Advantages: Preferred for MuSK-positive MG, predictable response
• Disadvantages: Requires central venous access, causes hypotension, depletes clotting factors

IVIG:

• Mechanism: Immunomodulation through multiple pathways including Fc receptor blockade
• Protocol: 2 g/kg divided over 2-5 days
• Onset: Improvement within 3-5 days
• Advantages: No central line needed, hemodynamically stable
• Disadvantages: Headache common, risks of renal injury, thrombosis, and aseptic meningitis

Key points:

• Both provide temporary improvement lasting 4-6 weeks
• Neither is a long-term solution - must be followed by maintenance immunosuppression
• The Barth 2011 trial showed no significant difference in efficacy
• In MuSK-MG, PLEX is preferred as IVIG response is often incomplete
• In pregnancy, both are safe; IVIG often preferred for ease of administration
• Cost is high for both modalities"

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11. Clinical Pearls and Common Mistakes

Clinical Pearls

1. FVC is king - O2 saturation drops late; monitor FVC and NIF serially
2. Intubate early - don't wait for respiratory arrest; declining trend is indication
3. Drug holiday - hold pyridostigmine in crisis; simplifies management
4. Precipitant hunting - always look for infection, medication trigger, or non-adherence
5. Steroids can worsen - start after PLEX/IVIG, use moderate initial doses
6. MuSK is different - more bulbar, worse response to pyridostigmine and IVIG, consider PLEX
7. Magnesium kills - remember this for obstetric patients
8. Sugammadex is safe - reliable reversal of rocuronium in MG patients

Common Mistakes in Exams

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12. Key Guidelines and Evidence Summary

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References

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