CONTENTS

• Rapid Reference 🚀
• Myasthenia Gravis:  Background information
  • Pathophysiology
  • Presentation
  • Diagnosis
  • Drugs to avoid in myasthenia gravis
• Myasthenic crisis:  diagnosis
  • Diagnosis of myasthenic crisis:  basics
  • Differentiation from cholinergic crisis
  • Triggers of myasthenic crisis
• Myasthenic crisis:  treatment
  • Blood gas monitoring
  • Bedside pulmonary function tests
  • Respiratory support
  • Nutrition & GI access
  • Pyridostigmine
  • Steroid
  • PLEX vs. IVIG
• Checkpoint inhibitor induced myasthenia gravis
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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myasthenic crisis management ✅

evaluation (more)

• Chest X-ray and lung ultrasound (exclude other lung disease).
• Electrolytes (including Ca/Mg/Phos), CBC with differential.
• Beta-HCG if pregnancy possible.
• Infectious workup or TSH level (if symptoms of infection or thyroid disease).
• Forced vital capacity (FVC).

respiratory support (more)

• Consider early HFNC or BiPAP if mild-moderate respiratory distress or tachypnea.
• Intubation only if clinically indicated.

pyridostigmine (more)

• New diagnosis of MG: May initiate at 60 mg q6
• Chronic MG not intubated: Continue prior dose unless extremely high
• May add glycopyrrolate to reduce oral secretions (e.g. 1 mg with each dose)

plasma exchange / IVIG (more)

• Plasma exchange is preferred (it is the fastest approach to stabilize disease).
• If plasma exchange is contraindicated/unavailable, may use IVIG.

monitoring (more)

• Most useful: Usual monitoring (vital signs, clinical appearance, subjective dyspnea, etc.)
• Forced vital capacity 2-3 times daily (DO NOT wake up patient for this).
• (Do not measure negative inspiratory force).

medications to avoid (more)

• Antibiotics:  Aminoglycosides, Fluoroquinolones, Macrolides (e.g., azithromycin), Telithromycin.
• Cardiovascular:  Beta-blockers, Class-Ia antiarrhythmics (especially procainamide), statins.
• Other drugs commonly used in ICU:  IV magnesium, corticosteroids, contrast dye (although modern contrast dyes are probably fine).
• (Miscellaneous & rare medications:  Checkpoint inhibitors, chloroquine/hydroxychloroquine, desferrioxamine, D-penicillamine, quinine.)   

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pathophysiology of MG

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basics

• Autoantibodies are formed which bind to acetylcholine receptors on skeletal muscle.
• Anti-acetylcholine antibodies impair transmission at the neuromuscular junction in a few ways:
  • Direct inhibition of acetylcholine binding to the muscle
  • Antibodies accelerate degradation of acetylcholine receptors, decreasing the number of receptors.
• Clinically this causes skeletal muscle weakness.

treatments

• Acetylcholinesterase inhibitors (e.g. physostigmine) – these decrease the breakdown of acetylcholine within the neuromuscular junction.  This may boost signaling of the muscle cell.
• Immunosuppressive therapies are aimed at reduction in the synthesis of auto-antibodies.
• Plasmapheresis may directly remove auto-antibodies.

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presentation of MG

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distribution

• Eyes and bulbar muscles tend to be involved early (ptosis and diplopia are common).
  • Only skeletal muscles are involved (not the pupils).
• Generalized weakness can also occur (e.g. involving diaphragm and limbs).
  • Limb weakness is usually proximal > distal.

features of weakness

• Fatigability:  ongoing effort rapidly provokes worsening weakness.  Strength improves with rest.
• Asymmetric and fluctuating in severity over time.
• Normal sensation, normal deep tendon reflexes, and normal pupillary reflexes.

epidemiology

• Incidence in women peaks in their 20s's-30's, whereas incidence in men peaks in their 60's-80's.(33896522)
• Can be associated with:
  • Thymoma or thymic hyperplasia.
  • Other autoimmune diseases (e.g., hyperthyroidism, lupus, rheumatoid arthritis, polymyositis).
  • Lymphoma.
  • Checkpoint inhibitor use.📖

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diagnosis of MG

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serologic types 

• 80% of patients have antibodies against the acetylcholine receptor (AcH-R).  The specificity of a positive anti-AcH antibody result is high.(33223079)
• 5% of patients are seronegative (with no detectable antibodies).
• 4% of patients have antibodies against muscle-specific receptor tyrosine kinase (MuSK, another protein involved in acetylcholine signaling)(33223079)  These patients are typically young women with prominent involvement of bulbar muscles and diaphragm.  They tend to have high disease severity with a high frequency of respiratory crises.  They tend to respond well to plasma exchange and prednisone, but less well to IVIG or pyridostigmine.(27358333)
• 2% of patients have antibodies against low-density lipoprotein receptor-related protein 4 (LPR4).(33896522)
• Serologies are not helpful for the initial diagnosis among critically ill patients, because sluggish turn-around time limits the ability of this test to guide immediate treatment decisions.

ice pack test

• Place ice pack over patient's eye that is affected with ptosis or ophthalmoparesis for 2-5 minutes.(31794470)
• Improvement following ice supports a diagnosis of myasthenia gravis.  This improvement occurs due to reduced activity of acetylcholinesterases at lower temperatures.(34618763)
• Test is cheap, safe, noninvasive – and surprisingly sensitive (~90%) and specific (~80%).(28916122)

electrodiagnostic testing (EMG)

• (1) Repeated stimulation causes rapid deterioration in muscle responses (fatigability).
  • Sensitivity isn't fantastic (usually ~50%, but closer to ~80% in myasthenic crisis).(33223079, 30743297)
  • A decrease of >10% in the compound motor action potential (CMAP) with repeated stimulation indicates a defect in neuromuscular transmission.(31794470)
• (2) Single-fiber EMG
  • In the ICU setting it is generally impossible due to electrical interferences.(30743297)
  • Single-fiber EMG compares contraction in closely adjacent muscle fibers in the same motor unit.  Desynchronized activity of adjacent fibers (“jitter”) supports a diagnosis of myasthenia gravis.  This has higher sensitivity than repeated stimulation (~90%, up to 99% if examining a weak muscle), but it's not entirely specific for myasthenia gravis.

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drugs to avoid in MG

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Many drugs have been implicated in exacerbation of myasthenia, but the evidentiary strength is generally very low.  This creates a challenging task of avoiding genuinely dangerous medications, yet not withholding useful medications due to unnecessary fear.  The list below is based on the 2020 international consensus guidelines for management of myasthenia gravis.(33144515)  This is also consistent with a recent literature review by Sheikh et al.(33917535)

antibiotics

• Aminoglycosides – May worsen MG, use cautiously if no alternative.
• Fluoroquinolones – Associated with worsening MG; use cautiously, if at all.
• Macrolides (e.g., erythromycin, clarithromycin, azithromycin) – May worsen MG; use cautiously, if at all.
• Telithromycin – Causes severe, often fatal exacerbation of MG.  Do not use.

cardiovascular

• Beta-blockers – Potentially dangerous, may worsen MG.  Use cautiously.  Even ophthalmic formulations can be problematic.
• Procainamide (and probably other Class-Ia antiarrhythmics) – May worsen MG; use with caution.
• Statins – May worsen or precipitate MG.  Evaluate closely for worsening MG when statin therapy initiated.

miscellaneous

• Intravenous magnesium – Use only if absolutely necessary and observe for worsening.  Safety might be improved by infusing magnesium very slowly, to avoid transient elevations in serum magnesium levels.
• Corticosteroids – Standard treatment for myasthenia, but may cause transient worsening during the first two weeks (discussed further below).
• Iodinated radiocontrast dye – Modern agents appear safer than prior agents.  Use cautiously and observe for worsening.
• Checkpoint inhibitors – Can precipitate or worsen MG.
• Chloroquine and hydroxychloroquine – may precipitate or worsen myasthenia, use only if necessary and observe for worsening.
• Botulinum toxin – Avoid use.
• Desferrioxamine – May worsen myasthenia.
• D-penicillamine – Strongly associated with causing myasthenia, avoid use.
• Quinine – Prohibited, except in some cases of malaria.
• Succinylcholine – May be ineffective in causing paralysis; more on this below.

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diagnosis of myasthenic crisis

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definition?

• The term “myasthenic crisis” is used by different authors in various ways, which may lead to confusion:
  • #1) Some authors use “myasthenic crisis” to refer solely to patients with myasthenia gravis exacerbation requiring intubation or noninvasive ventilation.(27907966)
  • #2) Some authors use “myasthenic crisis” to refer to any exacerbation of myasthenia gravis which causes or threatens to cause frank respiratory failure.(28916122)
• The broader definition of myasthenic crisis (#2) is used here.
• Myasthenic crisis may be the initial manifestation of myasthenia gravis in about 15-20% of patients.(30743297)

Don't assume that every patient with myasthenia gravis who presents with dyspnea has a myasthenic crisis!  Patients with myasthenia gravis can have cardiopulmonary disease like anyone else (e.g., pneumonia, heart failure, pulmonary embolism).

diagnosis of a myasthenic crisis requires two components:

• (1) Careful cardiopulmonary evaluation with exclusion of other active processes:
  • At a minimum this should involve a thoughtful history, chest X-ray, EKG, and lung ultrasonography.
  • Other tests added as necessary (e.g. CT angiography to exclude PE).
• (2) Evidence of worsening muscular weakness:
  • History and physical may be helpful (e.g. patient reports increasing limb weakness and this is confirmed on exam).
  • Forced Vital Capacity (FVC) should be measured if the patient isn't extremely dyspneic.  Forced vital capacity should be reduced in order to make a diagnosis of myasthenic crisis.

differential diagnosis of a myasthenic crisis: related entities to consider

• (1) Cholinergic crisis – more on this below.
• (2) Adrenal crisis:  Many patients with myasthenia are maintained on chronic prednisone for months or years.  Adrenal crisis may occur in the following situations:
  • (1) Prednisone is abruptly stopped (e.g., due to weakness or inability to swallow medications).
  • (2) Patient on chronic low-dose prednisone (e.g., 5 mg) is exposed to a new source of physiologic stress.
  • (The chapter on adrenal crisis is here.)
• (3) Thyroid storm or myxedema coma – Autoimmune thyroid disease is associated with myasthenia gravis.

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myasthenic vs cholinergic crisis

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what is a cholinergic crisis?

• Excessive doses of acetylcholinesterase inhibitor (e.g. pyridostigmine) lead to excessive levels of acetylcholine, which acts as a depolarizing paralytic! (similar to succinylcholine).
• Cholinergic crisis is widely feared, but in modern practice this is almost nonexistent.
  • Historically, higher doses of pyridostigmine were used, so cholinergic crisis was a more relevant problem.
  • Cholinergic crisis doesn't occur in patients taking standard pharmacologic doses of pyridostigmine (<120 mg every 3 hours).(30743297)
  • Cholinergic crisis can occur if patients are self-medicating with excessive doses of pyridostigmine.(Torbey, 2019)

clinical features of a cholinergic crisis

• (1) Patient has a history of using escalating doses of acetylcholinesterase inhibitor medication.
  • Cholinergic crisis is unlikely if pyridostigmine dose is below 120 mg q3hr.
• (2) Fasciculation of skeletal muscles.
• (3) Features of acetylcholine excess affecting the autonomic nervous system:
  • Nausea/vomiting, diarrhea, salivation, lacrimation, diaphoresis.
  • Miosis.
  • Bradycardia.

management of cholinergic crisis

• Withhold any further administration of acetylcholinesterase inhibitor.
• Supportive therapy (e.g., intubation if clinically warranted).
• Once the patient has recovered, lower doses of acetylcholinesterase may be re-introduced.

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triggers of myasthenic crisis

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In addition to treatment of the myasthenia gravis, it may be important to treat the trigger of the crisis.  In ~15-20% of patients, myasthenic crisis may be the initial presentation of myasthenia.(32733360)  In many other patients, myasthenic crisis may be precipitated by another problem, including:

• Infection (especially pneumonia).
• Electrolyte abnormality (essentially any abnormality, including Ca/Phos/Mg).
• Thyroid disease (either hypothyroid or hyperthyroid; note that myasthenia gravis is associated with autoimmune thyroid disease).
• Surgery/trauma.
• Pregnancy, delivery.
• Medications:
  • Medications that exacerbate myasthenia (list above).
  • Nonadherence with myasthenia gravis medications (e.g., pyridostigmine)
  • Tapering of immunosuppressive medications.
  • Initiation of steroid.(Nelson 2020)

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blood gas monitoring

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blood gas is worthless in patients without chronic respiratory dysfunction

• Patients without chronic respiratory dysfunction should have a normal respiratory drive.  These patients shouldn't become hypercapnic until they are totally exhausted and frankly dying.
  • This assumes that they aren't on other medications that would blunt their respiratory drive (e.g., opioids).
• Hypercapnia is an extremely late finding in this context.
• It is generally accepted that blood gas monitoring has no role in most patients with myasthenia.

blood gas measurement may be somewhat useful in patients with chronic hypercapnia

• Patients with chronic hypercapnia (e.g., due to severe COPD) don't have a normal respiratory drive.  These patients may develop insidiously worsening hypercapnia without looking terrible.
  • Rather than developing respiratory extremis, these patients may quietly accumulate CO2 and become sleepy (due to CO2 narcosis).
• Blood gas analysis may therefore be useful in a patient with altered mental status plus chronic hypercapnia.
• Please note however that the decision to intubate is still clinical.  Blood gas is mainly useful to determine whether or not the patient is profoundly hypercapnic (not to track the precise pCO2 value over time).
  • For example: In a COPD patient with myasthenia gravis and hypercapnia, if the patient looked OK clinically then treatment with BiPAP might be the best option.

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bedside pulmonary function tests

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bedside respiratory monitoring consists of two tests:

• Negative Inspiratory Force (NIF)
  • This is the largest amount of negative pressure that the patient is able to exert when inhaling (video above).
  • This test is uncomfortable and effort-dependent.   There is no role for this test in myasthenia gravis (more on this below).
• Forced Vital Capacity (FVC)
  • This is the largest volume breath the patient is able to take.
  • Forced vital capacity is an integrated reflection of multiple parameters:  inspiratory strength, expiratory strength, and lung compliance.  The holistic nature of the forced vital capacity may make it a better predictor of respiratory failure than the negative inspiratory force (which measures only diaphragmatic strength).
  • Forced vital capacity is more reproducible and less uncomfortable than the negative inspiratory force.

Respiratory monitoring is grossly over-utilized.  There is no evidence to support frequent monitoring of respiratory mechanics in myasthenia gravis.  Available data are borrowed from wholly unimpressive studies of patients with Guillain-Barre Syndrome.(11405803, 4033410, 1928954, 12545029, 17110282, 24378177)  Guillain-Barre Syndrome is fundamentally different from myasthenia gravis, so this data doesn't apply (myasthenic patients fluctuate more than patients Guillain-Barre Syndrome).  Available studies involving myasthenia gravis actually show that pulmonary function testing fails to predict outcomes!(8522671, 18195139)  Let's start off by debunking some common problems with respiratory monitoring:

(1) why frequent respiratory monitoring may cause problems

• Interferes with sleep/rest (waking up patients to check pulmonary function tests is just plain evil).
• May exhaust the patient.
• May cause panic due to random variation in testing (if you do enough repeat testing, then eventually the numbers will decrease solely due to random chance).

Measures such as vital capacity and blood gas levels have limited value, since deterioration can be rapid and unexpected as a result of the characteristic myasthenic fatigability.  -Gilhus NE 2016 (28029925)

(2) why the negative inspiratory force (NIF) should rarely be measured

• NIF is more uncomfortable and less reproducible than the forced vital capacity.
• NIF has not been shown to add any independent information beyond what is provided by the forced vital capacity.(21748507)
  • Just use the forced vital capacity alone – this is a simpler and better approach.
  • (Theoretically in a patient with abnormal anatomy, such as prior pneumonectomy, NIF could be helpful.)

(3) intubation should never be performed solely based on pulmonary function tests

• Never decide to intubate based solely on pulmonary function tests for the following reasons:
  • Studies relating risk of intubation to pulmonary function tests are generally low quality and retrospective.
  • Pulmonary function tests are highly effort-dependent.
• The decision to intubate is primarily clinical.  Trends in pulmonary function tests may be helpful, but this is only a small piece of the decision (more on this below).

(4) beware of positional changes

• Patients with diaphragmatic weakness (such as myasthenia patients) will have a higher forced vital capacity when sitting up, compared to lying down.
• Any serial monitoring should ideally be done using a uniform position.

That said, there are some situations where pulmonary function testing can be useful.

(1) establishing the diagnosis & triage.

• Admission forced vital capacity is probably the most useful measurement.
• If admission FVC is normal and the patient is dyspneic, this suggests that something else is going on (e.g. pulmonary embolism, heart failure).  It also suggests that the patient may not require ICU level monitoring for myasthenia gravis.
• If the admission FVC is significantly low (e.g. <30 cc/kg):
  • This supports the diagnosis of myasthenic crisis.
  • This supports triage to an ICU for higher intensity monitoring.

(2) tracking response to therapy 

• Intermittently measuring the FVC can help determine how the patient is responding to therapy.
• Response to treatment takes time, so measuring the FVC twice or three times daily is probably fine.
• To be significant, changes should represent a consistent trend over several measurements (not just one aberrant measurement).

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respiratory support

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noninvasive respiratory support (HFNC or BiPAP)

• In order to work, high-flow nasal cannula (HFNC) or BiPAP must be started early, when the patient is in only mild respiratory distress.  The goal is to reduce the work of breathing and thereby prevent respiratory exhaustion.
  • These modalities will fail if initiated when the patient is already in extremis.
• When in doubt regarding whether the patient needs any support at all, consider high-flow nasal cannula (HFNC).  This is extremely safe and may reduce work of breathing (due to reduced anatomic dead space, with improved ventilatory efficiency).
• Evidentiary support is strongest for BiPAP, so this might be the first-line therapy for mild-moderate dyspnea.(18195139, 12451217)  If BiPAP cannot be tolerated or is contraindicated (e.g. due to intolerance or significant respiratory secretions), then HFNC may be tried.
• Close supervision in an ICU is required to ensure that these modalities are working (e.g., on BiPAP, the minute ventilation and tidal volume should be monitored).

decision to intubate

• The decision to intubate should NOT be made solely on the basis of pulmonary function tests, as discussed above.
• Intubation is always a clinical decision.  Components to consider may include the following (and especially the overall trajectory over time):
  • Look:
    • Patient appearance.
    • Respiratory rate.
    • Work of breathing, use of accessory muscles.
  • Cough:  Cough efficacy, ability to clear secretions, and ability to protect airway.
  • Strength:  Trends in weakness (e.g. especially neck flexion weakness, which may tend to track with respiratory muscle weakness).
  • FVC:  Trends in forced vital capacity.
  • Oxygenation:  Generally, myasthenia shouldn't cause significant hypoxemia.  Progressively worsening hypoxemia is a fairly poor sign which may suggest progressive atelectasis or aspiration.
  • Chest radiograph:  signs of worsening lobar collapse or aspiration would support the need for intubation.
• When in doubt, prepare for intubation and continue to monitor the patient carefully.

intubation procedure

• A non-depolarizing paralytic should be used (e.g. rocuronium).  The dose should be reduced by ~50% compared to the usual dose (e.g. a dose of ~0.6 mg/kg rocuronium may be reasonable).
  • Succinylcholine may fail to work due to reduced acetylcholine receptor density on muscle.
• Patients with dysautonomia due to GBS may be at risk of hypotension and/or bradycardia following intubation.  Consider having epinephrine ready to manage this complication.

tracheostomy

• Patients can generally be extubated within 1-2 weeks, with only ~20% of intubated patients requiring tracheostomy.(Nelson, 2020; 34618763)  Consequently, efforts generally focus on weaning mechanical ventilation rather than early tracheostomy.  Aggressive management of myasthenia gravis (e.g., plasma exchange) may enhance muscle strength and facilitate early extubation.
• Risk factors for inability to extubate include:(34618763)
  • Older age.
  • Comorbidities, such as pneumonia.
  • Late-onset myasthenia gravis.

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nutrition & GI access

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Some patients may have bulbar weakness causing dysphagia and risk of aspiration.

• If the patient is unable to protect their airway (e.g. inability to handle secretions, gurgling), then intubation is required.
• If the patient is able to protect their airway but is at increased risk for aspiration, there should be a low threshold to place a small-bore nasoenteric feeding tube.

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pyridostigmine

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basics

• Pyridostigmine is an acetylcholinesterase inhibitor.  It increases levels of acetylcholine in the synapse, improving nerve transmission.
• Excessive doses of pyridostigmine can be problematic for a few reasons:
  • (1) Increased secretions can be problematic, especially in patients with bulbar weakness or weak cough.
  • (2) Profoundly excessive doses can cause a cholinergic crisis (with currently used dosing, this is rare; more on this above).
• Glycopyrrolate or hyoscyamine may be used to reduce secretions caused by pyridostigmine (e.g., 1 mg glycopyrrolate or 0.125 mg hyoscyamine with each dose of physostigmine).(27907966, 29655452)  

general dosing information

• The starting dose is often 60 mg PO q6hr.
• The dose may be up-titrated to a maximum dose of 120 mg q4hr.
• Pyridostigmine can be given intravenously, but at 1/30th the dose of oral medication.
• Always be cautious for emergence of anticholinergic side-effects (e.g., increased secretions, bradycardia).

approach to pyridostigmine in a myasthenic crisis

• There isn't much evidence on this (with available literature nicely reviewed by Prado et al.).(34292475)  Reasonable practice might be as follows:
• Intubated patients, previously on chronic pyridostigmine:
  • Pyridostigmine is generally held initially to reduce airway secretions and increase sensitivity to pyridostigmine (a brief drug holiday may increase responsiveness when treatment is resumed).
  • Pyridostigmine should be restarted as the patient is approaching extubation.(27907966)
• Non-intubated patients, previously on chronic pyridostigmine:
  • Continue the patient's home dosing regimen.
  • Pyridostigmine should never be stopped in patients who are not intubated.(33896522)  One cause of myasthenic crisis is nonadherence with pyridostigmine, so it doesn't make sense to hold the patient's pyridostigmine – this could make matters even worse.
• New diagnosis of myasthenia (pyridostigmine naive patient)
  • It may be reasonable to start at a low dose (e.g., 60 mg PO q6hr).

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steroid & immunomodulatory treatment

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steroid

• Steroid is generally used to reduce production of anti-acetylcholine antibody.  A reasonable dose may be ~60-80 mg/day prednisone.
• Steroid takes 2-3 weeks to cause clinical improvement.  Initiation of steroid may actually cause a brief clinical deterioration.  Therefore, it might be ideal to delay steroid initiation for several days after initial admission (until patient has started improving).(27358333)  An alternative approach is to start steroid at a low dose (e.g., 20 mg prednisone) and then gradually up-titrate the dose.
  • ⚠️ There's no rush to start steroid immediately.  Discuss this with the neurology team.

alternative immunosuppression

• If steroid is contraindicated or previously ineffective, other treatments may be used (e.g., azathioprine, cyclosporine, rituximab, methotrexate).
• These agents will take forever to start working – so again, there's no rush here.

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PLEX versus IVIG

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There is no high-quality evidence regarding the selection of PLEX vs. IVIG.  However, most experts and guidelines believe that plasma exchange works more quickly.(27358333)

plasma exchange (PLEX) is first-line for severe exacerbation 

• Plasma exchange usually causes improvement in a few days.  It directly removes anti-acetylcholine receptor antibody from the body.
• The main advantage of plasma exchange is more rapid response compared to IVIG (which may take some weeks to see improvement).(32733360)  Rapid efficacy is especially important for patients who are at risk of requiring intubation, or patients who have been intubated (because the risk of ventilator-associated complications rises with each additional day of invasive ventilation).

IVIG may be useful for less severe exacerbations

• IVIG takes longer to work (e.g., 2-3 weeks), but the efficacy may be more sustained.
• IVIG can be used in situations where plasma exchange is unavailable or contraindicated.
• The dose of IVIG is 2 grams/kg, usually divided over 2 or 5 days.

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checkpoint inhibitor induced myasthenia gravis

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basics

• Checkpoint inhibitors may exacerbate myasthenia gravis, or cause de novo illness (more frequently the latter).
• Myasthenia usually occurs about a month after initiation of checkpoint inhibitor therapy (with a range of 6 days to 16 weeks).(33144515)
• Usually associated with anti-PD1 monotherapy or combination therapy.(32487905)

clinical features

• The usual presentation is with typical findings of myasthenia gravis (e.g., ptosis, diplopia, dysphagia, weakness, and dyspnea).(32487905)
• May have disproportionately severe respiratory and bulbar weakness, with a greater tendency to present with myasthenic crisis.(31794471)  

differential diagnosis includes:

• Myositis or Miller-Fisher variant of Guillain-Barre syndrome may present with prominent ocular/bulbar symptoms.
  • Checkpoint-induced oculobulbar myositis may mimic myasthenia gravis closely.
• Patients may often have a combination of myasthenia with simultaneous myositis, myocarditis, and/or thyroiditis (33144515) 
  • ⚠️ The combination of myasthenia gravis, myositis, and myocarditis is common.  The presence of any one of these three should prompt evaluation for all three disorders.  Among patients with myasthenia gravis, ~16% may have myositis and ~9% may have myocarditis.(34172516)
• Dyspnea may be due to checkpoint pneumonitis.
• Patients may be suffering from various other neurologic complications from cancer (more on these here)(REF).

evaluation

• Creatinine kinase and aldolase (to evaluate for myositis).
• Acetylcholine receptor and anti-striated muscle antibodies (although these tests may have reduced sensitivity for checkpoint-induced myasthenia gravis).
• May consider EKG and troponin (to evaluate for checkpoint myocarditis).
• TSH and free T4 (noting that checkpoint inhibitors may cause pituitary or thyroid gland dysfunction).
• MRI of brain and/or spine may be useful, depending on anatomic distribution of weakness
• Electrodiagnostic studies (these may not have excellent performance, but they offer the ability to evaluate broadly for myositis, polyneuropathy, and/or myasthenia gravis).

treatment

• Pyridostigmine starting 30 mg TID and up-titrating to a maximum of 120 mg QID as tolerated.
• Prednisone 1-1.5 mg/kg/day.  Early aggressive treatment with high-dose steroids may be helpful.(33144515)  
• Intravenous immunoglobulin (IVIG; 0.4 grams/kg/day for five days) or plasmapheresis for severe symptoms (including any dyspnea, facial weakness, or dysphagia)
  • Make sure to draw serologies before these therapies.
• Avoid medications that can worsen myasthenia (beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, macrolides) – see a full list above.

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Don't assume that a dyspneic patient with myasthenia gravis is necessarily having a myasthenic crisis:  these patients may also have any other cause of respiratory failure (e.g. pneumonia, heart failure).
• Don't harass patients with scheduled and extremely frequent measurements of pulmonary mechanics.
• Don't intubate patients based on arbitrary cutoff values in pulmonary mechanics (there's zero data to support this practice).
• Be extremely careful about starting new medications in patients with myasthenia gravis – consider the list of contraindicated medications above.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
•  = Link to supplemental media.

Going further

• Five pearls for the dyspneic patient with GBS or MG (PulmCrit)
• Myasthenia Gravis (Chris Nickson, LITFL)
• Myasthenia Gravis (First10EM, Justin Morgenstern)
• Myasthenia Gravis (WikiEM)