Edrophonium test

Edrophonium is a very short-acting cholinesterase inhibitor: the effect appears within less than a minute and has gone after 5–10 minutes. That makes the test useful only if you have selected an objectively measurable finding in advance — usually ptosis or fatigable gaze palsy — that can be assessed before and during the window of effect. The muscarinic effect may at the same time produce marked bradycardia and, rarely, asystole, and the test must therefore never be performed without atropine, ECG monitoring and access to airway support.

Indications

• Clinically suspected myasthenia gravis in a patient with clear, objectively verifiable fatigable symptoms.
• Assessment of whether residual weakness in a patient with known myasthenia responds to further cholinesterase inhibition.

The test has a sensitivity of around 60 % and is not specific: motor neurone disease, myopathies and Lambert–Eaton syndrome may also give a positive result. A negative test does not exclude myasthenia gravis.

Today the test plays a marginal role in Sweden. Edrophonium is available only as a named-patient (licensed import) product, and the diagnosis instead rests on antibody analysis (AChR antibodies in about 80 % of generalised and around half of ocular myasthenia, thereafter MuSK and LRP4 antibodies) and on neurophysiology (repetitive nerve stimulation with a decrement ≥ 10 % at 3 Hz, sensitivity about 75 %; single-fibre EMG about 95 %).

Contraindications

• Known hypersensitivity to edrophonium.
• Mechanical obstruction of the bowel or the urinary tract.
• Marked bradycardia, sick sinus syndrome or high-grade AV block without pacemaker protection.
• Asthma and other marked obstructive airways disease — relative; the risk of bronchospasm is real.
• Hypotension and haemodynamic instability.
• Respiratory compromise during an ongoing crisis. Distinguish the conditions instead by temporarily withdrawing the cholinesterase inhibitor, under monitoring in a setting where the airway can be secured.

Preparation and equipment

• Edrophonium 10 mg/mL, 1 mL (named-patient product — order well in advance).
• Atropine 0.5 mg for premedication, plus further atropine drawn up in a syringe as a standby dose. Glycopyrronium (Robinul) 0.2 mg is an alternative premedication.
• Peripheral venous cannula, saline flush.
• ECG monitoring, pulse oximetry and blood pressure measurement throughout the test.
• Oxygen, suction, a bag and mask, and access to equipment and competence for advanced life support in the room.
• Two people: one who injects and monitors, one who assesses and documents muscle function.

Define the outcome measure before the test. Measure the size of the ptosis in millimetres, the time to diplopia on upward gaze, or the number of seconds the patient can hold the head lifted off the couch. Filming before and during the test is helpful. A test without a predetermined measure becomes a subjective guess.

Procedure

1. Check the indication and contraindications, attach ECG monitoring and insert a venous cannula.
2. Document the baseline status of the chosen finding — measurement, photograph or video.
3. Give atropine 0.5 mg intravenously (alternatively glycopyrronium 0.2 mg) to reduce the risk of a cholinergic vagal reaction with bradycardia. Wait 5–10 minutes.
4. Give 2 mg of edrophonium intravenously as a test dose. Observe pulse, blood pressure and muscle strength for a few minutes.
5. If the patient tolerates the test dose without troublesome adverse effects, give a further 8 mg intravenously, slowly. Rapid injection increases the risk of nicotinic effects with paradoxically increasing weakness.
6. Assess the chosen finding continuously during the window of effect, 40 seconds to 5–10 minutes after the injection.
7. Stop the test in the event of bradycardia, bronchospasm, marked salivation or increasing weakness, and give atropine.
8. Monitor for at least 30 minutes after the test has been completed.

flowchart TD
  A[Objectively measurable fatigable finding chosen and documented] --> B[ECG monitoring, venous cannula, atropine on standby]
  B --> C[Atropine 0.5 mg iv or glycopyrronium 0.2 mg iv]
  C --> D[Wait 5 to 10 minutes]
  D --> E[Edrophonium 2 mg iv as a test dose]
  E --> F{Is the dose tolerated?}
  F -- No: bradycardia or bronchospasm --> G[Stop, give atropine, monitor]
  F -- Yes --> H[Edrophonium 8 mg iv slowly]
  H --> I{Clear objective improvement within 3 minutes?}
  I -- Yes --> J[Positive test: supports myasthenia gravis but is not specific]
  I -- No --> K[Negative test: does not exclude myasthenia, proceed with antibodies and neurophysiology]

Alternatives when edrophonium is not available

Interpretation

• A positive test requires clear, objective symptomatic improvement within 3 minutes — not that the patient feels stronger.
• Subjective improvement without a measurable change does not count. The placebo effect is considerable.
• A positive test supports a disorder of neuromuscular transmission but does not establish the diagnosis. Antibodies and neurophysiology must be performed whatever the result.
• If the patient is taking pyridostigmine, the drug must be withdrawn at least 12 hours before neurophysiological examination so that the findings are not masked.

Myasthenic versus cholinergic crisis

Both conditions produce increasing weakness and impending respiratory failure. What distinguishes cholinergic crisis is prominent cholinergic symptoms: fasciculations, muscle cramps, miosis, increased lacrimation and salivation, increased bronchial secretion, abdominal pain, vomiting, diarrhoea, sweating and bradycardia. Cholinergic crisis occurs above all at pyridostigmine doses above about 500 mg per day.

flowchart TD
  A[Increasing weakness in a patient with known myasthenia] --> B[Secure the airway and breathing first: intensive care or high-dependency bed]
  B --> C{Cholinergic signs: miosis, salivation, fasciculations, diarrhoea, bradycardia?}
  C -- Yes --> D[Suspect cholinergic crisis]
  C -- No --> E[Suspect myasthenic crisis]
  D --> F[Temporarily withdraw the cholinesterase inhibitor under monitoring]
  F --> G{Does the patient improve?}
  G -- Yes --> H[Cholinergic crisis confirmed: inadequate immunomodulation, review that treatment]
  G -- No --> E
  E --> I[Plasma exchange or IVIG early, consider steroids, neostigmine according to schedule]

Do not use the edrophonium test to distinguish myasthenic from cholinergic crisis. In cholinergic crisis the dose may worsen the weakness and precipitate respiratory arrest. The simplest and safest approach is to withdraw the cholinesterase inhibitor temporarily with the patient in a place where ventilation can be provided. Note also that the blood gases may be normal right up to the point at which the patient stops breathing — follow the respiratory rate, the vital capacity and the clinical impression, not the blood gas alone.

Complications

• Bradycardia and, rarely, asystole — the most serious risk and the reason for premedication with atropine and for ECG monitoring.
• Bronchospasm and increased bronchial secretion, particularly in patients with asthma.
• Muscarinic effects: salivation, lacrimation, sweating, abdominal pain, nausea, vomiting, diarrhoea, urinary urgency.
• Fasciculations and muscle cramps.
• Cholinergic weakness after too rapid or too large a dose, with paradoxically increasing paresis.
• Syncope and hypotension.

Aftercare and follow-up

The patient is monitored until the muscarinic symptoms have subsided, usually within 30 minutes. Document the dose, the times, the measured outcome before and after, and any adverse effects — preferably with a photograph or video, which is what can be shown to the next assessor.

Further investigation is carried out irrespective of the test result: AChR antibodies, and if these are negative MuSK and LRP4 antibodies, repetitive nerve stimulation and, where needed, single-fibre EMG. Computed tomography of the thorax to look for thymoma must always be performed in confirmed myasthenia gravis. Tell the patient that infection, stress, surgery, pregnancy and certain drugs can rapidly worsen the condition and that medical help should then be sought early.

Common pitfalls

• Testing without a predetermined objective measure. Without a measurement before and after, the assessment becomes arbitrary.
• Omitting premedication with atropine — the vagal reaction is the dangerous part of the test.
• Injecting the whole dose too rapidly instead of a fractionated 2 mg followed by 8 mg.
• Testing instead of managing the airway in a patient with incipient respiratory failure.
• Using the test to distinguish myasthenic from cholinergic crisis.
• Interpreting a negative test as excluding myasthenia — the sensitivity is about 60 %.
• Interpreting a positive test as diagnostic — other neuromuscular diseases may respond.
• Forgetting that pyridostigmine must be paused for at least 12 hours before neurophysiological examination.