Myasthenia testing and treatment

Diagnostic Testing Ladder in Myasthenia Gravis

1. The Ice Pack Test

The ice pack test is the primary, non-invasive bedside diagnostic modality for myasthenic ptosis:

• Physiological Basis: Cooling inhibits the enzymatic degradation kinetics of acetylcholinesterase (AChE) within the synaptic cleft and optimizes the open-time probability of post-synaptic AChRs, allowing acetylcholine to linger and bind more effectively.
• Protocol: The vertical palpebral fissure height is measured at baseline. An ice pack (or crushed ice wrapped in a surgical glove) is placed over the closed ptotic eyelid for 2 minutes (or up to 5 minutes if well tolerated). The ice pack is removed, and the palpebral fissure is remeasured immediately.
• Diagnostic Threshold: An elevation of $\ge 2\text{ mm}$ in palpebral fissure height represents a positive test (sensitivity ~80%, specificity ~90-95%).

2. Pharmacological Testing: Edrophonium (Tensilon) Test

Edrophonium chloride is a synthetic, short-acting, reversible acetylcholinesterase inhibitor with an onset of action within 30 to 60 seconds and a duration of 5 to 10 minutes:

• Historical edrophonium test: A supervised short-acting cholinesterase-inhibitor challenge was formerly used to assess objective improvement. Availability and current use vary; serious bradycardia and respiratory adverse effects require resuscitation capability. It is not a routine unsupervised diagnostic step, and a response alone does not establish myasthenia.
• Historical test safety: Edrophonium can cause bradyarrhythmia and bronchospasm. Where this historical test is still used, specialist monitoring and resuscitation capability, including appropriate atropine, are required. It is not a routine unsupervised diagnostic trial; dose and rescue arrangements follow the local protocol.
• Current Role: Due to the risk of life-threatening arrhythmias, edrophonium is rarely utilized in modern European centers, having been largely superseded by the ice pack test, serology, and single-fiber electromyography.

3. Serological Assays

• AChR Binding Antibodies: Initial serological test. Highly specific (>99%), but positive in only ~50% of pure ocular MG and ~85% of generalized MG.
• Anti-MuSK Assays: Indicated in AChR-negative patients. Essential because MuSK-positive patients respond poorly to standard AChE inhibitors and require specialized immunotherapy.
• Anti-LRP4 Antibodies: Second-line evaluation in double-seronegative patients.

4. Electrophysiological Testing

• Repetitive Nerve Stimulation (RNS): Low-frequency (2 to 3 Hz) supramaximal electrical nerve stimulation is delivered to motor nerves while recording compound muscle action potentials (CMAPs). A progressive decremental response of $>10\%$ between the first and fourth or fifth CMAP waveform confirms post-synaptic neuromuscular block. Sensitivity is low in pure ocular MG (~30%), but high in generalized disease (~75%).
• Single-fibre electromyography (SFEMG): Measures variability of neuromuscular transmission (jitter) and can detect impulse blocking. It is sensitive for transmission disorders, but performance depends on the muscle, technique and presentation. A normal orbicularis study does not reliably exclude ocular MG in isolated diplopia; increased jitter can also occur in other disorders. Integrate the examination, antibodies and electrophysiology. See the presentation-specific diagnostic study and 2024 prospective jitter study.

5. Mediastinal Imaging: Thymoma Screening

The thymus gland plays a fundamental role in the breakdown of self-tolerance in AChR-positive MG. Contrast-enhanced chest CT or MRI is mandatory in all newly diagnosed myasthenic patients to evaluate the mediastinum:

• Thymic Follicular Hyperplasia: Present in approximately 65% of AChR-positive patients (typically young females).
• Thymoma: Present in 10% to 15% of patients (typically older males). Thymomas are true epithelial neoplasms that may exhibit local invasion, requiring surgical oncological resection.
• The MGTX Trial: The landmark international randomised MGTX trial demonstrated that in non-thymomatous, generalized AChR-positive myasthenia gravis aged 18 to 65 years, transsternal thymectomy significantly improves clinical outcomes, reduces requirements for oral prednisone, and lowers hospital readmission rates over a 3- to 5-year period.

Medical & Immunological Management of Myasthenia Gravis

Therapy in myasthenia gravis is tailored according to whether disease is purely ocular or generalized, antibody status, and disease severity:

1. Acetylcholinesterase Inhibitors (Symptomatic First-Line):

   • Pyridostigmine Bromide (Mestinon): Oral, reversible inhibitor of AChE. Standard starting dosage is 60 mg orally three to four times daily (half-life ~3-4 hours). It enhances functional transmission at the NMJ without modifying underlying autoimmunity.
   • Muscarinic Side Effects: Abdominal cramping, diarrhoea, hyperperistalsis, nausea, increased lacrimation/salivation. Fasciculations are a nicotinic effect, distinct from these muscarinic effects. Treated with oral muscarinic antagonists that do not cross the blood-brain barrier (e.g. propantheline bromide or glycopyrrolate).
   • MuSK Caveat: Patients with anti-MuSK myasthenia gravis frequently do not respond to pyridostigmine and may suffer severe paradoxical worsening, muscle cramping, and fasciculations.

2. Corticosteroids (Immunosuppression):

   • Oral Prednisolone: Indicated when symptoms remain functionally debilitating despite pyridostigmine or when ocular MG threatens to generalize. Started at a low dose (10-20 mg/day) and titrated upward gradually (by 5-10 mg every week to 1 mg/kg/day) to avoid paradoxical steroid-induced transient exacerbations of myasthenic weakness during the first 7 to 10 days of high-dose therapy.

3. Steroid-Sparing Immunosuppressants:

   • Azathioprine: First-line steroid-sparing agent in Europe (dosage 2-3 mg/kg/day). Thiopurine methyltransferase (TPMT) enzyme activity must be verified prior to initiation to prevent catastrophic bone marrow aplasia.
   • Mycophenolate Mofetil: Inhibits inosine monophosphate dehydrogenase; well tolerated with low hepatotoxicity.
   • Rituximab (Anti-CD20): B-cell depleting monoclonal antibody. Regarded as the treatment of choice for refractory anti-MuSK myasthenia gravis, often achieving prolonged clinical remissions.

4. Rescue Therapies for Myasthenic Crisis:

   • Myasthenic Crisis: An acute, life-threatening exacerbation characterized by respiratory failure (diaphragmatic weakness) or severe bulbar failure (aspiration risk), often precipitated by systemic infection, surgery, or abrupt drug withdrawal.
   • Intravenous Immunoglobulin (IVIG): Administered at 2 g/kg total dose divided over 2 to 5 days.
   • Therapeutic Plasma Exchange (PLEX): Typically 5 exchanges (3-4 liters per exchange) on alternate days over 10 to 14 days, directly filtering pathogenic autoantibodies from the plasma. PLEX and IVIG are rescue options; choice depends on urgency, comorbidities, vascular access and local expertise. Airway and respiratory assessment take priority.