Residency · Residency · Neurology

Myasthenia Gravis: Diagnosis and Management

Overview

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction (NMJ) mediated by antibodies directed against postsynaptic components. It has a prevalence of approximately 20 per 100,000 and shows a bimodal age distribution, affecting women predominantly between ages 20 and 40 and men between ages 60 and 80. The clinical hallmark is fatigable weakness that worsens with repetitive use and improves with rest. MG can become life-threatening when respiratory muscles are affected, a condition known as myasthenic crisis.

Pathophysiology

Normal NMJ Transmission

At the normal neuromuscular junction, acetylcholine (ACh) is released from presynaptic motor nerve terminal vesicles, crosses the synaptic cleft, and binds to nicotinic ACh receptors (AChR) on the postsynaptic muscle membrane. A critical concept is the safety factor: the normal NMJ releases substantially more ACh than the minimum needed to generate a muscle action potential, providing a margin that ensures reliable transmission under varying conditions.

Antibody-Mediated Mechanisms

AChR antibodies, present in the majority of generalized MG, cause disease through complement-mediated destruction of the postsynaptic membrane, cross-linking and accelerated internalization of AChR, and direct blockade of the ACh binding site. MuSK antibodies interfere with AChR clustering at the NMJ through disruption of the agrin-LRP4-MuSK signaling pathway and notably do not activate complement. LRP4 antibodies are rare and disrupt agrin signaling. All of these mechanisms reduce the safety factor for NMJ transmission, resulting in failure of signal propagation during repeated stimulation.

Antibody Subtypes and Clinical Correlations

AChR-Antibody MG (~85% of generalized MG)

AChR-antibody MG is the most common subtype and is associated with thymic abnormalities: thymic hyperplasia in approximately 65% (especially in young-onset disease) or thymoma in 10-15%. Patients present with generalized weakness and ocular involvement in most cases.

MuSK-Antibody MG (~5-8% of generalized MG)

MuSK-antibody MG predominantly affects young women and presents with prominent bulbar and facial weakness including dysarthria, dysphagia, and facial weakness, often with a characteristic "head drop" presentation. Ocular involvement is less common initially. Unusually for MG, tongue and facial atrophy may develop. This subtype is less responsive to cholinesterase inhibitors (which may actually worsen symptoms) but responds well to rituximab. Thymectomy is generally not indicated because there is no underlying thymic pathology.

Seronegative MG (~5-10%)

Seronegative MG is negative for AChR and MuSK antibodies by standard assays. Some of these patients harbor low-affinity AChR antibodies detectable only by cell-based assay (CBA), while others may have LRP4, agrin, or other less well-characterized antibodies. The clinical presentation is similar to AChR-MG, and patients generally respond to standard therapies.

Ocular MG

Ocular MG is characterized by weakness limited to the extraocular muscles, levator palpebrae, and orbicularis oculi, presenting with ptosis and/or diplopia. Approximately 50% of ocular MG patients will generalize within 2 years; however, if the disease remains purely ocular for 2 years, the risk of subsequent generalization is low. AChR antibodies are positive in only about 50% of pure ocular MG cases.

<image>Diagram of the neuromuscular junction showing the targets of AChR, MuSK, and LRP4 antibodies with their respective mechanisms of pathology</image>

Clinical Features

Pattern of Weakness

Ocular involvement produces ptosis (often asymmetric and shifting between sides) and diplopia; the Cogan lid twitch sign, a brief overshoot of the eyelid on upgaze after looking down, is a characteristic finding. Bulbar weakness manifests as dysarthria with nasal speech quality, dysphagia, jaw fatigue with prolonged chewing, and facial weakness producing a "myasthenic snarl" with attempted smiling. Limb weakness is proximal greater than distal, with the upper limbs often affected early. Respiratory weakness involves the diaphragm and intercostal muscles and may present insidiously. Neck flexor weakness exceeds extensor weakness and can produce head drop.

Fatigability

The defining feature of MG is weakness that worsens with sustained or repetitive activity and improves with rest. Ptosis worsens with sustained upgaze, which can be demonstrated with the sustained upgaze test held for 60 seconds. The curtain sign is elicited when elevating the more ptotic eyelid causes the contralateral lid to droop, reflecting the brain's compensatory innervation being redistributed.

MGFA Clinical Classification

The Myasthenia Gravis Foundation of America classification stratifies disease severity: Class I is ocular disease only, Class II is mild generalized (with IIa being limb predominant and IIb bulbar predominant), Class III is moderate generalized, Class IV is severe generalized, and Class V indicates the need for intubation.

Diagnostic Testing

Bedside Tests

The ice pack test involves applying an ice pack to the closed eyelid for 2 minutes and observing for improvement in ptosis, with a sensitivity of approximately 80% for ocular MG. It works because cooling inhibits acetylcholinesterase activity, improving NMJ transmission. The edrophonium (Tensilon) test uses a rapid-acting cholinesterase inhibitor to produce transient objective improvement in weakness, but it is rarely used now due to cardiac risks (bradycardia, bronchospasm) and requires atropine at bedside. The sleep test, in which the patient rests with eyes closed for 30 minutes, can demonstrate improvement in ptosis supportive of MG.

Serological Testing

The serological workup begins with AChR binding antibodies (the most sensitive test for generalized MG), supplemented by AChR modulating and blocking antibodies for additional sensitivity. If AChR antibodies are negative, MuSK antibodies should be tested. LRP4 antibodies are available at research or specialized laboratories. If both standard AChR and MuSK testing is negative, a cell-based assay for AChR should be pursued. Striational antibodies (anti-titin, anti-ryanodine receptor) are associated with thymoma and should be screened in late-onset MG and as part of the thymoma workup.

Electrodiagnostic Studies

Repetitive nerve stimulation (RNS) at 3 Hz tests for a greater than 10% decrement in CMAP amplitude between the first and fourth or fifth response. It is most sensitive in proximal muscles such as the trapezius and facial nerve, with sensitivity of approximately 75% in generalized MG but only 30% in ocular MG. Single-fiber EMG (SFEMG) is the most sensitive test for NMJ dysfunction, with sensitivity exceeding 95% in generalized MG and approximately 85% in ocular MG. It demonstrates increased jitter and blocking but is not specific to MG, as it is abnormal in any condition affecting the NMJ or motor neuron.

CT Chest

All MG patients require chest CT (or MRI) to evaluate for thymoma, which is present in 10-15% of MG patients and may be invasive. Thymic hyperplasia does not require imaging for detection, as the thymus often appears normal on CT in this setting.

<image>Repetitive nerve stimulation waveforms showing normal response versus the characteristic decremental pattern in myasthenia gravis</image>

Treatment

Symptomatic Therapy

Pyridostigmine (Mestinon), an acetylcholinesterase inhibitor, is the first-line symptomatic therapy. The starting dose is 30 mg three times daily, titrated to 60-90 mg every 4-6 hours. Side effects reflect cholinergic excess and include diarrhea, abdominal cramps, increased secretions, and bradycardia. Cholinergic crisis from overdose causes paradoxical weakness with prominent muscarinic symptoms but is rare with modern dosing. In MuSK-MG, pyridostigmine is less effective and may worsen fasciculations and cramps; lower doses or avoidance is recommended.

Immunosuppressive Therapy

Corticosteroids

Prednisone is started at a low dose of 10-20 mg/day and increased slowly to avoid early steroid-induced worsening, which affects 10-50% of patients in the first 1-2 weeks of high-dose therapy. The target dose is 0.5-1 mg/kg/day, maintained for several months before slow taper. Most patients require long-term steroid-sparing agents. For moderate-severe disease, inpatient initiation should be considered given the risk of early exacerbation.

Steroid-Sparing Agents

Azathioprine is the most commonly used steroid-sparing agent worldwide, with an onset of action of 6-12 months; TPMT enzyme activity should be checked before starting. Mycophenolate mofetil is widely used with an onset of 3-6 months, though two negative randomized controlled trials (criticized for short duration and study design) have tempered enthusiasm. Cyclosporine is effective but limited by nephrotoxicity. Tacrolimus is popular in Asia, has fewer side effects than cyclosporine, and may have a faster onset than azathioprine. Methotrexate is used occasionally with limited evidence.

Rituximab

Rituximab is an anti-CD20 B-cell depleting monoclonal antibody that is particularly effective in MuSK-MG, where it may induce prolonged remission. It is increasingly used in AChR-MG as a steroid-sparing agent, especially in refractory cases. Although not yet FDA-approved for MG, the evidence base is growing.

Complement Inhibitors

Eculizumab (Soliris) is an anti-C5 complement inhibitor FDA-approved for generalized AChR-positive MG. Ravulizumab (Ultomiris) is a long-acting anti-C5 inhibitor also FDA-approved, requiring less frequent dosing (every 8 weeks versus every 2 weeks for eculizumab). Zilucoplan is a subcutaneous C5 inhibitor that has also received FDA approval. All complement inhibitors require meningococcal vaccination due to the risk of Neisseria meningitidis infection, and they are reserved for refractory generalized AChR-MG.

FcRn Inhibitors

Efgartigimod (Vyvgart) blocks the neonatal Fc receptor, reducing IgG levels including pathogenic antibodies, and is FDA-approved for generalized AChR-positive MG. It is administered intravenously every 4 weeks in cycles of 4 infusions, with a subcutaneous formulation (Vyvgart Hytrulo) also available. Rozanolixizumab is a subcutaneous FcRn inhibitor that has also received FDA approval. These agents represent a paradigm shift in MG management, offering targeted IgG reduction without broad immunosuppression.

Thymectomy

Thymectomy is mandatory for thymoma regardless of MG status. For non-thymomatous generalized AChR-MG, the MGTX trial demonstrated that thymectomy plus prednisone was superior to prednisone alone, producing lower steroid requirements and better clinical outcomes at 3 years. It is best performed in patients aged 18-65 with AChR-positive generalized MG and disease duration less than 5 years. Thymectomy is not indicated in MuSK-MG because there is no thymic pathology. Minimally invasive approaches (video-assisted thoracoscopic and robotic) are preferred.

<image>Treatment algorithm for myasthenia gravis showing stepwise escalation from pyridostigmine through immunosuppression to targeted biologic therapies based on disease severity and antibody subtype</image>

Clinical Pearls

Thyroid function should always be checked in MG patients because autoimmune thyroid disease coexists in approximately 10% and can independently cause fatigue and weakness. MuSK-MG patients often have severe bulbar symptoms disproportionate to limb weakness, may worsen on pyridostigmine, and should be considered for rituximab early. The ice pack test is a simple, safe bedside test for ptosis that avoids the risks of edrophonium; it works by cooling the NMJ and slowing acetylcholinesterase activity. If ocular symptoms have been present for more than 2 years without generalization, the risk of future generalization is very low (less than 15%). Medications that can exacerbate MG include aminoglycosides, fluoroquinolones, macrolides, beta-blockers, calcium channel blockers, magnesium, D-penicillamine, immune checkpoint inhibitors, and botulinum toxin. Checkpoint inhibitor-associated MG is increasingly recognized in oncology patients and can present as de novo disease or exacerbation of pre-existing MG, sometimes with fulminant severity. Before any surgery, the anesthesiology team must be informed of MG because patients may have succinylcholine resistance and increased sensitivity to non-depolarizing neuromuscular blocking agents. In refractory generalized MG, the new complement and FcRn inhibitors offer a targeted approach, though they are expensive and require ongoing monitoring.

References

• Gilhus NE, Tzartos S, Evoli A, et al. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30.
• Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis (MGTX). N Engl J Med. 2016;375(6):511-522.
• Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN). Lancet Neurol. 2017;16(12):976-986.
• Howard JF Jr, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT). Lancet Neurol. 2021;20(7):526-536.
• Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419-425.

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