How should I diagnose and manage a patient with myasthenia gravis, including pyridostigmine dosing, corticosteroid and immunosuppressant therapy, thymectomy, and treatment of myasthenic crisis?

Diagnosis and Management of Myasthenia Gravis

Diagnostic Approach

Begin with serologic testing for anti-acetylcholine receptor (AChR) antibodies, which confirm the diagnosis in approximately 80% of generalized MG cases, followed by single-fiber EMG if antibodies are negative, as this has >90% sensitivity and is considered the gold standard. 1, 2

Initial Diagnostic Testing

• Order AChR antibodies first – present in 80% of generalized MG but only 50% of purely ocular MG 1, 2
• If AChR-negative, test anti-MuSK antibodies – approximately one-third of seronegative patients will be MuSK-positive 1, 2
• Include anti-striated muscle antibodies in the initial workup 1, 2
• Anti-LRP4 antibodies may be considered in seronegative cases, as they are associated with both generalized and ocular MG 3, 1

Electrophysiologic Studies

• Single-fiber EMG is the gold standard with >90% sensitivity for ocular myasthenia 3, 1, 2
• Repetitive nerve stimulation is less sensitive (positive in only one-third of ocular cases) but more widely available 3, 1

Bedside Clinical Tests

• Ice pack test – Apply ice pack over closed eyes for 2 minutes (for ptosis) or 5 minutes (for strabismus); a reduction of ptosis by approximately 2 mm or improvement in ocular alignment is highly specific for MG 3, 1
• Rest test without ice can also provide supportive diagnostic information 3
• Edrophonium (Tensilon) test – 95% sensitive for generalized MG and 86% for ocular MG, but requires experienced practitioners with atropine (0.4-0.5 mg IV) immediately available due to muscarinic side effects (tearing, salivation, bradycardia, bronchospasm, hypotension) 3, 1

Essential Supplementary Workup After Diagnosis

• CT chest with contrast to evaluate for thymoma, which occurs in 10-20% of AChR-positive patients 2
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle involvement 1, 2
• Troponin and ECG (consider echocardiogram or cardiac MRI) to rule out myocarditis 1, 2
• CPK, aldolase, ESR, and CRP to evaluate for concurrent myositis 2

Key Diagnostic Pitfalls

Pupils are characteristically NOT affected in myasthenia gravis – if pupils are abnormal, immediately prioritize evaluation for third nerve palsy, Horner syndrome, or other neurologic causes over MG 1. This pupil-sparing pattern occurs because MG affects nicotinic receptors at the neuromuscular junction, not the autonomic nervous system responsible for pupillary function 1.

Dysphagia is a critical warning sign – oropharyngeal and bulbar weakness, especially dysphagia, are present in more than 50% of cases that precede myasthenic crisis 1

Treatment Algorithm

First-Line: Symptomatic Treatment

Start pyridostigmine at 30 mg orally three times daily and gradually increase to a maximum of 120 mg four times daily based on symptom response. 1, 2, 4

• Approximately 50% of patients, particularly those with ocular/strabismus manifestations, show minimal response to pyridostigmine alone and require escalation to immunosuppressive therapy 3, 1, 2
• Cholinergic crisis warning – overdosage of pyridostigmine can result in cholinergic crisis characterized by increasing muscle weakness that may lead to respiratory failure and death 5
• Differentiate cholinergic crisis from myasthenic crisis using edrophonium testing and clinical judgment; cholinergic crisis requires prompt withdrawal of all anticholinesterase drugs and immediate atropine administration 5

Second-Line: Corticosteroids (MGFA Class I-II)

For patients with Grade 2 or higher symptoms (mild generalized weakness) who have inadequate response to pyridostigmine, add prednisone starting at 0.5-1.5 mg/kg orally daily. 1, 2, 4

• Corticosteroids demonstrate superior efficacy with 66-85% positive response rates compared to pyridostigmine's 50% response rate 3, 1, 2, 4
• Begin tapering prednisone 3-4 weeks after initiation based on symptom improvement 4
• Early corticosteroid treatment is warranted when ocular motility abnormalities persist despite pyridostigmine, as ocular symptoms are highly variable and not readily remedied with prisms 2

Third-Line: Steroid-Sparing Immunosuppressants

Azathioprine is the first-choice steroid-sparing immunosuppressant for moderate to severe disease, though it requires several months to achieve therapeutic effect. 1, 4

• Other options under investigation include cyclosporine, mycophenolate mofetil, and cyclophosphamide 6, 7, 8

Acute/Rescue Therapy (MGFA Class III-V)

For moderate to severe disease or myasthenic crisis, immediately initiate IVIG at 2 g/kg IV over 5 days (0.4 g/kg/day) or plasmapheresis for 3-5 days. 1, 2, 4

• Median duration of myasthenic crisis is approximately 2 weeks (12-14 days of ventilation) under sufficient treatment 9
• Early intubation to secure the airway is essential due to bulbar symptoms with aspiration and/or respiratory insufficiency 9
• Mortality from myasthenic crisis is approximately 2-5%, with contemporary prognosis favorable due to improved intensive care 6, 9

Thymectomy

Always perform thymectomy when thymoma is present; evaluate thymectomy in all AChR-positive patients with generalized MG up to age 65 years, as it may substantially reduce symptoms. 3, 1, 2

• Approximately 30-50% of patients with thymomas have myasthenia gravis 1
• In approximately 20% of thymoma patients, mortality is related to myasthenia gravis 1
• Minimally invasive and robotic-assisted thymectomy surgery has revolutionized surgical management 10

Novel Therapies for Refractory Disease

Efgartigimod alfa-fcab is FDA-approved specifically for AChR-positive patients who are refractory to conventional therapy. 2

Rituximab has a role in refractory MG as an escalation option 9, 10, 8

Critical Medication Avoidance

Immediately review and discontinue medications that worsen myasthenia, including β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics. 1, 2, 4

Monitoring and Prognosis

Regular pulmonary function assessment is crucial, as 50-80% of patients with initial ocular symptoms develop generalized myasthenia within a few years, most commonly within the first two years. 1, 2

• Daily neurologic review and frequent pulmonary function assessment for Grade 3-4 patients 2
• ICU-level monitoring may be necessary for rapidly progressive symptoms or respiratory muscle weakness 1, 2
• The lifetime risk of recurrence of a crisis is approximately 30% 9
• Remission or stabilization of disease is often possible after 2-3 years of treatment 3

Management of Ocular Myasthenia

Strabismus surgery should only be considered after disease stabilization, typically requiring 2-3 years of medical treatment, and requires particular care with anesthetic agents given potential respiratory muscle weakness. 3, 2

• Diplopia and strabismus are highly variable and not readily remedied with prism 3
• Surgical management with or without adjustable sutures has met with modest success; more than one procedure may prove necessary 3

Multidisciplinary Collaboration

Diagnosis and management requires collaboration between an experienced ophthalmologist and neurologist, with potential involvement of cardiothoracic surgery for thymectomy. 3, 2