Myasthenia gravis (MG) was first recognized as a distinct clinical entity by Thomas Willis in 1672, although his account was overlooked until 1903. Detailed clinical descriptions in the late 19th century by Samuel Wilks (1877), Wilhelm Erb (1879), Hermann Oppenheim (1887), and Samuel Goldflam (1893) established the characteristic picture of fluctuating, fatigable weakness, and Friedrich Jolly proposed the name “myasthenia gravis” around 1895. The autoimmune basis was hypothesized by John Simpson in 1960 and proven in the 1970s, when antibodies against the acetylcholine receptor (AChR) were shown to be pathogenic. Symptomatic treatment began with Mary Broadfoot Walker’s demonstration of physostigmine (1934) and neostigmine (1935); thymectomy was introduced by Alfred Blalock, and modern respiratory support and immunotherapy reduced mortality from nearly 100% in severe early-20th-century cases to under 5% today. The regulatory approval of the complement inhibitor eculizumab in 2017 opened the current era of targeted biologic therapy.

• The English physician Thomas Willis gave the first recognizable account of fatigable weakness with recovery after rest in 1672 (in Latin); this description was largely unnoticed until it was rediscovered in 1903.^[1][2]
• The first modern clinical description is attributed to Samuel Wilks (London) in 1877. Toward the close of the 19th century, Wilhelm Erb of Heidelberg (1879) described a “new bulbar symptom complex,” Hermann Oppenheim of Berlin (1887) reported similar cases, and Samuel Goldflam of Warsaw (1893) provided a detailed account emphasizing fatigability, diurnal and day-to-day fluctuation, and remissions and exacerbations.^[1][3]

• Friedrich Jolly proposed the term “myasthenia gravis pseudoparalytica” — combining a Greek-derived term for muscle weakness with the Latin word for “grave” or “severe” — to describe progressive weakness on repetitive stimulation with recovery after rest. The modifier was later dropped, and “myasthenia gravis” became the accepted name worldwide. Most sources date this to 1895, although one account places Jolly’s presentation to the Berlin Society for Psychiatry and Nervous Disease on November 13, 1899.^[4][3]

• The autoimmune nature of MG was hypothesized by John Simpson in 1960 (with related work by Nastuk and colleagues, 1959).^[5]
• Definitive proof came in the 1970s: Patrick and Lindstrom (1973) showed that rabbits immunized with purified AChR developed myasthenic weakness, Drachman and colleagues demonstrated reduced AChR numbers in myasthenic muscle using radiolabeled snake toxin, and Lindstrom and associates (1976) detected serum anti-AChR antibodies in approximately 85–90% of patients. By 1977 the antibody-mediated character was established through passive IgG transfer, localization of IgG and complement on the postsynaptic membrane, and the benefit of plasmapheresis.^[3][6]
• Muscle-specific kinase (MuSK) was identified as a second major autoantigen (Hoch et al., 2001), followed later by LRP4.^[7]

• In 1934, house officer Mary Broadfoot Walker, reasoning that MG resembled curare poisoning, produced a striking (though temporary) improvement with physostigmine, a partial curare antagonist. In 1935 she demonstrated relief with neostigmine (Prostigmin). Her observation both provided symptomatic therapy and localized the defect to the neuromuscular junction.^[2][8]
• Edrophonium was introduced around 1950 and pyridostigmine in the mid-1950s.^[5]

• Alfred Blalock observed remission after removing a thymic tumor and subsequently proposed thymectomy even in patients without a tumor, establishing thymus-directed surgery for MG (reported around 1936–1940).^[9][5]
• The benefit of thymectomy, long supported only by anecdotal case series, was confirmed by the randomized MGTX trial (reported 2016) in nonthymomatous AChR-antibody-positive MG.^[9][10]

• Mechanical ventilation (1950s), building on the “iron lung” and positive-pressure ventilation, dramatically reduced death from myasthenic crisis.^[11]
• Corticosteroids and plasmapheresis (1960s), azathioprine (1960s–1970s), cyclosporine (1980s), intravenous immunoglobulin (1980s–1990s), and mycophenolate mofetil (1990s–2000s) were introduced sequentially. MG mortality fell from approximately 30% before 1960 to under 5% in the modern era.^[11][12]

• Rituximab was the first monoclonal antibody used in MG, chiefly for refractory and MuSK-antibody-positive disease.^[12]
• A new era began with the approval of the complement inhibitor eculizumab in 2017 (REGAIN trial), followed by additional complement inhibitors (ravulizumab, zilucoplan) and neonatal Fc receptor (FcRn) antagonists (efgartigimod, approved 2021; rozanolixizumab; nipocalimab).^[12][13]

• An often-cited putative early American case is Chief Opechancanough, described retrospectively from 17th-century Virginian chronicles as having fatigue and weakness; this is an anecdotal historical account rather than a formal first description of the disease.^[10]

Myasthenia gravis (MG) is not defined by a single list of subtypes but is classified along several complementary axes that are applied together: clinical distribution (ocular vs generalized), severity by the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, autoantibody status (AChR, MuSK, LRP4, or seronegative), age at onset (juvenile, early-, late-, and very-late-onset), and the presence of a thymoma. These axes carry prognostic and therapeutic implications and are used in combination to define the clinically actionable subgroup. The genetically determined congenital myasthenic syndromes are antibody-negative disorders of the neuromuscular junction and are distinct from autoimmune MG.

• Ocular MG is confined to the extraocular muscles (ptosis, diplopia) for an extended period.^[1]
• Generalized MG involves bulbar, facial, axial, respiratory, and/or limb muscles. Most patients present with ocular symptoms; approximately 50–80% generalize, usually within 2 years, after which conversion becomes unlikely.^[2]

The MGFA Clinical Classification replaced the older Osserman system and grades maximal severity and distribution:^[3][4]

• Class I: Ocular weakness only; all other muscle strength normal.
• Class II: Mild generalized weakness (IIa limb/axial-predominant; IIb bulbar/respiratory-predominant).
• Class III: Moderate generalized weakness (IIIa/IIIb as above).
• Class IV: Severe generalized weakness (IVa/IVb as above).
• Class V: Intubation, with or without mechanical ventilation (routine postoperative use excluded); a feeding tube without intubation is classified as IVb.

The MGFA class is subjective and non-linear and, per the MGFA Task Force, should not be used to measure treatment response. The MGFA Post-Intervention Status (e.g., complete stable remission, pharmacologic remission, minimal manifestations) together with a quantitative scale such as the Quantitative Myasthenia Gravis (QMG) score is used for that purpose.^[5]

• AChR antibody-positive: ~80–85% of generalized and ~50% of ocular MG; antibodies are predominantly complement-activating IgG1/IgG3.^[1][6]
• MuSK antibody-positive: ~5–8% of MG; predominantly non-complement-activating IgG4; prominent facial, bulbar, and respiratory involvement, frequent crises, and poor response to acetylcholinesterase inhibitors.^[7][8]
• LRP4 antibody-positive: ~1–5% of MG and a highly variable proportion (~1–54%) of double-seronegative patients depending on geography and assay; predominantly IgG1; may co-occur with AChR or MuSK antibodies and in healthy individuals.^[1][9]
• Seronegative: No AChR or MuSK antibodies on standard radioimmunoassay (~10–15%). Live or fixed cell-based assays detect clustered-AChR or MuSK antibodies in roughly one-third of these patients (in one large cohort, 19.5% clustered AChR and 8.5% MuSK).^[10][11]

• Juvenile-onset: ≤18 years.^[1]
• Early-onset (EOMG): <50 years; female predominance, thymic follicular hyperplasia, higher AChR titers.^[12][13]
• Late-onset (LOMG): ≥50 years; male predominance, thymic atrophy, frequent striational antibodies (titin, ryanodine receptor).^[14][13]
• Very-late-onset (VLOMG): ≥65 years; increasingly common, high AChR positivity, low frequency of thymic abnormalities.^[15]

The 50-year cutoff is conventional but not universal (thresholds of 40–65 years have been used).^[14][12]

A distinct paraneoplastic subgroup considered separately from the age-defined groups. Thymoma occurs in ~10–15% of MG patients; TAMG is nearly always AChR antibody-positive (99–100%), presents around age 50–55 with no clear sex predilection, is usually generalized, and carries a higher risk of myasthenic crisis.^[16][13]

• Congenital myasthenic syndromes (CMS) are inherited (Mendelian) defects in neuromuscular-junction genes (presynaptic, synaptic, or postsynaptic), are antibody-negative, and are not a subtype of autoimmune MG (see Myasthenia gravis differential diagnosis).^[17]
• Transient neonatal MG is autoimmune, caused by passive transplacental transfer of maternal antibodies; it occurs in ~10–20% of infants of mothers with MG and resolves over weeks to ~3 months (see Myasthenia gravis natural history, complications, and prognosis).^[18]

Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder of the postsynaptic neuromuscular junction (NMJ) in which pathogenic IgG autoantibodies reduce the number or function of postsynaptic proteins, lowering the safety factor for neuromuscular transmission and producing fluctuating, fatigable weakness. The principal antigenic targets are the nicotinic acetylcholine receptor (AChR, ~80–85%), muscle-specific kinase (MuSK, ~5–8%), and lipoprotein receptor-related protein 4 (LRP4, ~1–5%). AChR antibodies (complement-fixing IgG1/IgG3) act through complement-mediated membrane destruction, antigenic modulation, and functional blockade, whereas MuSK antibodies (predominantly non-complement-fixing IgG4) block the LRP4–MuSK interaction and disperse AChR clusters. Loss of immune self-tolerance—centered on the thymus in early-onset AChR-MG—drives autoantibody production, and susceptibility is strongly influenced by subtype-specific HLA and non-HLA immunogenetic loci.

• A nerve action potential opens presynaptic voltage-gated calcium channels, triggering vesicular release of acetylcholine (ACh) into the synaptic cleft.^[1]
• ACh binds the postsynaptic AChR—a pentamer of two α1, one β1, one δ, and one ε (adult) or γ (fetal) subunit—generating an endplate potential that, when above threshold, triggers a muscle action potential; acetylcholinesterase terminates the signal.^[1][2]
• Postsynaptic AChR density is maintained by the agrin–LRP4–MuSK–Dok7 clustering pathway: nerve-derived agrin binds LRP4, which complexes with and dimerizes MuSK; activated MuSK recruits Dok7 and rapsyn to cluster AChRs opposite ACh release sites. Normal transmission carries a large “safety factor,” and MG pathology reduces this margin so that weakness worsens with repetitive activity.^[3][4]

AChR antibodies are predominantly complement-fixing IgG1/IgG3 directed at the extracellular α1 main immunogenic region and reduce AChR number and function by three mechanisms:^[1][5]

• Complement activation (dominant effector): Bound antibody fixes C1q, driving the classical cascade to membrane attack complex (MAC) formation, which destroys the postsynaptic membrane, causes loss of AChRs and simplification of junctional folds (widening the cleft), and reduces voltage-gated sodium channels—raising the firing threshold. Complement-deficient (C3/C4/C5/C6) animals resist experimental autoimmune MG, and human NMJs show IgG, C3, and C9 deposits with complement consumption during exacerbations.^[2][6]
• Antigenic modulation: Divalent antibody cross-links AChRs, accelerating internalization and lysosomal degradation faster than resynthesis.^[5][7]
• Functional blockade: Some antibodies sterically block the ACh binding site.^[5][8]

Individual monoclonal AChR autoantibody clones can execute more than one of these mechanisms simultaneously, so complement, modulation, and blockade are not mediated by separate antibody populations.^[9]

• MuSK antibodies are predominantly IgG4, which cannot fix complement and bind Fc receptors weakly. Pathogenic IgG4 becomes functionally monovalent through Fab-arm exchange and blocks the LRP4–MuSK interaction, abolishing MuSK activation, dispersing existing AChR clusters, and causing synaptic disintegration—without complement-mediated destruction.^[10][11]
• IgG1–3 MuSK antibodies can also disperse preformed (Dok7-driven) AChR clusters and contribute to pathology.^[12]
• Because MuSK also anchors acetylcholinesterase via collagen Q, MuSK antibodies may delocalize acetylcholinesterase, helping to explain the frequent intolerance of acetylcholinesterase inhibitors in MuSK-MG. The thymus is generally normal and thymectomy is not beneficial in this subtype.^[10][13]

• LRP4 antibodies are predominantly IgG1 (often with IgG2/IgG3), obstruct the agrin–LRP4 interaction, reduce agrin-induced MuSK activation and AChR clustering, and can also activate complement; passive transfer of patient IgG reproduces myasthenic weakness with fragmented AChR clusters in mice.^[14][15]
• In seronegative MG (no AChR/MuSK antibodies on standard radioimmunoassay), cell-based assays detect clustered-AChR or MuSK antibodies in a substantial fraction, implying the same postsynaptic mechanisms with antibodies below conventional detection.^[16]
• Striational and cytoplasmic antibodies (titin, ryanodine receptor, striated muscle) are biomarkers of thymoma or disease severity rather than primary pathogenic effectors and are addressed under Myasthenia gravis laboratory findings.^[17]

• MG reflects a breakdown of self-tolerance driving CD4+ T cell–dependent B cell production of high-affinity autoantibodies in germinal centers of the thymus and lymph nodes.^[18][19]
• In early-onset AChR-MG, the thymus is the site of autosensitization, showing follicular hyperplasia with ectopic germinal centers, neoangiogenesis, and chemokine overexpression (features of a tertiary lymphoid organ); thymic epithelial and myoid cells express AChR, autoreactive T and B cells and plasma cells are present, and a persistent type I interferon signature is detected. Thymoma-associated MG is nearly always AChR-positive.^[20][21]

• Heritability and monozygotic concordance are approximately 35%, with HLA the strongest signal and subtype-specific associations: early-onset AChR-MG with HLA-B*08:01 (ancestral haplotype AH8.1); late-onset with HLA-DRB1*15:01/DR2/B7 and DQA1; MuSK-MG with HLA-DR14–DQ5.^[22][23]
• Genome-wide association studies confirm non-HLA loci including PTPN22, CTLA4, TNIP1, and TNFRSF11A, plus the MG-specific CHRNA1 (encoding the AChR α-subunit). HLA associations differ in Asian populations (e.g., HLA-DRB1*08:03 with late-onset MG in Japanese cohorts).^[23][24][25]

• Thymic abnormalities (follicular hyperplasia in early-onset AChR-MG; thymoma in ~10–15%) are strongly associated with MG; other autoimmune diseases (e.g., autoimmune thyroid disease) co-occur, particularly in early-onset disease (see Myasthenia gravis causes and Myasthenia gravis classification).^[20][21]

Myasthenia gravis (MG) is a chronic autoimmune disorder of the postsynaptic neuromuscular junction (NMJ) in which pathogenic autoantibodies impair acetylcholine-mediated neuromuscular transmission, resulting in fluctuating, fatigable skeletal muscle weakness that typically worsens with activity and improves with rest. MG is the most common acquired disorder of the NMJ and ranges in severity from isolated ocular manifestations to life-threatening myasthenic crisis with respiratory failure.^[1][2]

The cardinal clinical feature of MG is painless, fluctuating, fatigable muscle weakness, often with diurnal variation and worsening later in the day. Ocular manifestations, particularly ptosis and diplopia, are common initial presentations. Approximately 80–85% of patients develop generalized disease, which may involve bulbar, facial, axial, respiratory, and proximal limb muscles. Disease severity varies from isolated ocular weakness to generalized weakness with potentially life-threatening respiratory compromise. (See Myasthenia gravis history and symptoms and Myasthenia gravis natural history, complications, and prognosis.)^[3][4]

MG has an estimated incidence of approximately 4–30 cases per million person-years and a prevalence of approximately 150–200 cases per million, with higher estimates reported in some populations. Incidence and prevalence have increased over time, particularly among older adults. Age at onset demonstrates a broadly bimodal distribution, with early-onset disease more frequently affecting women and late-onset disease increasingly represented among older men. (See Myasthenia gravis epidemiology and demographics.)^[2][5][6]

MG is classified according to the autoantibodies associated with impaired neuromuscular transmission. The principal subtypes are acetylcholine receptor antibody-positive (AChR-MG), muscle-specific kinase antibody-positive (MuSK-MG), and lipoprotein receptor-related protein 4 antibody-positive (LRP4-MG). A proportion of patients remain seronegative on standard antibody assays despite a compatible clinical presentation.

Antibody subtype has diagnostic, prognostic, and therapeutic implications. AChR and LRP4 antibodies are predominantly IgG1–3 subclasses capable of activating complement, whereas MuSK antibodies are predominantly IgG4 and generally do not activate complement through the classical pathway. (See Myasthenia gravis classification, Myasthenia gravis pathophysiology, and Myasthenia gravis laboratory findings.)^[7][8]

The diagnosis of MG is based on a compatible clinical presentation supported by serologic testing and electrodiagnostic studies. Initial evaluation typically includes testing for AChR antibodies, with additional antibody testing and electrodiagnostic assessment when clinically indicated. Repetitive nerve stimulation and single-fiber electromyography are important diagnostic studies, particularly when initial serologic testing is negative or inconclusive.

Chest imaging, generally with computed tomography (CT), is indicated in patients with confirmed MG to evaluate for thymoma. Diagnostic interpretation must account for the clinical phenotype, test sensitivity, and limitations of individual investigations. (See Myasthenia gravis diagnosis, Myasthenia gravis laboratory findings, Myasthenia gravis other diagnostic studies, and Myasthenia gravis CT findings.)^[9][7][2]

The management of MG is individualized according to disease severity, antibody subtype, clinical manifestations, treatment response, and the presence of thymoma. The principal treatment objectives are to achieve remission or minimal manifestation status, preserve functional independence, prevent exacerbations, and minimize treatment-related adverse effects.

Major treatment approaches include:

• Symptomatic therapy: Pyridostigmine improves neuromuscular transmission and is commonly used for symptomatic relief, although its effectiveness and tolerability vary by antibody subtype.
• Immunotherapy: Corticosteroids and steroid-sparing immunosuppressive agents, including azathioprine and mycophenolate mofetil, are used to control autoimmune disease. Rituximab is an important treatment option, particularly in selected patients with MuSK-MG.
• Thymectomy: Surgical removal of the thymus is indicated for thymoma and is an established treatment option in selected patients with nonthymomatous, generalized AChR-MG.
• Rapid immunomodulatory therapy: Intravenous immunoglobulin (IVIg) and plasma exchange are used for severe exacerbations, myasthenic crisis, and selected situations requiring a rapid therapeutic response.
• Targeted biologic therapies: Complement inhibitors, including Eculizumab, Ravulizumab, and Zilucoplan, and neonatal Fc receptor (FcRn) antagonists, including Efgartigimod, Rozanolixizumab, and Nipocalimab, have expanded treatment options for selected patients with generalized MG.

Treatment selection and sequencing depend on antibody subtype, disease activity, prior treatment response, comorbidities, and access to therapy. The optimal placement of newer targeted biologics relative to conventional immunosuppressive therapies remains an evolving area of clinical guidance. (See Myasthenia gravis medical therapy and Myasthenia gravis surgical therapy.)^{[10][11][7][8]}

• Recognize fatigability: Fluctuating weakness that worsens with sustained activity and improves with rest is a key clinical clue to MG.
• Evaluate for thymoma: Chest imaging is required as part of the evaluation of confirmed MG because of the clinically important association with thymoma.
• Interpret serology in context: Negative standard antibody testing does not exclude MG. Additional serologic and electrodiagnostic investigations may be warranted when clinical suspicion remains high.
• Consider antibody subtype: AChR-MG and MuSK-MG may differ in clinical presentation and treatment response; antibody status should inform therapeutic decisions.
• Recognize respiratory deterioration: Rapidly progressive bulbar or respiratory weakness may indicate impending myasthenic crisis and requires urgent assessment.
• Monitor clinical burden: Validated instruments such as the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale can help quantify symptoms and monitor treatment response.

(See Myasthenia gravis history and symptoms, Myasthenia gravis physical examination, Myasthenia gravis laboratory findings, and Myasthenia gravis natural history, complications, and prognosis.)^[3][9][12]

Differential diagnosis for Myasthenia gravis includes: adult Botulism, infant Botulism, guillian-Barre syndrome, eaton lambert syndrome, electrolyte disturbance, organophosphate poisoning, tick paralysis, tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosisand myositis.

Myasthenia gravis should be differentiated from other causes of muscle weakness, hypotonia and flaccid paralysis. The differentials include the following:^{[1][1][2][3][4][5][6]_Botulism_|_CDC-7|[7][8][9][10][11][12][13][14][15][16]}

The incidence of Myasthenia gravis is approximately 7-23 new cases per year. The prevalence of Myasthenia gravis is approximately 70-320 per million and increasing since 20^th century. The age of onset in Myasthenia gravis follows a bimodal distribution. The early type (before age of 50) is female predominant and the late type (after age of 60) is male predominant. Between the age of 50-60 there is no significant different between male and female. Some studies demonstrated that the incidence, prevalence and the severity of this disease is higher in African/Americans.

The incidence of Myasthenia gravis is approximately 7-23 new cases per year.^[1][2][3][4]

The prevalence of Myasthenia gravis is approximately 70-320 per million and increasing since 20^th century.^[1][2][4][5]

The age of onset in Myasthenia gravis follows a bimodal distribution. The early type (before age of 50) is female predominant and the late type (after age of 60) is male predominant. Between the age of 50-60 there is no significant different between male and female.^[6]

Some studies demonstrated that the incidence, prevalence and the severity of this disease is higher in African/Americans.^[7][8]  

• The majority of [disease name] cases are reported in [geographical region].

• [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Myasthenia gravis (MG) is a complex autoimmune disease of the neuromuscular junction in which disease risk reflects interaction between genetic susceptibility, demographic factors, thymic disease, immune dysregulation, environmental exposures, and drug-related triggers. Genetic susceptibility, including HLA associations and other inherited risk loci, is discussed in the genetics microchapter. This section focuses on clinically relevant risk factors for MG onset, drug-induced MG, and factors that may precipitate MG exacerbation or myasthenic crisis.

MG demonstrates a characteristic sex-dependent distribution that varies by age of onset. Early-onset MG, usually defined as onset before age 50 years, is more common in women. Late-onset MG is slightly more common in men, and very-late-onset MG demonstrates a clearer male predominance.^[1][2] This age-sex pattern is clinically important because late-onset MG in older men is increasingly recognized and may be underdiagnosed when fatigable weakness is attributed to frailty, stroke, pulmonary disease, or medication adverse effects.

Age at onset is both a classification feature and a risk modifier. Contemporary epidemiologic studies suggest that the incidence and prevalence of MG have increased over recent decades, particularly among older adults, likely because of improved recognition, better diagnostic testing, population aging, and longer survival.^[1] A large contemporary cohort reported peak incidence in older age groups, including patients aged 70-74 years.^[2]

In the Swedish nationwide GEMG study, smoking at disease onset was associated with increased risk of early-onset MG, with a stronger association in AChR-antibody-positive early-onset MG.^[3] Use of Swedish snuff, a high-nicotine smokeless tobacco product, was also associated with increased early-onset MG risk.^[3] These findings suggest that nicotine exposure may be a subtype-specific risk factor rather than a uniform risk factor across all MG phenotypes.

The Swedish nationwide GEMG study reported an inverse association between alcohol consumption and MG risk, particularly in late-onset MG.^[3] This finding is observational, may be affected by residual confounding or reverse causality, and should not be interpreted as a recommendation to consume alcohol for MG prevention.

Respiratory infections are common triggers of MG exacerbation and myasthenic crisis.^[4] Specific infectious agents have been investigated as possible triggers for MG onset, including Epstein-Barr virus, human papillomavirus, and poliovirus; however, a systematic review concluded that evidence for a causal relationship between specific pathogens and MG onset remains limited.^[14] During the COVID-19 pandemic, MG worsening was reported in a substantial proportion of infected patients, supporting the clinical importance of respiratory infection prevention and early management in established MG.^[15]

Stress-related disorders are associated with increased risk of autoimmune diseases broadly, but MG-specific evidence for stress as an independent cause of MG onset is limited.^[16] In established MG, chronic stress, depression, and personality-related stress vulnerability have been associated with relapse risk and symptom burden in observational studies.^[17][18]

Approximately 15% of patients with MG have another autoimmune disease, most often in early-onset MG and thymic hyperplasia.^[5] A Danish nationwide case-control study found that patients with MG were more likely than matched controls to have another autoimmune disease before or after MG diagnosis.^[6]

Commonly associated autoimmune diseases include:

• Autoimmune thyroid disease, including Graves disease and autoimmune thyroiditis
• Systemic lupus erythematosus
• Pernicious anemia
• Rheumatoid arthritis
• Neuromyelitis optica, especially aquaporin-4 antibody-associated disease

The presence of one autoimmune disease should increase clinical suspicion for additional autoimmune disease when symptoms are compatible. Thyroid disease is particularly relevant because ocular thyroid disease may mimic ocular MG and because thyroid dysfunction may worsen fatigue or weakness.

Thymoma is present in approximately 10-20% of patients with MG, and approximately 30% of patients with thymoma develop MG.^[7][8] Thymoma-associated MG is typically AChR-antibody-positive, generalized, and clinically more severe than purely ocular MG.^[7] WHO type B1 and B2 thymomas have been associated with higher likelihood of MG association.^[19]

A small proportion of patients with thymoma may develop new-onset MG after thymectomy. Preoperative AChR antibody positivity or higher AChR antibody titers may identify patients at increased risk for post-thymectomy MG.^[8]

Drug-induced MG should be distinguished from medication-triggered worsening of established MG. Drug-induced MG refers to de novo autoimmune MG or MG-like disease occurring after exposure to a medication, whereas medication-triggered worsening reflects impaired neuromuscular transmission or immune activation in a patient with known or subclinical MG.^[9]

Immune checkpoint inhibitors may cause de novo MG or unmask preexisting MG. The estimated frequency of MG among patients treated with PD-1 inhibitors is 0.12-0.2%, with median onset approximately 4 weeks after ICI initiation.^[20] ICI-associated MG is clinically important because of its severity: bulbar involvement occurs in approximately 75%, respiratory failure in approximately 45-65%, concurrent myositis in approximately 37-51%, and concurrent myocarditis in approximately 8-16%. Mortality ranges from approximately 28% to 38% across systematic reviews, with respiratory failure as the most common cause of death. AChR antibodies are elevated in approximately 58-66% of tested patients; MuSK antibodies have not been detected in ICI-induced MG.^[10][21]

Patients with suspected ICI-associated MG should be evaluated for overlap with myositis and myocarditis, including creatine kinase, aldolase, troponin, and electrocardiogram when clinically appropriate.^[22]

D-penicillamine, used historically for rheumatoid arthritis and Wilson disease, can induce MG, usually with AChR antibodies and rarely with concurrent MuSK antibodies.^[23] D-penicillamine-induced MG is often reversible after drug discontinuation, although immunotherapy may be required in some patients.^[24][25]

Interferons and selected tyrosine kinase inhibitors have been reported to induce or unmask MG, but the evidence is less robust than for immune checkpoint inhibitors and D-penicillamine.^[9]

Medication review is essential in all patients with known or suspected MG. The following medications may worsen MG or precipitate exacerbation. Risk varies by drug, dose, route, baseline MG severity, respiratory reserve, and availability of alternatives.

Myasthenic crisis is respiratory failure caused by MG-related weakness. Approximately 15-20% of patients with MG experience crisis at least once.^[4][33][34]

Common triggers include:

• Infection, especially upper respiratory infection, bronchitis, pneumonia, and sepsis
• Exposure to drugs that impair neuromuscular transmission
• Recent surgery, trauma, or perioperative exposure to neuromuscular blocking agents
• Pregnancy or the postpartum period
  • Exacerbation of MG occurs in approximately 19-50% of pregnancies, most commonly in the first trimester, with postpartum exacerbations in approximately 27%. Myasthenic crisis occurs in approximately 6.4% of women with MG during pregnancy and approximately 8.2% in the postpartum period.^[29][35]
  • A Swedish nationwide cohort study found no increased risk of MG hospitalization during pregnancy itself, but the postpartum period was associated with increased risk of prolonged MG admissions.^[36]
• Intravenous magnesium exposure in pregnant patients with MG
• Rapid tapering, discontinuation, or inadequate dosing of immunotherapy
• High-dose corticosteroid initiation in high-risk patients
• Vaccination, rarely reported as a temporal trigger; in most patients with MG, the benefits of recommended vaccination generally outweigh the risk of disease worsening^[4]
• No identifiable trigger, which occurs in approximately 30-40% of crises^[4]

Risk factors for crisis include prior crisis, prominent oropharyngeal weakness, severe generalized symptoms, MuSK antibody positivity, thymoma, and reduced respiratory reserve.^[4]

• Do not assume MG is primarily a disease of young women. Late-onset MG is increasingly common and often affects older men.^[2]
• Do not prescribe fluoroquinolones, macrolides, aminoglycosides, magnesium, or neuromuscular blocking agents without checking for MG history and assessing respiratory reserve.^[9]
• Do not give telithromycin to patients with MG. Telithromycin is contraindicated in MG and is no longer commercially available in the United States.^[7][26]
• Do not overlook ICI-associated MG in patients receiving cancer immunotherapy who develop ptosis, diplopia, dysphagia, dysarthria, dyspnea, or proximal weakness.^[10]
• Do not treat suspected ICI-associated MG as an isolated neurologic adverse event without evaluating for concurrent myositis and myocarditis.^[22]
• Do not start high-dose corticosteroids in severe generalized or bulbar MG without a monitoring plan, because early transient worsening may precipitate crisis.^[4]
• Do not rely on stress as a stand-alone explanation for MG onset; the evidence is stronger for stress as a disease activity modifier than as an independent causal risk factor.

For patient information click here.

Population-based screening for asymptomatic myasthenia gravis (MG) is not recommended. The clinically relevant screening performed after MG is diagnosed consists of evaluation for thymoma, associated autoimmune disease, and safety risks before immunosuppressive therapy.

Chest imaging to exclude thymoma is considered mandatory in all patients with confirmed MG, regardless of antibody status, age, or ocular versus generalized phenotype. This recommendation is based primarily on expert consensus and observational evidence rather than randomized trials.^[1][2]

Approximately 10–20% of patients with MG have a thymoma.^[3][4] Detection of thymoma changes management because thymoma generally requires surgical evaluation.

• Chest CT is the standard initial imaging study. Non-contrast CT is a reasonable initial approach because available evidence indicates comparable sensitivity for thymoma detection. Whether iodinated contrast exacerbates myasthenic weakness is controversial: one retrospective study reported more acute (within 1 day) exacerbations after contrast CT (6.3% vs 0.6%), whereas other data found no meaningful excess and attributed worsening to alternative causes. The American College of Radiology (ACR) does not consider MG a clear contraindication and advises against withholding contrast when it is clinically indicated. Because non-contrast CT has comparable sensitivity for thymoma, it is a reasonable initial study and conveniently avoids this uncertainty.^[5][6][7][1]
• MRI aids differentiation of thymic malignancy from thymic cyst or hyperplasia and may be preferred over CT for this purpose, potentially avoiding unnecessary thymectomy. Chemical-shift and diffusion-weighted techniques are particularly useful for equivocal thymic masses. MRI is also an appropriate alternative when iodinated contrast is undesirable.^[8][9]
• Thymoma is strongly associated with AChR-antibody-positive MG and is very uncommon in MuSK-positive or seronegative MG; nevertheless, chest imaging should not be omitted on the basis of antibody status.^[1]
• Imaging can identify a thymic mass but cannot reliably establish thymic hyperplasia as a histologic diagnosis. A radiologic report of “thymic hyperplasia” should therefore be interpreted cautiously.^[10]
• Thymic hyperplasia occurs in both MG and Graves disease and therefore should not be used by itself to distinguish the two conditions.^[11]
• Thymoma may be missed on initial imaging. In a patient who has not undergone thymectomy, new or worsening myasthenic symptoms should prompt consideration of repeat imaging when clinically appropriate.^[10]

MG frequently coexists with other autoimmune disorders, particularly thyroid disease. Baseline thyroid function testing should be obtained at diagnosis. Thyroid autoimmunity is present in approximately 10% of patients with MG, overt thyroid dysfunction in approximately 7%, and thyroid antibodies in approximately 20–30%.^[12]

Thyroid dysfunction may contribute to or aggravate ocular and generalized symptoms. Thyroid function should be reassessed in a previously stable patient with unexplained clinical worsening, particularly when ocular findings change.^[13][11]

Additional autoimmune or paraneoplastic disorders should be evaluated according to the clinical context. Patients with thymoma-associated MG may warrant particular attention to associated autoimmune conditions and paraneoplastic syndromes.

Emerging population-based data suggest an increased prevalence of extrathymic neoplasms among patients with MG, largely associated with thymoma rather than AChR antibodies alone.^[4]

There is currently no established guideline recommendation for routine extrathymic malignancy screening in all patients with MG. In higher-risk patients, particularly older males and those with thymoma, clinicians may consider heightened malignancy vigilance, including age-appropriate evaluation and clinically directed intrathoracic imaging, dermatologic examination, and CBC. Prospective validation is lacking.^[4]

Before initiating corticosteroids or nonsteroidal immunosuppression, baseline testing should identify latent infections and factors that affect treatment safety and monitoring.^[14][15]

Recommended baseline assessment includes:

• CBC with differential, serum creatinine, and liver function tests for baseline assessment and subsequent treatment monitoring.
• Latent tuberculosis testing with a tuberculin skin test or interferon-gamma release assay before immunosuppression.^[13][14]
• Hepatitis B screening; patients with hepatitis B core antibody positivity receiving rituximab require appropriate viral monitoring.^[14]
• HIV testing in patients age 65 years or younger and in older patients with relevant risk exposures.^[14]
• Pregnancy testing when clinically applicable in people of childbearing potential.^[14]
• TPMT activity before azathioprine, when available. Absent TPMT activity is a contraindication to azathioprine, while reduced activity warrants dose reduction because of increased risk of severe myelotoxicity.^[16]
• Vaccination status review before immunosuppression.
• For anticipated long-term corticosteroid therapy, assess baseline metabolic and bone health, including glucose, blood pressure, and osteoporosis risk.^[17]

• Do not screen asymptomatic populations for MG.
• Obtain chest imaging in every patient with confirmed MG to evaluate for thymoma, regardless of antibody status or clinical phenotype.
• CT is an appropriate initial chest imaging study; non-contrast CT may be preferred when avoidance of iodinated contrast is desirable, while MRI can provide additional tissue characterization and may help avoid unnecessary thymectomy.
• Iodinated contrast is not a clear contraindication in MG; the relationship between contrast administration and MG exacerbation remains controversial.
• Check thyroid function at diagnosis and reassess thyroid function when previously stable patients develop unexplained worsening.
• Evaluate additional autoimmune disorders according to clinical context.
• Before immunosuppression, perform infection, hematologic, renal, hepatic, vaccination, and treatment-specific safety assessment.
• Consider heightened vigilance for extrathymic malignancy in selected higher-risk patients, but recognize that routine screening is not yet established.

Natural history: The age at onset of AChR-antibody-positive MG is bimodal, divided at age 50 into early-onset MG ( < 50 years, female-predominant, often associated with thymic hyperplasia) and late-onset MG ( ≥ 50 years, male-predominant). Approximately 85% of patients present with ocular symptoms, most commonly ptosis and diplopia. About 15% remain purely ocular, while the remainder develop generalized disease, with most generalization occurring within the first 2 years and occurring more frequently in AChR-antibody-positive patients. The disease course is largely established early, with approximately 77–82% of patients reaching maximal weakness within the first 2–3 years.^[1][2][3]

Complications: The major acute complication is myasthenic crisis—respiratory failure caused by respiratory or bulbar muscle weakness requiring ventilatory support—which affects approximately 15% of patients and occurs predominantly during the early years of disease.^[1] Long-term morbidity also arises from chronic immunosuppressive and immunomodulatory therapy, including corticosteroids and nonsteroidal immunosuppressants, as well as from acute treatments such as plasma exchange and intravenous immunoglobulin.^[4]

Prognosis: Prognosis in the modern treatment era is generally favorable. More than 60% of patients with recently diagnosed generalized MG eventually achieve long-term freedom from symptoms or minimal manifestation status, with most clinical improvement occurring within the first 2 years.^[5] Disease-related mortality has fallen substantially—from roughly 70% in the pre-treatment era to approximately 2% in modern series—although mortality in myasthenic crisis remains higher, generally < 5% in contemporary U.S. cohorts and higher in some international series and older patients.^[6][7] Favorable prognostic factors include younger age at onset, milder disease and shorter disease duration at diagnosis, seronegativity, thymic hyperplasia, and early thymectomy when indicated; the effect of sex on outcome is inconsistent across cohorts.^[3][8][9] Unfavorable factors include onset at ≥ 50 years, severe bulbar disease, and thymoma.^[3]

The clinical course of myasthenia gravis (MG) is generally established early. Approximately 77–82% of patients reach maximal weakness within the first 2–3 years after onset. Thereafter, patients may improve, remain stable, or enter remission. Fluctuating, fatigable weakness remains characteristic throughout the disease course, and symptomatic relapses may occur even after prolonged periods of clinical stability.^[3][1][5]

Ocular symptoms are common at MG onset. Approximately 15–25% of patients remain with purely ocular MG, whereas a substantial proportion subsequently develop generalized disease.^[10]

A systematic review and meta-analysis estimated that a pooled 39% (95% CI 32–47%, low certainty) of patients with ocular MG convert to secondary generalized disease, with most generalization occurring within the first 2 years.^[10] Reported generalization rates vary among cohorts. Punga et al. reported that 17–50% of patients generalize within 6–12 months and 61–85% within 2 years, with a smaller proportion generalizing thereafter.^[1] AChR-seropositive patients may generalize substantially earlier than seronegative patients, with one cohort reporting median times of approximately 5 versus 21 months.^[11]

Risk factors associated with generalization include AChR-antibody positivity, thymic hyperplasia, bilateral ptosis, and abnormal repetitive nerve stimulation.^[12] In juvenile MG specifically, pubertal onset is a strong predictor of subsequent generalization (OR approximately 5), with a median conversion time of approximately 2.75 years.^[13]

Patients who remain ocular for several years have a lower subsequent risk of generalization, but a stable ocular presentation does not completely exclude later generalized disease.^[1][11]

Clinical course and prognosis vary by serologic and clinical subgroup.^[14]

• MuSK-MG is characterized by prominent bulbar, facial, neck, and respiratory weakness and a higher risk of myasthenic crisis. Ocular weakness may diminish over time while bulbar and generalized weakness persists. Response to acetylcholinesterase inhibitors may be limited.^[15][14]
• Late-onset AChR-MG and thymoma-associated MG are associated with higher crisis and mortality risk.^[3][1]
• Differences in disease severity between antibody subgroups may diminish over longer-term follow-up with consistent immunosuppressive treatment.^[16]

Myasthenic crisis is the major acute complication of MG, characterized by respiratory failure requiring noninvasive or invasive ventilatory support due to respiratory muscle weakness and/or bulbar-related upper-airway compromise. Approximately 15–20% of patients experience myasthenic crisis, with risk concentrated particularly during the first several years of disease.^[7]

Myasthenic crisis affects up to 20% of patients at least once during their lifetime. The annual incidence is approximately 2.5% across patients with MG, and the mean lead time from diagnosis to first crisis is approximately 8–12 months.^[17][7]

Common precipitating factors include:

• Respiratory infection, the most common identified trigger
• Aspiration
• Surgery, including thymectomy
• Pregnancy and childbirth
• Rapid reduction of immunosuppressive therapy
• Initiation of corticosteroids
• Medications known to worsen neuromuscular transmission, including fluoroquinolones, aminoglycosides, tetracyclines, telithromycin, magnesium, quinine, and botulinum toxin^[1][7]

No precipitating factor is identified in a substantial proportion of crises.^[7]

Patients at higher risk include those with prior crisis, severe oropharyngeal disease, MuSK antibodies, thymoma, and late-onset AChR-positive MG.^[7]

Warning features include worsening bulbar dysfunction, dysphagia or choking, dyspnea or tachypnea, orthopnea, accessory-muscle use, paradoxical breathing, and difficulty managing secretions.^[1]

Management requires ICU-level monitoring and, when indicated, ventilatory support and rapid immunomodulatory rescue therapy with plasma exchange or intravenous immunoglobulin. Detailed treatment selection and dosing belong in Myasthenia gravis medical therapy.^[18]

Most patients are weaned from ventilatory support within about 1 month. Reported crisis mortality varies by setting: contemporary U.S. inpatient cohorts report approximately 2–5%, whereas international series from Germany and China report approximately 12–15%, and mortality among hospitalized patients has been cited as high as 12–18%. Mortality is strongly age-dependent—approaching zero below age 40 but rising to roughly 18% among patients aged 65–84 years and nearly 50% among those aged ≥85 years for 30-day post-discharge mortality after crisis admission in U.S. data—and is driven largely by comorbidity.^{[7][19][1][20]}

Approximately one-third of crisis survivors experience a subsequent crisis. Prolonged intubation lasting more than 2 weeks is associated with greater functional dependence at discharge, with dependence reported in approximately 77% versus 36% of patients with shorter ventilation. Crisis itself does not appear to worsen the long-term MG prognosis.^[7]

Cholinergic crisis caused by excessive acetylcholinesterase inhibitor exposure is now uncommon but remains a potential cause of acute worsening. Excess cholinergic activity can also increase airway secretions and complicate respiratory management.^[18]

Treatment-related morbidity is an important component of the long-term MG disease burden.

• Corticosteroids: initiation may cause transient worsening of weakness. Longer-term complications include weight gain, hyperglycemia, hypertension, osteoporosis, cataract, glaucoma, skin fragility, gastrointestinal complications, mood or cognitive effects, and cardiovascular risk.^[14]
• Azathioprine: myelosuppression, hepatotoxicity, macrocytosis, and potential long-term malignancy risk. TPMT assessment is used to identify patients at increased risk of severe myelotoxicity.
• Complement inhibitors: eculizumab, ravulizumab, and zilucoplan increase susceptibility to meningococcal infection; appropriate vaccination is required before complement inhibition according to treatment guidance.^[21]
• FcRn inhibitors: efgartigimod, rozanolixizumab, and nipocalimab reduce circulating IgG and may increase infection risk; headache is also reported with this drug class.^[21]
• Intravenous immunoglobulin: potential complications include headache, aseptic meningitis, thrombosis, renal injury, and hypersensitivity reactions.^[18]
• Plasma exchange: potential complications include vascular-access infection, hemodynamic instability, and thrombosis.^[18]

Overall prognosis has improved substantially in the modern treatment era. With current symptomatic, immunosuppressive, and supportive therapy, most patients achieve substantial improvement, and steady disease progression is uncommon. Life expectancy is generally close to that of the general population, although risk varies substantially by age, disease subgroup, comorbidity, and complications.^[14]

Mortality has declined dramatically compared with the pre-intensive-care era. Modern generalized-MG cohorts demonstrate substantially better long-term outcomes, with more than 60% eventually achieving long-term freedom from symptoms including minimal manifestation status; most improvement occurs during the first 2 years of follow-up.^[5][6]

Approximately 10–15% of patients remain treatment-refractory in modern cohorts.^[5]

Complete stable remission (CSR) is uncommon. Contemporary patient-reported data suggest that fewer than 10% achieve complete stable remission, defined as absence of MG symptoms without medication.^[22]

An earlier Italian cohort reported a cumulative CSR probability of approximately 21% by 10 years, with greater likelihood associated with younger onset, milder clinical stage, and shorter disease duration at diagnosis.^[8]

These factors are associations rather than absolute predictors of individual outcome.^{[3][14][1][8]}

Cancer-related mortality is increased in thymoma-associated MG, and mortality generally increases with older age and comorbidity.^[1]

• The disease course is generally established early, with approximately 80% of patients reaching maximal weakness within 2–3 years.^[3]
• A pooled 39% of patients with ocular MG develop secondary generalized disease, with most conversions occurring within the first 2 years.^[10]
• Myasthenic crisis affects up to 20% of patients during their lifetime, with an annual incidence of approximately 2.5%.^[17][7]
• Myasthenic crisis is commonly preceded by worsening bulbar or respiratory symptoms and is frequently triggered by infection, aspiration, surgery, medication exposure, or treatment changes.^[1][7]
• Crisis mortality varies substantially by population and age; older patients and those with significant comorbidity have the highest mortality risk.^[19][20]
• MuSK-MG, thymoma-associated MG, and late-onset AChR-positive MG are associated with greater crisis risk.^[7][1]
• Corticosteroid initiation can transiently worsen weakness and is a recognized precipitant of crisis.^[18]
• Complete stable remission is uncommon; long-term minimal manifestation status or substantial improvement is a more realistic treatment outcome for many patients.^[22]

• Assuming stable ocular disease permanently excludes subsequent generalization.
• Attributing every episode of acute worsening to cholinergic crisis; true cholinergic crisis is now uncommon.^[18]
• Overlooking preventable crisis triggers, particularly respiratory infection, aspiration, potentially aggravating medications, and corticosteroid initiation.^[1][7]
• Failing to recognize the distinct clinical and prognostic profile of MuSK-MG.^[15]
• Forgetting the meningococcal infection risk associated with complement inhibitors.^[21]