Guideline sources The following summarized guidelines for the evaluation and management of myasthenia gravis (MG) are prepared by our editorial team based on guidelines from the American College of Chest Physicians (ACCP 2023), the American Academy of Neurology (AAN 2020; 2011), the Myasthenia Gravis Foundation of America (MGFA 2016), the Society of Critical Care Medicine (SCCM 2016), the European Society of Medical Oncology (ESMO 2015), and the European Federation of Neurological Societies (EFNS 2014; 2010). 1 2 3 4 5 6 7 8 9 9 9 9 10 Definition MG is an autoimmune disorder characterized by fatigable muscle weakness which results from antibodies targeting the postsynaptic neuromuscular membrane. 9 https://web.pathway.md/diseases/recUF7zzc07bEVKXS 1/9 6/30/23, 1:06 AM Myasthenia gravis Pathway Epidemiology MG is caused by autoantibodies directed mainly against AChRs (AChR), muscle-specific kinase (MuSK), and lipoprotein receptor-related peptide (LRP4). 9 Pathophysiology The incidence and prevalence rate of MG is estimated at 0.53 cases per 100,000 person-years and 7.8 persons per 100,000 population, respectively. 10 Disease course Antibodies belonging to IgG1 and IgG3 subclass direct antibodies mainly against AChRs, which disrupt neuromuscular transmission causing ocular, oropharyngeal, limb, axial, and respiratory muscle weakness. Thymoma and myasthenia crisis may even cause death. 9 Prognosis and risk of recurrence Mortality associated with MG is about 5-14%. 9 Guidelines 1. Diagnostic investigations Clinical assessment: obtain clinical evaluation by physicians skilled in the evaluation of neuromuscular disease. E Respiratory evaluation: obtain pulmonary function testing to assist with management decisions in patients with neuromuscular disease at risk for respiratory complications. E Show 3 more 2. Respiratory support Airway clearance: consider offering glossopharyngeal breathing for lung volume recruitment and airway clearance in patients with hypoventilation. C Show 4 more Noninvasive ventilation: initiate noninvasive ventilation in patients with chronic respiratory failure. B Show 4 more Invasive ventilation: consider offering invasive home mechanical ventilation via tracheostomy as an alternative to noninvasive ventilation in patients failing or intolerant of noninvasive ventilation (including extended daytime noninvasive ventilation use), worsening bulbar function, frequent aspiration, insufficient cough, episodes of chest infection despite adequate secretion management, or declining lung function. C https://web.pathway.md/diseases/recUF7zzc07bEVKXS 2/9 6/30/23, 1:06 AM Myasthenia gravis Pathway 3. Medical management Setting of care: admit patients with impending crisis to hospital and obtain close observation of respiratory and bulbar function, with the ability to transfer to an ICU if it progresses to manifest crisis. E Show 2 more Acetylcholinesterase inhibitors: As per MGFA 2016 guidelines: Recognize that many patients with MuSK MG respond poorly to acetylcholinesterase inhibitors, and conventional pyridostigmine doses frequently induce side effects. E Administer pyridostigmine as part of the initial treatment in most patients with MG. Adjust pyridostigmine dose as needed, based on symptoms. Recognize that the ability to discontinue pyridostigmine can be an indicator that the patient has met treatment goals and may guide the tapering of other therapies. E As per EFNS 2010 guidelines: Administer acetylcholinesterase inhibitors as first-line therapy in all forms of MG. E Prefer pyridostigmine over ephedrine for the symptomatic treatment of patients with MG. B Corticosteroids: As per MGFA 2016 guidelines: Administer corticosteroids or immunosuppressive therapy in all patients with MG failed to meet treatment goals after an adequate trial of pyridostigmine. E Recognize that patients with MuSK MG appear to respond well to corticosteroids and to many corticosteroid-sparing immunosuppressive agents, and they tend to remain dependent on prednisone despite concomitant treatment with corticosteroid-sparing agents. E As per EFNS 2010 guidelines, administer oral prednisolone as the first choice drug when immunosuppressive drugs are necessary in patients with MG. Initiate prednisolone covered by bisphosphonate and antacid and azathioprine. E Show 2 more Immunosuppressants: As per MGFA 2016 guidelines, administer corticosteroids or immunosuppressive therapy in all patients with MG failed to meet treatment goals after an adequate trial of pyridostigmine. E Show 8 more As per EFNS 2010 guidelines, consider initiating immunosuppressive agents in all patients with progressive MG symptoms. Recognize that patients with a thymoma and other patients with anti-titin and anti-RyR antibodies usually have a severe disease requiring more aggressive treatment strategies. C Show 7 more Rituximab: Administer rituximab as an early therapeutic option in patients with MuSK antibody-positive MG having an unsatisfactory response to initial immunotherapy. E https://web.pathway.md/diseases/recUF7zzc07bEVKXS 3/9 6/30/23, 1:06 AM Myasthenia gravis Pathway Consider administering rituximab in patients with refractory MG in addition to the previously mentioned immunosuppressive agents. E Intravenous immunoglobulin: As per MGFA 2016 guidelines, administer IVIG as short-term treatment option in patients with MG in the following circumstances: life-threatening signs such as respiratory insufficiency or dysphagia preparation for surgery in patients with significant bulbar dysfunction a rapid response to treatment is needed other treatments are insufficiently effective before initiating corticosteroids if deemed necessary to prevent or minimize exacerbations. E Show 8 more As per EFNS 2010 guidelines, administer IVIG in patients with MG MG with rapidly progressive disease, in preparation of weak patients for surgery including thymectomy, and as an adjuvant to minimize long-term side effects of oral immunosuppressive therapy. A Amifampridine: do not use amifampridine in patients with autoimmune MG, although it may prove useful in some forms of congenital myasthenia. D 4. Nonpharmacologic interventions Physical training: consider offering physical training in patients with mild MG as it is safe and produces some improvement in muscle force. C 5. Therapeutic procedures Plasma exchange: As per MGFA 2016 guidelines, perform plasma exchange as short-term treatment option in patients with MG in the following circumstances: life-threatening signs such as respiratory insufficiency or dysphagia preparation for surgery in patients with significant bulbar dysfunction a rapid response to treatment is needed other treatments are insufficiently effective before initiating corticosteroids if deemed necessary to prevent or minimize exacerbations. E Show 7 more As per AAN 2011 guidelines, insufficient evidence to recommend for or against plasma exchange in patients with MG. I As per EFNS 2010 guidelines: Perform plasma exchange as a short-term treatment in patients with MG, especially in severe cases to induce remission and in preparation for surgery. B https://web.pathway.md/diseases/recUF7zzc07bEVKXS 4/9 6/30/23, 1:06 AM Myasthenia gravis Pathway Do not perform repeated plasma exchange for achieving continuous and lasting immunosuppression. D Palliative radiotherapy: consider offering palliative radiotherapy in the appropriate clinical setting, in elderly or multimorbid patients with thymoma. Consider following small thymomas without treatment unless they are enlarging or become symptomatic. E 6. Perioperative care Neuromuscular blockade: Administer a reduced dose (based on peripheral nerve stimulation with train-of-four monitoring) of a neuromuscular blocking agent in patients with MG. E Insufficient evidence to recommend monitoring a specific muscle group in patients with MG undergoing treatment with neuromuscular blocking agents. I 7. Surgical interventions Thymectomy: As per MGFA 2016 guidelines, perform thymectomy as an option to potentially avoid or minimize the dose or duration of immunotherapy in patients with non-thymomatous MG, or if patients fail to respond to an initial trial of immunotherapy or have intolerable side effects from that therapy. Recognize that thymectomy for MG is an elective procedure because of the long delay in onset of effect. Perform thymectomy when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function. E Show 5 more As per EFNS 2010 guidelines: Consider performing thymectomy, ideally within 1 year of disease onset, in patients with antibody-positive early-onset generalized MG failed to adequately respond to pyridostigmine therapy. C Recognize that the main aim of thymectomy in patients with MG with thymoma is to treat the tumor rather than for any effect on the disease. Perform thymectomy once thymoma is diagnosed, irrespective of the severity of MG. E 8. Specific circumstances Pediatric patients: recognize that pediatric patients with acquired autoimmune ocular MG are more likely than adult patients to go into spontaneous remission. Consider administering pyridostigmine as initial therapy in young pediatric patients with only ocular symptoms of MG. Consider initiating immunotherapy if goals of therapy are not met. E Show 2 more Pregnant patients: https://web.pathway.md/diseases/recUF7zzc07bEVKXS 5/9 6/30/23, 1:06 AM Myasthenia gravis Pathway As per MGFA 2016 guidelines, institute pregnancy planning well in advance to allow time for optimization of myasthenic clinical status and to minimize risks to the fetus. E Show 11 more As per EFNS 2010 guidelines, discontinue mycophenolate mofetil and other new drugs with no safety data 3 months before conception. E Patients with ocular myasthenia: administer pyridostigmine as first-line symptomatic therapy in patients with ocular myasthenia. E Show 9 more 9. Patient education General counseling: educate patients with clinical MG or even isolated positive anti-AChR antibodies about the risks of myasthenic crisis in specific situations, such as stress or administration of certain drugs. B Preoperative counseling: Discuss thymectomy with 18-65 years old patients with non-thymomatous AChR antibodies- positive generalized MG, clearly indicating the anticipated benefits and risks of the procedures and uncertainties surrounding the magnitude of these benefits and risks. B Counsel patients with non-thymomatous AChR antibodies-positive generalized MG considering minimally invasive thymectomy techniques that it is uncertain whether the benefit attained by extended transsternal thymectomy will also be attained by minimally invasive approaches. B 10. Preventative measures Influenza vaccination: offer seasonal flu vaccination in patients with MG. E Clinical findings Symptoms Past medical history Anxiety Depression Change in voice Graves' disease Difficulty chewing Rheumatoid arthritis Diplopia SLE Dysarthria after long period of speaking Thymic hypoplasia Thymoma Dysphagia Ocular exam Fatigue Food in mouth after swallowing Cogan's lid twitch sign Food regurgitation Ectropion Muscle weakness peek sign https://web.pathway.md/diseases/recUF7zzc07bEVKXS 6/9 6/30/23, 1:06 AM Myasthenia gravis Pathway Shortness of breath Serological findings Weakness in the legs anti-AChR antibodies Neurological exam anti-Kv1.4 antibodies Dysarthria anti-LRP4 antibodies Nystagmus anti-MuSK antibodies Ptosis anti-agrin antibodies Quiver eye movements anti-ryanodine receptor antibodies Head and neck exam anti-titin antibodies Nasal speech Diagnostic procedures EMG findings anticholinesterase test ice test repetitive nerve stimulation rest test sleep test anticholinesterase test Likelihood Ratios Pertinent positives The following findings increase the probability of myasthenia gravis in adults. 10 11 Finding LR+ Value Positive sleep test 53 Positive anti-MuSK antibodies 38 Positive peek sign 30 Positive ice test 24 very fast, small-twitch, "lightning-" or "jerk"-like movements of the eyes upon changing direction of gaze Show 5 more Pertinent negatives The following findings decrease the probability of myasthenia gravis in adults. 10 13 Finding LR- Value Negative sleep test 0.01 Negative anticholinesterase test 0.11 Negative ice test 0.16 Negative anti-AChR antibodies 0.2 very fast, small-twitch, "lightning-" or "jerk"-like movements of the eyes upon changing direction of gaze Show 5 more https://web.pathway.md/diseases/recUF7zzc07bEVKXS 7/9 6/30/23, 1:06 AM Myasthenia gravis Pathway Studies 2021 ADAPT In adult patients with myasthenia gravis and a Myasthenia Gravis Activities of Daily Living score 5, efgartigimod was superior to placebo with respect to the percentage of positive anti-AChR antibody patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at cycle 1. James F Howard Jr et al. Lancet Neurol. 2021 Jul. References 1. Sanders DB, Wolfe GI, Benatar M et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87 4 419 25. Open 2. G O Skeie, S Apostolski, A Evoli et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010 Jul;17 7 893 902. Open 3. Akram Khan, Lindsy Frazer-Green, Reshma Amin et al. Respiratory Management of Patients with Neuromuscular Weakness: An American College of Chest Physicians Clinical Practice Guideline and Expert Panel Report. Chest. 2023 Mar 13;S0012 3692 23 00353 7. Open 4. Gary S Gronseth, Richard Barohn, Pushpa Narayanaswami. Practice advisory: Thymectomy for myasthenia gravis (practice parameter update): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2020 Apr 21;94 16 705 709. Open 5. E Kerty, A Elsais, Z Argov et al. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol. 2014 May;21 5 687 93. Open 6. Murray MJ, DeBlock H, Erstad B et al. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med. 2016 Nov;44 11 2079 2103. Open 7. Cortese I, Chaudhry V, So YT et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011 Jan 18;76 3 294 300. Open 8. N Girard, E Ruffini, A Marx et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v40 55. Open 9. Gwathmey KG, Burns TM. Myasthenia Gravis. Semin Neurol. 2015 Aug;35 4 327 39. Open 10. Carr AS, Cardwell CR, McCarron PO et al. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010 Jun 18;10 46. Open 11. Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis?. JAMA. 2005 Apr 20;293 15 1906 14. Open 12. Chan KH, Lachance DH, Harper CM et al. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve. 2007 Nov;36 5 651 8. Open https://web.pathway.md/diseases/recUF7zzc07bEVKXS 8/9 6/30/23, 1:06 AM Myasthenia gravis Pathway 13. Simel D, Rennie D. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis. Mayo Clin Proc. 2009 Nov; 84 11 1045. Open 14. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004 Mar;24 1 31 9. Open 15. James F Howard Jr, Vera Bril, Tuan Vu et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis ADAPT a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20 7 526 536. Open 16. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 17. Pushpa Narayanaswami, Donald B Sanders, Gil Wolfe et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021 Jan 19;96 3 114 122. Open https://web.pathway.md/diseases/recUF7zzc07bEVKXS 9/9