Myasthenia gravis
Review Article

Myasthenia gravis

Sayena Jabbehdari1, Karl C. Golnik2

1Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA; 2Department of Ophthalmology, University of Cincinnati and the Cincinnati Eye Institute, Cincinnati, Ohio, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Sayena Jabbehdari, MD. Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA. Email: Sayena1990@yahoo.com.

Abstract: Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder which causes fluctuating weakness in ocular, bulbar and limb skeletal muscles. There are two major clinical types of MG. Ocular MG (OMG) affects extra ocular muscles associated with eye movement and eyelid function and generalized MG results in muscle weakness throughout the body. Patients with OMG have painless fluctuating extra ocular muscles weakness, diplopia and ptosis accompanied by normal visual acuity and pupillary function. Frequently, patients with OMG develop generalized MG over 24 months. Pure OMG is more often earlier in onset (<45 years) than generalized MG. It can also occur as part of an immune-genetic disorder or paraneoplastic syndrome related to thymus tumors. Diagnosis is based on clinical manifestations, laboratory findings, electrophysiological evaluation and pharmacologic tests. Therapeutic strategies for MG consist of symptom relieving medications (e.g., acetylcholine esterase inhibitors), immunosuppressive agents, and surgical intervention (e.g., thymectomy).

Keywords: Myasthenia gravis (MG); autoimmune disorder; neuro-ophthalmology

Received: 09 April 2018; Accepted: 06 May 2018; Published: 15 May 2018.

doi: 10.21037/aes.2018.05.02

Myasthenia gravis (MG) as an autoimmune disorder characterized by deposition of antibodies in the neuromuscular junction (NMJ), and weakness of skeletal and extraocular muscles. MG is classified as either ocular or generalized forms based on the locations of involved muscles, types of autoantibodies, the age of onset and thymus abnormalities (1). Immunoglobulin (Ig) G1 and IgG3 antibodies are deposited in NMJ in most MG cases (2). These two immunoglobulins bind to acetylcholine receptors in postsynaptic membrane and cause complement-mediated damage (3). Eighty-five percent of patients with the generalized form of MG have antibodies to the acetylcholine receptor but these antibodies (ACHR-Ab) are found in only 50% of those with purely ocular MG (2). In cases without acetylcholine receptor antibodies, antibodies against muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) and agrin may be present (4). In an individual patient the AchR and MuSK antibodies do not occur together but in some cases LRP4 and agrin antibodies are presented with AchR and MuSK antibodies in single patient (5). MuSK related-MG mostly occurs in younger age and female patients and it is also responsible in 70% of seronegative cases (no detectable AChR antibodies) (6,7).

In general, the incidence of MG is 0.04 to 5/100,000 person per year and the prevalence of MG is 0.5 to 12.5/100,000 person per year (8). It affects all ages, genders and ethnicity with a male dominant pattern in OMG. Epidemiological studies have reported the risk of developing MG in first grade relatives or siblings to be about 4.5% which shows a strong genetic background (9,10). Both incidence and prevalence of MG are increasing, especially in older patients (11,12). Pediatric MG may also present with a variety of ocular motility abnormalities or blepharoptosis. As in adults, early diagnosis should be considered to reduce MG related complications such as bulbar and respiratory muscles weakness which could be life threatening (3,13).

Clinical presentation

The primary presentation of MG in more than 80% of cases are ocular symptoms (ptosis and/or diplopia), although other muscle involvement can cause dysphagia, dysarthria, difficulty in chewing food, change in voice, extremity weakness and dyspnea (14). One hallmark of MG is cyclic relapse, remission and crises of symptoms (1), including muscle fatigability and fluctuating weakness (15). The weakness gets worse with repetitive muscle usage and improves with rest and cold temperature. Difficulties with swallowing and respiration occur in severe cases of MG; producing myasthenic crisis. The severity of MG varies from one case to another and even within an individual (14). Patients with OMG often develop the generalized form of MG in the first 2 years of disease; prednisolone may delay or prevent the onset of generalized form of MG and also can control the ocular symptoms (16,17). Also other autoimmune comorbidities such as Graves’ disease, antibody positive thyroid disease and also thymus hyperplasia may increase the risk for MG generalization in the first six months of disease (18). In ocular form of MG with MUSK antibodies, chronic ocular muscle paresis is common and conjugated gaze limitation is related to low functional disabilities (19).

The symptoms of ocular MG include any combination of ptosis, diplopia and trouble focusing or each of them as an isolated finding due to fluctuating weakness of extraocular muscles (14). Pupillary reaction, sensory function and visual acuity all are normal in MG (20). Ptosis can be either unilateral or bilateral, and may fatigue with sustained upward gaze (14). OMG can mimic any painless ophthalmoplegia with or without ptosis (21). Diplopia is a common symptom because weakened extraocular muscle causes misalignment of the eyes. The lid elevation after vertical saccade of downward gaze, named Cogan’s lid twitch, can be seen in ocular form of MG (22). Hypermetric saccade, jerky eye movement, inter-saccadic fatigue and gaze-evoked nystagmus can be seen in OMG (22).

The differential diagnosis of MG could include all supra, inter and infra nuclear efferent system disorders, ocular motor cranial nerve palsy (without pupil involvement), Lambert Eaton, Thyroid ophthalmoplegia, Kearns-Sayre disease, chronic and progressive external ophthalmoplegia, and levator dehiscence (14,20). Furthermore, in patients with double vision and concurrent thyroid related orbitopathy, the co-existing of MG should be considered especially if exotropia is present (23).

Diagnosis

Diagnosis of MG generally begins with a physician assessing the symptoms and performing a physical examination, laboratory, imaging, pharmacology and physiological testing (24). ACHR-Ab is required to confirm a diagnosis of MG; however, for patients with ocular MG, blood tests have high false negative results (up to 50%) (15). In 80% to 90% of cases with generalized form of MG, the circulatory autoantibodies are detected (24). Worsening ptosis in sustained upward gaze is pathognomonic for OMG (14). The “sleep” test is conducted by having the patient close their eyes for a period of 30 minutes and observing transient improvement or resolution of ptosis immediately after the eyes are open. Improvement after rest can be used for MG diagnosis confirmation (1). The ice test may be used to differentiate myasthenic ptosis from non-myasthenic causes. The ice test as an easy, economic and specific test in which an ice pack is placed on a ptotic eyelid for 2 minutes. Improvement in ptosis of greater than 1 mm is highly sensitive and specific for OMG. One caveat is that if there is complete ptosis, the ice test is often negative (20). Edrophonium chloride and or neostigmine inhibit acetylcholinesterase and thus reversal of ptosis and/or ophthalmoplegia after administration confirms the diagnosis of MG. Administration of these drugs should be considered with caution in cases of heart disease and beta blocker or digoxin usage due to cardiovascular adverse effect. These invasive tests with potentially critical side effect are increasingly being replaced by fatigue, rest and ice tests (14).

Recently, the novel “forced eyelid closure test” (FECT) for diagnosis of ocular form of MG has been introduced. It is an easy test with 94% sensitivity and 91% specificity (25). In this screening test, patients were asked to squeeze their eyelids for a short time (5–10 seconds), open and fixate at the first position. The upward eyelids overshoot reported as a positive FECT (25).

Electromyography (EMG) and single fiber EMG are the most accurate methods to diagnose MG especially in seronegative cases, as they measure the electrical responses of muscles from stimulation to the nerves. Decrease in compound muscle action potential in stimulated nerves is shown in MG patients (26). There is high specificity and low sensitivity of repetitive nerve stimulation owing to minimal muscle involvement in ocular MG (24). Single fiber EMG has higher sensitivity than repetitive stimulation of nerves. The single fiber EMG abnormalities have been reported in up to 99% of patients with MG (14).

Despite the variety of tests available for MG, diagnosis can still be difficult. Neuroimaging is recommended for suspected cases of OMG if a definitive diagnosis cannot be made because OMG can mimic so many other causes of ophthalmoplegia and ptosis (14).

Treatment

OMG is usually co-managed by neurology and ophthalmology. Treatment should be individualized based on symptoms at the time of presentation, disease severity, and age (15,27,28). There are four main treatment options for ocular MG: short course based on symptom relief, long term immunomodulation, rapid immunomodulation, and surgery (5,29). Most clinicians begin with pyridostigmine (Mestinon) to inhibit acetylcholinesterase. Side effects of pyridostigmine including diarrhea, abdominal cramps, nausea, and vomiting occur at variable dosages and thus dosage is usually gradually increased based on side effects and treatment effects. Patients with MuSK antibody related-MG may require higher dosage of pyridostigmine (5). In myasthenic crisis, intravenous administration of pyridostigmine may be used (30). Corticosteroids are often used alone or in combination with pyridostigmine in low and moderate doses to control the immune response. The long-term corticosteroid side effects such as osteoporosis, diabetes, high blood pressure, sleep disturbance, and emotional changes limits their role in chronic management (5). The “Efficacy of Prednisone for the Treatment of Ocular Myasthenia” clinical trial which was done to assess the risk and safety of corticosteroid therapy suggests there is a beneficial effect of low dose treatment on prevention of ocular to generalized MG progression (31). Other immunosuppressive treatments include azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, rituximab and cyclophosphamide (Table 1).

Table 1

Immunotherapy in myasthenia gravis

Name Sample size Type of study Treatment Conclusion
Tindall et al., 1993 (32) 39 Clinical therapeutic trial Cyclosporine A Continuous steroid dosage reduction-35% discontinued cyclosporine A due to side effect
Heckmann et al., 2011 (33) 31 Single-blinded trial Methotrexate versus azathioprine Methotrexate was the great choice of steroid sparing-similar to azathioprine in efficacy and tolerability
Hehir et al., 2010 (34) 102 patients Randomized, controlled trial Mycophenolate mofetil Improve AChR-positive MG with mycophenolate mofetil and prednisone-prednisone dosage reduction
Muscle Study Group, 2008 (35) 80 patients Double-blind controlled trials Mycophenolate mofetil with prednisone No differences between mycophenolate mofetil with prednisone 20 mg/day and prednisone 20 mg/day alone
Sanders et al., 2008 (36) 176 patients Phase III, randomized trial Mycophenolate mofetil Mycophenolate mofetil was not superior to placebo
Yoshikawa et al., 2011 (37) 80 patients Randomized, double-blind, placebo-controlled Tacrolimus Good steroid sparing agent
Benatar et al., 2006 (38) Updated review Corticosteroids and azathioprine Probable effect of corticosteroids and azathioprine in reducing the risk of progression to GMG
Nagane et al., 2010 (39) 28 patients Prospective open trial Cyclosporine micro emulsion Improved the MG severity, decreasing steroid dosage—no adverse effect was reported

MG, myasthenia gravis.

Other than symptomatic relief, Wong and associates reported a 30% reduction of ocular MG progression to generalized form after early immunosuppressant therapy (40).

Plasma exchange, intravenous Ig and plasmapheresis are applied for rapid immunomodulation in unstable and refractory MG cases with disabling symptoms. Intravenous immunoglobulins (IVIGs) including polyclonal immunoglobulins suppress inflammation via Fab or Fc fragments (5). It should be administrated in dosage of 0.4 g/kg per day for 5 consecutive days or 1 g/kg per day for 2 days. IVIG can be helpful during myasthenic crisis to reduce the period of mechanical ventilation. Complications include allergic/anaphylactic reactions, pulmonary edema due to fluid overload, headache, viral hepatitis and aseptic meningitis (5). In addition, plasmapheresis has therapeutic effects based on the mechanism of removing the circulatory, pathogenic immune factors and autoantibodies. It could be applied in refractory cases for stabilization prior to thymectomy and/or high dose corticosteroid pulse therapy (41).

There are several medications which should be avoided in myasthenic patients regarding exacerbation or unmasking MG including Telithromycin, a new ketolide antibiotic (42); Fluoroquinolones (43,44); Streptomycin (45); Quinidine (46) and hydroxychloroquine (47) and beta-blockers.

A new pathway treatment in MG may be the Agrin-LRP4-MUSK signaling cascade. Agrin interacts with LRP4 to activate the MuSK tyrosine kinase receptor. MuSK and LRP4 prepare complex network of interacting proteins which is necessary for AChR clustering. Agrin-LRP4-MuSK signaling cascade drives acetylcholine receptors and secure signal transduction in the NMJ (48). Another new treatment is Eculizumab (humanized monoclonal antibodies) which inhibits the complement system in AChR antibody positive patients. Eculizumab should be applied as a 35 min intravenous infusion (each 30 mL vial contains 300 mg of eculizumab). It may be a valuable emerging therapy in AChR antibody positive adults MG or refractory generalized MG (49). More experiments should be done to figure out the tolerability, appropriate period of treatment, long term efficacy and complications.

The role of thymus and thymic B cells in anti-acetylcholine receptor antibodies production in MG has been clearly reported and thus thymectomy may have beneficial effect (Table 2) (1,11,52,64-66). Mediastinal imaging should be obtained to rule out thymoma. Thymectomy should be done if thymoma is present and even if not, should be considered in cases of medication intolerability, insufficient treatment effect and severe complications of first line treatment (5,31).

Table 2

Thymectomy in myasthenia gravis

Name Year Type of study Sample size Conclusion
Nakamura et al. (50) 1996 Retrospective Study 22 patients Is effective in OMG if done during 12 months of symptoms
Liu et al. (51) 2011 Retrospective Study 115 patients 58.2% of patients showed the improvement in ocular symptoms
Wolfe et al. (52) 2016 Randomized trial 126 patients Improving clinical outcomes after thymectomy
Cea et al. (53) 2013 Review article of randomized controlled trials No clinical trial with meaningful report of the thymectomy’s efficacy until 2013
Kerty et al. (54) 2014 Review article Thymectomy may modify the symptoms of ocular MG
Yuan et al. (55) 2007 Retrospective paired cohort study 48 patients Good prognosis and therapeutic option for increase probability of remission in seronegative MG patients after thymectomy
Guillermo et al. (56) 2004 Retrospective, descriptive, comparative 71 patients Better prognosis in seronegative MG patients after thymectomy
Jaretzki et al. (57) 1988 Prospective cohort 95 patients Good prognosis of generalized MG after thymectomy
Uzawa et al. (58) 2015 Retrospective Study 39 patients Beneficial effect in generalized late onset of MG and thymic hyperplasia
Liu et al. (59) 2016 Retrospective Study 31 patients Thymectomy is the effective treatment for MG patients with history of crises
Kaufman et al. (60) 2016 Retrospective review of a prospectively maintained database 317 patients Long term stable remission with long term follow up after thymectomy in patients with MG
Bak et al. (61) 2016 Retrospective Study 345 patients Thymectomy combined with immunotherapy was reported as a satisfactory treatment with long term remission rate
Keijzers et al. (62) 2015 Retrospective Study 85 patients No significant difference in the remission rate of patients with or without anti-AChR antibodies after thymectomy
Yu et al. (63) 2015 Retrospective Study 306 patients Satisfactory remission rate with both extended thymectomy and immunotherapy

MG, myasthenia gravis; OMG, ocular MG.

Although the treatment goal in OMG is symptomatic relief, sometimes ptosis and/or ophthalmoplegia are refractory. Local treatments for ptosis can include eyelid crutches or surgery if the ptosis is fairly stable (54,67). Occlusion of one eye can be used in the short term for diplopia. If the ocular misalignment is fairly stable, prism glasses can be considered. If the misalignment is very stable, strabismus surgery can be considered (67), Although strabismus surgery can be helpful, some complications including worsening diplopia and exposure keratopathy have been reported (67-69).

Summary

MG can mimic most ocular motility disorders and will be encountered by every ophthalmologist. One must be aware of its systemic manifestations and usually co-manage with a neurologist. Diagnosis can be difficult as there is no test that absolutely rules out this condition. Thus, one must be aware of the various tests described and on occasion trust their clinical judgement. It is often successfully treated with one or more of the methods described above.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Karl C. Golnik and Andrew G. Lee) for the series “Neuro-ophthalmology” published in Annals of Eye Science. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes.2018.05.02). The series “Neuro-ophthalmology” was commissioned by the editorial office without any funding or sponsorship. KCG served as unpaid Guest Editor of the series and serves as an Associate Editor-in-Chief of Annals of Eye Science. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun 2014;48-49:143-8. [Crossref] [PubMed]
  2. Peragallo JH, Bitrian E, Kupersmith MJ, et al. Relationship between age, gender, and race in patients presenting with myasthenia gravis with only ocular manifestations. J Neuroophthalmol 2016;36:29-32. [Crossref] [PubMed]
  3. Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res 2016;5. pii: F1000 Faculty Rev-1513.
  4. Verschuuren JJ, Huijbers MG, Plomp JJ, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013;12:918-23. [Crossref] [PubMed]
  5. Melzer N, Ruck T, Fuhr P, et al. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. J Neurol 2016;263:1473-94. [Crossref] [PubMed]
  6. Pasnoor M, Wolfe GI, Nations S, et al. Clinical findings in MuSK‐antibody positive myasthenia gravis: A US experience. Muscle Nerve 2010;41:370-4. [Crossref] [PubMed]
  7. Hoch W, McConville J, Helms S, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7:365. [Crossref] [PubMed]
  8. Nair AG, Patil-Chhablani P, Venkatramani DV, et al. Ocular myasthenia gravis: a review. Indian J Ophthalmol 2014;62:985-91. [Crossref] [PubMed]
  9. Carr AS, Cardwell CR, McCarron PO, et al. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol 2010;10:46. [Crossref] [PubMed]
  10. Hemminki K, Li X, Sundquist K. Familial risks for diseases of myoneural junction and muscle in siblings based on hospitalizations and deaths in sweden. Twin Res Hum Genet 2006;9:573-9. [Crossref] [PubMed]
  11. Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol 2016;263:826-34. [Crossref] [PubMed]
  12. Weizer JS, Lee AG, Coats DK. Myasthenia gravis with ocular involvement in older patients. Can J Ophthalmol 2001;36:26-33. [Crossref] [PubMed]
  13. McCreery KM, Hussein MA, Lee AG, et al. Major review: the clinical spectrum of pediatric myasthenia gravis: blepharoptosis, ophthalmoplegia and strabismus. A report of 14 cases. Binocul Vis Strabismus Q 2002;17:181-6. [PubMed]
  14. Bhavana Sharma M, Mamatha Pasnoor M, Mazen MDM, et al. Treatment Refractory Ocular Symptoms in Myasthenia Gravis: Clinical and Therapeutic Profile CK Symposium. 2018.
  15. Gwathmey KG, Burns TM. Myasthenia Gravis. Semin Neurol 2015;35:327-39. [Crossref] [PubMed]
  16. Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol 2009;256:1314-20. [Crossref] [PubMed]
  17. Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists' management guidelines. Pract Neurol 2015;15:199-206. [Crossref] [PubMed]
  18. Wang L, Zhang Y, He M. Clinical predictors for the prognosis of myasthenia gravis. BMC Neurol 2017;17:77. [Crossref] [PubMed]
  19. Evoli A, Alboini PE, Iorio R, et al. Pattern of ocular involvement in myasthenia gravis with MuSK antibodies. J Neurol Neurosurg Psychiatry 2017;88:761-3. [Crossref] [PubMed]
  20. Golnik KC, Pena R, Lee AG, et al. An ice test for the diagnosis of myasthenia gravis. Ophthalmology 1999;106:1282-6. [Crossref] [PubMed]
  21. Lee AG. Ocular myasthenia gravis. Curr Opin Ophthalmol 1996;7:39-41. [Crossref] [PubMed]
  22. Lee AG, Brazis PW. Clinical pathways in neuro-ophthalmology: an evidence-based approach. Thieme, 2003.
  23. Chen CS, Lee AW, Miller NR, et al. Double vision in a patient with thyroid disease: what's the big deal? Surv Ophthalmol 2007;52:434-9. [Crossref] [PubMed]
  24. Okun MS, Charriez CM, Bhatti MT, et al. Tensilon and the diagnosis of myasthenia gravis: are we using the Tensilon test too much? Neurologist 2001;7:295-9. [Crossref] [PubMed]
  25. Apinyawasisuk S, Zhou X, Tian JJ, et al. Validity of Forced Eyelid Closure Test: A Novel Clinical Screening Test for Ocular Myasthenia Gravis. J Neuroophthalmol 2017;37:253-7. [Crossref] [PubMed]
  26. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis 2007;2:44. [Crossref] [PubMed]
  27. Tung CI, Chao D, Al-Zubidi N, et al. Invasive thymoma in ocular myasthenia gravis: diagnostic and prognostic implications. J Neuroophthalmol 2013;33:307-8. [Crossref] [PubMed]
  28. Gilhus NE. Myasthenia Gravis. N Engl J Med 2016;375:2570-81. [Crossref] [PubMed]
  29. Lee JI, Jander S. Myasthenia gravis: recent advances in immunopathology and therapy. Expert Rev Neurother 2017;17:287-99. [Crossref] [PubMed]
  30. Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010;17:893-902. [Crossref] [PubMed]
  31. Benatar M, McDermott MP, Sanders DB, et al. Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized, controlled trial. Muscle Nerve 2016;53:363-9. [Crossref] [PubMed]
  32. Tindall RS, Phillips JT, Rollins JA, et al. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 1993;681:539-51. [Crossref] [PubMed]
  33. Heckmann JM, Rawoot A, Bateman K, et al. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 2011;11:97. [Crossref] [PubMed]
  34. Hehir MK, Burns TM, Alpers J, et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 2010;41:593-8. [Crossref] [PubMed]
  35. Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008;71:394-9. [Crossref] [PubMed]
  36. Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008;71:400-6. [Crossref] [PubMed]
  37. Yoshikawa H, Kiuchi T, Saida T, et al. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011;82:970-7. [Crossref] [PubMed]
  38. Benatar M, Kaminski H. Medical and surgical treatment for ocular myasthenia. Cochrane Database Syst Rev 2006;2:CD005081 [PubMed]
  39. Nagane Y, Suzuki S, Suzuki N, et al. Two-year treatment with cyclosporine microemulsion for responder myasthenia gravis patients. Eur Neurol 2010;64:186-90. [Crossref] [PubMed]
  40. Wong SH, Plant GT, Cornblath W. Does treatment of ocular myasthenia gravis with early immunosuppressive therapy prevent secondarily generalization and should it be offered to all such patients? J Neuroophthalmol 2016;36:98-102. [Crossref] [PubMed]
  41. Schroder A, Linker RA, Gold R. Plasmapheresis for neurological disorders. Expert Rev Neurother 2009;9:1331-9. [Crossref] [PubMed]
  42. Perrot X, Bernard N, Vial C, et al. Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment. Neurology 2006;67:2256-8. [Crossref] [PubMed]
  43. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf 2011;34:839-47. [Crossref] [PubMed]
  44. Gutierrez-Gutierrez G, Sereno M, Garcia Vaquero C, et al. Levofloxacin-induced myasthenic crisis. J Emerg Med 2013;45:260-1. [Crossref] [PubMed]
  45. Hokkanen E, Toivakka E. Streptomycin-induced neuromuscular fatigue in myasthenia gravis. Ann Clin Res 1969;1:220-6. [PubMed]
  46. Stoffer SS, Chandler JH. Quinidine-induced exacerbation of myasthenia gravis in patient with Graves' disease. Arch Intern Med 1980;140:283-4. [Crossref] [PubMed]
  47. Varan O, Kucuk H, Tufan A. Myasthenia gravis due to hydroxychloroquine. Reumatismo 2016;67:125. [Crossref] [PubMed]
  48. Ohno K, Ohkawara B, Ito M. Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders. Expert Opin Ther Targets 2017;21:949-58. [Crossref] [PubMed]
  49. Dhillon S. Eculizumab: A Review in Generalized Myasthenia Gravis. Drugs 2018;78:367-76. [Crossref] [PubMed]
  50. Nakamura H, Taniguchi Y, Suzuki Y, et al. Delayed remission after thymectomy for myasthenia gravis of the purely ocular type. J Thorac Cardiovasc Surg 1996;112:371-5. [Crossref] [PubMed]
  51. Liu Z, Feng H, Yeung SC, et al. Extended transsternal thymectomy for the treatment of ocular myasthenia gravis. Ann Thorac Surg 2011;92:1993-9. [Crossref] [PubMed]
  52. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 2016;375:511-22. [Crossref] [PubMed]
  53. Cea G, Benatar M, Verdugo RJ, et al. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database Syst Rev 2013;CD008111 [PubMed]
  54. Kerty E, Elsais A, Argov Z, et al. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol 2014;21:687-93. [Crossref] [PubMed]
  55. Yuan HK, Huang BS, Kung SY, et al. The effectiveness of thymectomy on seronegative generalized myasthenia gravis: comparing with seropositive cases. Acta Neurol Scand 2007;115:181-4. [Crossref] [PubMed]
  56. Guillermo G, Téllez‐Zenteno J, Weder‐Cisneros N, et al. Response of thymectomy: clinical and pathological characteristics among seronegative and seropositive myasthenia gravis patients. Acta Neurologica Scandinavica 2004;109:217-21. [Crossref] [PubMed]
  57. Jaretzki A 3rd, Penn AS, Younger DS, et al. "Maximal" thymectomy for myasthenia gravis. Results. J Thorac Cardiovasc Surg 1988;95:747-57. [PubMed]
  58. Uzawa A, Kawaguchi N, Kanai T, et al. Two-year outcome of thymectomy in non-thymomatous late-onset myasthenia gravis. J Neurol 2015;262:1019-23. [Crossref] [PubMed]
  59. Liu Z, Lai Y, Yao S, et al. Clinical Outcomes of Thymectomy in Myasthenia Gravis Patients with a History of Crisis. World J Surg 2016;40:2681-7. [Crossref] [PubMed]
  60. Kaufman AJ, Palatt J, Sivak M, et al. Thymectomy for myasthenia gravis: complete stable remission and associated prognostic factors in over 1000 cases. Semin Thorac Cardiovasc Surg 2016;28:561-8. [Crossref] [PubMed]
  61. Bak V, Spalek P, Rajcok M, et al. Importance of thymectomy and prognostic factors in the complex treatment of myasthenia gravis. Bratisl Lek Listy 2016;117:195-200. [PubMed]
  62. Keijzers M, Damoiseaux J, Vigneron A, et al. Do associated auto-antibodies influence the outcome of myasthenia gravis after thymectomy? Autoimmunity 2015;48:552-5. [Crossref] [PubMed]
  63. Yu S, Li F, Chen B, et al. Eight-year follow-up of patients with myasthenia gravis after thymectomy. Acta Neurol Scand 2015;131:94-101. [Crossref] [PubMed]
  64. Marx A, Pfister F, Schalke B, et al. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013;12:875-84. [Crossref] [PubMed]
  65. Tiamkao S, Pranboon S, Thepsuthammarat K, et al. Factors predicting the outcomes of elderly hospitalized myasthenia gravis patients: a national database study. Int J Gen Med 2017;10:131-5. [Crossref] [PubMed]
  66. Taioli E, Paschal PK, Liu B, et al. Comparison of Conservative Treatment and Thymectomy on Myasthenia Gravis Outcome. Ann Thorac Surg 2016;102:1805-13. [Crossref] [PubMed]
  67. Bentley CR, Dawson E, Lee JP. Active management in patients with ocular manifestations of myasthenia gravis. Eye (Lond) 2001;15:18-22. [Crossref] [PubMed]
  68. Morris OC, O'Day J. Strabismus surgery in the management of diplopia caused by myasthenia gravis. Br J Ophthalmol 2004;88:832. [PubMed]
  69. Bradley EA, Bartley GB, Chapman KL, et al. Surgical correction of blepharoptosis in patients with myasthenia gravis. Ophthal Plast Reconstr Surg 2001;17:103-10. [Crossref] [PubMed]
doi: 10.21037/aes.2018.05.02
Cite this article as: Jabbehdari S, Golnik KC. Myasthenia gravis. Ann Eye Sci 2018;3:23.

Article Options

Download Citation

Share