Etiology

• Primary autoimmune disorder in which cross-linking, acetylcholine, receptor-specific autoantibodies induce binding, internalization, and destruction of nicotinic acetylcholine receptors (AChR) at the neuromuscular junction
• 0–70% of seronegative patients with myasthenia have autoantibodies against muscle-specific tyrosine kinase, a transmembrane muscle protein at the neuromuscular junction. (Rodríguez Cruz, JAMA Neurol. 2015)

Epidemiology

• The disease is characterized by fatigable muscle weakness.
• Most common neuromuscular transmission-related disorder; incidence of 25–140 million people worldwide (Silvestri, J Clin Neuromusc Dis 2014)
• About 10–20% of patients with myasthenia gravis have a thymoma versus 2.5–3.2/1,000,000 people without MG (Filosso, Lung Cancer, 2015).
• About 20% of adult patients with MG present with its ocular variant.
• Of adults who present with ocular myasthenia, variable rates of conversion to generalized weakness have been reported.
• Among 158 patients, over the course of 2 years, 20.9% of all patients, 10.5% of immunosuppressant-treated patients, and 18.3% of nonimmunosuppressed patients converted to generalized disease. Conversion occurred after 2 years in 30% (Nagia, Ophthalmology 2015).
• In a cohort of 147 patients, prednisone treatment reduced conversion rate from 36% to 7% over 2 years (Kupersmith, Arch Neurol 2003).
• Historically, in 56 patients studied over 2 years, conversion rate was 90% within 3 years (Monsul, J Neurol Sci 2004).
• 11.1% rate with prednisone therapy after two years
• 34.5% without prednisone after two years
• Acute respiratory failure requiring mechanical ventilation is called myasthenic crisis, and occurs in about 10% of patients with generalized myasthenia.

History

Patients can present with fatigable, irregular muscle weakness. This can manifest itself as ptosis and/or strabismus with or without new onset proximal muscle weakness.

Clinical features

• The disease is characterized by fatigable muscle weakness. Elderly patients with motor neuron diseases, such as stroke and Parkinson's disease, can mimic the clinical symptoms of myasthenia, including dysphagia, fatigue, and slurred speech. As a result, myasthenia to be a consideration when evaluating elderly patients with acquired ptosis.
• The classic clinical sign of fatigable ptosis on prolonged upgaze is not consistent. Therefore, this is not a sufficient screening test when myasthenia is suspected (Toyka, Neurology 2006).
• Cogan lid twitch
• Initially described by Cogan (Cogan, Arch Ophthalmol 1965)
• Patients looks down for 15 seconds, looks up, and returns to primary position.
• On return to primary position, positive Cogan sign is defined by overshoot of the upper eyelid.
• Reported to be 99% specific, 75% sensitive (Singman, J Neuroophthalmol 2011).
• Other classic signs include neck weakness resulting in head drop and neck pain, change in speech during office visit, or evidence of proximal muscle fatigue evident by difficulty getting out of a chair or upper extremity weakness.

Testing

• Ice test
• Described in 1979 (Neurology 29:1075, 1979), but became popular later (Golnik, Ophthalmology 1999) as the availability of edrophonium became problematic. Ice is applied to the lid for 2–3 minutes and results in improvement of ptosis in a very high percentage of patients, with sensitivity and specificity of 90–95%.
• In a small series directly comparing the ice test with the rest test, improvement in ptosis was much greater with the ice test – median 4.5 mm vs. 2 mm. (Kubis, Ophthalmology 2000).
• Interestingly, application of a warm compress can also improve the ptosis and increasing ambient temperature can improve muscle weakness in generalized myasthenia patients (Movaghar, Ophthalmology 2000).
• Edrophonium (Tensilon) test
• Involves intravenous administration of a short-acting acetyl cholinesterase inhibitor
• Especially helpful when ptosis is the presenting symptom
• High sensitivity (95%)
• Performed less commonly because of risk of life-threatening bradycardia and because serologic testing is a less-invasive means of confirming the diagnosis
• Edrophonium production in the US was halted by the manufacturer (Baxter) in 2008, then resumed by the generic manufacturer Mylan Institutional (formerly Bioniche Pharma) under the name Enlon. It is available in a 15‑ml injectable vial at a concentration of 10 mg/ml and as Enlon Plus, a premixed combination of edrophonium 10 mg/ml and atropine 0.14 mg/ml.
• Dose
• For children who weigh less than 34 kg, a typical edrophonium test begins with a 0.5‑mg test dose, followed by 1‑mg doses repeated every minute for a maximum total dose of 5 mg.
• For adults, a similar test dose is used followed by 1–2‑mg doses, repeated every minute to a maximum dose of 10 mg. Heart rate is monitored throughout the test. (Chiang, Muscle Nerve 2009).
• Muscarinic symptoms including nausea, sweating, pupillary constriction, diarrhea, salivation are likely. Bradycardia and hypotension can occur.
• Electrophysiological tests
• Specific electrophysiological tests, such as repetitive nerve stimulation and single-fiber electromyography (EMG), are usually required to make the diagnosis of myasthenia.
• Repetitive nerve stimulation is specific for myasthenia gravis. A motor nerve is stimulated at 2 to 5 Hz while recording the compound motor action potential. Progressive decrement in amplitude is the diagnostic finding. The sternocleidomastoid and facial muscles can be tested.
• Results of single-fiber electromyographic tests are abnormal in about 95% of cases of myasthenia gravis. Single-fiber EMG, recording action potentials that progressively decrease in amplitude, is more sensitive (92 to 100%) than repetitive nerve stimulation, but also less specific, and it has a lower sensitivity(about 70%) in patients with purely ocular disease.
• Standard nerve-conduction and electromyographic studies are performed to detect other pathology that can coexist with myasthenia gravis.
• There are grades of severity in single-fiber EMG abnormalities. In the orbicularis oculi muscle, the degree of severity correlates with the level of acetylcholine receptor antibody titers (Chiang, Muscle Nerve 2009).

Testing for staging, fundamental impairment

• CT scans: Computed tomography of the thorax is required in all patients with myasthenia gravis to exclude the presence of a thymoma.
• Serologic testing:
• About 80% of patients with generalized myasthenia gravis have antibodies to the acetylcholine receptor.
• In a study of 677 Italian patients with generalized myasthenia gravis, 517 (76%) were AChR-positive, 55 (8%) patients were MuSK-positive, and 105 (16%) patients were double negative.
• Clinical stage at onset was more severe for MuSK-positive patients. (Baggi, Neurology 2013).
• MuSKAb are ordered for patients who are acetylcholine receptor antibody.
• There is a seroconversion rate of 10 to 20% among initially seronegative patients. Antibody tests should be repeated after 1 year.
• Ocular myasthenia patients can remain seronegative. Among seronegative patients there are some with low-level antibodies, the clinical significance of which is not known.

Medical therapy

Acetylcholinesterase inhibitors:

• Acetylcholinesterase inhibitors, such as pyridostigmine, are first-line treatment, but provide short-lived symptomatic relief (Bhatti, Surv Ophthalmol 2003).
• No known placebo versus drug trials
• Acetylcholinesterase inhibitors do not appear to influence the rate of generalization (Sommer, J Neurol Neurosurg Psychiatry 1997).
• In children, the initial pyridostigmine dose is 0.5–1 mg/kg every 4 to 6 hours. For adults, the starting dose is 30 or 60 mg every 4 to 6 hours. The maximum total dose is 7 mg/kg/day.
• Pyridostigmine is less useful in patients with antibodies to muscle-specific tyrosine kinase. Side effects (Kerty, Eur J Neurol 2014):
• Generally related to increased concentration of acetylcholine
• Secretions
• GI side effects (diarrhea, nausea, cramps)
• Bradycardia
• Sweating

Oral steroids and immunosuppressants:

• Oral steroids provide additional benefit as a generalized immunosuppressant.
• High-dose steroids can transiently exacerbate weakness.
• Azathioprine:
• Purine analogue; inhibits DNA synthesis and cell proliferation
• Instituted at 2.3–5 mg/kg/day and maintained at 1 mg/kg/day
• Reduced conversion to generalized myasthenia gravis to 12% (as opposed to 64% in untreated patients) (Sommer, J Neurol Neurosurg Psychiatry, 1997; Kerty, Eur J Neurol 2014)
• Risks:
• Possible several month induction period
• Leukopenia, thrombocytopenia
• Hepatotoxicity
• Nausea, emesis
• Neoplasia
• Mycophenolate mofetil
• Prevents replication of B- and T-cells
• In a cohort of 31 patients over 4.2 years, 87% of patients who were converted from corticosteroids to mycophenolate remained well controlled and without progression (Chan, J Neurol 2008).
• Methotrexate (Heckmann, BMC Neurol 2011)
• Inhibitor of dihydrofolate reductase, prevents lymphocyte proliferation
• In generalized myasthenia gravis, efficacy is similar to that of azathioprine
• Third-line immunosuppressants include tacrolimus, and cyclosporine.
• Rituximab, intravenous immunoglobulin and plasma exchange are reserved for rapidly deteriorating myasthenia gravis and myasthenic crisis.

Medications to avoid

It is generally advisable to avoid certain medications in myasthenia patients, including aminoglycosides and quinolone antibiotics, because they have been reported in some cases to exacerbate the disease.

Surgery

• Thymectomy
• Thymectomy should always be performed if a thymoma is present.
• Thymectomy is also considered in nonthymomatous generalized myasthenia gravis patients with antibodies to the acetylcholine receptor who are less than 50 years old.
• In a series of 172 patients with myasthenia in Hamburg, Germany, excluding those with thymoma or thymic carcinoma, there were significantly more myasthenia-related deaths among patients who did not undergo thymectomy and significantly more patients with improvement of symptoms and remission among those who did. The percentage of patients who developed myasthenic crisis or required plasmapheresis was similar between the 2 groups (Bachmann, Surgery 2009)
• Thymectomy is not generally recommended in patients with antibodies to muscle specific tyrosine kinase, late onset myasthenia, or purely ocular disease.
• Myasthenic ptosis
• There is not a significant amount of published data on the surgical management of ptosis in myasthenia. Frontalis suspension can be better than levator advancement for myasthenic ptosis, and is certainly reasonable when levator function is very poor and frontalis excursion is relatively intact.
• Among 16 ptosis repairs performed on 10 myasthenia patients (8 ocular myasthenia and 2 generalized disease), at the Mayo Clinic from 1985 to 1999, 9 underwent levator advancement, 6 frontalis suspension, and 1 tarsomyectomy. It is difficult to quantify the response to surgery with a variable ptosis, but among the levator advancement patients, 2 required additional surgery, and among the frontalis suspension patients, 1 developed exposure keratopathy (Bradley, OPRS 2001).

In contrast to adults, progression in preadolescent patients from ocular myasthenia to generalized disease is much less common, occurring in 10–15% of cases. Among 21 cases of purely ocular myasthenia treated at the Children's Hospital of Los Angeles, confirmed in all but one case by a positive edrophonium test, onset of symptoms ranged from 7–57 months of age and only 3 (15%) cases progressed to systemic disease (Ortiz, Ophthalmology 2008).

Among all pediatric myasthenia patients, about a third have only ocular disease. In Alberta, Canada, among 52 cases of juvenile onset myasthenia gravis, there were 34 cases of generalized and 18 cases of ocular myasthenia. Age at onset ranged from birth to 17 years for the generalized form and 18 months to 11 years for the ocular subtype. The rate of antibody positivity is similar to adults or slightly lower. Acetylcholine receptor antibodies were found in 67% of generalized cases and 44% of ocular myasthenia patients in the Alberta study. Response to pyridostigmine was excellent in this group, noted in 33 (100%) of 33 generalized cases and 88% of ocular cases. (VanderPluym, Pediatrics 2013)

In a study of 24 cases of myasthenia diagnosed before age 15, ptosis was present in 96% of cases (n = 23) (Kim, Ophthalmology 2003).

Among 34 juvenile myasthenia cases at The Hospital for Sick Children in Toronto, 14 patients underwent thymectomy and none had thymoma. A third of those 34 patients (n = 8) went into long term asymptomatic remission and required no further medical treatment. Half of these patients (n = 4) had undergone thymectomy (Mullaney, Ophthalmology 2000).

Response to thymectomy is variable in the pediatric population. In a study of 50 juvenile onset myasthenia patients at Children's Memorial Hospital in Chicago, 13 patients underwent thymectomy. A quarter of those patients (n = 4) had a complete remission and no further medication was needed. A quarter (n = 3) had improvement and required less medication, a quarter (n = 3) had slight improvement and required the same medication and a quarter (n = 3) showed no change. (Della Marina, Neuropediatrics 2014).

Similarly, among 39 juvenile myasthenia patients treated at the Children's Hospital of Philadelphia, complete disease resolution occurred in 25% (n = 10) within 5 years. In this cohort, thymectomy was performed in 38% (n = 15) and medical treatment involved pyridostigmine alone (38%) or in combination with steroids (49%) with 10% of patients requiring other medical treatment. (Pineles, AJO 2010).

Amblyopia associated with myasthenia has been documented in the literature. Vigilance is necessary with patching regimens and surgical intervention for ptosis and strabismus.

1. Myasthenia Gravis Foundation of America
2. Bachmann K et al. Thymectomy is more effective than conservative treatment for myasthenia gravis regarding outcome and clinical improvement. Surgery. 145:392, 2009.
3. Baggi F et al. Complete stable remission and autoantibody specificity in myasthenia gravis. Neurology. 80(2):188-95, 2013.
4. Bhatti MT. Double Trouble. Surv Ophthalmol, 48: 347-55, 2003.
5. Bradley EA et al. Surgical correction of blepharoptosis in patients with myasthenia gravis. Ophthal Plast Reconstr Surg. 2001 Mar;17(2):103-10.
6. Chan JW. Mycophenolate mofetil for ocular myasthenia. J Neurol. 2008; 255: 510–513.
7. Chiang LM et al. Juvenile myasthenia gravis. Muscle Nerve. 2009 Apr;39(4):423-31
8. Cogan DG. Myasthenia gravis: a review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol. 1965;74:217-221.
9. Della Marina A et al. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014 Apr;45(2):75-83. doi: 10.1055/s-0033-1364181. Epub 2014 Jan 27.
10. Filosso PL, Evangelista A, Ruffini E, et al. Does myasthenia gravis influence overall survival and cumulative incidence of recurrence in thymoma patients? A Retrospective clinicopathological multicentre analysis on 797 patients. Lung Cancer. 2015 Mar 15, epub ahead of print
11. Golnik, KC et al. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 1999 Jul;106(7):1282-6.
12. 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, 5;11:97, 2011.
13. Kerty E, Elsais A, Argov Z, et al. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol. 21(5):687-93, 2014.)
14. Kim JH et al. Childhood ocular myasthenia gravis. Ophthalmology. 110:1458, 2003
15. Kubis KC et al. The ice test versus the rest test in myasthenia gravis. Ophthalmology. 2000 Nov;107(11):1995-8.
16. Kupersmith MJ, Latkany R, and Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol. 60(2):243-8, 2003.
17. Monsul NT, Patwa HS, Knorr AM, et al. The effect of prednisone on the progression from ocular to generalized myasthenia gravis. Neurol Sci, 217(2):131-3, 2004.
18. Movaghar M et al. Effect of local heat versus ice on blepharoptosis resulting from ocular myasthenia. Ophthalmology. 2000 Dec;107(12):2209-14.
19. Mullaney P et al. The natural history and ophthalmic involvement in childhood myasthenia gravis at the hospital for sick children. Ophthalmology. 107:504, 2000
20. Nagia L, Lemos J, Abusamra K, et al. Prognosis of ocular myasthenia gravis. Ophthalmology, 2015 Apr 17, epub ahead of print
21. Ortiz S et al. Long-term outcomes of pediatric ocular myasthenia gravis. Ophthalmology. 115:1245, 2008)
22. Pineles SL et al. Visual and systemic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol. 2010 Oct;150(4):453-459.
23. Rodríguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis. JAMA Neurol. 2015 Apr 20, epub ahead of print
24. Silvestri NJ and Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromusc Dis, 15: 167-74, 2014
25. Singman EL1, Matta NS, and Silbert DI. Use of the Cogan lid twitch to identify myasthenia gravis. J Neuroophthalmol. 31(3):239-40, 2011.
26. Sommer N et al. Ocular myasthenia gravis: response to long-term immunosuppressive treatment. J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):156-62.
27. Toyka KV. Ptosis in myasthenia gravis: Extended fatigue and recovery bedside test. Neurol. 67: 1524, 2006.
28. VanderPluym J et al. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics. 132:e939, 2013.