Painless, droopy eyelid or double vision that is variable throughout the day or worse when the individual is fatigued; may have weakness of facial muscles, proximal limb muscles, and difficulty swallowing or breathing.

• Eaton–Lambert syndrome: A myasthenia-like paraneoplastic condition associated with carcinoma, especially lung cancer. Isolated eye signs do not occur, although eye signs may accompany systemic signs of weakness. Unlike myasthenia, muscle strength increases after exercise. Electromyography (EMG) distinguishes between the two conditions.
• Myasthenia-like syndrome due to medication (e.g., penicillamine, aminoglycosides).
• CPEO: No diurnal variation of symptoms or relation to fatigue; usually a negative intravenous edrophonium chloride test. Typically no diplopia. See 10.12, CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA.
• Kearns–Sayre syndrome: CPEO and retinal pigmentary degeneration in a young person; heart block develops. See 10.12, CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA.
• Third cranial nerve palsy: Pupil may be involved, no orbicularis weakness, no fatigability, no diurnal variation. See 10.5, ISOLATED THIRD CRANIAL NERVE PALSY.
• Horner syndrome: Miosis accompanies the ptosis. Pupil does not dilate well in darkness. See 10.2, HORNER SYNDROME.
• Levator muscle dehiscence or disinsertion: High eyelid crease on the side of the droopy eyelid, no variability of eyelid droop, no orbicularis weakness.
• Thyroid eye disease: No ptosis. May have eyelid retraction or eyelid lag, may or may not have exophthalmos, no diurnal variation of diplopia. Graves disease occurs in 5% of patients with myasthenia gravis. See 7.2.1, THYROID EYE DISEASE.
• Idiopathic orbital inflammatory syndrome: Proptosis, pain, ocular injection. See 7.2.2, IDIOPATHIC ORBITAL INFLAMMATORY SYNDROME.
• Myotonic dystrophy: May have ptosis and rarely, gaze restriction. After a handshake, these patients are often unable to release their grip (myotonia). Polychromatic lenticular deposits (“Christmas tree” cataract) and pigmentary retinopathy present.

NOTE:

Myasthenia may mimic cranial nerve palsies, but the pupil is never involved.

Autoimmune antibody-mediated disease; sometimes associated with underlying thyroid dysfunction. May be associated with thymic enlargement, representing either a benign thymoma or rarely a malignant thymoma. Increased incidence of other autoimmune disease (e.g., systemic lupus erythematosus, MS, rheumatoid arthritis). All age groups may be affected.

Work-Up

1. History: Do the signs fluctuate throughout the day and worsen with fatigue? Any systemic weakness? Difficulty swallowing, chewing, or breathing? Medications (worsened by beta-blockers, macrolides)?
2. Assess for presence of fatigability: Measure the degree of ptosis in primary gaze. Have the patient focus on your finger in upgaze for 1 minute. Observe whether the ptosis worsens.
3. Assess orbicularis strength by asking the patient to squeeze the eyelids shut while you attempt to force them open.
4. Test pupillary function. This will always be normal in myasthenia gravis.
5. Blood test for acetylcholine receptor antibodies (binding, blocking, and modulating). An elevated antibody titer establishes the diagnosis of myasthenia. However, values may be positive in only 60% to 88% of patients with myasthenia and are less likely to be positive in purely ocular myasthenia gravis. Anti muscle–specific kinase (MUSK) antibodies are found in some patients who are negative for acetylcholine receptor antibodies, but those patients usually have systemic findings and have signs/symptoms that are not isolated to extraocular muscle function.
6. In adults, ice test (see later), rest test (see later), or, if cardiac monitoring present, edrophonium chloride or neostigmine test may confirm the diagnosis.
7. For the ice test, an ice pack is placed over closed ptotic eye(s) for 2 minutes. Improvement of ptosis by at least 2 mm is a positive test for myasthenia gravis (see Figures 10.11.1 and 10.11.2).
8. In children, observation for improvement immediately after a 1- to 2-hour nap (sleep test) is a safe alternative. A similar rest test (keeping eyes closed) for 30 minutes in adults may be similarly diagnostic.
9. Check swallowing and breathing function as well as proximal limb muscle strength to rule out systemic involvement.
10. Thyroid function tests (including thyroid-stimulating hormone [TSH]).
11. CT scan of the chest to rule out thymoma.
12. Consider ANA, rheumatoid factor, and other tests to rule out other autoimmune disease.
13. A single-fiber EMG including the orbicularis muscle may be performed if other testing is negative and the diagnosis is still suspected. May be the most sensitive test for involvement of the ocular muscles.

NOTE:

Cholinergic crisis, syncopal episode, and respiratory arrest, although rare, may be precipitated by the edrophonium chloride test. Treatment includes atropine 0.4 mg i.v., while monitoring vital signs. Consider pretreating with atropine to prevent problems.

NOTE:

Intramuscular neostigmine may be used instead of edrophonium chloride in children or in patients where injecting intravenous medication is problematic. The effect has a longer onset and lasts for approximately 2 to 4 hours.

Refer to a neurologist familiar with this disease.

1. If the patient is having difficulty swallowing or breathing, urgent hospitalization for plasmapheresis, intravenous immunoglobulin (IVIG), neuromuscular disease specialist consult, and respiratory support may be indicated.
2. If the condition is mild, purely ocular, and is not disturbing to the patient, therapy need not be instituted (the patient may patch one eye as needed).
3. If the condition is disturbing or more severe, an oral anticholinesterase agent such as pyridostigmine should be given (often starting with 30 mg p.o. t.i.d. gradually increasing to an approximate dose of 60 mg p.o. q.i.d. for an adult). The dosage must be adjusted according to the response. Patients rarely benefit from >120 mg p.o. q3h of pyridostigmine. Overdosage may produce cholinergic crisis.
4. If symptoms persist, consider systemic steroids. There is no uniform agreement concerning the dosage. One option is to start with prednisone 20 mg p.o. daily, increasing the dose slowly until the patient is receiving 100 mg/d. These patients may require hospitalization for several days when a high-dose regimen of steroids is employed.
5. Azathioprine (2-3 mg/kg/d) may be helpful in older patients. Other medications to consider include mycophenolate mofetil and cyclosporine. Some patients with systemic myasthenia are treated with regularly scheduled IVIG or plasmapheresis.
6. Treat any underlying thyroid disease or infection.
7. Surgical removal of the thymus can be performed. This is indicated for anyone with thymoma. It may also improve symptoms in patients with generalized myasthenia without thymoma.

NOTE:

Steroid use in myasthenia may precipitate respiratory crisis in the first 2 weeks of treatment. Therefore, in patients with systemic symptoms, hospitalization to begin steroids is required.

Follow-Up

1. If systemic muscular weakness is present, patients need to be monitored every 1 to 4 days by an appropriate medical specialist until improvement is demonstrated.
2. Patients who have had their isolated ocular abnormality for an extended time (e.g., months) should be seen every 4 to 6 months and if proven to be stable, every 6 to 12 months.
3. Patients should always be warned to return immediately if swallowing or breathing difficulties arise. After isolated ocular myasthenia has been present for 2 to 3 years, progression to systemic involvement is unlikely.

NOTE:

Newborn infants of myasthenic mothers should be observed carefully for signs of myasthenia because acetylcholine receptor antibodies may cross the placenta. Poor sucking reflex, ptosis or decreased muscle tone may be seen.