Ophthalmologists are often the first physicians encountered by patients with ptosis and/or diplopia. Myasthenia gravis should always be considered in these patients. Any pattern of ophthalmoplegia, ocular misalignment, or ptosis can occur. Fortunately, there are signs and symptoms that are virtually pathognomic for this condition. Simple, safe office testing can help in confirming the diagnosis.

Adult-onset myasthenia gravis is an autoimmune disorder in which acetylcholine receptor antibodies attack the post-synaptic membrane of the neuromuscular junction. MG may be either ocular, generalized or initially ocular with progression to systemic involvement. Variable or fatigable symptoms and signs should increase the level of suspicion.

Symptoms
Ocular symptoms of myasthenia gravis are caused by weakness of the levator palpebrae, extraocular muscles or orbicularis oculi. Variability and fatigability are hallmarks. Ptosis may be unilateral or bilateral and is often worse at the end of the day. However, ptosis of many etiologies may worsen as the frontalis muscle fatigues. Although patients with nonmyasthenic ptosis will note worsening during the course of the day, it is typically mild. The level of suspicion for myasthenia gravis should increase dramatically if the patient has to hold the eyelid open to see at the end of the day.

Diplopia may also be fatigable and variable. Patients may note constant or transient diplopia in primary position or only in extreme gaze. The level of suspicion for myasthenia should increase if the patient notes episodes of both horizontal and vertical diplopia. Occasionally, patients with mild misalignment will not recognize two separate images and complain of blurry vision due to superimposed images. Inquire as to whether the blur resolves with each eye covered. Look for subtle ocular misalignment.

Patients rarely complain of incomplete eyelid closure but they might note symptoms of corneal exposure if orbicularis weakness is severe. I recently saw a woman who had undergone an extensive negative evaluation for diplopia. She had no ptosis but when asked, noted that her left eyelid did not seem to close fully by the end of the day. Further evaluation confirmed myasthenia gravis.

In a patient with ptosis and/or diplopia, proximal muscle weakness, change in character of voice, and difficulty chewing, swallowing or breathing suggest possible systemic MG. These patients will not always volunteer non-ocular symptoms. I like to ask them if their current problem is completely limited to their eyes or if there are any other new problems with the rest of their body.

Signs
Signs of MG may be obvious or so mild as to be asymptomatic. Finding subtle ptosis or ocular misalignment in a patient with other symptoms of MG may clinch the diagnosis.

Figure 1. These pictures were taken every 20 seconds over a one-minute interval. Note variable bilateral ptosis.

Quantitate ptosis by measuring marginal reflex distance or palpebral fissure height. Look for fatigability and variability of ptosis by having the patient maintain upgaze for about a minute. Myasthenic ptosis may be variable throughout the exam without any attempts at fatiguing the levator muscle (See Figure 1). Cogan’s lid twitch sign is elicited by having the patient look downward, then upward. If this is present, the eyelid will initially elevate but then settle into a lower, stable position.

Figure 2. Moderate digital pressure easily elevates the eyelid despite attempted forceful eyelid closure.

Always check for orbicularis weakness by asking the patient to squeeze his eyelids shut tightly. Use finger pressure to try and overcome the blepharospasm (See Figure 2). Lagophthalmos may be present or develop if orbicularis weakness is present.

Ophthalmoplegia may be unilateral or bilateral, and, as with ptosis, may be present as an isolated sign of myasthenia. Ophthalmoplegia may also be fatigable and can be tested by having the patient sustain extreme gaze for a minute or so. Mild ophthalmoplegia may not be obvious when testing ductions and versions; ocular misalignment in extreme gaze may be the only sign (See Figure 3). Always check alignment in each position of gaze; misalignment may be subtle, intermittent and variable.

Figure 3. Note left upper eyelid ptosis and mild depression, adduction deficits OS.

Myasthenia can mimic any pattern of misalignment. I have seen patients thought to have cranial nerve palsies and internuclear ophthalmoplegia who proved to be myasthenic. Alignment variability during the examination should increase the level of suspicion for myasthenia. If your measurements differ from the orthoptist’s, resident’s or technician’s, consider MG.

Diagnosis—Office Testing
If the patient has signs of MG, then simple office testing may clinch the diagnosis. The sleep or rest test can be done if ptosis is present. Evaluate the patient before and after 30 minutes of rest with the eyelids closed (See Figure 4).¹ Ask the patient to keep his eyes closed until the examiner is ready to measure palpebral fissures. There is debate as to exactly how much time is necessary to produce a significant improvement in ptosis. Improvement in ophthalmoplegia/alignment after rest has not been evaluated. As with other tests for myasthenia gravis, the sleep test is not 100-percent sensitive.

Figure 4A (top) Before rest test. Note the asymmetric ptosis. Figure 4B. After 30 minute rest test. Note the bilateral improvement of ptosis.

Alternatively, if ptosis is present, an ice test can be done. Evaluate the patient before and after a two-minute application of ice to the ptotic eyelid.^2-5 A 2-mm improvement in ptosis is thought to be highly sensitive and specific for myasthenia gravis. Measurement of the palpebral fissure must be made within 10 seconds of ice removal because the eyelid quickly regains body temperature. False negatives do occur, in particular in patients with complete ptosis and no levator function.⁵ Debate exists as to whether the ice test is simply a two-minute “rest test.” The most recent work indicates that, although a two-minute rest will improve ptosis, a two-minute ice test is more sensitive and dramatic.⁶ Ophthalmoplegia does not improve with ice testing.

Edrophonium (Tensilon) testing remains the gold standard for the diagnosis of ocular MG. Intravenous injection of this acetylcholine sterase inhibitor should result in improvement of ptosis and/or ophthalmoplegia. Initially, 2 mg edrophonium is administered intravenously. If there’s no response, 8 mg edrophonium is administered. Keep a 1-mg vial of atropine nearby in case significant bradycardia develops.

The estimated sensitivity of edrophonium testing is 86 percent in ocular and 95 percent in systemic myasthenia.⁷ False-positive responses have been reported in patients with a variety of conditions including tumors, multiple sclerosis and diabetic cranial nerve palsies. Additionally, edrophonium administration may produce serious side effects including significant bradycardia, loss of consciousness and death.⁸

Minimal or extremely variable signs produce difficulty in interpreting the test results. I would avoid this test if minimal signs or variability preclude judging the results unequivocally.

Diagnosis—Ancillary Testing
Anti-Acetylcholine Receptor Antibodies (anti-ACHR-ab) are detected in more than 90 percent of patients with generalized myasthenia but in only 45-65 percent of patients with ocular myasthenia.⁹ Typically, assays for anti-AChR-ab identify the binding antibody but testing for blocking and modulating antibodies may increase the assay yield.¹⁰ The presence of anti-AChR-ab in the serum is highly specific for myasthenia; however, false-positive elevations may occur in first-degree relatives of patients with myasthenia and in patients with amyotrophic lateral sclerosis, primary biliary cirrhosis and tardive dyskinesia.

Repetitive nerve stimulation and single fiber electromyography are the most useful types of electrophysiologic testing. Repetitive nerve stimulation is a much more sensitive test in generalized myasthenia (60-85 percent) than in ocular myasthenia (18-35 percent).¹¹ Single fiber electromyography is more sensitive (91-100 percent of patients with generalized MG and 80-88 percent of patients with ocular MG) but may be more difficult to obtain than repetitive nerve stimulation.¹²

Muscle biopsy allows quantitation of available acetylcholine receptors¹³ and detection of immune complexes at the motor endplate.¹⁴ This is thought to be highly sensitive and specific but is difficult to obtain and only available at a few centers. This should probably be reserved for patients in whom all other testing is negative but clinical suspicion remains high.

Treatment
More than 60 percent of patients who present with ocular MG develop systemic involvement. Thus, I always obtain systemic neurologic evaluation in patients with ocular myasthenia.

Thymoma occurs in 10-20 percent of patients and is more common after the age of 40.^15,16 Computed tomographic scan of the chest should be obtained. Thymectomy should be done in any patient with thymoma and may be considered in patients without thymoma who are not well-controlled on mestinon.

I usually rely on the neurologist to institute medical treatment. Pyridostigmine bromide (Mestinon), a cholinesterase inhibitor, is typically the first-line therapy. Side effects include diarrhea, tearing and fasciculations. If mestinon is ineffective, thymectomy or immunosuppressive drugs (prednisone, cyclosporine, azathioprine) should be considered. Plasmapheresis or intravenous human immune globulin are used if the patient develops acute respiratory distress or difficulty swallowing. 

Dr. Golnik practices at the Cincinnati Eye Institute in the Departments of Ophthalmology, Neurology, and Neurosurgery at the University of Cincinnati.

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