• Neuro-Ophthalmology/Orbit

    Many diseases mimic the ocular manifestations of ocular and generalized myasthenia gravis. The clinical history and examination provide the most important data for making the diagnosis of myasthenia. Patients with ocular myasthenia often have negative serum tests for acetylcholine receptor antibodies, and recently published studies confirm that several office-based tests can aid in the diagnosis of ocular myasthenia in particular. Knowledge of the electrophysiologic tests available will also expand the clinician’s armamentarium. Since no one perfect diagnostic or clinical test exists for ocular myasthenia (OM), it is critical to understand the advantages and limitations of all the diagnostic techniques available.

    Ocular Manifestations

    Ptosis and diplopia are the initial complaints in 75% of myasthenic patients, eventually developing in at least 90% of all myasthenic patients. About 30%–40% of patients will remain ocular myasthenics, and 50%–70% progress to generalized myasthenia gravis (MG), typically within the first 2 years of presentation.1-3 The following are some of the more salient features of the ocular manifestations of MG:

    • Ptosis may be unilateral or bilateral. It is usually asymmetric, occurring in association with diplopia. Variability of the ptosis and diplopia is the hallmark of MG.

    • If ptosis is asymmetric, 1 lid may be retracted. Innervational tone is supplied to both ptotic lids, with enough innervation to allow the more ptotic lid to clear the pupil. This induces the less ptotic lid to become comparatively retracted, in accordance with Hering’s law of equal innervation. However, when the more ptotic lid is manually elevated, the retracted lid droops, a sign considered specific for myasthenia gravis. This has been termed “enhanced ptosis.”1-3

    • Cogan’s lid-twitch sign is tested by asking the patient to look down for 10–15 seconds and then to look into primary position. The ptotic eyelid overshoots briefly before returning to its normally ptotic position. Cogan’s lid-twitch sign has long been considered a characteristic of MG, but the sensitivity and specificity has been found to be relatively low, and other conditions may cause the lid twitch. Presence of Cogan’s lid twitch may increase the suspicion of MG, but it is not diagnostic (J Neurol Sci. 2007;256(1–2):84–85).

    • Diplopia secondary to paresis to 1 or more of the extraocular muscles is the second most frequent presenting symptom and is usually associated with ptosis. MG can imitate any single or multiple cranial nerve palsy. Nearly 90% of patients who present with diplopia have associated ptosis. The severity varies from complete paralysis to subtle weakness, which may produce isolated nystagmus. Also seen are hypometric large saccades and hypermetric small saccades.1-3

    • Weakness of the orbicularis oculi muscle is often found in MG and OM. Normally, with gentle lid closure there should be no lagophthalmos, and the eyelashes should be buried with forced closure. The “peek-a-boo” sign describes the gradual appearance of lagophthalmos during eyelid closure owing to a weakness of the orbicularis oculi. Initially, the orbicularis oculi is able to produce tight lid closure, but this is followed by fatigue, which leads to separation of the lids, with the patient appearing to peek at the examiner. The sign is not specific for OM and has been seen in other seventh-nerve disorders.1-3

    • Pupils, by routine exam techniques, are normal in MG. Diminished accommodation has been observed in some studies of patients with OM.

    The clinician should also ask about facial or limb weakness and difficulty with speech and swallowing.

    Diagnostic Evaluation


    Acetylcholine receptors and other autoantibodies

    The clinician may order 3 types of acetylcholine receptor (AChR) antibody tests: binding, blocking, and modulating. Ninety percent of patients with generalized MG will have a positive binding antibody, but only 50% of OM patients will have a positive test. Modulating antibodies increase the diagnostic yield slightly. Blocking antibodies are found only in a small percentage of MG patients. AChR antibodies can be found in other autoimmune conditions such as lupus, thyroid eye disease, thymoma, rheumatoid arthritis, and inflammatory neuropathies.

    Antibodies to striated muscle have also been noted in MG. They are elevated in 30% of adult MG patients and are associated with thymoma, and they are positive in 80% of thymomatous MG Thymoma occurs in 5%–20% of patients with generalized MG, but it is rare in OM patients.

    Of generalized MG patients, 30%–50% who are without antibodies against AChR have been found to have antibodies against muscle-specific kinase (MuSK). MuSK antibodies have been studied in very few OM patients, so the importance of this antibody in patients with OM is unknown.

    Clinical Tests


     

    Ice, sleep, and rest tests

    The ice test, which uses local cooling via icepacks to the eyelids for 2–5 minutes, has a reportedly high degree and sensitivity (90% and 100% respectively) for ptosis. Cooling is believed to reduce acetylcholinesterase activity, making more acetylcholine available at the neuromuscular junction. The ice test is typically used for evaluation of ptosis, as cooling of deep orbital tissues and extraocular muscles is more difficult. The test is positive if the lid elevates 2 mm and the result lasts about 1 minute.1-3,5

    The sleep test is performed by having the patient sleep for 30 minutes. One study revealed 100% specificity and sensitivity of this test in patients with edrophonium-confirmed OM with ptosis and with extraocular muscle (EOM) dysfunction (Clin Neurophysiol. 2000;111(7):1203–1207).

    The rest test is a miniature sleep test, performed by having the patient close the eyelids for 2–5 minutes. This quick test may reveal diagnostic improvement in ptosis or EOM imbalance.1-3,5

    Edrophonium and other acetylcholinesterase inhibitor tests

    Infusion of IV edrophonium chloride (Tensilon) is a highly sensitive test for generalized MG and OM.1-3,5 The test is most useful where there is demonstrated improvement in ptosis or in extraocular muscle motility. Ptosis responds best to edrophonium, while EOM weakness does not respond as well. Only unequivocal improvement in the muscle or muscles in question should be interpreted as a positive test. Positive tests have been described in other conditions. The complications of the Tensilon test are bradycardia and syncope. Other muscarinic side effects are common, such as tearing, salivation, sweating, abdominal cramps, and nausea. Atropine should be available to reverse the bradycardia.

    Neostigmine methylsulfate is a longer-acting cholinesterase that is administered intramuscularly. It is an alternative to Tensilon and is particularly useful in children. A therapeutic trial of oral pyridostigmine (Mestinon) may result in improved muscle strength.

    Electrophysiologic tests

    Repetitive nerve stimulation (RNS) is a widely available test in which an electric current is used to excite a muscle while the electrical signal from the stimulated muscle is recorded. The muscle is stimulated repeatedly while recording the action potentials from the excited muscle. A decremental response is found in neuromuscular junction disease when testing affected muscles. The reported sensitivity of RNS for diagnosing generalized MG is 53%–100% and is 10%–17% in OM. Thus, RNS is rarely used to test for OM.1-3,5

    Single-fiber electromyography (SFEMG) is the most sensitive test for neuromuscular transmission (Neuromuscul disord. 2006;16(7):459–467). The EMG needle is inserted into the weak muscle, and in the case of OM, the needle would be inserted into the orbicularis oculi or levator muscle. The sensitivity of SFEMG is quoted at 62%–100% in OM. Unfortunately, this test is not widely available and is operator-dependent.

    Summary

    There is no single best test to diagnose OM. The symptoms of variable ptosis and diplopia are highly suggestive of the diagnosis. EOM weakness and ptosis with orbicularis oculi weakness are exam findings that are highly suggestive of OM. Presence of AChR antibodies are highly suspicious for OM, but there are rare false positives, and many patients with OM have negative test results. The ice test (for ptosis) and the sleep test (for ptosis and EOM weakness) are inexpensive, noninvasive tests with excellent sensitivity and specificity. Edrophonium or neostigmine are excellent tests in cases with obvious pretest weakness in the orbicularis oculi or in the extraocular muscle or muscles. RNS and SFEMG are used less often by ophthalmologists, possibly secondary to the lack of availability of experienced electrophysiologists and the ophthalmologists’ inexperience with interpreting these tests.

     

    References

    1. Kusner LL, Puwanant A, Kaminski HJ. Ocular myasthenia: diagnosis, treatment, and pathogenesis. Neurologist. 2006;12(5):231–239.
    2. Elrod RD, Weinberg DA. Ocular Myasthenia Gravis. Ophthalmol Clin North Am. 2004;17:275–309.
    3. Meriggioli MN, Sanders DB. Advances in the diagnosis of neuromuscular junction disorders.Am J Phys Med Rehabil. 2005;84(8):627–638.
    4. Van Stavern GP, Bhatt A, Haviland J, Black EH. A prospective study assessing the utility of Cogan’s lid twitch sign in patients with isolated unilateral or bilateral ptosis.J Neurol Sci. 2007;256(1–2):84–85.
    5. Odel JG, Winterkorn JM, Behrens MM. The sleep test for myasthenia gravis: a safe alternative to Tensilon. J Clin Neuroophthal . 1991;11(4):288–292.
    6. Padua L, Stalberg E, LoMonaco M, et al. SFEMG in ocular myasthenia gravis diagnosis.Clin Neurophysiol. 2000;111(7):1203–1207.
    7. Benatar M. A systematic review of diagnostic studies in myasthenia gravis.Neuromuscul disord. 2006;16(7):459–467.

    Author Disclosure

    Dr. Edmond states that she has no financial relationship with the manufacturer of any product discussed in this article or with the manufacturer of any competing product.