Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(10):1332–1338.

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O’Connor P; CHAMPS. The effects of intramuscular interferon beta-1a in patients with high risk for development of multiple sclerosis: a post hoc analysis of data from CHAMPS. Clin Ther. 2003;25(11):2865–2874.

Rudick RA, Sandrock A. Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother. 2004;4(4):571–580.

Myasthenia Gravis

Myasthenia gravis (MG) is an immunologic disorder characterized by variable and fatigable weakness. Symptoms may improve with rest. Most patients with MG incur neuro-ophthalmic abnormalities. Although the disease is usually a systemic disorder, one-half of affected patients have ocular symptoms and signs at onset. The pathophysiology arises from antibodies that cause a decrease in the number of acetylcholine receptors available. Myasthenia gravis may be caused, unmasked, or worsened by numerous types of medications, including antiarrhythmics, antibiotics, chemotherapeutic drugs, antiepileptics, quinolones, penicillamine, corticosteroids, β-blockers, and calcium channel blockers.

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Smith KH. Myasthenia gravis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2003, module 4.

Clinical presentation of myasthenia gravis

The hallmarks of MG are fluctuation and fatigability (although these are not invariably present). Clinical signs and symptoms usually worsen in the evening and with use of the eyes and may improve with rest. The most common sign of MG is unilateral or bilateral ptosis. The extent of ptosis tends to vary, with the eyelid more ptotic in the evening, after exertion, or after prolonged upward gaze. Cogan eyelid twitch, elicited by having the patient initiate saccades during refixation from downgaze to upgaze, is a brief overelevation of the upper eyelid. Another eyelid sign is enhancement of ptosis; in keeping with Hering’s law of motor correspondence (equal and simultaneous innervation); when the more ptotic eyelid is elevated manually, the less ptotic eyelid inevitably falls (see Chapter 11, Fig 11- 3). Fatigue of ptosis should be assessed by asking the patient to sustain upgaze for 1 minute or longer.

Myasthenia gravis frequently causes diplopia. The diplopia may be variable, both during the day and from one day to another. The ocular motility pattern may simulate ocular motor cranial nerve paresis (usually sixth nerve or partial, pupil-sparing, third nerve palsy), internuclear ophthalmoplegia, supranuclear motility disturbances (eg, gaze palsies), or isolated muscle “palsy” (eg, isolated inferior rectus). Total ophthalmoplegia can occur. Any changing pattern of diplopia, with or without ptosis, should suggest MG. As with ptosis, motility fatigue can also be assessed by having the patient sustain gaze in the direction of paresis. Orbicularis oculi weakness is often present in patients with ocular MG and, if present, can be diagnostically crucial in differentiating MG from other causes of external ophthalmoplegia.

Pupillary abnormalities and sensory disturbances are not associated with MG, and their presence should provoke a search for another diagnosis. Systemic symptoms and signs that are associated with MG include weakness in the muscles of mastication and in the extensors of the neck, trunk, and limbs; dysphagia; hoarseness; dysarthria; and dyspnea. Dysphagia and dyspnea can be life threatening and

require prompt treatment. Thyroid eye disease occurs in about 5% of MG patients and should be suspected if a patient with MG exhibits exotropia, which can occasionally complicate the clinical ophthalmic findings.

Diagnosis of myasthenia gravis

The diagnosis of MG is made clinically by identifying typical signs and symptoms, pharmacologically by overcoming the receptor block through the administration of acetylcholinesterase inhibitors, serologically by demonstrating elevated anti–acetylcholine receptor antibody titers or anti–muscle- specific kinase antibody, and electrophysiologically by results of electromyography (EMG).

If an obvious abnormality is present on examination, results of an edrophonium chloride (a shortacting acetylcholinesterase inhibitor) test, a sleep test, or an ice-pack test can confirm the diagnosis of MG. Edrophonium chloride tests are not commonly performed in eye clinics, as rare but serious adverse effects from administration of the drug can occur; these include bradycardia, respiratory arrest, bronchospasm, syncopal episodes, or cholinergic crisis. Thus, consultation with the primary physician before performing the test is recommended for patients with a history of cardiac or pulmonary disease. Atropine sulfate (0.4–0.6 mg) should be available immediately, if needed. Some physicians pretreat with atropine (0.4 mg subcutaneously) before administering the edrophonium. Patients should also be warned of the possibility of the short-lived but often discomforting effects of fasciculations, sweating, lacrimation, abdominal cramping, nausea, vomiting, and salivation. In most protocols, a small test dose of 2 mg (0.2 mL) edrophonium is first injected intravenously, and the patient is observed for 60 seconds. If the symptoms disappear or decrease (for example, the eyelid elevates or motility improves), the test result is considered positive and can be discontinued. If no response is elicited, additional doses of 4 mg, up to a total of 10 mg, are given. When the ocular symptom is marked (eg, complete ptosis), the endpoint (eyelid elevation) is often dramatic. However, a subtle deficit, such as minimal diplopia, may require use of other means to better define the endpoint. Maddox rod tests with prisms or diplopia fields may be performed before and after edrophonium (see Chapter 8). False-positive responses are rare. A negative test result does not exclude the diagnosis of MG, and repeat testing at a later date may be needed.

An alternative to the edrophonium test is the neostigmine methylsulfate test. This test is particularly useful for children and for adults without ptosis who may require a longer observation period for accurate ocular alignment measurements than that allowed by edrophonium testing. Adverse reactions are similar to those for edrophonium, the most frequent of which are salivation, fasciculations, and gastrointestinal discomfort. Intramuscular neostigmine and atropine are injected concurrently. A positive test result produces improvement of signs within 30–45 minutes.

The sleep test is a safe, simple office test that eliminates the need for edrophonium testing in many patients. After having the baseline deficit documented (ie, measurements of ptosis, motility disturbance), the patient rests quietly with eyes closed for 30 minutes. The measurements are repeated immediately after the patient “wakes up” and opens his or her eyes. Improvement after rest is highly suggestive of MG.

The ice-pack test is often helpful for diagnosing MG, but only if the patient has ptosis. An ice pack is placed over lightly closed eyes for 2 minutes. Improvement of ptosis occurs in most patients with MG (Fig 14-2). One exception is the patient with complete myasthenic ptosis; the cooling effect may be insufficient to overcome the severe weakness in these patients.

Figure 14-2 A, 57-year-old woman with myasthenia gravis presented with moderate, variable left ptosis. B, The left ptosis improved after a 2-minute ice-pack test. (Courtesy of Karl C. Golnik, MD.)

Other diagnostic tests for MG include serum assays for anti–acetylcholine receptor antibodies or anti–muscle-specific kinase (MuSK) antibodies and electrophysiologic testing. Three types of acetylcholine receptor antibody tests are commercially available. Tests for binding antibodies are usually requested, because these antibodies are detected in approximately 90% of patients with generalized MG and in 50% of patients with ocular MG. Blocking antibodies are rarely present (1%) without binding antibodies. Modulating antibodies are present as frequently as binding antibodies. Blocking and modulating antibody testing is usually reserved for patients who test negative for the binding antibody and for whom evidence of autoimmune MG is necessary. An assay for anti-MuSK antibodies may detect MG in some patients who do not have anti–acetylcholine receptor antibodies. In 2012, a new autoantibody was identified in patients with MG who were seronegative for both MuSK and acetylcholine receptor. Antibodies against the low-density lipoprotein receptor–related protein (LRP4) may be a novel diagnostic marker, but additional studies will need to be performed to fully characterize this antibody.

Electromyographic repetitive nerve stimulation shows a characteristic decremental response in many patients with systemic MG. Single-fiber EMG is most sensitive for MG. All patients with MG must be investigated radiologically for thymomas, which are observed on computed tomography (CT) scans in 10% of these patients. Malignant thymomas are present in a small percentage of patients. Because there is a high coexistence of MG with other autoimmune disorders, serologic testing should be done for thyroid dysfunction and pernicious anemia.

Evoli A, Tonali PA, Padua L, et al. Clinical correlates of anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003;126(pt 10):2304–2311.

Golnik K, Pena R, Lee A, Eggenberger ER. An ice test in the diagnosis of myasthenia gravis. Ophthalmology. 1999;106(7):1282–1286.

Mercelis R, Merckaert V. Diagnostic utility of stimulated single-fiber electromyography of the orbicularis oculi muscle in patients with suspected ocular myasthenia. Muscle Nerve. 2011;43(2):168–170.

Odel JG, Winterkorn JM, Behrens MM. The sleep test for myasthenia gravis. A safe alternative to Tensilon. J Clin Neuroophthalmol. 1991;11(4):288–292.

Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChRand MuSK-antibody-negative myasthenia gravis. J. Neurol. 2012;259(3):427–435.

Treatment of myasthenia gravis

Symptomatic, nonpharmacologic treatment for ptosis or diplopia may include use of a patch, ptosis crutch, or prisms, although prisms are typically used when the variability is small and with the understanding that the treatment is not always helpful. Pharmacologic treatment for MG includes use

of acetylcholinesterase inhibitors (such as neostigmine and pyridostigmine), corticosteroids, and other immunosuppressant drugs. Thymectomy is reserved for patients with a thymoma and for patients with generalized MG who have thymic enlargement. Short-term therapies such as intravenous immunoglobulin or plasmapheresis are occasionally necessary.

Myasthenia gravis is a systemic disease with disastrous potential. Although purely ocular MG does exist, systemic MG will develop over the next 2 years in up to 85% of patients who present with ocular MG. Because MG patients may develop respiratory and other life-threatening manifestations, it is prudent to manage their care in cooperation with a neurologist. If ocular signs remain truly isolated for more than 2 years, the disease is likely to remain clinically ocular; nevertheless, late conversion to generalized MG is possible.

Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. 2003;61(12):1652–1661.

Thyroid Eye Disease

Thyroid eye disease (TED), also known as thyroid-associated orbitopathy and Graves ophthalmopathy, is an autoimmune inflammatory disorder whose underlying cause remains unknown. The clinical signs, however, are characteristic and may include a combination of eyelid retraction, eyelid lag, proptosis, restrictive extraocular myopathy, and optic neuropathy. The disease activity in the 2 eyes may be remarkably asymmetric. Although typically associated with hyperthyroidism, TED may accompany hypothyroidism or, in rare cases, Hashimoto thyroiditis. Some patients have characteristic eye findings without objective evidence of thyroid dysfunction (termed euthyroid Graves disease). The course of the eye disease does not necessarily parallel the activity of the thyroid gland or the treatment of thyroid abnormalities.

Eyelid signs of thyroid eye disease

Upper eyelid retraction is often one of the first clinical signs of TED (Fig 14-3A). When accompanied by eyelid lag (decreased depression of the eyelid when the patient looks downward), it is virtually pathognomonic for TED. Mild asymmetric eyelid retraction is occasionally mistaken for contralateral ptosis. Old photographs can be examined to resolve questions of which eye has the abnormal eyelid position.

Figure 14-3 Ocular manifestations of Graves disease. A, Left eyelid retraction, proptosis, and fat prolapse into upper and lower eyelids. B, Marked limitation of elevation of the right eye due to restriction by an enlarged inferior rectus muscle. C, Coronal CT scan showing bilateral enlargement of all rectus muscles. (Part A courtesy of Steven A. Newman, MD; parts B, C

courtesy of Karl C. Golnik, MD.)

Proptosis in thyroid eye disease

The proptosis observed in approximately two-thirds of patients with TED tends to be strictly axial without dystopia. Asymmetric degrees of proptosis are not at all uncommon; in some cases, the involvement may appear to be unilateral. Any patient with suspected TED should have measurements of the exophthalmos taken with an exophthalmometer. With severe proptosis, incomplete eyelid closure may result in corneal drying accompanied by discomfort and blurred vision.

Extraocular myopathy in thyroid eye disease

Extraocular muscle enlargement often restricts ocular rotation (Fig 14-3B, C). Most patients with ophthalmoplegia have asymmetric involvement that often leads to ocular misalignment and diplopia. Clinically, the inferior rectus muscle is most commonly involved, followed by the medial rectus and superior rectus. As discussed in Chapter 8, TED is the most common cause of restrictive strabismus.

Compressive optic neuropathy in thyroid eye disease

In 5% of patients with TED, the muscles are sufficiently enlarged at the apex of the orbit to compress