The patient believed that his dislopia was due to inactivity while he was in prison.

Your Diagnosis
How would you approach this case? Does this patient require additional tests? What is your diagnosis? How would you manage this patient? What is the likely prognosis?

Discussion
Color testing was normal O.U. Extraocular muscle movement was remarkable for bilateral abduction deficits, with 90% abduction for the right and 80% abduction for the left. There was no apparent eyelid fatigue upon sustained upgaze and no Cogan"s eyelid twitch. The patient did have significant weakness of the orbicularis oculi O.U. by the forcible squeeze test.

Cover testing uncovered a variable 4 to 14 prism diopters exodeviation in primary gaze, 8 prism diopters of esodeviation on right gaze, 16 prism diopters of esodeviation on left gaze and 2 prism diopters of esodeviation on up gaze. Right gaze also revealed 4 prism diopters of right hyperdeviation, and left gaze revealed 2 prism diopters of left hyperdeviation. All other cranial nerves appeared to be functioning normally.

Additional testing included inquiries regarding tinnitus, dizziness, disequilibrium and nausea. While these symptoms were not present, the patient did report severe headaches radiating from the back of the neck that stretched over the forehead, for the previous two weeks. A blood workup for acetylcholine receptor (ACh-R)-binding antibodies was ordered and found positive.

The diagnosis in this case is myasthenia gravis (MG). The result of the patient"s blood work: antibody levels of 170nmol/l. The average is less than 0.1nmol/l. We referred the patient to a neurologist who confirmed our suspicions. The neurologist initiated prednisolone therapy of 60mg per day with intentions of starting the patient on Imuran (azathioprine, Prometheus Laboratories) immunosuppression therapy. A computed axial tomography (CAT) scan was ordered to rule out a thymoma. The test returned negative.

Myasthenia gravis is a disorder that causes fatigue of the body"s muscles.^1-5 It is a chronic autoimmune disorder of the neuromuscular junction of striated muscles.^1,3,5 Common problems are weakness of the limbs, breathing problems and ocular problems. Of patients who have MG, 70% to 75% initially present with ocular MG.^1,3,5 However, only 13% of these patients develop no additional symptoms. The rest develop generalized MG (weakness throughout the body).^3,5

Several components of the neuromuscular junction are altered in patients who have MG. In normal individuals, acetylcholine molecules are released into a neuromuscular junction where they bind to acetylcholine receptors to signal the muscle to carry out an action. If there is a change to either the number of receptors or the number of acetylcholine molecules, the synapse begins to break down, leading to the effect of muscle weakness.¹ In patients with MG, the number of available acetylcholine receptors may only be 11% to 30% of that found in normal individuals.⁵

Individuals with MG also possess ACh-R antibodies in the synaptic junction. As many as 50% to 75% of ocular MG patients test positive for ACh-R antibodies, while 80% to 98% of generalized MG patients test positive.^1,3,5 These antibodies serve three negative functions to the receptor: they act as a receptor blockade; they cause complement-mediated membrane damage; and they accelerate the degradation of the receptors.1

Give special attention to the thorax of any patient who has MG. There is a high prevalence of thymic hyperplasia and thymoma associated with this malady.^1,5 Younger patients (under age 20) seem to have an increased risk for thymic hyperplasia, though 65% to 70% of patients with MG will test positive. Thymomas are present in 5% to 20% of MG patients and are more common in those over age 60.¹ Neuroimaging techniques are the method of choice for detecting these complications.

The prevalence of MG is two to 10 cases per 100,000, and the age of onset is usually 26 years for women and 31 years for men.⁵ Women usually present with generalized MG at a rate of 3 to 4:1 compared with men.⁵ However, men usually outnumber women in ocular MG, especially after the age of 41.¹

The most common ocular symptoms are related to the eyelid and are noted as increasing in severity toward the end of the day.^1-5 Eyelid ptosis is often variable and can be unilateral or bilateral. Eyelid retraction is often noticed in the contralateral eye and will resume a normal position as the ptotic eye is covered or assisted to its normal level. This is the result of Herring"s law of equal innervation.³

Several simple tests also help to indicate the possibility of MG. Optometrist Larry Gray, former associate professor at Pennsylvania College of Optometry, described the tests for potential MG patients as "Tease "em, freeze "em, squeeze "em and sleep "em."

Tease test. Having the patient look up for an extended period of time often "teases out" a ptotic MG eyelid. 

Freeze test. An ice pack can sometimes be used to enhance function, as acetylcholinesterase, the enzyme that breaks down the acetylcholine in the neurosynaptic cleft, is deactivated by cold temperature.

Squeeze test. MG patients tend to have weak orbicularis muscles. You can test this by asking the patient to close his eyes as tight as he can. Then, forcibly attempt to open the patient"s eyelids. In normal patients, this is difficult.

Sleep test. Interestingly, the opposite of the tease test also works: When a patient sleeps or rests, the amount of neurotransmitter in the cleft increases and, upon waking, helps the patient demonstrate increased function.

The Cogan"s lid twitch test is also useful. To do this, have the patient look down for 10 to 20 seconds and then look straight to primary gaze. You"ll observe the ptotic lid overshoot the normal posture and then return to the normal resting position. This happens due to the relaxation of the levator muscle, which then fatigues quickly.¹
 
Diplopia is also a major symptom of MG. This may be seen in up to 90% of MG patients.¹ This symptom is due to a paresis of one of the extraocular muscles. The medial rectus is the most common muscle affected, though the inferior rectus, superior oblique and lateral rectus may be affected as well.³ Saccadic problems are often associated with diplopia. Undershoots and overshoots of the saccades also are a common phenomenon.³

While several studies have shown that prolonged testing may produce delayed pupillary responses and accommodative changes, MG does not involve the pupil. If the pupils are affected, a different diagnosis is necessary.^1,3

Differential diagnoses include any neurological problems associated with nerve palsies. Cranial nerve III, IV, and VI palsies secondary to any tumor, aneurysm and trauma must be ruled out. Space-occupying lesions of the cavernous sinus and orbit must also be investigated. Additionally, mitochondrial disorders are plausible. Lambert-Eaton myasthenic syndrome, Kearns-Sayre syndrome, chronic progressive ophthalmoplegia, mitochondrial encephalopathy-lactic acidosis, stroke-like episodes (MELAS), and myclonic epilepsy and ragged red fibers (MERFF) are a few mitochondrial disorders that are possible.⁴ Thyroid disorders, myotonic dystrophies, muscular dystrophies, and oculopharyngeal dystrophies should also be ruled out. Finally, exposure to toxins and drugs, such as snake and spider venom, botulism, and recreational drug use also deserve consideration.^1,4,5

The diagnosis of MG can be made through pharmaceutical tests, objective tests, electrophysiologic studies, biopsies and laboratory tests.

The most common test is the Tensilon (edrophonium chloride, Valeant Pharmaceuticals) test. Tensilon is injected into the body and acts as an anticholinesterase drug that increases the amount of available acetylcholine to the synapse.² This has long been the gold standard diagnostic test for MG. This test does have the potential for serious complications. Muscarinic side effects including salivation, tearing, increased respiratory secretions (mucus), nausea, vomiting and muscle cramps are possible. The test must be accompanied by cardiovascular monitoring to ensure the patient does not become bradycardic.⁵ If the patient does have MG, the patient will show greater alertness, a resolution of the ptosis, and a relief of symptoms within a few minutes.

Laboratory studies can be highly diagnostic of MG. Positive ACh-R antibody assay tests can be up to 98% diagnostic.⁴ The workup should include an assay including binding, blocking and modulating antibodies. The binding antibodies are the most diagnostic, while blocking antibodies are the least diagnostic. When all the tests are administered together, they are almost 100% diagnostic.^1,5 Other lab tests include anti-muscle specific receptor tyrosine kinase antibodies and antistriational antibodies.¹

Single fiber electromyography is used to measure the action potential evoked on a muscle fiber. The time interval between the firing of two muscle fibers from a single motor unit is called jitter. This is low in normal fibers because they should be firing at roughly the same time. In MG patients, this jitter occurs at a higher rate due to the variability of the stimulus reaching each muscle fiber.²

The treatment of MG is varied. Pharmaceutical agents, local treatment and thymectomy are the main methods of treatment.^1-5 The treatment of choice is different for ocular MG versus generalized MG. Ocular MG responds well to low-dose oral corticosteroids.⁵ Local treatment options such as lid crutches and lid taping are useful for ptosis. Artificial tears are useful for dry eye symptoms. Ground-in prism and Fresnel prism are useful in the treatment of some cases that produce diplopia. Strabismus surgery is possible if a stable angle of deviation is proven. Botulism toxin has proven beneficial for patients who have had stable conditions and do not have a fluctuation in their disorder.³

Generalized MG patients respond well to acetylcholinesterase inhibitors.⁵ This group of drugs is the first-line treatment for MG. They enhance the activity of acetylcholine by inhibiting acetylcholinesterase in the synaptic junction. The most used drug in this class is Mestinon (pyridostigmine bromide, Valeant Pharmaceuticals), 60mg t.i.d. to start. The side effects are the same muscarinic effects listed previously, but to a lesser degree. Patients with cardiac problems should be monitored closely. Imuran is the second most used drug in this class. Its method of action is not well understood, but it probably inhibits DNA and RNA synthesis.¹ The preparation seems to work well in conjunction with steroid treatment. Tests show the effectiveness at 70% to 90%.¹ Adverse effects to this medicine are hepatotoxicity and hematologic abnormalities, which should be monitored closely.

Corticosteroids have been used for generalized MG, though their greatest effect are on ptosis and diplopia. Thymectomy and plasmaphoresis are also beneficial treatments, yet their success is not as great as Mestinon and Imuran.¹

Thanks to John D. Bissell, O.D., at Pennsylvania College of Optometry, for contributing this case. 

1. Elrod RD, Weinberg DA. Ocular myasthenia gravis. Ophthalmol Clin North Am 2004 Sep;17(3):275-309.
2. Neugebauer A, Kirsch A, Fricke J, Rssman W. New onset of crossed eyes in an adult. Surv Ophthalmol 2001 Jan-Feb;45(4):335-44.
3. Bentley CR, Dawson E, Lee JP. Active management in patients with ocular manifestations of myasthenia gravis. Eye 2001 Feb;15(Pt 1):18-22.
4. Ebner R. Peripheral ocular motor disorders. Curr Opin Ophthalmol 1994 Dec;5(6):23-8.
5. March GA Jr, Johnson LN. Ocular myasthenia gravis. J Natl Med Assoc 1993 Sep;85(9):681-4.