SIGNS AND SYMPTOMS
It is widely understood that Graves' disease is inherited. However, why one person develops the disease at one age and another years later, even when they are related, is not known. The disease probably needs other factors to activate it. Recently, some studies have suggested smoking as a risk factor. Studies of those who do smoke reveal abnormal lower-activity T-suppressor lymphocytes, and therefore smoking makes a patient immunosuppressed.
Signs of a thyroid disorder can be seen in the eye at different stages of the disease. Symptoms may include some of the signs of hyperthyroidism (e.g., in Graves' disease), in which case the diagnosis is obvious. More frequently, the patient consults an ophthalmologist, complaining of lid retraction and mild exophthalmos before the onset of the systemic signs of hyperthyroidism or before results of laboratory tests are positive. The most frustrating form of eye involvement is that which sometimes occurs after ablation of the hyperactive thyroid gland, when all the systemic signs and laboratory tests have returned to normal.
Although exophthalmos is the best-known symptom of thyroid disease, it may not always be obvious. Even though the condition is present, some patients neither look nor measure particularly exophthalmic owing to the position of their eyes. In such cases, comparison of the patient's present appearance with that in old photographs may be of help. Conversely, some patients who appear exophthalmic may have appeared that way all their lives; prominent or protruding eyes may be a family characteristic. More rarely, patients may complain of unilateral exophthalmos, the condition most obvious to them, when in reality they may have enophthalmos on the other side owing to an old orbital cellulitis or they may have suffered trauma with orbital hemorrhage and perhaps a fracture of the orbital floor. All of these conditions can cause absorption of orbital fat and enophthalmos.
Exophthalmic measurements are not difficult, but practice with the instruments involved is required to get reliable results. I prefer the Krahn instrument because of the lining-up mechanism that is built into the system. The part of this instrument that brackets the eye includes mirrors with a millimeter scale. This device permits measurement of the anterior surface of the cornea. In addition, the mirror has two red lines that must be lined up before the observer takes this reading, which ensures that the testing circumstances will be the same for every examination. A measurement of 19 mm represents the upper limit of normal for the anterior surface of the cornea: 95% of the population have measurements below this value. However, as previously indicated, a patient who normally measures 16 mm and now measures 19 mm is becoming exophthalmic.
Ophthalmoplegia is a prominent feature of thyroid disease, whereas diplopia is not. If diplopia is present, the patient will probably mention it; however, the patient will usually not compensate for it by putting a patch over one eye or closing an eye as does a patient who has experienced the sudden onset of a sixth cranial nerve paralysis. Limitation of ocular motion is usually in the upward di-rection and is caused by restriction of the globe by the inferior muscles rather than by weakness of the elevator muscles. This condition can be confirmed by finding restriction of the globe in the forced duction test, which is a particularly significant test when the extraocular muscles are affected before exophthalmos or lid retraction indicates the nature of the disease. Since the inferior muscles are primarily affected, an attempt at up-gaze causes compression of the globe owing to restriction caused by these muscles. This compression in turn raises the intraocular pressure and creates a false impression of glaucoma. Measurement of the intraocular pressure with the eye in down-gaze and in up-gaze should demonstrate a difference in pressure (Fig. 6.29, A and B).
Figure 6.29. Enlarged muscles due to thyroid disease. A. Axial view makes muscles appears as a mass. B. Coronal view shows all muscles enlarged.
Lid retraction, as has been pointed out by McLean and Norton, may be unilateral and precede all other signs of hyperthyroidism by years. Moreover, lid retraction may occur even in the absence of exophthalmos. The lid is considered retracted when the sclera shows between the upper lid margin and the superior limbus. The fact that the sclera is showing above the limbus indicates that that eye is more likely to be the affected one rather than that the other eye has a ptosis. An exception to this rule occurs when one eye is hypotropic to the other eye, which is fixing. This condition may leave sclera showing above in the hypotropic eye.
Periorbital edema may be caused by several conditions in addition to thyroid disease. As the lid tissues become more relaxed with age, some patients, particularly women, may complain of swelling that is worse on arising in the morning. Periorbital edema also occurs in association with orbital infection, trichinosis, renal disease, and myxedema. In early thyroid disorders, the skin edema is usually pale and soft, rather than red and brawny, as it usually is in severe infection. In Graves' disease, which is marked by the rapid onset and progression of exophthalmos, the edema is firm and the eyes red and swollen. The more severe the exophthalmos and the more acute its onset, the greater the chemosis, redness, and congestion of the globe.
Prominent conjunctival vessels over the lateral rectus muscles are often seen before significant chemosis and congestion of the rest of the ocular vessels occur.
Foreign-body sensation is a common complaint, particularly in patients with a combination of up-gaze defect, exophthalmos, and lid retraction—all of which lead to corneal exposure, which is most easily seen in the inferior cornea. Examination following application of fluorescein is best done with the slit lamp, because the punctate staining will be superficial and mild in contrast to the obvious staining usually seen in the case of an outright abrasion. Patients frequently complain of foreign-body sensation early in the course of thyroid disease, even though no staining is evident. Photophobia is also a frequent complaint in thyroid disease, even with minimal corneal involvement.
Severe corneal exposure can lead to corneal ulcers, to infection, and, eventually, to scarring or perforation. Extreme exophthalmos requires constant observation and appropriate treatment to prevent such complications. On occasion, the treatment may even include surgery to decompress the orbit.
Optic nerve involvement as evidenced by decreased visual acuity is seen in the most severe cases of exophthalmos; it is most likely to develop when the exophthalmos is rapidly progressive and accompanied by numerous inflammatory signs. Optic neuropathy is certainly not caused by mechanical stretching of the optic nerve. The intraorbital portion of the nerve measures about 30 mm, whereas the distance from the posterior aspect of the globe to the beginning of the optic canal is 18 mm. Thus, there is 12 mm of play in this S-shaped nerve before mechanical stretch occurs—far in excess of the 7 to 10 mm of exophthalmos seen in the most severe cases. Decreased acuity may be caused by compression of the nerve and its vascular supply by enlarged muscles. A de-crease in acuity can also be ascribed to changes in the corneal epithelium owing to a lack of adequate precorneal tear film or to punctate epithelial changes.
Brawny scleritis, which causes a decrease in acuity owing to macular involvement, can also occur as a consequence of hyperthyroidism. Dilation of the pupil and examination with the fundus contact lens may reveal horizontal retinal macular striae and a thickened elevated choroid in the posterior pole.
Myasthenla gravis develops in about 5% of patients with hyperthyroidism, usually late in the course of the disease. Myasthenia gravis should be suspected in a patient whose hyperthyroidism has been arrested but who suddenly begins to complain of diplopia and shows increased muscle imbalance. A resurgence of the signs and symptoms of hyperthyroidism is usually presumed, even though the patient is euthyroid by laboratory standards. Steroid therapy usually results in minimal improvement.
A Tensilon test is usually diagnostic of myasthenia gravis. Also helpful in diagnosing cases of secondary myasthenia after hyperthyroidism is a lessening of the previous lid retraction or the development of an out-right ptosis. A Tensilon test may not only reduce the ptosis but also return the lid to its previously retracted position during the period when the Tensilon is effective.
In rare instances, resurgence of ocular symptoms in treated cases of hyperthyroidism is iatrogenic in origin. Many patients who have undergone thyroid ablation with 131I are given thyroid replacement therapy. Since over a long period some normal thyroid function may return, the initial replacement dosage may require adjustment to avoid an iatrogenic recurrence of hyperthyroidism.
THYROID FUNCTION TESTS (FIG. 6.30)
The three most common causes of hyperthyroidism are (a) Graves' disease—stimulation of the thyroid by circulating thyroid stimulating immunoglobulins, (b) toxic nodular goiter—autonomous production of hormone by one or more nodules within the thyroid, and (c) thyroiditis—leakage of stored thyroid hormone from an inflamed gland. All three may be associated with eye signs including lid retraction, stare, and lid lag. Exophthalmos and diplopia, on the other hand, are specifically associated with Graves' disease and are caused by an autoimmune process involving the extraocular muscles and orbital connective tissues.
Whenever the possibility of Graves' ophthalmopathy is raised by complaints related to proptosis or diplopia, one must evaluate the patient for hyperthyroidism. Since the thyroid disease and the ophthalmopathy are separate components of the underlying auto-immune process, the hyperthyroidism may precede, occur simultaneously with, or follow the ocular pathology. Therefore, the patient with proptosis or diplopia may have (a) diagnostic elevations of routine thyroid function tests, (b) "borderline" levels of thyroid hormone with or without hyperthyroid symptoms, or (c) normal thyroid tests. Each of these conditions will require a different diagnostic and therapeutic approach (Fig. 6.30).
OVERT HYPERTHYROIDISM. A simple and inexpensive set of routine thyroid function tests is usually all that is necessary to confirm the diagnosis of hyperthyroidism in a symptomatic patient. This includes measurement of the serum thyroxin (T4) level, Measurement of the serum-binding capacity for (e.g., the T3 resin-uptake test, T3RU), and calculation of a free thyroxin index
(FTI). An elevated F I I in a patient with hyperthyroid symptoms plus ophthalmopathy is sufficient to make a diagnosis of Graves' disease.
The rationale for measuring both T4 and T3RU is as follows: Most of the T4 in serum is bound to large carrier proteins and therefore cannot enter the cells. The bound is in equilibrium with a tiny amount of free (and therefore active) hormone. Unfortunately, it is difficult to measure the free '1, level directly; in addition, free T4 is affected by variations in the concentration of the binding proteins. Assessment of the serum binding capacity for T4 allows one to adjust for alterations in binding proteins, Multiplying the T4 level by the T3RU yields the FTI, which roughly parallels the actual free T4 in serum and, therefore, reflects the thyroid status of the patient.
BORDERLINE HYPERTHYROIDISM. When routine thyroid function tests reveal a T4 level and an FTI that are at the upper limit of normal or only slightly elevated, additional tests are required to evaluate the thyroid status. Two approaches are possible.
First, one can measure the serum level of thyroid-stimulating hormone (TSH). Ultra-sensitive TSH assays have become the standard in most clinical laboratories. Unlike older methods, these can reliably distinguish low normal levels from frankly low levels. Overproduction of T4 and triiodothyronine (T3) by the thyroid, as in Graves' disease, suppresses TSH secretion by the pituitary. A level of TSH below the normal range strongly suggests hyperthyroidism.
Second, one can measure the level of T3 in serum by means of a specific radioim-munoassay (RIA). T3 is the most potent thyroid hormone, but it circulates at much lower concentrations than T4. The level of T3 is routinely elevated in hyperthyroid patients; in Graves' hyperthyroidism, the T3 is usually elevated out of proportion to the T4 level. Therefore, in a patient with ophthalmopathy and a borderline high T4 and FTI, the detection of an unequivocal elevation of T3 by RIA would strongly support a diagnosis of Graves' disease.
EUTHYROID GRAVES' DISEASE. Graves' ophthalmopathy may precede all signs and symptoms of hyperthyroidism, occasionally by many years. Therefore, one may be faced with a patient with diplopia and/or exophthalmos but with a normal routine FTI and T3 by RIA. In these cases, ancillary tests may be used, or one may make the diagnosis by excluding other possibilities.
Graves' hyperthyroidism is caused by the production of thyroid-stimulating immunoglobulin (TSI) as part of an autoimmune process. Assays for TSI are now commercially available and, in theory, could confirm a diagnosis of Graves' disease even in the absence of biochemical hyperthyroidism, However, TSI may be detectable in only half of all patients with euthyroid Graves' ophthalmopathy. In addition, this test is expensive and difficult to perform. A more useful approach is to obtain a CT scan of the orbits; the demonstration of bilateral extraocular muscle thickening would favor a diagnosis of Graves' ophthalmopathy, whereas unilateral thickening or mass effect would suggest an alternative diagnosis.
In all forms of thyroid disease, restoration of a euthyroid state is the ultimate goal. In regard to ocular involvement, treatment falls into both the medical and surgical categories.
MEDICAL TREATMENT. The aim of medical treatment is to minimize the patient discomfort that accompanies thyroid disease with ocular involvement. Severe periorbital swelling in the morning can be lessened somewhat if the patient sleeps with the head elevated. If corneal exposure owing to severe exophthalmos or paralysis of up-gaze is a problem, taping the lid shut or filling the palpebral fissure with some bland ointment at night can be of value. Lid taping may not be totally successful, however, because the partially open palpebral fissure may allow the tape to scrape the cornea. Should this problem occur, creating a moisture chamber by taping the edges of a piece of plastic wrap (e.g., Saran) to the skin at the orbital rim may afford some relief. The frequent use of some form of artificial tears can help to alleviate the foreign-body sensation as well as the symptoms of mild superficial punctate keratitis. Occasionally, the physician must resort to rather thick artificial tears in the form of a 1% solution of methylcellulose. I usually reserve this type of medication for the most severe cases, since it is rather sticky and esthetically repugnant to the patient.
Lid retraction is probably the sign most obvious to patients and the one that bothers them the most cosmetically. A method of treatment devised by Gay involves the use of topical guanethidine to create a chemical Horner syndrome with slight ptosis. Although this treatment aroused considerable interest in England, it is not standard accepted treatment in the United States. I have tried Gay's method on several patients but found it of little value in facilitating normal lid function, particularly if the lid retraction Was longstanding, with fibrotic changes in the levator tendon. The use of systemic steroids should be reserved for cases of diplopia in which the onset is rapid and progressive and for exophthalmos accompanied by significant inflammatory signs. The differentiation for the lid retraction in thyroid disease from Collier's sign in midbrain disease is usually not a problem when the entire clinical picture is considered. However, the lid retraction of thyroid disease stays elevated in down-gaze.
SURGICAL TREATMENT. In my opinion, surgical treatment should be restricted to cases in which the ocular involvement is severe.
In some patients, the eyes appear paralyzed with respect to up-gaze, when in fact, changes in the inferior muscles are restricting the upward movement of the globe. Surgical correction of this defect primarily involves weakening the depressor muscles, which are really the main offenders.
Surgical procedure to improve the appearance of patients with exophthalmos and lid retraction should be considered only if these two signs are stable. If they are, a small lateral tarsorrhaphy may be performed to reduce the prominent appearance of the eye. (A too-aggressive lateral tarsorrhaphy may give the eyes a squashed appearance.) Most patients are grateful for an improvement in their appearance, even though the lids have not been brought down to a fully normal position.
Cases of severe progressive exophthalmos with loss of vision, severe recurrent corneal ulcers, and exposure keratitis require careful treatment to prevent permanent loss of vision. In the past, a lateral Kronlein resection to decompress the orbit was the standard procedure. More recently, there has been some interest in combining the lateral Kronlein procedure with the creation of a surgical blowout fracture, thus, it is hoped, improving both the exophthalmos and the vision. On the other hand, many cases involving acutely progressive signs can be managed with systemic steroids, constant care of the corneal exposure problem, and a little patience.
As Drachman et al. have so well pointed out, the pathologic differences between neuropathic and myopathic processes are not as clear-cut as was once believed. Myasthenia gravis is a chronic disease marked by weakness of the voluntary muscles, particularly the muscles involved in facial expression, mastication, swallowing, movement of the proximal limb girdle, and lid and ocular motility. Myasthenia gravis affecting ocular and lid motility can occur first as an isolated ptosis owing to a weak levator muscle. Biopsy of the affected muscle is rarely helpful in diagnosing myasthenia gravis, since it seldom reveals the specific changes that occur as a result of this disease. Moreover, because the biopsy is performed on the levator tendon rather than the muscle itself, the test is often inconclusive.
SIGNS AND SYMPTOMS
Although myasthenia gravis affects many muscle groups, the ocular signs, particularly ptosis, are frequently the earliest indication of the presence of this disease. In fact, ocular symptoms are the only sign in at least 15% of patients. Ptosis without ophthalmoplegia may be present for some time before weakness of the extraocular muscles is detectable. This gives a false sense of the disease as if limited to only a few muscles. However, a biopsy of other asymptomatic uninvolved muscles will reveal a reduced number of receptors. This suggests that myasthenia gravis is a more diffuse immunologic disease that is expressed to different degrees in different muscle groups.
Some patients may mask or partially overcome a minimal ptosis (as in Horner syndrome) by contracting the frontalis muscle (furrowing the brow). A patient suffering from myasthenia gravis is usually unable to furrow the brow, since the frontalis muscle is just as weak as the levator muscle. A rare exception occurs in cases of asymmetric myasthenia gravis. When patients with this condition attempt to contract the frontalis muscle, no correction for the ptosis occurs on the abnormal side. On the unaffected side, the contraction of the frontalis muscle causes the lid to retract. This action may lead to an erroneous diagnosis of thyroid myopathy.
The application of Hering's law has been one of the more popular explanations for lid retraction, but it does not explain all cases. For example, cases that demonstrate lid retraction briefly after prolonged up-gaze are explained by posttetanic facilitation. Hering's law also does not apply to those with lid retraction after demonstrating Cogan's lid twitch sign. In those who show a more permanent lid retraction, consider concomitant thyroid disease, since it appears in 10% of myasthenics. A patient who prefers fixing with the eye that has the ptotic lid may retract the other lid in an effort to lift the ptotic lid to adequately clear the pupil. This is an application of Hering's law. A way to test this hypothesis is to manually lift the ptotic lid, so no innervation is necessary, and watch the retracted lid on the other side drop down.
The Tensilon test is helpful in the diagnosis of asymmetric myasthenia gravis, because after the injection of this drug, the lid on the ptotic side retracts immediately. With the Tensilon test, lid retraction may occasionally be observed on the normal side also, even though the patient is not contracting the frontalis muscle. This retraction indicates some bilateral, although asymmetric, levator weakness.
Up-gaze is the direction in which the patient initially develops symptoms of diplopia. Weakness of convergence, particularly during extensive reading, also causes symptoms to develop. These symptoms are frequently misinterpreted as signs that the patient needs stronger eyeglasses. Thus, many different strengths of eyeglasses, even some with prisms, are prescribed before myasthenia gravis is discovered as the true cause of the diplopia. In an attempt to strengthen weakening convergence, the entire near reflex may be invoked, causing an increase in accommodation. This will cause a pseudo myopia.
Since weakness of up-gaze may not be manifest on primary gaze, the patient should be instructed to rotate the eye well up and to sustain it in that position. Sustained up-gaze tends to make the ptosis clearly evident and may also reveal a diplopia that may not be obvious on simple inspection. Some physicians prefer to have patients move their eyes up and down rapidly and to open and close their lids quickly to fatigue the muscles. I find the sustained up-gaze maneuver to be equally successful. Blinking during the test may be enough to overcome the fatigue phenomenon. Patients may not be aware that they are suffering from weak ocular motility, since the ptosis that has led them to seek treatment may cover the pupil in extremes of up-gaze and therefore obscure the diplopia.
The worsening of the diplopia and ptosis seen on exercising the ocular muscles in myasthenia gravis does not occur in patients with partial third cranial nerve paralysis, regardless of how long they sustain a gaze in the field of action of the weak muscles.
The key sign differentiating myasthenia gravis from third cranial nerve paralysis is the absence of pupillary signs in myasthenia gravis. If pupillary signs are present, either two disease conditions are present or the diagnosis of myasthenia gravis is incorrect. If spasm of the near reflex causes paralysis of abduction, look for pupillary signs consistent with the diagnosis of third cranial nerve paralysis. The ophthalmic signs of myasthenia gravis are all external, sparing pupil and accommodation functions. There have been reports by Herishanu and by Dutton that describe pupillary fatigue and sluggish light response. These patients will also improve with anticholinesterase medications. If the extraocular muscles appear normal, electromyographic studies will still show abnormal saccadic velocities. The stapedius is rarely involved; its weakness causes hyperacusis.
In contrast to the good orbicularis muscle function but weak elevator muscle function typical of third cranial nerve paralysis, a patient with weak elevator muscles owing to Myasthenia gravis may also have weak orbicularis muscles. Ignoring this fact, particularly in view of the possibility that the patient may have some difficulty with up-gaze, may lead to a severe corneal exposure problem if a surgical procedure for ptosis is attempted. (The orbicularis muscle can be tested by forcing the lids open after the patient has been instructed to squeeze them shut.)
The myasthenic crisis is one of the most feared complications of myasthenia gravis. Overtreatment of myasthenia gravis with cholinergic drugs results in clinical findings similar to those in the myasthenic crisis. The most serious complication of both conditions is respiratóry paralysis, with tracheotomy sometimes required.
Myasthenia gravis takes three forms in infancy and childhood. All of them respond to anticholinesterase medication. All three also show similar and appropriate EMG responses of a decrement in motor units in response to repetitive nerve stimulation. Other features of the disease serve to differentiate the causes of all three types.
The neonatal form is seen in infants born or myasthenic mothers and is probably secondary to the transfer of antibodies to the acetylcholine receptors. Symptoms occur during the first day of life and in over 78% of cases, which differs from the original description. The most common sign is a poor sucking reflex despite an alert infant eager to eat. Eye signs, such as ptosis and motility disturbances, which are so common in adult-onset myasthenia, occur in only about 15% of neonatal myasthenia.
The second type is the congenital form, which probably results from a genetically transmitted disease rather than a circulating antibody. A prominent sign is extraocular muscle abnormalities with a minor amount of generalized weakness, which is the reverse of the neonatal form.
The third form is called juvenile; its onset is usually after 1 year of age, and most cases occur after the age of 10. As in the adult form, ptosis and diplopia are the prominent initial features.
An autoimmune response is suggested as the mechanism in the juvenile and adult forms, and an antiacetylcholine receptor antibody can be identified in a high percentage of cases. No antibody to the acetylcholine receptor is found in the congenital form, which is genetically transferred.
The normal vesicle contains 10,000 acetylcholine molecules. In the Eaton-Lambert syndrome, the production and availability of acetylcholine as well as the number of molecules per vesicle are normal. The problem is in releasing these molecules to produce a muscle response. In myasthenia gravis, there is a reduction in the number of acetylcholine receptors because of antibody interference.
EATON-LAMBERT SYNDROME. Eaton-Lambert syndrome is a myasthenia gravis-like condition that occurs as a consequence of carcinoma elsewhere in the body. Isolated eye signs, however, have not been reported; therefore, Eaton-Lambert syndrome need not be considered if the presenting symptom is isolated ophthalmoplegia or isolated ptosis. The significant features are absent or decreased deep tendon reflexes, proximal muscle weakness, and increasing (rather than decreasing) muscle strength after voluntary exercise. Electromyography serves to definitely distinguish the Eaton-Lambert syndrome from true myasthenia gravis. In the Eaton-Lambert syndrome, a recruitment of motor units occurs with continual stimulation, rather than the dropout that occurs in myasthenia gravis.
The myasthenic syndrome of Eaton-Lambert affects many different muscle groups but, remarkably, spares the ocular muscles, unlike true myasthenia. There have been isolated reports of diplopia, but these are extremely rare. A remote effect of carcinoma has been the development of polyneuropathies that develop slowly over months and are predominantly distal, symmetric, and sensorimotor in type. These patients develop severe weakness and atrophy, ataxia, and sensory loss in the limbs. A mixed sensorimotor form of myasthenic syndrome is five times more common than a pure sensory form; usually, there is no remission and steady progression. This is seen in 2 to 5% of all patients with malignancy. Carcinoma of the lung accounts for 50% of the sensorimotor form and 75% of the pure sensory form. There is also a type that takes the form of polymyositis; this syndrome, secondary to carcinoma, is seen in about 15% of all patients with polymyositis and typically appears after the age of 50. The proportion of these cases owing to bronchogenic carcinoma is higher than in other forms of carcinoma. In cases of Eaton-Lambert syndrome not resulting from oat cell carcinoma, either the DR3 or HLA B8 antigen is found. Either of these antigens is also found in the Eaton-Lambert cases secondary to carcinoma. They appear to be immunologically connected and may have some crossover in therapy.
MYASTHENIA-LIKE SYNDROMES SECONDARY TO MEDICATION. The mechanism of drug-induced myasthenic syndromes varies from drug group to drug group. With d-penicillamine, an antiacetylcholine receptor antibody develops. With antibiotics such as neomycin, streptomycin, kanamycin, polymyxin B sulfate, dihydrostreptomycin, viomycin sulfate, and colistin sulfate, neuromuscular blocking effects occur for other reasons. These effects may not be related only to the use of these medications; they have been more frequently reported after general anesthesia. They also may not necessarily be related to the stress of surgery but rather to other factors influencing neuromuscular transmission, such as neuromuscular blocking agents (e.g., succinylcholine), or to a decrease in serum and tissue calcium.
As ophthalmologists, we rarely see serious systemic problems develop from the medications we prescribe. However, timolol can be absorbed enough to change pulse rates and cause psychiatric symptoms. This drug, which is a beta-adrenergic blocker, can also precipitate congestive heart failure, hypotension, and asthma. There are also cases of timolol making myasthenia gravis worse; the exact mechanism of this effect is not known, although beta-adrenergic blockers are known to have a depressor effect on the neuromuscular junction.
TESTS FOR MYASTHENIA GRAVIS
When evaluating patients suspected of having myasthenia gravis, the major procedure is the Tensilon test, which is specific for myasthenia gravis. Tensilon is an intravenous medication that competes with acetylcholine for the enzyme acetylcholinesterase at the myoneural junction. This allows increased effectiveness of acetylcholine at that junction and improvement of muscular function. There have been infrequent reports of a positive Tensilon test with compressive lesions. These patients also have improved symptomatology with anticholinesterase medications. However, results of the Tensilon test are not always positive, even in obvious cases. It is also true that the Tensilon test may not be positive at the onset of the disease but may become positive as the condition progresses. For this reason, the test should be repeated at intervals if results are negative early in the course of the disease.
The Tensilon test should be done in three stages. Initially the patient should be free of all cholinesterase inhibitors. The patient should then be given an injection of atropine to prevent undue vagal responses. I do not do this routinely, and a recent survey of neuro-ophthalmologists revealed that most do not use atropine but have it on hand. The amount given is usually inadequate and is given too close to the actual test to be of any therapeutic value. The first part of the test is to give a 0.1-mL dose of Tensilon intravenously and observe the reaction over 2 to 3 minutes. Patients may experience salivation, mild sweating, perioral vesiculation, and nausea, but rarely bradycardia and hypotension. If no change is noted in the lid or motility defects, then more Tensilon is given. The best response to look for is in the lid position rather than motility. Fasciculations of the lids is common and does not represent a positive response. Instead of giving 0.9 mL in one bolus, it is better to give it in 0.2-mL increments at 30-second intervals.
Occasionally with the higher 0.9-ml dose, the defects appear to get worse, not stay the rime or get better. Sometimes an improvement in a motility abnormality may not reflect improvement in a myasthenic muscle but rather weakening of its antagonists. The reason for this is that the ocular 'muscles have two types of motor endplates, called en grappe and en plaque. In myasthenia gravis, one type of fibers may be affected more than the other. In this situation, one set reacts positively to Tensilon and the other is made worse by Tensilon.
Since a positive response to Tensilon usually occurs in about 30 seconds and is over within 1 to 3 minutes, the precise ocular function to be tested should be determined before the testing procedure is begun. A total ocular motility examination should not be attempted during the short period in which Tensilon is effective, since the key signs of a positive reaction may be missed. If ptosis is the most obvious sign of myasthenia gravis, improvement in this condition is the sign to look for during the first 2 or 3 minutes of the testing procedure. A positive response to Tensilon is usually diagnostic of myasthenia gravis, although false-positive tests have been rarely reported in pontine glioma, orbital apex syndrome, polymyositis, ocular inyositis, and botulism.
The Tensilon test is not positive nearly as often as we suspect the diagnosis of myasthenia gravis. For confirmation, Miller, Morris, and Maguire use intramuscular neostigmine with detailed orthoptic measurements before and during the test. This procedure in association with electromyographic studies is said to yield a higher number of positive results for myasthenia than Tensilon alone.
Before Tensilon became available, small doses of curare were used to test for myasthenia gravis. Patients with myasthenia gravis are supersensitive to curare; however, this difficult and dangerous drug was all but abandoned with the advent of Tensilon.
Another once-popular test that has fallen by the wayside involved the use of quinine a drug that made the myasthenic process worse. Although quinine is no longer used in the testing procedure, this drug may still subtly alter the results of other tests, because many patients drink quinine water or take quinine compounds, which aggravate the myasthenia gravis symptoms. Therefore, unless history taking includes a specific question about the use of quinine in any form, the physician may remain unaware that such a practice is making the myasthenia gravis worse or at least making treatment more difficult. The theory behind quinine ingestion is that the drug lessens the sensitivity of the motor endplate and thus holds the firing of the muscle neurofibrils to a minimum. It is commonly given for night leg cramps.
The Tensilon test may also be done in conjunction with tonography. In fact, this modification is recommended for patients who respond negatively to the Tensilon test. In this procedure, the patient is given an intravenous drip of normal saline solution. The tonometer is placed on the eye, and the normal slope of the tonography curve is followed. A small amount of saline solution is then injected into the tubing, following which, the slope of the curve is again observed. The saline injection should cause no change. Tensilon is now injected into the same tubing. If the muscles are normal, no reaction occurs. A positive reaction, which consists of a sudden increase in the pressure in the eye, owing to cocontraction of the extraocular muscles, is diagnostic of myasthenia gravis.
Another variation of the Tensilon test involves cooling the eye muscles to 29°C for several minutes to decrease the activity of acetylcholinesterase. This is done by putting ice in a rubber glove and placing it over the closed eye for 2 minutes. Then the Tensilon test is repeated. This procedure increases the chances for a positive response. In recent years, an assay for antiacetylcholinesterase receptor antibodies has become available. This assay is positive in 88% of generalized myasthenia gravis cases but drops to a disappointing 60% in purely ocular cases.
Investigation of the thymus gland is also essential because of its relationship to the disease. The removal of the thymus gland except in cases of thymoma is still controversial. A CT scan of the thymus gland sometimes can be too good and give positive results that are not confirmed with a thymic gland biopsy. Therefore, a linear tomogram can be useful.
Electromyographic studies can be quite useful. The problem in testing ocular muscles or the levator is a difficult technique. Failure to get a positive test may be the result of placing the recording needle in the tendon rather than the muscle. There are several types of recording techniques. There is evaluation of neuromuscular jitter by single fiber recording and a repetitive supramaximal motor nerve stimulation technique.
The affected fibers are distinctive with a Gomori trichrome stain and are called ragged red fibers. This results from a deposit between myofibrils and adjacent to the plasma membrane of mitochondria.
In the treatment of myasthenia gravis, anticholinesterase medications, such as Prostigmin, are the drugs of choice. The main problem with this group of drugs is the possibility of an overdose and consequent cholinergic crisis. Moreover, the use of these drugs is particularly difficult when the myasthenia gravis is confined to the ocular muscles. As a result, a therapeutic dose for the ocular muscles may be too toxic for normal skeletal muscles.
Steroids are now being used to treat advanced cases of myasthenia gravis that are not responding well to anticholinesterase medication. Such patients are started on steroids in daily doses of up to 100 mg per day and maintained at that level until symptoms stabilize. The dosage is then reduced to a minimal amount on an alternate-day program until the medication can be discontinued, perhaps after many months.
Thymectomy in women or removal of solitary thymomas is still appropriate and efficacious therapy. In some clinics, thymectomies are being performed with good success even on men without thymomas.
In myasthenic patients, a surgical procedure for ptosis should be approached with extreme caution. A perfect ptosis repair may leave the cornea exposed during the day, because of a weak orbicularis muscle, and at night, because of an inadequate Bell's phenomenon owing to ophthalmoplegia. If the ptosis is severe and the lid covers the pupil, a surgical procedure may be considered; however, the amount of ptosis should be stable, the degree of Bell's phenomenon reasonable, and the ptosis repair less than complete.
Progressive External Ophthalmoplegia
Once a myopathy with ptosis as the most prominent feature has been diagnosed, the differential diagnosis is essentially either myasthenia gravis or progressive external ophthalmoplegia (PEO).
The onset of PEO can be between infancy and 50 years of age, but PEO commonly begins in persons over 20 years of age. Frequently, a family history of this condition exists. Because of the variable expression of the disease, examine other family members for evidence of the disease. The initial family history is frequently negative.
The pigmentary retinopathy is not like retinitis pigmentosa. A bone spicule appearance and equatorial location is not seen in the Kearns-Sayre syndrome. This pigmentary retinopathy is more like salt and pepper and is located at the posterior pole. The ERG is not as abnormal as in retinitis pigmentosa patients.
As in myasthenia gravis, a long interval may elapse between the development of ptosis and involvement of the extraocular muscles. The muscles controlling up-gaze are the first group involved in both myasthenia gravis and PEO. In contrast to myasthenia gravis, PEO is associated with a negative Tensilon test and the absence of diurnal variation or relation to fatigue.
The four syndromes discussed in the following paragraphs are not simply other forms of PEO. Although they all have PEO as part of the clinical picture, they also have abnormalities of the nervous, cardiac, and hematopoietic systems that differentiate them from PEO. When PEO is diagnosed, it is essential that these other diseases be ruled out because they are more serious than PEO and are, in fact, life threatening.
Oculopharyngeal dystrophy of Victor, which may occur sporadically or be inherited as a dominant trait, involves external ophthalmoplegia and pharyngeal weakness. Pilelal and limb girdle weakness have also been reported in association with this condition.
Kearns-Sayre syndrome is made up of PEO, retinitis pigmentosa, and heart block in young people. Therefore, in all cases of PEG, a good ophthalmoscopic examination and electrocardiogram should be performed; if the PEO is associated with the Kearns-Sayre syndrome, death from heart block is a possibility.
Bassen-Kornzweig syndrome consists of a broad mixture of signs, one of which includes PEO. Diarrhea owing to poor absorption of lipids from the gastrointestinal tract may precede the onset of PEO by a few weeks to several years. Patients with this syndrome are also deficient in serum cholesterol and beta-lipoproteins. Pigmentary degeneration of the retina is seen in some cases. Some patients have a positive Babinski reflex, sensory loss, ataxia, optic atrophy, and an increase in cerebrospinal fluid protein. Acanthocytosis of the red blood cells is another laboratory sign that is of assistance in diagnosing Bassen-Kornzweig syndrome.
Refsum syndrome, which is rather uncommon, should be suggested by a combination of PEO, retinitis pigmentosa, and polyneuropathy. Presence of these conditions should prompt a test for phytanic acid level, which is elevated in this disorder. Less significant diagnostic signs are cerebellar ataxia, hearing loss, anosmia, ichthyosis, and epiphyseal dysplasia.
Pseudotumor of the Orbit
In addition to chemosis, pain, and exophthalmos, pseudotumor of the orbit has an inflammatory sign similar to that which occurs in orbital cellulitis. The congestion of the vessels is usually not as prominent as in cellulitis, but the difference is difficult to evaluate. Pseudotumor of the orbit is usually unilateral, and the ophthalmoplegia is usually marked. Onset can occur at any age, but I usually see it in women between 30 and 50 years of age. Occasionally, the inflammatory signs are minimal, and diplopia is present, with involvement of only one muscle and pain on motion—a combination that makes diagnosis more difficult. In early cases of pain in the orbit, exophthalmometer readings on each visit may reveal a gradual development of exophthalmos. This changing pattern facilitates diagnosis of pseudotumor of the orbit before the frank signs of this condition become obvious. The usual differential diagnoses of cellulitis or an infiltrating lesion must be ruled out because no specific tests are available to establish the presence of these diseases. On the other hand, the possibility of a lymphoma of the orbit should be considered.
Patients with pseudotumor of the orbit respond very well to systemic steroids; however, discontinuance of steroid therapy often leads to recurrence of the disease. I have had to keep many of my patients on steroid medication for months, and in some cases up to a year. Even when steroid medication is apparently withdrawn successfully, the disease can recur months or years later.
Myositis has the same signs and symptoms as pseudotumor of the orbit, and it is treated with steroids with the same degree of effectiveness.
Trichinosis is uncommon in the United States, and in the few cases that occur, a carefully taken history will reveal that the patient has recently eaten pork. In addition to the gastrointestinal problems and eosinophilia that are symptomatic of trichinosis, the main ocular symptoms are periorbital swelling, marked pain on movement, and, occasionally, diplopia. Examination of the globe itself does not reveal the inflammatory signs usually associated with pseudotumor or myositis. Petechial hemorrhages of the conjunctiva are frequently seen.
Although diplopia is not a sign of myotonic dystrophy, this disease is discussed in this chapter because it is a myopathic process. Patients suffering from myotonic dystrophy frequently have ptosis, which is also an early sign of myasthenia gravis and PEO. Therefore, prior to the onset of diplopia in ptotic patients, the possibility of myotonic dystrophy should be considered in the course of the differential diagnosis.
Ptosis is certainly not the earliest sign of myotonic dystrophy. However, in known cases, ptosis is part of this syndrome and should be so regarded in the absence of other signs of third cranial nerve paralysis, such as pupillary involvement. Restriction of gaze occurs less frequently but is also a sign oh myotonic dystrophy. Other associated eye signs are a positive Schirmer's test, keratitis sicca, ocular hypotony averaging 10 mm of mercury, decreased corneal sensitivity, decreased dark adaptation as shown by the electroretinogram, and, in a small number of cases, a starlike retinal pigmentary degeneration.
The handclasp sign is easily elicited and dramatic. After a firm handshake, the patient is unable to release his or her grasp. Similarly, after forced closure of the lids, the patient may be unable to open the eyes on command (or at will).
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