THYROID OCULAR MYOPATHY* BY Barton L. Hodes, MD (BY INVITATION)
AND David E. Shoch, MD INTRODUCTION
THE CLINICAL RELATIONSHIP BETWEEN THYROID DISEASE AND ORBITAL DISEASE HAS
been recognized since early in the nineteenth century. Although Graves' has received most of the credit for calling this to our attention, Parry2 clearly described the entity of goiterous enlargement of the thyroid gland and exophthalmos ten years earlier. Nonetheless, the eponym "Graves' Ophthalmopathy" has become the standard term with which physicians describe the orbital disease which results from or is related to thyroid abnormalities. In 1969, Werner3 proposed a classification of the eye signs of Graves' disease which gained immediate acceptance by the medical community after endorsement by the American Thyroid Association. This classification was developed by a committee under the chairmanship of Doctor Werne-r and included representatives of many medical specialties. The mnemonic NOSPECS (Table I) represents the first letter of each class of signs and is said to separate what was previously called "noninfiltrative" (NO) from "infiltrative" (SPECS) forms of the disease. In addition, a pathogenetic mechanism was implied by Doctor Werner in his statement: "Each class usually includes the involvement indicated in the preceding class." The progression of ophthalmopathy (more properly orbitopathy) may thus be thought of as: thyrotoxicosis and its resultant sympathetic hypertonus, inflammatory orbitopathy, proptosis, extraocular muscle involvement, and sight loss from corneal exposure or optic nerve compression. We believe that this progression, although often clinically relevant in a descriptive sense, does not accurately represent the nature of thyroid orbitopathy. Ultrasonographic observations made at our institution and the University ofIowa indicate that the basic abnormality in patients with signs and symptoms of orbitopathy and proven thyroid disease is a panmyositis. On the basis of accumulated data, we feel that all ofthe signs and symptoms of thyroid orbitopathy are the results of involvement of the muscles by an *From the Department of Ophthalmology, Northwestern University Medical Chicago, Illinois. TR. AM. OPHTH. Soc. vol. LXXVII, 1979
School,
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TABLE I WERNER'S CLASSIFICATION (ABRIDGED)
0 1 2 3 4 5 6
No signs or symptoms Only signs, no symptoms Soft tissue involvement Proptosis Extraocular muscle involvement Corneal exposure Sight loss, optic nerve
inflammatory process; the lone exception is the reversible eyelid retraction due to overaction of Mueller's muscle. METHODS
The evidence upon which we base our thesis was gathered with both contact B-scan ultrasonography and standardized A-scan ultrasonography. With contact B-scan, the transducer is applied to the topically anesthetized bulbar conjunctiva so that the to-and-fro oscillation of the transducer is linearly aligned with the medial or lateral rectus muscle; the instrument is coupled to the globe with gonioscopic methylcellulose (Fig 1A, B). The medial rectus muscle is examined with the transducer applied to the temporal bulbar conjunctiva and the eye in maximal adduction, while the lateral rectus is examined with the transducer on the nasal bulbar conjunctiva and the eye in maximal abduction. These positionings orient the scan plane along the A-P axis of the muscle being examined with minimal discomfort to the patient; similar positioning for examination of the superior and inferior muscles is quite uncomfortable for the patient and adds little if anything to the diagnostic yield. Standardized A-scan is also a contact method; the small transducer is applied without coupling material to the topically anesthetized bulbar conjunctiva (Fig 2). With the patient's eye in the primary position, the sound beam is oriented perpendicular to the muscle being examined. Since muscle tissue is more homogeneous to the examining sound wavelength than orbital tissues, the borders ofthe muscles can be identified and defects demonstrated within the orbital fat patterns which represent the muscles themselves and thus their thickness actually measured. The method of standardized A-scan and its measurements is considerably more sensitive and accurate than B-scan and is capable of identifying minimal enlargements of extraocular muscles which can at best only be suggested by B-scan. * *The instruments used in these examinations were the Bronson-Turner Ophthalmic Contact B-scan, and the Kretztechnik 7200 MA Ophthalmic A-scan.
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transducer apphed to the temporal bulbar conjunctiva for exarnination of muscle. B: Schematic representation of the path of the sound bearn for examination of the medial rectus muscle.
A: The contact B-scan
the medial
rectus
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FIGURE 2
The A-scan transducer is applied to the temporal bulbar conjunctiva for measurement of the medial rectus muscle.
Examples of the type of data obtainable are shown in figures 3, 4 and 5. Figure 3 A is of a patient with obvious thyroid orbitopathy and 3 B is a B-scan with inflammatory changes identifiable within the orbital fat. Figure 4 is a schematic representation of 3 B. The cross-hatched area is Tenon's space, the stippled area is orbital fat, and the dark band is extraocular muscle. Figure 5 A shows the A-scan ofa normal extraocular muscle and figure 5 B the A-scan of a patient with thyroid orbitopathy. As will be demonstrated later, accurate figures have been generated by examination of hundreds of normal patients which give an upper limit for normal A-scan values. RESULTS
The following reports describe a series of patients who fell into various Werner's classes beginning with the most severe and progressing to minimal involvement and point out the presence or absence of extraocular muscle involvement in each case.
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FIGURE 3
A: A patient with class 6 orbitopathy. B: On contact B-scan, such patients show echo-free zones
outlining their extraocular muscles.
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FIGURE 4
A schematic representation of what is seen in Figure 3B. The cross-hatched area is Tenon's space, the stippled area orbital fat tissue, and the dark band extraocular muscle.
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I
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-
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FIGURE 5
A: An A-scan echogram of a normal extraocular muscle. B: An A-scan echogram of a thickened extraocular muscle.
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CASE 1, Class 6 This 60-year-old woman (Fig 6A, B, and Fig 7) was treated with 1311 for thyrotoxicosis several years ago. During the two years prior to this examination, she experienced gradually increasing proptosis which ultimately led to this picture. Visual acuity was decreased to 20/400 in both eyes, there was marked periorbital swelling, and both orbits were "frozen." All twelve extraocular muscles were massively thickened; this was confirmed by computerized tomography (CT). Here the clinical picture is evident and we would expect abnormal scans whether B, A or CT. CASE 2, Class 4 This 61-year-old woman (Fig 8A and B) presented with a history of having been treated with 131I several years before the onset of horizontal diplopia. Clinically, she was found to have periorbital swelling, an exotropia, and positive forced ductions. Ultrasonographically, all four horizontal rectus muscles were significantly thickened.
Again, the scan is simply confirmatory of an obvious clinical diagnosis. CASE 3, Class 4 This 56-year-old woman (Fig 9A, B, and Fig 10) presented with the sole complaint of vertical double vision. Her past history was negative with regard to thyroid disease. She was eumetabolic, but subsequently was found to have a positive thyrotropin releasing hormone (IRH) test. Clinically, she was completely unable to elevate the right eye; forced ductions were positive. Motility of the left eye was normal. There was no proptosis or any other sign of thyroid orbitopathy. Ultrasonographic measurement ofher horizontal recti showed them to be thicker than normal on the right and at the upper limits of normal on the left.
The presence of thyroid disease was a little more difficult to establish, but an abnormal scan is to be expected in class 4 patients. As an aside we might note that in cases 2 and 3 we see one of the fundamental inconsistencies of the Werner classification; patient 3 presented as a "pure" motility abnormality whereas 2 showed the full spectrum of orbital involvement including periorbital edema and proptosis. However both are graded class 4. CASE 4, Class 3 This 44-year-old woman (Fig 1 1A and B) presented with a history of having been treated for thyrotoxicosis several years previously. She was asymptomatic but was referred for an orbital echogram because of the incidental finding of unilateral left-sided proptosis. Extraocular muscles showed a full range of motion. On ultrasound examination, however, the medial and lateral recti of the left orbit were
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FIGURE 6
(Case 1, class 6) A: The clinical appearance of this patient when first seen was typical for advanced thyroid orbitopathy. B: On A-scan, all of her extraocular muscles were massively enlarged, a finding which was confirmed by computerized tomography (See Fig 7).
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thicker than normal while those of the right orbit approached the upper limits of normal. Extraocular muscle involvement is not considered a part of class 3 orbitopathy; however, it is seen to be present here. CASE 5, Class 1 This 39-year-old woman (Fig 12A and B) presented with documented and successfully treated thyrotoxicosis. She was eumetabolic at the time of our examination. Her presenting complaint was obvious disfiguring retraction of her right upper eyelid. She had no other ocular complaints. On clinical examination, the only abnormality was the widening of the right lid fissure. There was no proptosis, edema, or motility abnormality present. Measurement of her horizontal recti showed that those of the right eye were thicker than normal and those of the left to be near the upper limits of normal. Although muscle involvement is clearly not considered part of class 1 orbitopathy, it is seen to be present in this patient as well.
FIGURE 7
Computerized tomographic scan of the patient shown in figure 6 showing thickened extraocular muscles.
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(Case 2, class 4) A: Clinical appearance ofpatient demonstrating gross exotropiaand periorbital swelling. B: All four horizontal recti were significantly thicker than normal. Note the size ofthe defect in the orbital fat pattern which represents one of the abnormally enlarged muscles.
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FIGURE 9
(Case 3, class 4) A: Patient with normal clinical appearance. B: The extraocular muscle defect is not well displayed but distinctly thicker than normal.
92 Hodes and Shoch CASE 6, Class 1 This 26-year-old woman (Fig 13A and B) was referred for orbital ultrasonography with a diagnosis of a possible orbital tumor. By conventional thyroid testing she was eumetabolic. She had already had cerebral angiography. Ultrasonographically (Fig 13B) the horizontal recti muscles of both eyes were enlarged and a diagnosis of thyroid orbitopathy was made. This diagnosis was subsequently confirmed by the demonstration of an autonomously functioning thyroid gland.
As in the case of patient 5, a patient with the sole finding of eyelid retraction (class 1) was shown to have abnormal extraocular muscles by A-scan echography. DISCUSSION
The original Werner classification of Graves' disease implied that thyroid ophthalmopathy might be staged like malignancies or graded like hypertensive retinopathy with the understanding that each class or grade in-
FIGURE 10
Computerized tomography ofthe patient shown in figure 9. The right inferior rectus muscle is shown to be abnormal as a tumor-like density at the orbital apex.
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FIGURE 11
(Case 4, class 3) A: Patient with asymptomatic proptosis of left eye. B: Asymptomatic unilateral proptosis. Fig 6 shows a thicker than normal horizontal rectus muscle.
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1B-I FIGURE
12
(Case 5, class 1) A: This patient's only complaint was lid retraction. B: Her extraocular muscles were measurably abnormal in thickness.
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(Case 6, class 1) A: This patient had less dramatic lid retraction than Case 5. B: Her extraocular muscles were abnormally thickened as well.
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cluded "all of the foregoing plus." However, in 1977, Werner himself proposed a modification of his original classification and stated that, "During a progressive course of eye changes, the process does not necessarily follow each ofthe classes, and it is not unusual for one or more classes to be skipped." Further he added that in the noninfiltrative orbitopathies, "The CT scan is usually negative and the ultrasonogram usually positive." Our report provides documentation for this statement. Hodes and Stern,9 working with contact B-scan ultrasonography, showed the pre-sence of abnormalities in the areas of the extraocular muscles of all patients with at least class 3 orbitopathy irrespective of the clinically observed status of the extraocular muscles. Echolucent zoneswhich are not found in normal patients-were uniformly identified surrounding the muscles and, to a lesser degree the optic nerve in all patients with moderate to advanced orbitopathy. Since publication of the initial series of observations, well over a hundred additional patients have been studied and have shown the same abnormalities. In addition, the same findings were observed in scans of all patients with orbital inflammatory diseases (dacryoadenitis, pseudotumor, posterior scleritis, etc.). Experimentally, identical findings were demonstrated after retrobulbar injections. It was concluded that these echolucent zones were actually accumulations of inflammatory edema fluid in the loose areolar connective tissue which surrounds these structures and that thyroid orbitopathy is a panmyositis, perhaps a panorbititis, from its outset. As mentioned earlier, Ossoinig and McNutt,`0 working at the University ofIowa, measured the extraocular muscle thickness and optic nerve diameTABLE
II MAXIMAL RECTUS MUSCLE AND OPTIC NERVE SIZES IN NORMAL POPULATION
MUSCLE OR NERVE
PERCENTILE
VALUE IN MILLIMETERS
VALUE IN MICROSECONDS
Rectus
95 90
5.40 4.58 4.32
7.2 6.1 5.8
Lateral
100 95 90
5.40 5.12 4.88
7.2 6.8 6.5
100 95 90
5.32 4.45 4.24
7.1 5.9 5.6
6.52 5.20 5.02 From Ossoinig and McNutt,10 reproduced with permission.
8.7 6.9 6.7
Superior
Rectus
Inferior Rectus
Medial
Rectus
100
100 95 90
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ters in one-hundred normal volunteers and an equal number of patients with signs and symptoms ofthyroid orbitopathy using standardized A-scan echography (Table II). They found statistically significant thickening of all extraocular muscles in their patients with thyroid orbitopathy when compared with their normals irrespective of presenting signs or symptoms. They also found that, in their patients with asymmetric orbital involvement, the muscles on the uninvolved side were either thicker than normal or were at the upper range of normal muscle thickness. It is particularly worthy of note that despite the fact that vertical muscle imbalances (simulating double elevator palsies) are early presenting signs in patients with thyroid orbitopathy, measurement.of the horizontal extraocular muscles identified the abnormal thickness in almost every case. The diagnostic yield increased only a couple of percentage points when the vertically acting muscles were measured. Similar observations were made by Hodes and Stern.9 They too, concluded that thyroid orbitopathy is a panmyositis regardless of its clinical presentation and that the diagnosis can be made with certainty even in the presence of the eumetabolic or hypometabolic state. How do the above observations and conclusions relate to thyroid orbitopathy in the clinical setting? Are there inconsistencies such as pointed out earlier with traditional concepts? Can these findings be applied to previously unexplained phenomen>i? There is no argument with the proven relationship between overt thyrotoxicosis and supersensitivity of Mueller's muscle to circulating norepinephrine causing retraction ofthe lids. The topical administration of guanethidine does cause many retracted eyelids to return to a normal or nearly normal position by inducing an adrenergic blockade. This clearly implicates sympathetic hypertonus as causative of eyelid retraction. But when sympathetic blockade fails to lower the eyelid, some mechanism other than a neurogenic one must be found; this is equally true when lid retraction is unilateral. We suggest that the explanation is a panmyositis involving the intimate relationship between the levator and Mueller's muscle. Inflammation is accompanied by an outpouring of fibrin and interstitial fluid. The two muscles can be expected to become swollen, less pliable, and even adherent to one another; this can explain eyelid retraction on a purely mechanical basis. Although it is true that symptoms ofvertical muscle imbalance precede symptoms of horizontal muscle imbalance, our data do not permit the conclusion that the vertically acting muscles are preferentially involved or involved to a greater extent than are the horizontally acting ones. There are twice as many vertically acting muscles as there are horizontally acting
Hodes and Shoch ones; the superior and inferior recti and obliques cross one another giving an anatomic focus for adhesions between them to occur as a result of a myositis; and fusional amplitudes for vertical image separations are much smaller than horizontal amplitudes. Considering these factors, it is not surprising that a myositis which involves all extraocular muscles causes early vertical muscle symptomatology and diplopia. Based upon our ultrasonographic findings, we feel that thyroid orbitopathy should be considered a panmyositis, the signs and symptoms of which can be explained on the basis of the mechanical and biochemical effects of inflammation. The only exception to this is reversible eyelid retraction and this can be attributed to sympathetic hypertonus of Mueller's muscle. Werner's classification of Graves' orbitopathy is a valuable descriptive tool but as he himselfhas pointed out it is not a mechanism for staging of the disease. The concept that a continuum of progression from mild to severe exists is pertinent for descriptive purposes but is not an appropriate pathogenetic explanation. 98
SUMMARY
Based upon the ultrasonographic evidence of extraocular muscle abnormalities in all patients with orbitopathy and proven thyroid disease, we conclude that the basic abnormality of thyroid orbitopathy is a panmyositis and that all of the classes described by Werner are expressions of different degrees and manifestations of the same pathologic process. This thesis is supported by presentation of cases of varying severity who have in common extraocular muscle abnormalities. We believe that the process we describe acceptably explains all of the eye signs of this common orbitopathy. 1. 2.
3. 4.
5. 6.
7.
8. 9.
REFERENCES Graves RJ: Clinical lectures. London Med Surgj 7:516, 1835. Parry CH: Collections fiom the Unpublished Papers of the Late Caleb Hilliel Parry. London, Underwoods, 1825, vol II, pp 111-120. Werner SC: Classification ofthe eye changes of Graves' disease. J Clin Endocrinol Metab 69:982, 1969. Hogan MJ, Zimmerman LE: Ophthalmic Pathology. Philadelphia, CV Mosby, 1962, p 736. Duane TD (ed): Clinical Ophthalmology. New York, Harper & Row, (2) 35:19, (1) 7:5, 1976. Werner SC, Ingbar SH: The Thyroid Gland. New York, Harper & Row, 1974, pp 535-543, p 868. Valenta LT, Lemarchand-Beraud T, Nemec J: Metastatic thyroid carcinoma provoking hyperthyroidism with elevated circulatig thyrostimulators. Am I Med 48:72, 1970. Moses RA: Adler's Physiology of the Eye. St Louis, CV Mosby Co, 1975, p 5. Hodes BL, Stern GA: Contact B-scan echographic diagnosis of ophthahnopathic Graves' disease. J Clin Ultrasound 3:255, 1975.
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10. Ossoinig KC, McNutt L: A-scan changes in Graves' disease. Read before the World Federation for Ultrasound in Medicine and Biology, San Francisco, Aug 4, 1976. 11. Werner SC: Modification of the classification of the eye changes of Graves' disease. Amj Ophthalmol 83:725, 1977.
DISCUSSION
DR MELVIN G. ALPER. I greatly appreciate the opportunity to discuss this excellent paper. I would like to thank Doctors Hodes and Shoch for sending me their manuscript and illustrations for review well in advance of this meeting. Studying many patients with Graves' orbitopathy by both contact B-scan and standardized A-scan ultrasonography, the authors reach three main conclusions: 1) The disease is a panmyositis or perhaps a panorbititis from its outset. 2) Horizontally acting muscles are as equally involved as the vertically acting ones despite the fact that vertical imbalance is clinically more common, and, 3) Werner's classification ofGraves' orbitopathy is a valuable descriptive tool for describing a continuum from mild to severe, but is not a mechanism for staging the disease nor for explaining pathogenesis. By means of study with computed tomographic(CT) scanning of many patients with Graves' orbitopathy we have demonstrated similar findings to those of the
authors. Orbital CT findings in Graves' disease demonstrate the fbllowing: 1) Exophthalmos. 2) Swollen extraocular muscles with normal insertions. 3) Increased orbital fat with prolapse through the orbital septum. 4) Bilateral involvement. Exophthalmos is readily seen on the transaxial scan and is measured by drawing an imaginary line from one anterolateral crest to the other. Swollen extraocular muscles are easily demonstrated on both transaxial and coronal sections. In the fourth generation scanners, we have been able to demonstrate all of the muscles except the inferior oblique. In a large series of patients with Graves' disease, we have noted that involvement of the horizontal recti muscles was the most commonly demonstrated. The medial rectus muscle was more severely affected than the lateral. The superior rectus muscle was least commonly affected. The inferior rectus muscle was the most severely involved of all and created the most debilitating symptoms. Because the x-ray beam is oblique to the axis of the inferior rectus muscle and does not demonstrate the entire length ofthe muscle, enlargement has been misinterpreted in the past as an apical or neurogenic tumor. Coronal sections, however, obviate this difficulty, clarifying the proper relationship of the muscle to the optic nerve. In addition, from studying coronal views, it is plausible to explain some forms of optic neuropathy by a compression phenomenon.
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In some patients with lid retraction, despite a good response to guanethedine drops, which would indicate increasd sympathetic tone of Mueller's muscle, enlargement of the levator-superior rectus muscle complex could still be seen. This corroborates the authors' observation that organic changes occur in this group of muscles. Histopathologic examination of muscle biopsies taken during corrective muscle surgery in Graves' orbitopathy shows swelling of the muscle and invasion by round cells. This confirms histologically the authors' contention that the basic disease process is a panmyositis. I concur wholeheartedly with the authors' conclusions and congratulate them for an excellent contribution. DR NATHANIEL BRONSON. I would certainly like to congratulate the authors on their nice paper. I noticed one of the B-scans showed edema ofthe orbital fat and maybe we're lucky in Southampton we don't have that much grade 6 change, but I've seen that only very rarely in the orbital fat or orbital edema. I'd be fascinated to see the relationship of the actual measurements of the muscles to the ultrasonographic changes. I've always wanted to see a study measuring mnuscles in these myopathies and just how much of a change would it show.
DR ROBERT M. DAY. I enjoyed Doctor Hodes' paper very much. I wonder, however, whether it is fair to say that the changes are limited to the muscles. Certainly all the orbital structures seem to be involved. A few years ago Doctor Algeron Reese pointed out that the lacrimal gland becomes involved, and in addition, there is chemosis of the conjunctiva, edema of the caruncle, and lid fullness. Other tissues beside the muscles are involved, although they may account for the changes that Doctor Hodes is describing. It has been said many times that the only definite statement which can be made about these various ocular changes is that no definite statement can be made. I met with Doctor Werner several times, along with others who were working on this classification, and I do not believe it was his intent to suggest that each class represented an increase in severity. I would like to quote from the fourth edition ofhis textbook on the thyroid which was published about six months ago. He stated: "The classes indicate more advanced, but not sequential, involvement by disease and are not meant to indicate a smooth progression. The system is in no sense a schema for charting the various manifestations of the eye disorders. The main purpose is to make possible a diagnostic summary for each patient. It also permits the experience of a physician or clinic to be summarized in a standardized way. Other physicians or clinics can then recognize the type of eye change being discussed." DR ROBERT KENNEDY. I feel this paper brings a very important subject to our attention. In my home town I have the privilege of seeing some of these patients referred by colleagues whom I consider my friends and by some of my colleagues whom I do not consider my friends. I feel the internist and ophthalmologist should
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101 learn to live together more closely in handling this problem. If nothing else, we certainly must realize the pleomorphic manifestations of this disease. Doctor Day and Doctor Carroll gave a paper on the optic nerve involvement with this disease before this Society some twelve years ago. At that time, I discussed a patient having suppression of vision who was treated by corticosteroids for six months in addition to a high vitamin intake. Vision was reduced to 20/200 OD and 3/200 OS and remained suppressed 17 and 21 months. The patient was seen by Doctor Walsh and other members of this Society. In about two years time, the vision came back to 20/20 in each eye. This single case is still an enigma when one tries to explain the mechanism for the reduced vision for this length of time, followed by full recovery. A recent patient in Rochester demonstrated vision and optic nerve suppression with diplopia 35 years after thyroidectomy. The vision and,diplopia immediately improved on corticosteroids. A third patient at our medical center had reduced vision and the manifestation of unilateral acute orbital inflammation 19 years after thyroid surgery. The internists and endocrinologists were not interested in this diagnosis or corticosteroid treatment until we had obtained a pathology specimen from one ofthe enlarged muscle masses. All three ofthese patients were considered medically euthyroid without problems despite their progressive orbital disease. These cases illustrate that the internist and ophthalmologist must realize the very pleomorphic manifestations of this disease., DR GUNTER K. VON NOORDEN. Have the authors attempted to correlate the CT scan findings of extraocular muscle thickening with the forced duction test? Does the forced duction test become positive before the patient becomes symptomatic and
has diplopia? DR ALBERT M . PoTrrs. I would like to thank the authors for their presentation because this is the first step toward a unified concept ofthis complex problem. I would like to call attention further to the increased hints in the literature that the origin for the panmyositis is a hypersensitivity reaction shared by the thyroid and the extraocular muscles. This is the only way for me to rationalize the optic neuritis that also occurs on occasion; namely, there must be some common antigen shared by interstitial tissue of the optic nerve and by the muscles themselves. The mechanical explanation of swollen muscles causing optic nerve disease, I think is not-quite acceptable. However I am at a loss to explain the papilledema which also occurs rarely in thyroid disease on an immunologic basis. Would one truly expect to find a swollen extraocular muscle in a long-standing case such as was shown on one of the slides rather than a shrunken fibrosed extraocular muscle? The latter is what one finds at operation on these cases late in the disease process. DR DAVID SHOCH. Doctor Hodes will close, but I thought I would expand on just two points in this paper. First is the question of lid retraction and.why it is sometimes reversible if we presume that there is in fact an organic chajige that takes place in the muscle itself with some adhesion occurring between the levator and the
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superior rectus. We think that the explanation is that there must be some stage of the disease, before the adhesion actually occurs when the retraction is simply overaction. (slide) It is our contention that early lid retraction is simply overaction of Mueller's muscle and since Mueller's muscle is sympathetically innervated, if one gets an increase in catecholamines in the blood then one may get a lid retraction. This can be shown by the fact that if one gives a patient an alpha blocker such as phentolamine (Regitine®) one does in fact get a reduction in the lid retraction. (slide) This next slide is taken from a paper by Sheldon Waldstein of our Endocrinology Department. You see a man with bilateral lid retraction due to thyrotoxicosis. (slide) This is after the instillation of Regitine in his right eye. The second picture is taken about 45 minutes after instillation. (slide) This is from another paper by the same author but showing a patient given systemic guanethidine 50 mg daily for three days. After three days the lids begin to come down. In short, ifone blocks the alpha receptors or uses a postganglionic block one can in fact change the lid position in thyroid disease before true fibrosis takes place. My second comment is made in an attempt to correct a historical inequity. (slide) This is Doctor Graves, a renowned Irish physician who regularly gave lectures at the Meath Hospital in Dublin which were later published in the London Medical and Surgical Journal. (slide) Here is the first page of the issue in which he published his lectures given in 1835. (slide) This is a page copied from the original manuscript and what it states is that Doctor Graves never did see a patient with thyroid disease and proptosis but that "a friend tells me of two patients who have protrusions of the eyes associated with a goiter." Doctor Graves did not actually see the patients himselfbut only reports what was told him by a friend. As you may gather I feel that the eponym "Graves' Disease" is thus a little unfair. The next slide is a picture of an English physician named Caleb Parry who described a patient with thyrotoxicosis ten years before Graves, that is in about 1825, but unfortunately this report was not published until after his death when all of Doctor Parry's collective papers were published. Among these papers was the description of a patient with proptosis and thyroid disease and so the question arises why is it not called Parry's Disease rather than Graves' Disease. There is a very involved story which I will not go into, but let me summarize by saying that since the time of Jesus great teachers have been crucified for not publishing. DR J. LAWTON SMITH. I should like to say I do not agree with the "NOSPECS" classification. To be specific, many patients with thyroid eye disease come in first with symptoms, and without signs. Their eyes are uncomfortable, they blink a lot, they are quite photophobic, and the eye examination is often negative. In fact, it is much more common for them to have symptoms without signs, than to present with signs without symptoms. It is important to do a Schirmer's test on these patients as there is a very high incidence ofpositive Schirmer's tests in patients with euthyroid Graves' disease. The second point that I see often is pathologic lid retraction. The next commonest one is diplopia, and these are more common than proptosis cases. The "NOSPEC S" classification doesn't indicate the frequency of the tight inferior rectus, then the tight medial rectus, and finally the tight superior rectus syn-
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dromes. Optic nerve involvement is very uncommon. One should also remember the association with myasthenia. Doctor Costin suggested the use of timolol for lid retraction. We tried this in two patients. Finally, I believe there should be a classification of the eye signs in thyroid eye disease prepared by ophthalmologists that would be more inclusive and representative of what we really see in practice. Have you tried timolol for lid retraction Doctor Shoch? DR DAVID SHOCH: Yes, we tried it and it doesn't work. DR J. LAWrON SMITH. One lady from Canada did like timolol for her lid retraction, so I would like to hear comments from others who have tried it. DR BARTON HODES. I would like to thank Doctors Alper, Bronson, Day, Kennedy, Von Noorden, Potts and Smith and an otherwise formidable audience for being gentle. I would first like to address Doctor Bronson's question ifI may and say that contact B-scan is a qualitative evaluation of what we are seeing in the orbit not a quantitative measure and so I don't believe we can draw any firm conclusions. Actually, in my experience, all patients with at least class 3 Graves' orbitopathy were found to have these abnormalities unequivocally with contact B-scan. In patients with milder orbitopathy the findings were more subtle and equivocal and when I originally wrote this, I included those as negatives or plus/minus. Doctor Day, I would agree with you that this is may very well be a panorbitopathy and not just a panmyositis, and I would be willing to investigate that further. I don't know that we can identify the chicken or the egg at this moment but the panorbitopathy may cause the involvement ofall the muscles or it may well be that the muscles lead to involvement of the orbit. Doctor Smith I would have expected to make a stronger statement. This would not be the first time that Doctor Smith has spoken more strongly than I, and I thank you for your comments. Doctor Kennedy, I would refer you to some work done by Harold Skalka in Birmingham who measured the optic nerves ofpatients with proven thyroid orbitopathy; I intentionally stayed away from the optic nerve for the sake of brevity. The optic nerves are definitely wider; the intrasheath distance is greater with standardized A-scan in patients who have proven thyroid orbitopathy than it is in the normal population and this may well explain the process in the optic nerve and optic neuritis. Doctor Von Noorden, I believe you were the one who asked if we equate our findings with forced ductions, and we have obviously done forced ductions on all of our patients. With mild enlargements of the extraocular muscles I don't feel that I am sophisticated enough to identify very minor resistance to the forced ductions. When the forced ductions are definitely positive in a patient who is asymptomatic from motility abnormalities I can identify those patients in the absence of symptoms.
AND David E. Shoch, MD INTRODUCTION
THE CLINICAL RELATIONSHIP BETWEEN THYROID DISEASE AND ORBITAL DISEASE HAS
been recognized since early in the nineteenth century. Although Graves' has received most of the credit for calling this to our attention, Parry2 clearly described the entity of goiterous enlargement of the thyroid gland and exophthalmos ten years earlier. Nonetheless, the eponym "Graves' Ophthalmopathy" has become the standard term with which physicians describe the orbital disease which results from or is related to thyroid abnormalities. In 1969, Werner3 proposed a classification of the eye signs of Graves' disease which gained immediate acceptance by the medical community after endorsement by the American Thyroid Association. This classification was developed by a committee under the chairmanship of Doctor Werne-r and included representatives of many medical specialties. The mnemonic NOSPECS (Table I) represents the first letter of each class of signs and is said to separate what was previously called "noninfiltrative" (NO) from "infiltrative" (SPECS) forms of the disease. In addition, a pathogenetic mechanism was implied by Doctor Werner in his statement: "Each class usually includes the involvement indicated in the preceding class." The progression of ophthalmopathy (more properly orbitopathy) may thus be thought of as: thyrotoxicosis and its resultant sympathetic hypertonus, inflammatory orbitopathy, proptosis, extraocular muscle involvement, and sight loss from corneal exposure or optic nerve compression. We believe that this progression, although often clinically relevant in a descriptive sense, does not accurately represent the nature of thyroid orbitopathy. Ultrasonographic observations made at our institution and the University ofIowa indicate that the basic abnormality in patients with signs and symptoms of orbitopathy and proven thyroid disease is a panmyositis. On the basis of accumulated data, we feel that all ofthe signs and symptoms of thyroid orbitopathy are the results of involvement of the muscles by an *From the Department of Ophthalmology, Northwestern University Medical Chicago, Illinois. TR. AM. OPHTH. Soc. vol. LXXVII, 1979
School,
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TABLE I WERNER'S CLASSIFICATION (ABRIDGED)
0 1 2 3 4 5 6
No signs or symptoms Only signs, no symptoms Soft tissue involvement Proptosis Extraocular muscle involvement Corneal exposure Sight loss, optic nerve
inflammatory process; the lone exception is the reversible eyelid retraction due to overaction of Mueller's muscle. METHODS
The evidence upon which we base our thesis was gathered with both contact B-scan ultrasonography and standardized A-scan ultrasonography. With contact B-scan, the transducer is applied to the topically anesthetized bulbar conjunctiva so that the to-and-fro oscillation of the transducer is linearly aligned with the medial or lateral rectus muscle; the instrument is coupled to the globe with gonioscopic methylcellulose (Fig 1A, B). The medial rectus muscle is examined with the transducer applied to the temporal bulbar conjunctiva and the eye in maximal adduction, while the lateral rectus is examined with the transducer on the nasal bulbar conjunctiva and the eye in maximal abduction. These positionings orient the scan plane along the A-P axis of the muscle being examined with minimal discomfort to the patient; similar positioning for examination of the superior and inferior muscles is quite uncomfortable for the patient and adds little if anything to the diagnostic yield. Standardized A-scan is also a contact method; the small transducer is applied without coupling material to the topically anesthetized bulbar conjunctiva (Fig 2). With the patient's eye in the primary position, the sound beam is oriented perpendicular to the muscle being examined. Since muscle tissue is more homogeneous to the examining sound wavelength than orbital tissues, the borders ofthe muscles can be identified and defects demonstrated within the orbital fat patterns which represent the muscles themselves and thus their thickness actually measured. The method of standardized A-scan and its measurements is considerably more sensitive and accurate than B-scan and is capable of identifying minimal enlargements of extraocular muscles which can at best only be suggested by B-scan. * *The instruments used in these examinations were the Bronson-Turner Ophthalmic Contact B-scan, and the Kretztechnik 7200 MA Ophthalmic A-scan.
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transducer apphed to the temporal bulbar conjunctiva for exarnination of muscle. B: Schematic representation of the path of the sound bearn for examination of the medial rectus muscle.
A: The contact B-scan
the medial
rectus
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FIGURE 2
The A-scan transducer is applied to the temporal bulbar conjunctiva for measurement of the medial rectus muscle.
Examples of the type of data obtainable are shown in figures 3, 4 and 5. Figure 3 A is of a patient with obvious thyroid orbitopathy and 3 B is a B-scan with inflammatory changes identifiable within the orbital fat. Figure 4 is a schematic representation of 3 B. The cross-hatched area is Tenon's space, the stippled area is orbital fat, and the dark band is extraocular muscle. Figure 5 A shows the A-scan ofa normal extraocular muscle and figure 5 B the A-scan of a patient with thyroid orbitopathy. As will be demonstrated later, accurate figures have been generated by examination of hundreds of normal patients which give an upper limit for normal A-scan values. RESULTS
The following reports describe a series of patients who fell into various Werner's classes beginning with the most severe and progressing to minimal involvement and point out the presence or absence of extraocular muscle involvement in each case.
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FIGURE 3
A: A patient with class 6 orbitopathy. B: On contact B-scan, such patients show echo-free zones
outlining their extraocular muscles.
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FIGURE 4
A schematic representation of what is seen in Figure 3B. The cross-hatched area is Tenon's space, the stippled area orbital fat tissue, and the dark band extraocular muscle.
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I
-
-
-
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-
-
FIGURE 5
A: An A-scan echogram of a normal extraocular muscle. B: An A-scan echogram of a thickened extraocular muscle.
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CASE 1, Class 6 This 60-year-old woman (Fig 6A, B, and Fig 7) was treated with 1311 for thyrotoxicosis several years ago. During the two years prior to this examination, she experienced gradually increasing proptosis which ultimately led to this picture. Visual acuity was decreased to 20/400 in both eyes, there was marked periorbital swelling, and both orbits were "frozen." All twelve extraocular muscles were massively thickened; this was confirmed by computerized tomography (CT). Here the clinical picture is evident and we would expect abnormal scans whether B, A or CT. CASE 2, Class 4 This 61-year-old woman (Fig 8A and B) presented with a history of having been treated with 131I several years before the onset of horizontal diplopia. Clinically, she was found to have periorbital swelling, an exotropia, and positive forced ductions. Ultrasonographically, all four horizontal rectus muscles were significantly thickened.
Again, the scan is simply confirmatory of an obvious clinical diagnosis. CASE 3, Class 4 This 56-year-old woman (Fig 9A, B, and Fig 10) presented with the sole complaint of vertical double vision. Her past history was negative with regard to thyroid disease. She was eumetabolic, but subsequently was found to have a positive thyrotropin releasing hormone (IRH) test. Clinically, she was completely unable to elevate the right eye; forced ductions were positive. Motility of the left eye was normal. There was no proptosis or any other sign of thyroid orbitopathy. Ultrasonographic measurement ofher horizontal recti showed them to be thicker than normal on the right and at the upper limits of normal on the left.
The presence of thyroid disease was a little more difficult to establish, but an abnormal scan is to be expected in class 4 patients. As an aside we might note that in cases 2 and 3 we see one of the fundamental inconsistencies of the Werner classification; patient 3 presented as a "pure" motility abnormality whereas 2 showed the full spectrum of orbital involvement including periorbital edema and proptosis. However both are graded class 4. CASE 4, Class 3 This 44-year-old woman (Fig 1 1A and B) presented with a history of having been treated for thyrotoxicosis several years previously. She was asymptomatic but was referred for an orbital echogram because of the incidental finding of unilateral left-sided proptosis. Extraocular muscles showed a full range of motion. On ultrasound examination, however, the medial and lateral recti of the left orbit were
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FIGURE 6
(Case 1, class 6) A: The clinical appearance of this patient when first seen was typical for advanced thyroid orbitopathy. B: On A-scan, all of her extraocular muscles were massively enlarged, a finding which was confirmed by computerized tomography (See Fig 7).
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thicker than normal while those of the right orbit approached the upper limits of normal. Extraocular muscle involvement is not considered a part of class 3 orbitopathy; however, it is seen to be present here. CASE 5, Class 1 This 39-year-old woman (Fig 12A and B) presented with documented and successfully treated thyrotoxicosis. She was eumetabolic at the time of our examination. Her presenting complaint was obvious disfiguring retraction of her right upper eyelid. She had no other ocular complaints. On clinical examination, the only abnormality was the widening of the right lid fissure. There was no proptosis, edema, or motility abnormality present. Measurement of her horizontal recti showed that those of the right eye were thicker than normal and those of the left to be near the upper limits of normal. Although muscle involvement is clearly not considered part of class 1 orbitopathy, it is seen to be present in this patient as well.
FIGURE 7
Computerized tomographic scan of the patient shown in figure 6 showing thickened extraocular muscles.
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(Case 2, class 4) A: Clinical appearance ofpatient demonstrating gross exotropiaand periorbital swelling. B: All four horizontal recti were significantly thicker than normal. Note the size ofthe defect in the orbital fat pattern which represents one of the abnormally enlarged muscles.
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FIGURE 9
(Case 3, class 4) A: Patient with normal clinical appearance. B: The extraocular muscle defect is not well displayed but distinctly thicker than normal.
92 Hodes and Shoch CASE 6, Class 1 This 26-year-old woman (Fig 13A and B) was referred for orbital ultrasonography with a diagnosis of a possible orbital tumor. By conventional thyroid testing she was eumetabolic. She had already had cerebral angiography. Ultrasonographically (Fig 13B) the horizontal recti muscles of both eyes were enlarged and a diagnosis of thyroid orbitopathy was made. This diagnosis was subsequently confirmed by the demonstration of an autonomously functioning thyroid gland.
As in the case of patient 5, a patient with the sole finding of eyelid retraction (class 1) was shown to have abnormal extraocular muscles by A-scan echography. DISCUSSION
The original Werner classification of Graves' disease implied that thyroid ophthalmopathy might be staged like malignancies or graded like hypertensive retinopathy with the understanding that each class or grade in-
FIGURE 10
Computerized tomography ofthe patient shown in figure 9. The right inferior rectus muscle is shown to be abnormal as a tumor-like density at the orbital apex.
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FIGURE 11
(Case 4, class 3) A: Patient with asymptomatic proptosis of left eye. B: Asymptomatic unilateral proptosis. Fig 6 shows a thicker than normal horizontal rectus muscle.
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1B-I FIGURE
12
(Case 5, class 1) A: This patient's only complaint was lid retraction. B: Her extraocular muscles were measurably abnormal in thickness.
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(Case 6, class 1) A: This patient had less dramatic lid retraction than Case 5. B: Her extraocular muscles were abnormally thickened as well.
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cluded "all of the foregoing plus." However, in 1977, Werner himself proposed a modification of his original classification and stated that, "During a progressive course of eye changes, the process does not necessarily follow each ofthe classes, and it is not unusual for one or more classes to be skipped." Further he added that in the noninfiltrative orbitopathies, "The CT scan is usually negative and the ultrasonogram usually positive." Our report provides documentation for this statement. Hodes and Stern,9 working with contact B-scan ultrasonography, showed the pre-sence of abnormalities in the areas of the extraocular muscles of all patients with at least class 3 orbitopathy irrespective of the clinically observed status of the extraocular muscles. Echolucent zoneswhich are not found in normal patients-were uniformly identified surrounding the muscles and, to a lesser degree the optic nerve in all patients with moderate to advanced orbitopathy. Since publication of the initial series of observations, well over a hundred additional patients have been studied and have shown the same abnormalities. In addition, the same findings were observed in scans of all patients with orbital inflammatory diseases (dacryoadenitis, pseudotumor, posterior scleritis, etc.). Experimentally, identical findings were demonstrated after retrobulbar injections. It was concluded that these echolucent zones were actually accumulations of inflammatory edema fluid in the loose areolar connective tissue which surrounds these structures and that thyroid orbitopathy is a panmyositis, perhaps a panorbititis, from its outset. As mentioned earlier, Ossoinig and McNutt,`0 working at the University ofIowa, measured the extraocular muscle thickness and optic nerve diameTABLE
II MAXIMAL RECTUS MUSCLE AND OPTIC NERVE SIZES IN NORMAL POPULATION
MUSCLE OR NERVE
PERCENTILE
VALUE IN MILLIMETERS
VALUE IN MICROSECONDS
Rectus
95 90
5.40 4.58 4.32
7.2 6.1 5.8
Lateral
100 95 90
5.40 5.12 4.88
7.2 6.8 6.5
100 95 90
5.32 4.45 4.24
7.1 5.9 5.6
6.52 5.20 5.02 From Ossoinig and McNutt,10 reproduced with permission.
8.7 6.9 6.7
Superior
Rectus
Inferior Rectus
Medial
Rectus
100
100 95 90
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ters in one-hundred normal volunteers and an equal number of patients with signs and symptoms ofthyroid orbitopathy using standardized A-scan echography (Table II). They found statistically significant thickening of all extraocular muscles in their patients with thyroid orbitopathy when compared with their normals irrespective of presenting signs or symptoms. They also found that, in their patients with asymmetric orbital involvement, the muscles on the uninvolved side were either thicker than normal or were at the upper range of normal muscle thickness. It is particularly worthy of note that despite the fact that vertical muscle imbalances (simulating double elevator palsies) are early presenting signs in patients with thyroid orbitopathy, measurement.of the horizontal extraocular muscles identified the abnormal thickness in almost every case. The diagnostic yield increased only a couple of percentage points when the vertically acting muscles were measured. Similar observations were made by Hodes and Stern.9 They too, concluded that thyroid orbitopathy is a panmyositis regardless of its clinical presentation and that the diagnosis can be made with certainty even in the presence of the eumetabolic or hypometabolic state. How do the above observations and conclusions relate to thyroid orbitopathy in the clinical setting? Are there inconsistencies such as pointed out earlier with traditional concepts? Can these findings be applied to previously unexplained phenomen>i? There is no argument with the proven relationship between overt thyrotoxicosis and supersensitivity of Mueller's muscle to circulating norepinephrine causing retraction ofthe lids. The topical administration of guanethidine does cause many retracted eyelids to return to a normal or nearly normal position by inducing an adrenergic blockade. This clearly implicates sympathetic hypertonus as causative of eyelid retraction. But when sympathetic blockade fails to lower the eyelid, some mechanism other than a neurogenic one must be found; this is equally true when lid retraction is unilateral. We suggest that the explanation is a panmyositis involving the intimate relationship between the levator and Mueller's muscle. Inflammation is accompanied by an outpouring of fibrin and interstitial fluid. The two muscles can be expected to become swollen, less pliable, and even adherent to one another; this can explain eyelid retraction on a purely mechanical basis. Although it is true that symptoms ofvertical muscle imbalance precede symptoms of horizontal muscle imbalance, our data do not permit the conclusion that the vertically acting muscles are preferentially involved or involved to a greater extent than are the horizontally acting ones. There are twice as many vertically acting muscles as there are horizontally acting
Hodes and Shoch ones; the superior and inferior recti and obliques cross one another giving an anatomic focus for adhesions between them to occur as a result of a myositis; and fusional amplitudes for vertical image separations are much smaller than horizontal amplitudes. Considering these factors, it is not surprising that a myositis which involves all extraocular muscles causes early vertical muscle symptomatology and diplopia. Based upon our ultrasonographic findings, we feel that thyroid orbitopathy should be considered a panmyositis, the signs and symptoms of which can be explained on the basis of the mechanical and biochemical effects of inflammation. The only exception to this is reversible eyelid retraction and this can be attributed to sympathetic hypertonus of Mueller's muscle. Werner's classification of Graves' orbitopathy is a valuable descriptive tool but as he himselfhas pointed out it is not a mechanism for staging of the disease. The concept that a continuum of progression from mild to severe exists is pertinent for descriptive purposes but is not an appropriate pathogenetic explanation. 98
SUMMARY
Based upon the ultrasonographic evidence of extraocular muscle abnormalities in all patients with orbitopathy and proven thyroid disease, we conclude that the basic abnormality of thyroid orbitopathy is a panmyositis and that all of the classes described by Werner are expressions of different degrees and manifestations of the same pathologic process. This thesis is supported by presentation of cases of varying severity who have in common extraocular muscle abnormalities. We believe that the process we describe acceptably explains all of the eye signs of this common orbitopathy. 1. 2.
3. 4.
5. 6.
7.
8. 9.
REFERENCES Graves RJ: Clinical lectures. London Med Surgj 7:516, 1835. Parry CH: Collections fiom the Unpublished Papers of the Late Caleb Hilliel Parry. London, Underwoods, 1825, vol II, pp 111-120. Werner SC: Classification ofthe eye changes of Graves' disease. J Clin Endocrinol Metab 69:982, 1969. Hogan MJ, Zimmerman LE: Ophthalmic Pathology. Philadelphia, CV Mosby, 1962, p 736. Duane TD (ed): Clinical Ophthalmology. New York, Harper & Row, (2) 35:19, (1) 7:5, 1976. Werner SC, Ingbar SH: The Thyroid Gland. New York, Harper & Row, 1974, pp 535-543, p 868. Valenta LT, Lemarchand-Beraud T, Nemec J: Metastatic thyroid carcinoma provoking hyperthyroidism with elevated circulatig thyrostimulators. Am I Med 48:72, 1970. Moses RA: Adler's Physiology of the Eye. St Louis, CV Mosby Co, 1975, p 5. Hodes BL, Stern GA: Contact B-scan echographic diagnosis of ophthahnopathic Graves' disease. J Clin Ultrasound 3:255, 1975.
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10. Ossoinig KC, McNutt L: A-scan changes in Graves' disease. Read before the World Federation for Ultrasound in Medicine and Biology, San Francisco, Aug 4, 1976. 11. Werner SC: Modification of the classification of the eye changes of Graves' disease. Amj Ophthalmol 83:725, 1977.
DISCUSSION
DR MELVIN G. ALPER. I greatly appreciate the opportunity to discuss this excellent paper. I would like to thank Doctors Hodes and Shoch for sending me their manuscript and illustrations for review well in advance of this meeting. Studying many patients with Graves' orbitopathy by both contact B-scan and standardized A-scan ultrasonography, the authors reach three main conclusions: 1) The disease is a panmyositis or perhaps a panorbititis from its outset. 2) Horizontally acting muscles are as equally involved as the vertically acting ones despite the fact that vertical imbalance is clinically more common, and, 3) Werner's classification ofGraves' orbitopathy is a valuable descriptive tool for describing a continuum from mild to severe, but is not a mechanism for staging the disease nor for explaining pathogenesis. By means of study with computed tomographic(CT) scanning of many patients with Graves' orbitopathy we have demonstrated similar findings to those of the
authors. Orbital CT findings in Graves' disease demonstrate the fbllowing: 1) Exophthalmos. 2) Swollen extraocular muscles with normal insertions. 3) Increased orbital fat with prolapse through the orbital septum. 4) Bilateral involvement. Exophthalmos is readily seen on the transaxial scan and is measured by drawing an imaginary line from one anterolateral crest to the other. Swollen extraocular muscles are easily demonstrated on both transaxial and coronal sections. In the fourth generation scanners, we have been able to demonstrate all of the muscles except the inferior oblique. In a large series of patients with Graves' disease, we have noted that involvement of the horizontal recti muscles was the most commonly demonstrated. The medial rectus muscle was more severely affected than the lateral. The superior rectus muscle was least commonly affected. The inferior rectus muscle was the most severely involved of all and created the most debilitating symptoms. Because the x-ray beam is oblique to the axis of the inferior rectus muscle and does not demonstrate the entire length ofthe muscle, enlargement has been misinterpreted in the past as an apical or neurogenic tumor. Coronal sections, however, obviate this difficulty, clarifying the proper relationship of the muscle to the optic nerve. In addition, from studying coronal views, it is plausible to explain some forms of optic neuropathy by a compression phenomenon.
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In some patients with lid retraction, despite a good response to guanethedine drops, which would indicate increasd sympathetic tone of Mueller's muscle, enlargement of the levator-superior rectus muscle complex could still be seen. This corroborates the authors' observation that organic changes occur in this group of muscles. Histopathologic examination of muscle biopsies taken during corrective muscle surgery in Graves' orbitopathy shows swelling of the muscle and invasion by round cells. This confirms histologically the authors' contention that the basic disease process is a panmyositis. I concur wholeheartedly with the authors' conclusions and congratulate them for an excellent contribution. DR NATHANIEL BRONSON. I would certainly like to congratulate the authors on their nice paper. I noticed one of the B-scans showed edema ofthe orbital fat and maybe we're lucky in Southampton we don't have that much grade 6 change, but I've seen that only very rarely in the orbital fat or orbital edema. I'd be fascinated to see the relationship of the actual measurements of the muscles to the ultrasonographic changes. I've always wanted to see a study measuring mnuscles in these myopathies and just how much of a change would it show.
DR ROBERT M. DAY. I enjoyed Doctor Hodes' paper very much. I wonder, however, whether it is fair to say that the changes are limited to the muscles. Certainly all the orbital structures seem to be involved. A few years ago Doctor Algeron Reese pointed out that the lacrimal gland becomes involved, and in addition, there is chemosis of the conjunctiva, edema of the caruncle, and lid fullness. Other tissues beside the muscles are involved, although they may account for the changes that Doctor Hodes is describing. It has been said many times that the only definite statement which can be made about these various ocular changes is that no definite statement can be made. I met with Doctor Werner several times, along with others who were working on this classification, and I do not believe it was his intent to suggest that each class represented an increase in severity. I would like to quote from the fourth edition ofhis textbook on the thyroid which was published about six months ago. He stated: "The classes indicate more advanced, but not sequential, involvement by disease and are not meant to indicate a smooth progression. The system is in no sense a schema for charting the various manifestations of the eye disorders. The main purpose is to make possible a diagnostic summary for each patient. It also permits the experience of a physician or clinic to be summarized in a standardized way. Other physicians or clinics can then recognize the type of eye change being discussed." DR ROBERT KENNEDY. I feel this paper brings a very important subject to our attention. In my home town I have the privilege of seeing some of these patients referred by colleagues whom I consider my friends and by some of my colleagues whom I do not consider my friends. I feel the internist and ophthalmologist should
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101 learn to live together more closely in handling this problem. If nothing else, we certainly must realize the pleomorphic manifestations of this disease. Doctor Day and Doctor Carroll gave a paper on the optic nerve involvement with this disease before this Society some twelve years ago. At that time, I discussed a patient having suppression of vision who was treated by corticosteroids for six months in addition to a high vitamin intake. Vision was reduced to 20/200 OD and 3/200 OS and remained suppressed 17 and 21 months. The patient was seen by Doctor Walsh and other members of this Society. In about two years time, the vision came back to 20/20 in each eye. This single case is still an enigma when one tries to explain the mechanism for the reduced vision for this length of time, followed by full recovery. A recent patient in Rochester demonstrated vision and optic nerve suppression with diplopia 35 years after thyroidectomy. The vision and,diplopia immediately improved on corticosteroids. A third patient at our medical center had reduced vision and the manifestation of unilateral acute orbital inflammation 19 years after thyroid surgery. The internists and endocrinologists were not interested in this diagnosis or corticosteroid treatment until we had obtained a pathology specimen from one ofthe enlarged muscle masses. All three ofthese patients were considered medically euthyroid without problems despite their progressive orbital disease. These cases illustrate that the internist and ophthalmologist must realize the very pleomorphic manifestations of this disease., DR GUNTER K. VON NOORDEN. Have the authors attempted to correlate the CT scan findings of extraocular muscle thickening with the forced duction test? Does the forced duction test become positive before the patient becomes symptomatic and
has diplopia? DR ALBERT M . PoTrrs. I would like to thank the authors for their presentation because this is the first step toward a unified concept ofthis complex problem. I would like to call attention further to the increased hints in the literature that the origin for the panmyositis is a hypersensitivity reaction shared by the thyroid and the extraocular muscles. This is the only way for me to rationalize the optic neuritis that also occurs on occasion; namely, there must be some common antigen shared by interstitial tissue of the optic nerve and by the muscles themselves. The mechanical explanation of swollen muscles causing optic nerve disease, I think is not-quite acceptable. However I am at a loss to explain the papilledema which also occurs rarely in thyroid disease on an immunologic basis. Would one truly expect to find a swollen extraocular muscle in a long-standing case such as was shown on one of the slides rather than a shrunken fibrosed extraocular muscle? The latter is what one finds at operation on these cases late in the disease process. DR DAVID SHOCH. Doctor Hodes will close, but I thought I would expand on just two points in this paper. First is the question of lid retraction and.why it is sometimes reversible if we presume that there is in fact an organic chajige that takes place in the muscle itself with some adhesion occurring between the levator and the
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superior rectus. We think that the explanation is that there must be some stage of the disease, before the adhesion actually occurs when the retraction is simply overaction. (slide) It is our contention that early lid retraction is simply overaction of Mueller's muscle and since Mueller's muscle is sympathetically innervated, if one gets an increase in catecholamines in the blood then one may get a lid retraction. This can be shown by the fact that if one gives a patient an alpha blocker such as phentolamine (Regitine®) one does in fact get a reduction in the lid retraction. (slide) This next slide is taken from a paper by Sheldon Waldstein of our Endocrinology Department. You see a man with bilateral lid retraction due to thyrotoxicosis. (slide) This is after the instillation of Regitine in his right eye. The second picture is taken about 45 minutes after instillation. (slide) This is from another paper by the same author but showing a patient given systemic guanethidine 50 mg daily for three days. After three days the lids begin to come down. In short, ifone blocks the alpha receptors or uses a postganglionic block one can in fact change the lid position in thyroid disease before true fibrosis takes place. My second comment is made in an attempt to correct a historical inequity. (slide) This is Doctor Graves, a renowned Irish physician who regularly gave lectures at the Meath Hospital in Dublin which were later published in the London Medical and Surgical Journal. (slide) Here is the first page of the issue in which he published his lectures given in 1835. (slide) This is a page copied from the original manuscript and what it states is that Doctor Graves never did see a patient with thyroid disease and proptosis but that "a friend tells me of two patients who have protrusions of the eyes associated with a goiter." Doctor Graves did not actually see the patients himselfbut only reports what was told him by a friend. As you may gather I feel that the eponym "Graves' Disease" is thus a little unfair. The next slide is a picture of an English physician named Caleb Parry who described a patient with thyrotoxicosis ten years before Graves, that is in about 1825, but unfortunately this report was not published until after his death when all of Doctor Parry's collective papers were published. Among these papers was the description of a patient with proptosis and thyroid disease and so the question arises why is it not called Parry's Disease rather than Graves' Disease. There is a very involved story which I will not go into, but let me summarize by saying that since the time of Jesus great teachers have been crucified for not publishing. DR J. LAWTON SMITH. I should like to say I do not agree with the "NOSPECS" classification. To be specific, many patients with thyroid eye disease come in first with symptoms, and without signs. Their eyes are uncomfortable, they blink a lot, they are quite photophobic, and the eye examination is often negative. In fact, it is much more common for them to have symptoms without signs, than to present with signs without symptoms. It is important to do a Schirmer's test on these patients as there is a very high incidence ofpositive Schirmer's tests in patients with euthyroid Graves' disease. The second point that I see often is pathologic lid retraction. The next commonest one is diplopia, and these are more common than proptosis cases. The "NOSPEC S" classification doesn't indicate the frequency of the tight inferior rectus, then the tight medial rectus, and finally the tight superior rectus syn-
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dromes. Optic nerve involvement is very uncommon. One should also remember the association with myasthenia. Doctor Costin suggested the use of timolol for lid retraction. We tried this in two patients. Finally, I believe there should be a classification of the eye signs in thyroid eye disease prepared by ophthalmologists that would be more inclusive and representative of what we really see in practice. Have you tried timolol for lid retraction Doctor Shoch? DR DAVID SHOCH: Yes, we tried it and it doesn't work. DR J. LAWrON SMITH. One lady from Canada did like timolol for her lid retraction, so I would like to hear comments from others who have tried it. DR BARTON HODES. I would like to thank Doctors Alper, Bronson, Day, Kennedy, Von Noorden, Potts and Smith and an otherwise formidable audience for being gentle. I would first like to address Doctor Bronson's question ifI may and say that contact B-scan is a qualitative evaluation of what we are seeing in the orbit not a quantitative measure and so I don't believe we can draw any firm conclusions. Actually, in my experience, all patients with at least class 3 Graves' orbitopathy were found to have these abnormalities unequivocally with contact B-scan. In patients with milder orbitopathy the findings were more subtle and equivocal and when I originally wrote this, I included those as negatives or plus/minus. Doctor Day, I would agree with you that this is may very well be a panorbitopathy and not just a panmyositis, and I would be willing to investigate that further. I don't know that we can identify the chicken or the egg at this moment but the panorbitopathy may cause the involvement ofall the muscles or it may well be that the muscles lead to involvement of the orbit. Doctor Smith I would have expected to make a stronger statement. This would not be the first time that Doctor Smith has spoken more strongly than I, and I thank you for your comments. Doctor Kennedy, I would refer you to some work done by Harold Skalka in Birmingham who measured the optic nerves ofpatients with proven thyroid orbitopathy; I intentionally stayed away from the optic nerve for the sake of brevity. The optic nerves are definitely wider; the intrasheath distance is greater with standardized A-scan in patients who have proven thyroid orbitopathy than it is in the normal population and this may well explain the process in the optic nerve and optic neuritis. Doctor Von Noorden, I believe you were the one who asked if we equate our findings with forced ductions, and we have obviously done forced ductions on all of our patients. With mild enlargements of the extraocular muscles I don't feel that I am sophisticated enough to identify very minor resistance to the forced ductions. When the forced ductions are definitely positive in a patient who is asymptomatic from motility abnormalities I can identify those patients in the absence of symptoms.
