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Show /. Clin. Neuro-ophthalmol. 1: 219-224, 1981. Graves' Orbitopathy and the Thyrotropin-Releasing Hormone (TRH) Test JAMES A. RUSH, M.D. JAY J. OLDER, M.D. Abstract The value of the thyrotropin-releasing hormone (TRH) test may be insufficiently emphasized in the diagnosis of patients with euthyroid Graves' disease who have unexplained proptosis or vertical diplopia. We saw three patients who had these orbital symptoms and normal routine serum thyroid studies. The orbital computed tomograms (CT) found an orbital myopathy in all, and the diagnosis of Graves' orbitopathy was made by an abnormal TRH test. Not all euthyr.>id Graves' patients will show a positive result, but in those who do, the test is diagnostic. The clinical summaries of our three patients and the applications of the thyrotropin-releasing hormone test in ophthalmic practice are reviewed. Introduction An absent response of serum thyroid-stimulating hormone (TSH) to an intravenous injection of synthetic thyrotropin-releasing hormone (TRH) is diagnostic of thyroid gland disease in patients who are not manifestly thyrotoxic.' The application of this test to patients who have orbital symptoms and are euthyroid is obvious, and previous reports have demonstrated the high sensitivity of this test in patients who have the orbitopathy of euthyroid Graves' disease. 2 . 3 We saw three patients who had unilateral proptosis, abnormal ocular motility, or both who had an abnormal TRH stimulation test. In ali cases a CT scan found an orbital myopathy, but the TRH test was more specific, less expensive, and unequivocal. Case Reports Case 1 A 66-year-old woman was seen on June 9, 1980, for evaluation of painless vertical diplopia that From the Department of Ophthalmology, University of South Florida College of Medicine, Tampa, Florida. September 1981 developed after a basketball struck the left side of her head 7 months previously. No other neurological symptoms had developed in the interval, and the diplopia was unchanged. A cranial CT scan, performed soon after the injUry, was negative. Twenty years earlier she had a subtotal thyroidectomy but was currently on no thyroid medication. Visual acuity was 20/20 in each eye. Results of an ocular examination were normal except for the motility findings. An 18 prism-diopter left hypertropia in primary position increased on gaze to the right and head tilt to the left. A moderate weakness of the superior oblique muscle and overaction of the left inferior oblique muscle were present. A traumatic left superior oblique paresis was diagnosed, and treatment was deferred. She was seen again on December 11, 1980, for increasing vertical diplopia. Three months previously she had been treated elsewhere for herpes zoster ophthalmicus that involved the skin of the left side of the forehead and nose but spared her eye. Visual acuity was 20/20 in both eyes. Conjunctival chemosis and upper lid retraction were absent (Fig. 1). Exophthalmometry readings at base 102 were 15 mm bilaterally. A residual left hypertropia was present, but elevation of the left eye was also impaired, and a forced duction test was positive. Intraocular pressures, 12 mm Hg in primary position bilaterally, increased in upgaze to 18 mm Hg in the right eye and 22 mm Hg in the left. A tensilon test was negative. A complete blood count and erythrocyte sedimentation rate were normal. A serum T4 was 10.3 mcg/dl (normal = 4.5-12.0), the T3 uptake was 29% (normal = 23-32%), and the free thyroxin index was 2.9 (normal = 1.0-3.8). Serum triiodothyronine (total T3) was 159 ng/dl (normal = 60200). A baseline TSH was 1.0 mlu/ml (normal = 0-7.3). Thirty minutes after injection of 500 mcg synthetic TRH (thypinone), the serum TSH level was 2.2 mlu/ml. A serum antinuclear antibody assay was negative. The thyroglobulin antibody titer was 40 (normal = less than 40). A microsomal antibody titer was 400 (normal = less than 100). Two weeks later, ocular irritation and bilateral 219 TRH Test Figure 1 (Rush and Older). Patient 1. Eyelid retraction and ocular injection are absent the day of the positive TSH test. Figure 2 (Rush and Older). Patient 1. Two weeks later. the upper eyelids are retracted, the conjunctiva are injected. and the left eye is hypotropic. lower eyelid swelling occurred. Visual acuity was 20/20 bilaterally, and ocular injection and conjunctival chemosis had developed. The left eye was hypotropic, further restricted in upgaze, and had 2 mm proptosis. Both upper eyelids were retracted (Fig. 2). An orbital CT scan found enlarged extraocular muscles, particularly prominent at the orbital apex inferiorly (Fig. 3). An endocrinology consultant found a multinodular goiter. Comment. A 66-year-old woman with a remote 2.20 history of thyroid gland surgery had several consecutive problems: a left superior oblique weakness, ipsilateral herpes zoster ophthalmicus, and, ultimately, dysthyroid orbitopathy bilaterally. The first orbital sign of euthyroid Graves' disease was restriction of elevation of the left eye. Proptosis and lid retraction developed after an abnormal TRH stimulation test was found. An orbital CT scan found enlarged extraocular muscles at the orbital apex. Journal of Clinical Neuro-ophthalmology ease 2 A 58-year-old man was evaluated on February 12,1981, for evaluation of painless vertical diplopia of 3 months' duration. There was no ocular irritation, lacrimation, or pain, and he had a negative past medical history. Visual acuity was 20/20 in each eye, and the pupils were normal. A six prismdiopter right hypertropia was present in primary Rush, Older position. Elevation of the left eye was severely impaired (Fig. 4) and forced duction testing was positive. Other ocular movements were normal. Exophthalmometry measurements at base 98 were 17, right eye, and 20, left eye. Lid retraction was absent. Intraocular pressures were 15 mm Hg in the right eye and 17 mm Hg in the left eye. Ophthalmoscopy was normal. A tensilon test was negative. A complete blood count, erythrocyte sed- Figure 3 (Rush and Older). Patient 1. An orbital CT scan showing enlarged extraocular muscles in the inferior orbital apex of the left orbit. Figure 4 (Rush and Older). Patient Z. Severe impairment of elevation of the left eye is present the day of the positive TSH test. September 1981 221 TRH Test imentation rate, and skull x-rays were normal. A serum T4 was 12.0 mcg/dl (normal = 4.5-12.0), the T3 uptake was 26% (normal = 23-32%), and a free thyroxin index was 3.1 (normal = 1.0-3.8). A serum triiodothyronine (total T3) was 157 ng/dl (normal = bO-200). A baseline TSH serum value was 1.2 mlu/ml (normal = 0-7.3 mlu/ml). Thirty minutes after TRH (thypinone) injection, the TSH value was 1.9 mlu/ml. An orbital CT scan found an enlarged left inferior rectus muscle (Fig. 5). A thyroglobulin antibody titer and a microsomal antibody titer were negative. Prednisone, starting in a daily dose of 80 mg and tapering over 2 weeks, was ineffective in releasing the inferior rectus restriction. Comment. This man had no past medical history of thyroid disease and had neither the soft tissue symptoms nor lid signs that patients with thyroid eye disease frequently have. A flat TRH stimulation test diagnosed dysthyroid myopathy, and an enlarged inferior rectus muscle was seen on CT scan. Case 3 A 33-year-old woman was seen on March 17, 1981, for evaluation of painless proptosis of the right eye for 2 months' duration. She denied pain, ocular irritation, double vision, or ocular injection but complained of a vague difficulty in "focusing." There was no previous thyroid gland disorder, and she was receiving no medication. Visual acuity was 20/20 in both eyes. Pupillomotor and ophthalmoscopic findings were normal. The right eye had 5 mm proptosis (Hertel at base 103: right eye 21 mm and left eye 16 mm). The right lid fissure measured 12 mm compared with 10 mm of the left lid fissure, and elevation of the right eye was impaired (Fig. 6). An endocrinology consultant found no abnormalities on physical examination. A complete blood count and erythrocyte sedimentation rate were normal. A serum T4 was 5.8 mgc/dl (normal = 4.5-11.5), the serum T3 uptake was 42% (normal = 35-45), and a free thyroxin index was 2.4 (normal = 1.5-5.2). An orbital CT scan found an enlarged inferior rectus muscle on the right (Fig. 7). A serum baseline TSH level was 1.4 mlu/ml (normal = 07.3 mlu/ml). Thirty minutes after intravenous injection of 500 mcg of TRH (thypinone), a serum TSH was 1.7 mlu/ml. Comment. This patient, who had no previous history of a thyroid gland disorder, had proptosis and impaired elevation of the right eye. An orbital CT scan showed an enlarged inferior rectus muscle and a nonresponsive TSH value was found in the serum. Discussion Graves' orbitopathy is the most common cause of exophthalmos, and the typical signs of lid retraction and restriction of upgaze can occur in patients who are euthyroid.4 . 5 If, in contrast, a euthyroid patient has proptosis or ophthalmoplegia but no lid retraction or orbital congestion, the diagnosis may be missed. In this study, none of the three euthyroid patients initially had typical ocular signs or symptoms to suggest the correct cause of 222 I i~ure 5 1I<",h .,"d Older). f'Jtil'nt 2. An orbital CT scan showing enlargement of the left inferior rectus muscle. Journal of Clinical Neuro-ophthalmology Rush, Older Figure 6 (Rush and Olderl. Patient 3. The right eye is proptotic and shows moderate impairment of elevation. Figure' (Rush and Old<'r). Pali<'nt 3. An orbital CT scan followin~ injertion <,f mntr."t O1.lter;.,1 shows an enlarg<,d inferior r<'ctus muscl<, af!<'r th<, r<,sults of .In .lbllorm.,1 TSH le,t. their monocular elevation restriction. The diagnosis of Graves' orbitopathy, principally involving the inferior rectus muscle, was made by the TRH test in these patients who had demonstrably enlarged inferior recti muscles on CT scans. The TRH test employs a pharmacologic manipulation of the hypothalmic-pituitary axis and relies on the expected rise of serum TSH that is liberated September 1981 from the pituitary gland under the influence of its hormonal antecedent TRH. A bolus of 500 mcg TRH is injected intravenously. Serum TSH is measured after 30 minutes. An increment of 5-30 mlu/ ml is expected in normal subjects, but patients with hyperthyroidism and a suppressed pituitary gland cannot respond, and a negligible serum increment results. Bec,lUse of the ease, availability, and clini- 223 TRH Test cal safety of the TRH stimulation test, and because it is occasionally positive in patients with a normal Cytomel suppression test~ (a traditional index of thyroid autonomy), the TRH test should be an integral part of the laboratory workup of a patient with unexplained proptosis or impaired elevation. Orbital examination by refined computed tomographic techniques have been helpful in diagnosing Graves' orbitopathy if enlarged extraocular muscles and an increase in the orbital fat are found.HTrokel and Hilal emphasize that the inferior rectus is the extraocular muscle most frequently abnormal in Graves' disease, followed by the medial and superior rectus respectively.H Although orbital myositis and carotid-cavernous fistulas can also cause enlargement of the extraocular muscles, differentiation of these conditions from Graves' disease is possible clinically. Enlarged extraocular muscles are occasionally seen in cases of orbital neoplasia, but CT scans usually also find a coexistant orbital mass.HSophisticated, thin-section (4 mm) CT techniques may not be universally available, however, and misinterpretation of some scans has resulted in a fruitless orbital exploration for suspected tumor.7 In cases where the CT scan is inconclusive, a TRH test would be a most useful diagnostic tool. In one series, an abnormal TRH test was found in 75% of 41 euthyroid patients suspected of having Graves' orbitopathy.2 Ten of the 41 had unilateral proptosis and no lid retraction, and, of these, eight had abnormal TRH test. Our three patients were also euthyroid, both clinically and chemically, and typical symptoms and signs of ophthalmic Graves' disease developed later. In contrast to earlier studies describing the usefulness of TRH tests in patients with typical dysthyroid features, this report emphasizes that TRH tests are diagnostic of Graves' orbitopathy in patients who may only have enlarged extraocular muscles determined by CT scan. Unfortunately, only 40% of all patients with euthyroid Graves' orbitopathy have an absent or blunted serum TSH response to exogenously administered TRH. lO • 11 Furthermore, exaggerated12 TSH responses may occur in some euthyroid patients with Graves' disease. We feel, however, that an unequivocally abnormal TRH test in patients 224 who lack other features of Graves' disease is diagnostic and predicts the subsequent development of familiar features of thyroid eye disease. References 1. Lawton, N.F., Ekins, R.P., and Nabarro, J,D.N.: Failure of pituitary response to thyrotropin-releasing hormone in euthyroid Graves' disease. Lancet 2: 14, 1971. 2. Lawton, N.F., Fells, P., and Lloyd, GA.S.: Medical investigation of dysthyroid eye disease. In Proceedings of the 3rd International Symposium on Orbital Disorders, Dr. W. Junk bv, Amsterdam, 1977, pp. 343-348. 3. Zakarija, M., McKenzie, J,M., and Banovac, K.: Clinical significance of assay of thyroid stimulating antibody in Graves' disease. Ann. Int. Med. 93 (part 1): 28, 1980. 4. Werner, S.: Euthyroid patients with early signs of Graves' disease. Am. f. Med. 18: 608, 1955. 5. Schneeberg, N.G: Recent advances in thyroid disease. In Neuor-ophtha/m%gy Focus 1980, J.L. Smith, Ed., Masson Publishing USA, Inc., New York, 1979, pp. 347-356. 6. Trokel, S.L, and Hilal, S.K.: Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography. Am. f. Ophtha/mol. 87: 503, 1979. 7. Kennerdell, J.5., and Maroon, J,C: CT scan appearance of dysthyroid orbit disease. Ann. Ophtha/mo/. 10: 153, 1978. 8. Hyman, B.N., and Johnson, P.C: Thyrotropin-releasing hormone (a test to diagnose Graves' opthalmopathy). Trans. Am. Acad. Ophtha/mo/. 79: 524, 1975. 9. Jackson, W.B., Tolis, G, and Chertman, M.: The TRH test: Its value in the diagnosis of Graves' Ophthalmopathy. Can. f. Ophtha/mo/. 13: 10, 1978. 10. Teng, CS., and Yeo, P.P.R.: OphthalmiC Graves' disease. Br. Med. f. 1: 273, 1977. 11. Spoor, T.C, and Kennerdell, J.S.: Thyrotropin-releasing hormone test and the diagnosis of dysthyroid orbitopathy. Ann. Ophtha/mo/. 13: 443, 1981. 12. Chopra, I.]., Chopra, U., and Orgazzi, J.: Abnormalities of the hypopthalamo-hypophyseal-thyroid axis in patients with Graves' Ophthalmopathy. f. Clin. Endocrino/. Metab. 37: 955, 1973. Write for reprints to: James A. Rush, M.D., 12901 N. 30th Street, Box 21, University of South Florida College of Medicine, Tampa, Florida 33612. Journal of Clinical Neuro-ophthalmology |
