6 Emergency treatment of Graves' ophthalmopathy R E B E C C A S. B A H N GEORGE B. B A R T L E Y COLUM A. GORMAN
Graves' ophthalmopathy is generally a chronic, slowly progressing or remitting disease. Although most often associated with hyperthyroidism, this condition can occur without clinical evidence of thyroid disease or it may precede or follow the onset of hyperthyroidism (Tamai et al, 1980; Gorman, 1983). The most common clinical features include eye discomfort, often described as 'eye pressure' or a 'gritty, sandy' sensation, double vision and protrusion of the globes. The severity of these symptoms may range from a mild inconvenience to the patient to intractable eye pain, constant and functionally limiting diplopia, severely impaired visual acuity or a disfiguring facial appearance (Bahn et al, 1990). Although many of the symptoms of Graves' ophthalmopathy are quite distressing to patients, the purpose of this report is to outline the diagnosis and treatment of the disease manifestations that are true ocular emergencies, namely optic neuropathy, corneal ulceration, subluxation of the globe, and severe periorbital oedema with chemosis. An internist or endocrinologist is often the first physician consulted by a patient with Graves' ophthalmopathy. However, an ophthalmologist generally manages the treatment of those patients with the most severe ocular complications. Therefore, to facilitate prompt referral to an ophthalmologist, the initial physician must be able to recognize the signs and symptoms that suggest the presence of an ocular emergency. Many of the clinical signs and symptoms of Graves' ophthalmopathy result from gross enlargement of the extraocular muscles and connective tissue spaces behind the globe. Because these tissues are contained within a confined space, any significant increase in their volume may result in anterior globe displacement (proptosis or exophthalmos), and may impede venous drainage from the orbit, resulting in periorbital, eyelid and conjunctival oedema. Compression of the optic nerve at the orbital apex may occur, resulting in optic neuropathy. Although the extraocular muscle bodies are grossly enlarged in Graves' ophthalmopathy, the muscle cells themselves are morphologically and functionally normal (Kroll and Kuwabara, 1966; Jensen, 1971). However, the connective tissue surrounding and investing the muscle cells, as well as Baillikre's Clinical Endocrinology and Metabolism-95 Vol. 6, No. 1, January 1992 Copyright © 1992, by Bailli6re Tindall ISBN 0-7020-1485-0 All rights of reproduction in any form reserved
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the remainder of the connective tissue within the orbit, is oedematous and contains increased quantities of glycosaminoglycans (Hufnagel et al, 1987; Riley, 1972). These hydrophilic macromolecules are a major product of connective tissue fibroblasts. The clinical features of Graves' ophthalmopathy can be explained by an increase in the volume of the retro-ocular tissues caused by glycosaminoglycan accumulation within the perimysial and retro-ocular connective tissues. The factors responsible for this glycosaminoglycan accumulation are not well understood, although stimulation of retro-ocular fibroblasts by cytokines or immunoglobulins may be important (Sisson et al, 1973; Korducki et al, 1992). Forward displacement of the globe occurs as. the muscle and connective tissue volume behind the eye increases, elevating the pressure within the confines of the bony orbit. Proptosis is partially limited by the orbital septum, a fibrous structure that extends circumferentially from the periosteum of the anterior orbital rim into the upper and lower lids, and by the posterior attachment of the extraocular muscles to the annulus of Zinn, a fibrous ring at the apex of the orbit. The elevated pressure behind the eye, counter-balanced by the forces attempting to limit anterior displacement of the globe, may cause significant pressure-type pain felt behind the eye. When the pressure within the retrobulbar tissues exceeds the forces
Figure 1. CT scan of orbitsin a patient with Graves'ophthalmopathy.The enlarged extraocular muscles at the apex of the right orbit (arrow) compress the optic nerve, causing optic neuropathy.
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counteracting proptosis, the rare complication of subluxation of the globe anterior to the eyelids may occur. The prevalence of optic neuropathy with marked visual loss in patients with Graves' ophthalmopathy is less than 5% (Henderson, 1958). Optic nerve compromise results from massive extraocular muscle swelling in the apex of the orbit (Figure 1). The optic nerve compression may also be in part due to particularly non-compliant, fibrotic muscles at the apex (Feldon et al, 1984). This compressive neuropathy causes ischaemic or direct pressure damage to the optic nerve that may be irreversible if prolonged. Severe optic neuropathy often occurs without significant proptosis in patients whose orbital septum efficiently limits proptosis despite marked increases in retrobulbar pressure. Such patients generally have significant resistance to retropulsion of the globe on physical examination (Frueh et al, 1985). Case reports in the literature describe Graves' optic neuropathy without evidence of extraocular muscle enlargement; short optic nerves on stretch or compression secondary to increased orbital fat volume appear to be possible causes (Anderson et al, 1989). Corneal ulceration as a complication of Graves' ophthalmopathy may result from extreme proptosis that precludes complete protection of the globe by the eyelids (lagophthalmos). Thus, the patient's ability to lubricate the eye by blinking or to close the eyelids during sleep is impaired. In this setting, exposure keratitis or even corneal ulceration may develop. In some patients who do not have significant proptosis, corneal involvement may result from severe fibrosis and functional shortening of the levator palpebrae superioris, the muscle that elevates the upper eyelid. Upper and/or lower eyelid retraction may prevent adequate lubrication and protection of the globe. EVALUATION OF CLINICAL SIGNS AND SYMPTOMS Certain symptoms described by patients with Graves' ophthalmopathy must be considered ocular emergencies until proven otherwise. Of particular concern is the complaint of 'blurry vision'. Impaired visual acuity due to optic neuropathy is classically associated with decreased colour vision and is usually bilateral and slowly progressive. However, the condition may be appreciated by the patient only as general blurriness of vision, or as no noticeable visual disturbance at all. In some cases, rapid visual impairment or features mimicking orbital cellulitis may occur (Dunne and Edis, 1985). Among 21 patients with optic neuropathy studied in retrospect, 14 patients reported a 1-12 month history of insidious visual loss before the initial examination. All 21 patients complained of orbital congestive symptoms preceding the visual loss by at least one month, with a median of 4 months. These symptoms included ocular discomfort, tearing, periorbital swelling and conjunctival erythema. No direct relationship existed between the degree of proptosis or congestive symptoms and the optic nerve compression. In no case was visual loss the only or initial complaint (Trobe et al, 1978). In contrast, momentary visual blurring that can be cleared by blinking
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VOS W.C. 20/40- 14/217:+1
VOD W.C.20/20 stowly 14/21 2/1000
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/1000
acl30
Figure 2. Visual field of a patient with Graves' optic neuropathy. Top: Tangent screen testing ('manual' perimetry) demonstrates a cecocentral scotoma for the right eye and an inferior altitudinal defect for the left eye. Bottom: Automated (computer-assisted) perimetry of the same patient is more sensitive in evincing inferior visual field loss in the right eye.
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is usually due to excess fluid on the surface of the cornea from irritative reflex tearing. Blurred vision that is ameliorated by closing either eye may indicate early extraocular muscle imbalance that is not yet perceived by the patient as diplopia (Bahn et al, 1990). Although limitation of eye elevation due to inferior rectus fibrosis is the most common motility abnormality noted in patients with Graves' ophthalmopathy, this pattern is less frequently seen in the subgroup with optic neuropathy. In these patients, eye movements are generally reduced more or less symmetrically in all directions (Trobe, 1981). As a result, affected patients may not experience diplopia. On CT scanning, these patients often have massive enlargement of all extraocular muscles, rather than the selective inferior and medial rectus enlargement commonly seen in patients with Graves' ophthalmopathy. The condition may be predominantly unilateral in approximately 15 % of cases (Trobe et al, 1978). Patients with Graves' optic neuropathy tend to be older (age 50-70 years) than the mean (age 44) of all patients with Graves' disease (Trobe, 1981). Early recognition of optic neuropathy is critical to preserve as much sight as possible as there is an inverse relationship between duration of visual loss and efficacy of treatment (Trobe, 1981; Bartalena et al, 1983). Unfortunately, incorrect or delayed diagnoses are sometimes made. In one study of 18 patients with optic nerve involvement, 15 were initially diagnosed as having visual loss due to cataracts, keratitis, macular degeneration, intracranial or orbital tumours, diabetes or malingering (Trobe and Glaser, 1978). If untreated, severe visual loss may ensue. A review of reports of 32 untreated eyes found that 7 patients were left with a visual acuity of 20/100 or worse, including 5 with final vision of finger counting to no light perception (Trobe, 1981). More common, however, are final visual acuities within the range of 20/30 to 20/50 from less severe optic neuropathy. Therefore, the complaint of consistently 'blurred vision' in a patient with Graves' ophthalmopathy warrants prompt referral to an ophthalmologist. The ophthalmological evaluation of a patient with optic neuropathy may demonstrate decreased visual acuity, impaired colour perception, or an afferent pupillary defect. An afferent pupillary defect is detected by the 'swinging flashlight test' in which the pupillary reactions to direct light are compared between the patient's two eyes; pupil dilation indicates decreased transmission in some portion (usually the optic nerve) of the afferent neural pathway. The optic disc may be swollen (25-33% of cases) or pale (10-20% of cases) (Trobe and Glaser, 1978), or the ophthalmoscopic appearance may be entirely normal. A visual field examination is helpful in the evaluation of possible optic neuropathy, and can be performed with a tangent screen, Goldman perimeter, or ideally, an automated perimeter. Characteristically, a central scotoma or an inferior altitudinal defect or scotoma is seen (Figure 2). CT scanning may be a helpful adjunctive test when optic neuropathy is suspected. In a study of 76 patients with Graves' ophthalmopathy, significant correlation of several mid-orbital axial CT parameters (including total muscle volume and orbit/fat ratio) with the presence of optic neuropathy was documented (Hallin and Feldon, 1988). Slit-lamp biomicroscopy, performed by an experienced ophthalmologist,
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is useful in evaluating corneal and conjunctival exposure from eyelid retraction and proptosis. Rose bengal or fluorescein is instilled into the inferior cul-de-sac; after distribution in the tear film, the stain binds to defects in the corneal epithelium. With significant exposure keratitis, a band of greyish-white, superficial, punctate, epithelial defects can be seen along the inferior bulbar conjunctiva and cornea. The cornea appears roughened rather than lustrous (Figure 3). Corneal ulceration is distinguished on slit-lamp biomicroscopy by marked, focal loss of continuity of the corneal epithelium, excavation into the corneal stroma, surrounding cellular infiltrates, and signs of inflammation in the anterior chamber. Although mild to moderate superficial keratopathy from exposure may cause ocular discomfort, true corneal ulceration results in extreme eye pain and is generally accompanied by marked conjunctival injection (erythema).
Figure 3. Slit-lamp photograph of severe exposure keratopathy. The corneal surface is irregular and roughened, and the eye is inflamed. This eye is at risk for progression to ulceration of the cornea that may result in severe visual loss.
Photophobia is typically severe and examination of the eye may be difficult. Generally, a patient with severe eye pain should be referred promptly to an ophthalmologist. As discussed previously, forces tending to counteract subluxation of the globe involve the restraint of the eye within the socket by the orbital septum and the posterior attachment of the extraocular muscles at the apex of the orbit. Additionally, the actual volume of the orbit is an important factor; a shallow socket is less able to maintain a severely proptotic globe in position. An extremely proptotic patient with marked eyelid retraction is at the highest risk for subluxation (Figure 4).
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Figure 4. Top: Subluxation of the globe in a patient with Graves' ophthalmopathy. Bottom: The same patient following transantral orbital decompression surgery.
TREATMENT
Optic neuropathy can be treated emergently with high-dose corticosteroids, supervoltage ( 4 6 meV) X-irradiation, or orbital decompression surgery. Although no controlled treatment protocol has been reported to date, there is evidence that each of these options is effective as acute therapy (Trobe and Glaser, 1978). Because spontaneous remission does occur occasionally, one group advocates observation with close follow-up for patients who have a visual acuity of 20/30 or better, with treatment for patients with progressive visual loss or with optic disc swelling (Dunne and Edis, 1985). Most commonly, however, medical treatment with corticosteroids is prescribed upon diagnosis of Graves' optic neuropathy. For the patient with rapidly decreasing vision due to optic neuropathy, or with severe periorbital oedema and chemosis, treatment with high doses of oral prednisone (100-140 mg per day) can be expected to effect dramatic improvement. Generally, clinical improvement from corticosteroids is evident within 72 h of initiation of prednisone and is maximal in 6-8 weeks. Therefore, further prolonged high-dose corticosteroid therapy without demonstrable benefit is not appropriate (Werner, 1966; Day and Carrol, 1968). In some patients, optic neuropathy initially responds well to highdose corticosteroids, but recurs following a reduction in dosage to more acceptable levels. The well-known side-effects of chronic high-dose corticosteroid therapy preclude this treatment as a long-term solution. No data support the use of intraorbital injections of corticosteroids or larger doses of corticosteroids (megadose therapy).
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If an initial positive response to steroids fails, due to intolerance of medication side-effects or to recurrence of optic neuropathy or severe inflammation at tapered doses, radiation therapy is frequently the next recommended treatment. One study (Ravin et al, 1975) described treatment with supervoltage X-irradiation of 37 patients with Graves' ophthalmopathy, 9 of whom had optic neuropathy. These 9 patients exhibited the most dramatic response to treatment in that series, with only one requiring further corticosteroids and decompression surgery. A total dose of 15002000 cGy fractionated over ten daily treatments, aimed at the orbital apices via laterally wedged portals, was used. This technique delivers a total dosage of less than 100 cGy to the lens, cornea, hypothalamus and pituitary. No intraocular complications or cataracts were reported in short-term (2 years or less) follow-up studies (Brennan et al, 1983). Another group reported good to excellent results of radiation treatment given to 141 patients with Graves' ophthalmopathy; only 4 eventually required orbital decompression surgery (Donaldson et al, 1973). A recent report of over 300 patients with 'symptomatic and progressive Graves' ophthalmopathy' described improvement in soft tissue signs, proptosis, ocular motility, keratopathy and visual acuity in 94% or more of cases with no long-term complications (Petersen et al, 1990). Concurrent use of orbital irradiation and systemic corticosteroids was successful in a recent trial of 36 patients with Graves' ophthalmopathy in which 72% of patients had a good response. Two of the patients had severe
SURGICAL RESULTS
131/143 eyes
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Figure 5. Results of transantral orbital decompression in 131/143 eyes: effect on visual acuity. The dark diagonal bar represents initial vision; lines to circles represent postoperative change in acuity. Numbers in circles are the numbers of eyes so changed. Very few eyes became worse; most improved, some from very poor vision preoperatively. From Younge (1984), with permission.
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visual loss but enjoyed complete restoration of sight following treatment (Bartalena et al, 1983). Orbital decompression surgery is considered by some practitioners to be the treatment of last resort for Graves' optic neuropathy (Kennerdell et al, 1981), but by others to be a useful early modality (Gorman et al, 1974; Younge, 1984; Hallin et al, 1988). Our approach to the treatment of Graves' optic neuropathy follows, in part, from our ready accessibility to surgeons with much experience in orbital decompression. If a patient with optic neuropathy simultaneously possesses other indications for decompression, such as significant proptosis or proptosis with extraocular muscle imbalance, we generally recommend early orbital decompression. We favour the transantral approach and have found the results of this procedure to be dramatic and predictable in more than 85-90% of patients (Younge, 1984) (Figure 5). In most cases there is an immediate partial improvement in vision followed by gradual further recovery. Transantral orbital decompression with removal of the orbital floor and portions of the nasal orbital wall and ethmoid sinus effectively decompresses the optic nerve, even though this approach does not involve the area of the orbital apex itself (Gorman et al, 1974). In a study by Hallin, 25 patients (48 eyes) underwent transantral decompression for Graves' optic neuropathy. Visual acuity improved in 77%, remained unchanged in 17% and worsened in 6%. Colour vision improved in 76%, remained unchanged in 20% and worsened in 4%. Visual fields improved in 67%, remained unchanged in 12% and worsened in 22%. Preoperative clinical and radiological findings did not correlate with postoperative visual outcome (Hallin et al, 1988). If a patient has optic neuropathy alone, without other indications for decompression surgery, we generally recommend a course of corticosteroids. We have found that optic neuropathy may respond to high-dose prednisone therapy and not recur upon tapering the medication to lower, better-tolerated doses (e.g. below 40mg a day with eventual discontinuation). However, often patients must be maintained on unacceptably high corticosteroid doses to alleviate the optic neuropathy. We usually recommend decompression for these patients with rapid tapering of corticosteroids postoperatively. When a corneal ulcer develops primarily as the result of severe proptosis, orbital decompression surgery is emergently indicated. Corneal ulceration or keratitis due to extreme eyelid retraction without significant proptosis may be treated by recessing the eyelid retractors to allow the lid to cover the eye. Occasionally, spacer grafts such as hard palate mucosa, auricular cartilage, or donor sclera are required to achieve proper eyelid positions. The corneal ulcer itself is treated with high-dose, high-frequency antimicrobial eyedrops after appropriate cultures have been taken. Severe corneal scarring may necessitate later penetrating keratoplasty (cornea transplant). Subluxation of the globe anterior to the eyelids typically is very painful, but some patients learn how to reposition the eyelids satisfactorily. The event is sufficiently distressing that most patients seek definitive treatment, which consists of orbital decompression and/or eyelid retraction surgery.
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SUMMARY
The ocular emergencies encountered in Graves' ophthalmopathy, namely optic neuropathy, corneal ulceration, subluxation of the globe, and severe periorbital oedema with chemosis have been discussed. Evaluation of the clinical signs and symptoms of these conditions, as well as their treatment, have been outlined. Of particular concern is the complaint of 'blurry vision' that may indicate the presence of optic neuropathy. Early recognition of this entity, with prompt referral to an ophthalmologist is important because there is an inverse relationship between duration of visual loss and efficacy of treatment. The ophthalmological evaluation of a patient with optic neuropathy may demonstrate decreased visual acuity, impaired colour perception, or an afferent pupillary defect. In addition, a visual field examination may be a helpful adjunctive test. Available therapy for optic neuropathy includes high-dose corticosteroids, supervoltage X-irradiation and orbital decompressive surgery. We have reviewed the literature concerning these modalities and outlined our approach to the treatment of optic neuropathy. In general, we recommend orbital decompression at an early stage for this condition. Another worrisome complaint is of 'eye pain'. In this case, distinction must be made between the causes that include ocular inflammation, corneal keratitis and corneal ulceration. The corneal ulceration is characterized by extreme eye pain and erythema, and may require surgical intervention. Severe ocular inflammation may respond well to a course of high-dose steroids. A combination of these ocular emergencies in a patient with Graves' ophthalmopathy necessitates careful consideration of the available treatment options. REFERENCES Anderson RL, Tweeten JP, Patrinely JR et al (1989) Dysthyroid optic neuropathy without evidence of extraocular muscle involvement. Ophthalmic Surgery 20" 568-574. Bahn RS, Garrity JA & Gorman CA (1990) Diagnosis and management of Graves' ophthalmopathy. Journal of Clinical Endocrinology and Metabolism 71: 559-563. Bartalena L, Marcocci C, Chiovato L e t al (1983) Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: comparison with systemic corticosteroids alone. Journal of Clinical Endocrinology and Metabolism 56: 1139-1144. Brennan MW, Leone CR & Janaki L (1983) Radiation therapy for Graves' disease. American Journal of Ophthalmology 96: 195-199. Day RM & Carroll FD (1968) Corticosteroids in the treatment of optic nerve involvement associated with thyroid dysfunction. Archives of Ophthalmology 79: 279-282. Donaldson SS, Bagshaw MA & Kriss JP (1973) Supervoltage orbital radiotherapy for Graves' ophthalmopathy. Journal of Clinical Endocrinology and Metabolism 37" 276-285. Dunne JW & Edis RH (1985) Optic nerve involvement in Graves' ophthalmopathy: a case report and review. Australian and New Zealand Journal of Medicine 15" 258-261. Feldon SE, Muramatsu S & Weiner JM (1984) Clinical classification of Graves' ophthalmopathy-identification of risk factors for optic neuropathy. Archives of Ophthalmology 102: 14691472. Frueh BR, Musch DC, Grill R et al (1985) Orbital compliance in Graves' eye disease. Ophthalmology 92" 657-665. Gorman CA (1983) Temporal relationship between onset of Graves' ophthalmopathy and diagnosis of thyrotoxicosis. Mayo Clinic Proceedings 58: 515-519.
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Gorman CA, DeSanto LW, MacCarty CS & Riley FC (1974) Optic neuropathy of Graves' disease--treatment by transantral orbital decompression. New England Journal of Medicine 290: 70-75. Hallin ES & Feldon SE (1988) Graves' ophthalmopathyl II. Correlation of clinical signs with measures derived from computed tomography. British Journal of Ophthalmology 72: 678-682. Hallin ES, Feldon SF & Luttrell (1988) Graves' ophthalmopathy. III. Effect of transantral orbital decompression on optic neuropathy. British Journal of Ophthalmology 72: 683687. Henderson JW (1958) Optic neuropathy of exophthalmic goiter (Graves' disease). Archives of Ophthalmology 59: 471-480. Hufnagel TJ, Hickey WJ, Cobbs W H e t al (1987) Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease. Ophthalmology 91: 1411-1419. Jensen SF (1971) Endocrine ophthalmoplegia: is it due to myopathy or to mechanical immobilization? Acta Ophthalmologica (Copenhagen) 49: 679-684. Kennerdell JS, Rosenbaum AE & E1 Hoshy MH (1981) Apical optic nerve compression of dysthyroid optic neuropathy on computed tomography. Archives of Ophthalmology 99: 807-809. Korducki JM, Loftus SJ, Ting AT et al (1992) Interleukin-1 stimulation of [3HI glycosaminoglycan accumulation in retro-ocular and pretibial fibroblasts: potential role in the extrathyroidal manifestations of Graves' disease. Presented at the 72nd annual meeting of the Endocrine Society, June, 1990 (abstract, in press). Kroll AJ & Kuwabara T (1966) Dysthyroid ocular myopathy: anatomy, histology, and electron microscopy. Archives of Ophthalmology 76: 244-257. Petersen IA, Kriss JP & McDougall IR (1990) Prognostic factors in the radiotherapy of Graves' ophthalmopathy. InternationalJournal of Radiation Oncology, Biology, Physics 19: 259264. Ravin JG, Sisson JC & Knapp WT (1975) Orbital radiation for the ocular changes of Graves' disease. American Journal of Ophthalmology 79: 285-288. Riley FC (1972) Orbital pathology in Graves' disease. Mayo Clinic Proceedings 47: 975-979. Sisson JC, Kothary P & Kirchick H (1973) The effects of lymphocytes, sera and long-acting thyroid stimulator from patients with Graves' disease on retrobulbar fibroblasts. Journal of Clinical Endocrinology and Metabolism 37: 17-24. Tamai H, Nakagawa T, Ohsako N et al (1980) Changes in thyroid function in patients with euthyroid Graves' disease. Journalof ClinicalEndocrinology and Metabolism50: 108--112. Trobe JD (1981) Optic nerve involvement in dysthyroidism. Ophthalmology 88: 488-492. Trobe JD, Glaser JS & Laflamme P (1978) Dysthyroid optic neuropathy---clinical profile and rationale for management. Archives of Ophthalmology 96: 1199-1209. Werner SC (1966) Prednisone in emergency treatment of malignant exophthalmos. Lancet i: 1004-1007. Younge BR (1984) Eye examination techniques in Graves' ophthalmopathy, In Gorman CA, Waller RR & Dyer JA (eds) The Eye and Orbit in Thyroid Disease, pp 143-153. New York: Raven Press.
Graves' ophthalmopathy is generally a chronic, slowly progressing or remitting disease. Although most often associated with hyperthyroidism, this condition can occur without clinical evidence of thyroid disease or it may precede or follow the onset of hyperthyroidism (Tamai et al, 1980; Gorman, 1983). The most common clinical features include eye discomfort, often described as 'eye pressure' or a 'gritty, sandy' sensation, double vision and protrusion of the globes. The severity of these symptoms may range from a mild inconvenience to the patient to intractable eye pain, constant and functionally limiting diplopia, severely impaired visual acuity or a disfiguring facial appearance (Bahn et al, 1990). Although many of the symptoms of Graves' ophthalmopathy are quite distressing to patients, the purpose of this report is to outline the diagnosis and treatment of the disease manifestations that are true ocular emergencies, namely optic neuropathy, corneal ulceration, subluxation of the globe, and severe periorbital oedema with chemosis. An internist or endocrinologist is often the first physician consulted by a patient with Graves' ophthalmopathy. However, an ophthalmologist generally manages the treatment of those patients with the most severe ocular complications. Therefore, to facilitate prompt referral to an ophthalmologist, the initial physician must be able to recognize the signs and symptoms that suggest the presence of an ocular emergency. Many of the clinical signs and symptoms of Graves' ophthalmopathy result from gross enlargement of the extraocular muscles and connective tissue spaces behind the globe. Because these tissues are contained within a confined space, any significant increase in their volume may result in anterior globe displacement (proptosis or exophthalmos), and may impede venous drainage from the orbit, resulting in periorbital, eyelid and conjunctival oedema. Compression of the optic nerve at the orbital apex may occur, resulting in optic neuropathy. Although the extraocular muscle bodies are grossly enlarged in Graves' ophthalmopathy, the muscle cells themselves are morphologically and functionally normal (Kroll and Kuwabara, 1966; Jensen, 1971). However, the connective tissue surrounding and investing the muscle cells, as well as Baillikre's Clinical Endocrinology and Metabolism-95 Vol. 6, No. 1, January 1992 Copyright © 1992, by Bailli6re Tindall ISBN 0-7020-1485-0 All rights of reproduction in any form reserved
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the remainder of the connective tissue within the orbit, is oedematous and contains increased quantities of glycosaminoglycans (Hufnagel et al, 1987; Riley, 1972). These hydrophilic macromolecules are a major product of connective tissue fibroblasts. The clinical features of Graves' ophthalmopathy can be explained by an increase in the volume of the retro-ocular tissues caused by glycosaminoglycan accumulation within the perimysial and retro-ocular connective tissues. The factors responsible for this glycosaminoglycan accumulation are not well understood, although stimulation of retro-ocular fibroblasts by cytokines or immunoglobulins may be important (Sisson et al, 1973; Korducki et al, 1992). Forward displacement of the globe occurs as. the muscle and connective tissue volume behind the eye increases, elevating the pressure within the confines of the bony orbit. Proptosis is partially limited by the orbital septum, a fibrous structure that extends circumferentially from the periosteum of the anterior orbital rim into the upper and lower lids, and by the posterior attachment of the extraocular muscles to the annulus of Zinn, a fibrous ring at the apex of the orbit. The elevated pressure behind the eye, counter-balanced by the forces attempting to limit anterior displacement of the globe, may cause significant pressure-type pain felt behind the eye. When the pressure within the retrobulbar tissues exceeds the forces
Figure 1. CT scan of orbitsin a patient with Graves'ophthalmopathy.The enlarged extraocular muscles at the apex of the right orbit (arrow) compress the optic nerve, causing optic neuropathy.
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counteracting proptosis, the rare complication of subluxation of the globe anterior to the eyelids may occur. The prevalence of optic neuropathy with marked visual loss in patients with Graves' ophthalmopathy is less than 5% (Henderson, 1958). Optic nerve compromise results from massive extraocular muscle swelling in the apex of the orbit (Figure 1). The optic nerve compression may also be in part due to particularly non-compliant, fibrotic muscles at the apex (Feldon et al, 1984). This compressive neuropathy causes ischaemic or direct pressure damage to the optic nerve that may be irreversible if prolonged. Severe optic neuropathy often occurs without significant proptosis in patients whose orbital septum efficiently limits proptosis despite marked increases in retrobulbar pressure. Such patients generally have significant resistance to retropulsion of the globe on physical examination (Frueh et al, 1985). Case reports in the literature describe Graves' optic neuropathy without evidence of extraocular muscle enlargement; short optic nerves on stretch or compression secondary to increased orbital fat volume appear to be possible causes (Anderson et al, 1989). Corneal ulceration as a complication of Graves' ophthalmopathy may result from extreme proptosis that precludes complete protection of the globe by the eyelids (lagophthalmos). Thus, the patient's ability to lubricate the eye by blinking or to close the eyelids during sleep is impaired. In this setting, exposure keratitis or even corneal ulceration may develop. In some patients who do not have significant proptosis, corneal involvement may result from severe fibrosis and functional shortening of the levator palpebrae superioris, the muscle that elevates the upper eyelid. Upper and/or lower eyelid retraction may prevent adequate lubrication and protection of the globe. EVALUATION OF CLINICAL SIGNS AND SYMPTOMS Certain symptoms described by patients with Graves' ophthalmopathy must be considered ocular emergencies until proven otherwise. Of particular concern is the complaint of 'blurry vision'. Impaired visual acuity due to optic neuropathy is classically associated with decreased colour vision and is usually bilateral and slowly progressive. However, the condition may be appreciated by the patient only as general blurriness of vision, or as no noticeable visual disturbance at all. In some cases, rapid visual impairment or features mimicking orbital cellulitis may occur (Dunne and Edis, 1985). Among 21 patients with optic neuropathy studied in retrospect, 14 patients reported a 1-12 month history of insidious visual loss before the initial examination. All 21 patients complained of orbital congestive symptoms preceding the visual loss by at least one month, with a median of 4 months. These symptoms included ocular discomfort, tearing, periorbital swelling and conjunctival erythema. No direct relationship existed between the degree of proptosis or congestive symptoms and the optic nerve compression. In no case was visual loss the only or initial complaint (Trobe et al, 1978). In contrast, momentary visual blurring that can be cleared by blinking
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VOS W.C. 20/40- 14/217:+1
VOD W.C.20/20 stowly 14/21 2/1000
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1,/1
5/1000
90130
/1000
acl30
Figure 2. Visual field of a patient with Graves' optic neuropathy. Top: Tangent screen testing ('manual' perimetry) demonstrates a cecocentral scotoma for the right eye and an inferior altitudinal defect for the left eye. Bottom: Automated (computer-assisted) perimetry of the same patient is more sensitive in evincing inferior visual field loss in the right eye.
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is usually due to excess fluid on the surface of the cornea from irritative reflex tearing. Blurred vision that is ameliorated by closing either eye may indicate early extraocular muscle imbalance that is not yet perceived by the patient as diplopia (Bahn et al, 1990). Although limitation of eye elevation due to inferior rectus fibrosis is the most common motility abnormality noted in patients with Graves' ophthalmopathy, this pattern is less frequently seen in the subgroup with optic neuropathy. In these patients, eye movements are generally reduced more or less symmetrically in all directions (Trobe, 1981). As a result, affected patients may not experience diplopia. On CT scanning, these patients often have massive enlargement of all extraocular muscles, rather than the selective inferior and medial rectus enlargement commonly seen in patients with Graves' ophthalmopathy. The condition may be predominantly unilateral in approximately 15 % of cases (Trobe et al, 1978). Patients with Graves' optic neuropathy tend to be older (age 50-70 years) than the mean (age 44) of all patients with Graves' disease (Trobe, 1981). Early recognition of optic neuropathy is critical to preserve as much sight as possible as there is an inverse relationship between duration of visual loss and efficacy of treatment (Trobe, 1981; Bartalena et al, 1983). Unfortunately, incorrect or delayed diagnoses are sometimes made. In one study of 18 patients with optic nerve involvement, 15 were initially diagnosed as having visual loss due to cataracts, keratitis, macular degeneration, intracranial or orbital tumours, diabetes or malingering (Trobe and Glaser, 1978). If untreated, severe visual loss may ensue. A review of reports of 32 untreated eyes found that 7 patients were left with a visual acuity of 20/100 or worse, including 5 with final vision of finger counting to no light perception (Trobe, 1981). More common, however, are final visual acuities within the range of 20/30 to 20/50 from less severe optic neuropathy. Therefore, the complaint of consistently 'blurred vision' in a patient with Graves' ophthalmopathy warrants prompt referral to an ophthalmologist. The ophthalmological evaluation of a patient with optic neuropathy may demonstrate decreased visual acuity, impaired colour perception, or an afferent pupillary defect. An afferent pupillary defect is detected by the 'swinging flashlight test' in which the pupillary reactions to direct light are compared between the patient's two eyes; pupil dilation indicates decreased transmission in some portion (usually the optic nerve) of the afferent neural pathway. The optic disc may be swollen (25-33% of cases) or pale (10-20% of cases) (Trobe and Glaser, 1978), or the ophthalmoscopic appearance may be entirely normal. A visual field examination is helpful in the evaluation of possible optic neuropathy, and can be performed with a tangent screen, Goldman perimeter, or ideally, an automated perimeter. Characteristically, a central scotoma or an inferior altitudinal defect or scotoma is seen (Figure 2). CT scanning may be a helpful adjunctive test when optic neuropathy is suspected. In a study of 76 patients with Graves' ophthalmopathy, significant correlation of several mid-orbital axial CT parameters (including total muscle volume and orbit/fat ratio) with the presence of optic neuropathy was documented (Hallin and Feldon, 1988). Slit-lamp biomicroscopy, performed by an experienced ophthalmologist,
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is useful in evaluating corneal and conjunctival exposure from eyelid retraction and proptosis. Rose bengal or fluorescein is instilled into the inferior cul-de-sac; after distribution in the tear film, the stain binds to defects in the corneal epithelium. With significant exposure keratitis, a band of greyish-white, superficial, punctate, epithelial defects can be seen along the inferior bulbar conjunctiva and cornea. The cornea appears roughened rather than lustrous (Figure 3). Corneal ulceration is distinguished on slit-lamp biomicroscopy by marked, focal loss of continuity of the corneal epithelium, excavation into the corneal stroma, surrounding cellular infiltrates, and signs of inflammation in the anterior chamber. Although mild to moderate superficial keratopathy from exposure may cause ocular discomfort, true corneal ulceration results in extreme eye pain and is generally accompanied by marked conjunctival injection (erythema).
Figure 3. Slit-lamp photograph of severe exposure keratopathy. The corneal surface is irregular and roughened, and the eye is inflamed. This eye is at risk for progression to ulceration of the cornea that may result in severe visual loss.
Photophobia is typically severe and examination of the eye may be difficult. Generally, a patient with severe eye pain should be referred promptly to an ophthalmologist. As discussed previously, forces tending to counteract subluxation of the globe involve the restraint of the eye within the socket by the orbital septum and the posterior attachment of the extraocular muscles at the apex of the orbit. Additionally, the actual volume of the orbit is an important factor; a shallow socket is less able to maintain a severely proptotic globe in position. An extremely proptotic patient with marked eyelid retraction is at the highest risk for subluxation (Figure 4).
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Figure 4. Top: Subluxation of the globe in a patient with Graves' ophthalmopathy. Bottom: The same patient following transantral orbital decompression surgery.
TREATMENT
Optic neuropathy can be treated emergently with high-dose corticosteroids, supervoltage ( 4 6 meV) X-irradiation, or orbital decompression surgery. Although no controlled treatment protocol has been reported to date, there is evidence that each of these options is effective as acute therapy (Trobe and Glaser, 1978). Because spontaneous remission does occur occasionally, one group advocates observation with close follow-up for patients who have a visual acuity of 20/30 or better, with treatment for patients with progressive visual loss or with optic disc swelling (Dunne and Edis, 1985). Most commonly, however, medical treatment with corticosteroids is prescribed upon diagnosis of Graves' optic neuropathy. For the patient with rapidly decreasing vision due to optic neuropathy, or with severe periorbital oedema and chemosis, treatment with high doses of oral prednisone (100-140 mg per day) can be expected to effect dramatic improvement. Generally, clinical improvement from corticosteroids is evident within 72 h of initiation of prednisone and is maximal in 6-8 weeks. Therefore, further prolonged high-dose corticosteroid therapy without demonstrable benefit is not appropriate (Werner, 1966; Day and Carrol, 1968). In some patients, optic neuropathy initially responds well to highdose corticosteroids, but recurs following a reduction in dosage to more acceptable levels. The well-known side-effects of chronic high-dose corticosteroid therapy preclude this treatment as a long-term solution. No data support the use of intraorbital injections of corticosteroids or larger doses of corticosteroids (megadose therapy).
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If an initial positive response to steroids fails, due to intolerance of medication side-effects or to recurrence of optic neuropathy or severe inflammation at tapered doses, radiation therapy is frequently the next recommended treatment. One study (Ravin et al, 1975) described treatment with supervoltage X-irradiation of 37 patients with Graves' ophthalmopathy, 9 of whom had optic neuropathy. These 9 patients exhibited the most dramatic response to treatment in that series, with only one requiring further corticosteroids and decompression surgery. A total dose of 15002000 cGy fractionated over ten daily treatments, aimed at the orbital apices via laterally wedged portals, was used. This technique delivers a total dosage of less than 100 cGy to the lens, cornea, hypothalamus and pituitary. No intraocular complications or cataracts were reported in short-term (2 years or less) follow-up studies (Brennan et al, 1983). Another group reported good to excellent results of radiation treatment given to 141 patients with Graves' ophthalmopathy; only 4 eventually required orbital decompression surgery (Donaldson et al, 1973). A recent report of over 300 patients with 'symptomatic and progressive Graves' ophthalmopathy' described improvement in soft tissue signs, proptosis, ocular motility, keratopathy and visual acuity in 94% or more of cases with no long-term complications (Petersen et al, 1990). Concurrent use of orbital irradiation and systemic corticosteroids was successful in a recent trial of 36 patients with Graves' ophthalmopathy in which 72% of patients had a good response. Two of the patients had severe
SURGICAL RESULTS
131/143 eyes
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Figure 5. Results of transantral orbital decompression in 131/143 eyes: effect on visual acuity. The dark diagonal bar represents initial vision; lines to circles represent postoperative change in acuity. Numbers in circles are the numbers of eyes so changed. Very few eyes became worse; most improved, some from very poor vision preoperatively. From Younge (1984), with permission.
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visual loss but enjoyed complete restoration of sight following treatment (Bartalena et al, 1983). Orbital decompression surgery is considered by some practitioners to be the treatment of last resort for Graves' optic neuropathy (Kennerdell et al, 1981), but by others to be a useful early modality (Gorman et al, 1974; Younge, 1984; Hallin et al, 1988). Our approach to the treatment of Graves' optic neuropathy follows, in part, from our ready accessibility to surgeons with much experience in orbital decompression. If a patient with optic neuropathy simultaneously possesses other indications for decompression, such as significant proptosis or proptosis with extraocular muscle imbalance, we generally recommend early orbital decompression. We favour the transantral approach and have found the results of this procedure to be dramatic and predictable in more than 85-90% of patients (Younge, 1984) (Figure 5). In most cases there is an immediate partial improvement in vision followed by gradual further recovery. Transantral orbital decompression with removal of the orbital floor and portions of the nasal orbital wall and ethmoid sinus effectively decompresses the optic nerve, even though this approach does not involve the area of the orbital apex itself (Gorman et al, 1974). In a study by Hallin, 25 patients (48 eyes) underwent transantral decompression for Graves' optic neuropathy. Visual acuity improved in 77%, remained unchanged in 17% and worsened in 6%. Colour vision improved in 76%, remained unchanged in 20% and worsened in 4%. Visual fields improved in 67%, remained unchanged in 12% and worsened in 22%. Preoperative clinical and radiological findings did not correlate with postoperative visual outcome (Hallin et al, 1988). If a patient has optic neuropathy alone, without other indications for decompression surgery, we generally recommend a course of corticosteroids. We have found that optic neuropathy may respond to high-dose prednisone therapy and not recur upon tapering the medication to lower, better-tolerated doses (e.g. below 40mg a day with eventual discontinuation). However, often patients must be maintained on unacceptably high corticosteroid doses to alleviate the optic neuropathy. We usually recommend decompression for these patients with rapid tapering of corticosteroids postoperatively. When a corneal ulcer develops primarily as the result of severe proptosis, orbital decompression surgery is emergently indicated. Corneal ulceration or keratitis due to extreme eyelid retraction without significant proptosis may be treated by recessing the eyelid retractors to allow the lid to cover the eye. Occasionally, spacer grafts such as hard palate mucosa, auricular cartilage, or donor sclera are required to achieve proper eyelid positions. The corneal ulcer itself is treated with high-dose, high-frequency antimicrobial eyedrops after appropriate cultures have been taken. Severe corneal scarring may necessitate later penetrating keratoplasty (cornea transplant). Subluxation of the globe anterior to the eyelids typically is very painful, but some patients learn how to reposition the eyelids satisfactorily. The event is sufficiently distressing that most patients seek definitive treatment, which consists of orbital decompression and/or eyelid retraction surgery.
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SUMMARY
The ocular emergencies encountered in Graves' ophthalmopathy, namely optic neuropathy, corneal ulceration, subluxation of the globe, and severe periorbital oedema with chemosis have been discussed. Evaluation of the clinical signs and symptoms of these conditions, as well as their treatment, have been outlined. Of particular concern is the complaint of 'blurry vision' that may indicate the presence of optic neuropathy. Early recognition of this entity, with prompt referral to an ophthalmologist is important because there is an inverse relationship between duration of visual loss and efficacy of treatment. The ophthalmological evaluation of a patient with optic neuropathy may demonstrate decreased visual acuity, impaired colour perception, or an afferent pupillary defect. In addition, a visual field examination may be a helpful adjunctive test. Available therapy for optic neuropathy includes high-dose corticosteroids, supervoltage X-irradiation and orbital decompressive surgery. We have reviewed the literature concerning these modalities and outlined our approach to the treatment of optic neuropathy. In general, we recommend orbital decompression at an early stage for this condition. Another worrisome complaint is of 'eye pain'. In this case, distinction must be made between the causes that include ocular inflammation, corneal keratitis and corneal ulceration. The corneal ulceration is characterized by extreme eye pain and erythema, and may require surgical intervention. Severe ocular inflammation may respond well to a course of high-dose steroids. A combination of these ocular emergencies in a patient with Graves' ophthalmopathy necessitates careful consideration of the available treatment options. REFERENCES Anderson RL, Tweeten JP, Patrinely JR et al (1989) Dysthyroid optic neuropathy without evidence of extraocular muscle involvement. Ophthalmic Surgery 20" 568-574. Bahn RS, Garrity JA & Gorman CA (1990) Diagnosis and management of Graves' ophthalmopathy. Journal of Clinical Endocrinology and Metabolism 71: 559-563. Bartalena L, Marcocci C, Chiovato L e t al (1983) Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: comparison with systemic corticosteroids alone. Journal of Clinical Endocrinology and Metabolism 56: 1139-1144. Brennan MW, Leone CR & Janaki L (1983) Radiation therapy for Graves' disease. American Journal of Ophthalmology 96: 195-199. Day RM & Carroll FD (1968) Corticosteroids in the treatment of optic nerve involvement associated with thyroid dysfunction. Archives of Ophthalmology 79: 279-282. Donaldson SS, Bagshaw MA & Kriss JP (1973) Supervoltage orbital radiotherapy for Graves' ophthalmopathy. Journal of Clinical Endocrinology and Metabolism 37" 276-285. Dunne JW & Edis RH (1985) Optic nerve involvement in Graves' ophthalmopathy: a case report and review. Australian and New Zealand Journal of Medicine 15" 258-261. Feldon SE, Muramatsu S & Weiner JM (1984) Clinical classification of Graves' ophthalmopathy-identification of risk factors for optic neuropathy. Archives of Ophthalmology 102: 14691472. Frueh BR, Musch DC, Grill R et al (1985) Orbital compliance in Graves' eye disease. Ophthalmology 92" 657-665. Gorman CA (1983) Temporal relationship between onset of Graves' ophthalmopathy and diagnosis of thyrotoxicosis. Mayo Clinic Proceedings 58: 515-519.
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Gorman CA, DeSanto LW, MacCarty CS & Riley FC (1974) Optic neuropathy of Graves' disease--treatment by transantral orbital decompression. New England Journal of Medicine 290: 70-75. Hallin ES & Feldon SE (1988) Graves' ophthalmopathyl II. Correlation of clinical signs with measures derived from computed tomography. British Journal of Ophthalmology 72: 678-682. Hallin ES, Feldon SF & Luttrell (1988) Graves' ophthalmopathy. III. Effect of transantral orbital decompression on optic neuropathy. British Journal of Ophthalmology 72: 683687. Henderson JW (1958) Optic neuropathy of exophthalmic goiter (Graves' disease). Archives of Ophthalmology 59: 471-480. Hufnagel TJ, Hickey WJ, Cobbs W H e t al (1987) Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease. Ophthalmology 91: 1411-1419. Jensen SF (1971) Endocrine ophthalmoplegia: is it due to myopathy or to mechanical immobilization? Acta Ophthalmologica (Copenhagen) 49: 679-684. Kennerdell JS, Rosenbaum AE & E1 Hoshy MH (1981) Apical optic nerve compression of dysthyroid optic neuropathy on computed tomography. Archives of Ophthalmology 99: 807-809. Korducki JM, Loftus SJ, Ting AT et al (1992) Interleukin-1 stimulation of [3HI glycosaminoglycan accumulation in retro-ocular and pretibial fibroblasts: potential role in the extrathyroidal manifestations of Graves' disease. Presented at the 72nd annual meeting of the Endocrine Society, June, 1990 (abstract, in press). Kroll AJ & Kuwabara T (1966) Dysthyroid ocular myopathy: anatomy, histology, and electron microscopy. Archives of Ophthalmology 76: 244-257. Petersen IA, Kriss JP & McDougall IR (1990) Prognostic factors in the radiotherapy of Graves' ophthalmopathy. InternationalJournal of Radiation Oncology, Biology, Physics 19: 259264. Ravin JG, Sisson JC & Knapp WT (1975) Orbital radiation for the ocular changes of Graves' disease. American Journal of Ophthalmology 79: 285-288. Riley FC (1972) Orbital pathology in Graves' disease. Mayo Clinic Proceedings 47: 975-979. Sisson JC, Kothary P & Kirchick H (1973) The effects of lymphocytes, sera and long-acting thyroid stimulator from patients with Graves' disease on retrobulbar fibroblasts. Journal of Clinical Endocrinology and Metabolism 37: 17-24. Tamai H, Nakagawa T, Ohsako N et al (1980) Changes in thyroid function in patients with euthyroid Graves' disease. Journalof ClinicalEndocrinology and Metabolism50: 108--112. Trobe JD (1981) Optic nerve involvement in dysthyroidism. Ophthalmology 88: 488-492. Trobe JD, Glaser JS & Laflamme P (1978) Dysthyroid optic neuropathy---clinical profile and rationale for management. Archives of Ophthalmology 96: 1199-1209. Werner SC (1966) Prednisone in emergency treatment of malignant exophthalmos. Lancet i: 1004-1007. Younge BR (1984) Eye examination techniques in Graves' ophthalmopathy, In Gorman CA, Waller RR & Dyer JA (eds) The Eye and Orbit in Thyroid Disease, pp 143-153. New York: Raven Press.
