Progression of Scleral Disease STEPHEN J. TUFT, FRACS, PETER G. WATSON, FRCS
Abstract: The clinical features of 290 patients with scleral inflammation were reviewed to determine whether a classification based on the anatomical site and clinical appearance of the disease at presentation reflected its natural history. The authors' results confirm that the majority of patients remain in the same clinical category throughout the course of their disease. Of the 104 (35.9%) patients who experienced a recurrence of their disease, only 12 had progressed from diffuse to nodular disease, and 10 patients who originally had nodular disease developed scleral necrosis. Patients with necrotizing scleritis were older than patients in the other groups and more frequently had an associated systemic disease than patients with either diffuse or nodular disease; necrotizing scleritis was the most difficult disease to treat. Diffuse anterior scleritis had a lower incidence of visual loss (9%) than either nodular scleritis (26%) or necrotizing disease (74%), and, therefore, the authors consider nodular scleritis a disease of intermediate severity between diffuse scleritis and necrotizing disease. In this series, 12% of patients presented with posterior scleritis, and visual loss was most frequent in this group (84%). Ophthalmology 1991; 98:467-471
Scleritis is a granulomatous inflammation of the scleral coat of the eye. It may be recognized clinically by the associated scleral edema that displaces the overlying episcleral vessels, which are, in tum, congested. 1 The clinical presentation and prognosis of scleritis is clearly not identical in all patients, and classifications of the disease have been developed that take this into account. The most frequently used criterion for classification is the clinical appearance of the disease; 1•2 other classifications based on either the etiologic agent 3 or the presumed component of the sclera that is the target for the inflammatory process are less useful. 4 The classification proposed by Watson and Hayreh 1 was derived from observation of the anatomical site of the inflammatory process and the associated changes in the scleral vasculature (Table 1). Although it was found that there was a degree of overlap between the diagnostic groups, clinical experience suggested that patients could be assigned to a specific category at their initial examination and that the subgroups of disease usually remained separate. Inherent in this classification was the observation that diffuse anterior scleritis tended to be a benign variant Originally received: September 6, 1990. Revision accepted: December 11, 1990. From the Department of Clinical Ophthalmology, Moorfields Eye Hospital, London. Correspondence to Peter G. Watson, FRCS, Moorfields Eye Hospital, City Rd, London EC1V 2PD, England.
of the disease, whereas the majority of ocular complications occurred after necrotizing scleritis. We have compared the natural history of nodular, diffuse, and necrotizing scleritis to determine if patients maintain their initial diagnostic category during recurrences of disease, or whether variations in the clinical appearance reflect grades of severity in a single disease process.
PATIENTS AND METHODS All patients who attended the scleritis clinic of Moorfields Eye Hospital between January 1986 and January 1988 were reviewed, and the natural history of their disease was assessed. Particular attention was paid to the diagnosis made at presentation and the diagnosis at subsequent exacerbations of disease. A number of different observers saw the patients during the study period, but one of us (PGW) had observed all the patients from the time of presentation and had reviewed the diagnosis during the course of the disease. The same diagnostic categories proposed by Watson and Hayreh 1 were used throughout the study, and, wherever possible, the diagnosis recorded in the clinical notes was substantiated by review of color clinical photographs and anterior segment fluorescein angiograms. For the purposes of this study, posterior scleritis was defined as scleral inflammation primarily arising posterior to the equator when visualized by indirect ophthalmoscopy through a dilated pupil; this 467
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Table 1. Clinical Classification of Scleral and Episcleral Inflammation Episcleritis Simple Nodular Scleritis Anterior scleritis Diffuse scleritis Nodular scleritis Necrotizing scleritis: with inflammation without inflammation Posterior scleritis Table 2. Distribution of Patients with Scleritis by Disease Group First Attack (F:M) Worst Attack (F:M) Diffuse 123 (42%) Nodular 90 (31 %) Necrotizing 42 (15%) 35 (12%) Posterior
(1.1:1) (1.4:1) (1.6:1) (1.5:1)
105 (36%) 98 (34%) 55 (19%) 32 (11%)
290 patients
(1.1:1) (1.3:1) (1.7:1) (1.7:1)
Multiple (F:M) 30 (28%)* 53 (54%) 14 (25%) 7 (21%)
290 patients
(1.1:1) (1.4:1) (3.7:1) (1.3:1)
104 patients
* Expressed as percentage of the worst disease episode. Cumulative Relative Frequencies
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erythrocyte sedimentation rate, and investigation for syphilis serology, immunoglobulins, and autoantibodies had been performed on the majority of patients. A record was made of any coexisting disease. The treatment of these patients was based on the incremental use of therapeutic agents to obtain remission. Oral nonsteroidal anti-inflammatory drugs (NSAIDs)flurbiprofen, 100 mg, three times a day, or indomethacin, 25 mg, three times a day-were used for mild disease if there was no evidence of vascular closure. Oral steroids, starting with prednisolone, 60 to 120 mg per day for 2 to 3 days and then reducing, were prescribed if there was either a failure of the inflammation to resolve on nonsteroidal agents or if there was clinical evidence at presentation of stasis of the episcleral and scleral circulations. Oral immunosuppressive agents (cyclophosphamide, azathioprine, or cyclosporin) and pulsed intravenous steroid and immunosuppressives (methylprednisolone, 500 mg to 1 gm and cyclophosphamide, 500 mg) were reserved for the minority of patients who failed to resolve with oral steroids or for patients who presented with scleral necrosis.5·6 Topical steroid drops (prednisolone, 0.3%; dexamethasone, 0.1%) were used as supplementary therapy but not as primary treatment. Intraorbital, but never subconjunctival, steroids have been used in exceptional circumstances. Since the distribution of patient data within groups was not normally distributed, the Kruskal-Wallis test was used to detect the presence of differences between disease groups, using the mean rank with appropriate adjustments for the number of comparisons. 7 Comparisons between individual groups were then made using the Mann-Whitney Utest.
RESULTS 0
20
40
60
80
100
AGE
Fig 1. Cumulative relative frequency of the age of presentation in years for the clinical groups of scleritis. I = nodular scleritis, 2 = posterior scleritis, 3 = diffuse anterior scleritis, 4 = necrotizing scleritis.
diagnosis was usually confirmed by observing scleral thickening with ultrasonography. As a consequence, eyes in which there was a posterior extension of scleritis arising in the anterior segment have not been included in this definition. Necrotizing scleritis with and without inflammation has been considered to be one disease group in this investigation. The following features were recorded for each patient: visual acuity loss, defined as a permanent drop in Snellen acuity of two or more lines; raised intraocular pressure, which persisted after the control of ocular inflammation; anterior uveitis; corneal infiltration; corneal guttering; scleral translucency and frank loss of scleral tissue. Operations performed for complications of scleritis included cataract extraction, corneal or scleral grafting, and drainage procedures for glaucoma. A chest x-ray, blood count, 468
A total of 290 consecutive patients were reviewed, 74 (25.5%) of whom had bilateral disease. The mean observation period was 6.9 years (standard deviation, 5.1 years; range, 8 months to 22.5 years). The female to male ratio was 1.27 to 1. The mean age ofthe group was 51.5 years (standard deviation, 15.7 years), comprising 50.0 years (standard deviation, 15.8 years) for males and 52.6 years (standard deviation, 17.4 years) for females. The numbers and sex distribution of patients within each diagnostic category at presentation and after their most severe recurrence are presented in Table 2. The mean age of patients presenting with diffuse anterior scleritis (45.8 years) was lower than patients with nodular disease (52.9 years), which was in tum lower than necrotizing disease (66.3 years). These differences were statistically significant (P < 0.004 and P < 0.001) (Fig 1). Multiple attacks of scleritis were documented in 35.9% of patients and these most frequently occurred in patients with nodular disease (54%) (Table 2). There was no difference in the age of onset of disease between patients who had a single attack or who went on to have multiple attacks of scleritis, but multiple attacks of necrotizing
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Fig 2. Top left, 54-year-old man who presented in December 1981 with left-sided diffuse anterior scleritis. Top right, during reactivation of disease in August 1986, a small scleral nodule developed at the insertion of the lateral rectus muscle. Bottom left, anterior segment fluorescein angiography performed at the first episode shows rapid and diffuse filling of scleral vasculature (time = 22.0 seconds after injection). Bottom right, angiography at the second episode demonstrates localized diffuse leakage (arrows) not present during the first attack (time = 19.4 seconds after injection). The vascular bifurcation (V) can be identified on both the bottom photographs.
scleritis were more frequent in females than in males (3.66 to 1). During the course of multiple attacks, a different form of scleritis, typically a more severe form of the disease, developed in a few of the patients ( 12%) (Fig 2, Table 3). The number of patients who progressed from diffuse to nodular scleritis was similar to the number who progressed from nodular to necrotizing scleritis. Both events were more common in females (2 to 1 and 4 to 1 ratios, respectively). The ocular complications for each diagnostic group are presented in Table 4. A loss of visual acuity was most common in patients with posterior scleritis; however, when anterior scleral disease was considered in isolation, the incidence of visual loss increased through diffuse to nodular disease and was the highest after necrotizing disease. The proportion of patients with glaucoma and corneal infiltration after an attack of nodular or necrotizing disease was similar. By definition, scleral loss only occurred during the course of necrotizing disease. Although necrotizing scleritis accounted for 19% of the patients in the series, 17 scleral patch grafts were performed on these
Table 3. Number of Patients Changing Clinical Groups During Recurrence of Scleritis (1 04 Patients) No change Diffuse to nodular Nodular to necrotizing Posterior to nodular Posterior to diffuse Diffuse to necrotizing Nodular to ·diffuse Necrotizing to nodular Nodular to pseudotumor
66
12 10
4
3 3 2
2
2
patients, which accounted for 56% of the complications that required surgery. A total of 16.8% of all patients had a positive rheumatoid factor and 10.3% had clinical rheumatoid arthritis. A positive rheumatoid titer was most frequent in patients with necrotizing disease (21%) and least frequent with diffuse anterior scleritis ( 14% ). A positive titer to antinuclear 469
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Table 4. Complications of Scleritis
Diffuse Nodular Necrotizing Posterior
Visual Loss
Glaucoma
Corneal Infiltration
Corneal Gutter
Cataract
Scleral Thinning
10 (9%)* 26 (26%) 41 (74%) 27 (84%)
10 (9%) 14 (14%) 6 (11%) 6 (19%)
20 (19%) 46 (47%) 21 (38%) 2 (6%)
3 (3%) 13 (13%) 22 (40%) 1 (3%)
1 (1%) 5 (5%) 11 (20%) 1 (3%)
13 (12%) 48 (49%) 55 (100%) 4 (12%)
* Expressed as percentage of the worst disease episode.
Table 5. Associated Systemic Disease in Scleritis Patients Rheumatoid arthritis Wegener's granulomatosis Ulcerative and Grahn's colitis Relapsing polychondritis Systemic lupus erythematosis Systemic arteritis Polyarteritis nodosa Behcet's disease Polymyalgia rheumatica Herpes zoster Raynaud's disease Ankylosing spondylitis Gout Sarcoidosis Rosacea Psoriasis
30 11 6 6 3
2 2 2 2 2 2
1 1 1 1 1 73 (25.2%)
Table 6. Number of Patients with Associated Systemic Disease Diffuse scleritis Nodular scleritis Necrotizing scleritis Posterior scleritis
14(13%) 28 (28%) 25 (45%) 6 (19%)
factor of greater than 1 in 10 ( 11%) and other associated systemic diseases (45%) also were more common in patients with necrotizing scleritis (Tables 5 and 6). The treatment used during the most severe attack of scleritis is listed by disease groups in Table 7. It may be seen that whereas ocular inflammation in 61% of patients with diffuse anterior scleritis resolved with NSAIDs, the majority (66%) of patients with nodular disease required a course of oral steroids. In contrast, no patients with necrotizing disease settled with NSAIDs, 29% required oral prednisolone, and 67% required immunosuppression. Overall, 69% of all patients needed steroid treatment and 30% required other forms of immunosuppression. The response of posterior scleritis to treatment was similar to that of nodular disease. The duration of treatment required to produce a resolution of disease also varied between groups. Patients with diffuse anterior scleritis usually received treatment for the shortest period (mean, 3.8 months), while the mean duration of treatment for patients with nodular or posterior disease was similar ( 16.4 and 21.6 months, respectively). The mean period of treatment of patients with 470
necrotizing disease (54.6 months) was significantly longer, due in part to a small number of patients who required long-term maintenance treatment to prevent recurrence of their disease (maxim urn treatment, 21 years).
DISCUSSION The term scleritis covers a spectrum of ocular disease that extends from a trivial self-limiting episode of inflammation to a sight-threatening necrotizing process. A descriptive classification of scleritis has been formulated that is based on clinical observation, and, although this tells us little about the etiology of the disease, it acts as an indicator of severity and is, thus, a guide to therapy. Despite reports that a proportion of patients with scleral nodules develop localized scleral necrosis, 2 •8•9 we have confirmed that the majority of patients maintain their disease group after presentation. There is an unavoidable bias toward severe disease in any tertiary referral clinic. However, the proportion of patients within the scleritis subgroups in this study differed from previous large retrospective series. 1•10•11 In particular, there was a higher incidence of posterior scleritis. This probably reflects the diagnostic criteria for posterior scleritis that have been applied in this study as well as an increased awareness of the condition. 12•13 An underreporting of posterior scleritis as a cause of ocular inflammation is suggested by studies of enucleated eyes in which 43 to 62% had either primary posterior scleritis or a posterior extension of anterior disease. 14 •15 Ocular complications as a result of scleritis were common and occurred in all clinical groups. However, the proportion of patients who lost vision differed. After attacks of anterior scleral disease, visual acuity loss was least common in diffuse anterior scleritis, intermediate in nodular disease, and most frequent after necrotizing scleritis. Posterior scleritis had the highest incidence of visual acuity loss, primarily from edema of the overlying retina 15 and involvement of the optic nerve and its sheaths. Cataract formation, especially posterior subcapsular change, was most common after necrotizing scleritis and may result from either local inflammation, anterior segment ischemia, or the chronic use of corticosteroids. The origin of raised intraocular pressure in association with scleritis is believed to be the result of progressive damage to the trabecular meshwork from granulomatous infiltration associated with the scleritis, to which is often added an an-
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Table 7. Maximum Treatment Required to Control Scleral Disease (290 Patients) Treatment Disease
Nil
Topical
NSAID
Diffuse Nodular Necrotizing Posterior
0 0 1* 0
4 (4%) 0 1* 0
64 (61%) 15(15%) 0 5 (16%)
5
84
Prednisolone 33 65 16 22
(31%) (66%) (29%) (69%)
136
Intravenous ME-Prednisolone and Immunosuppression 4 (4%) 18 (18%) 37 (67%) 5 (16%) 64
NSAID = nonsteroidal anti-inflammatory drug. * Scleral necrosis developed while patient was taking systemic steroid for rheumatoid arthritis.
terior uveitis and edema of the overlying sclera; 16 the incidence of glaucoma in this study (9 .1%) is comparable with the figures of 11.6% and 22% reported in other series.t,lO,t6 A recurrence of scleral inflammation occurred in 35.7% of patients during the course of their disease; most frequently in female patients with nodular scleritis. However, only a third of these patients were believed to have changed their clinical category during the course of their disease. There was a particularly strong tendency for women who were rheumatoid positive to progress to necrotizing disease. Scleritis has been linked with numerous connective tissue disorders, but, in the majority of cases, no underlying disease could be detected. 1·2 •10 Rheumatoid arthritis is the connective tissue disorder most commonly associated with scleral disease. A patient's age and sex also are related to the development of scleritis; patients presenting with necrotizing disease were significantly older than the other groups, which may be related to the onset of systemic vasculitis. Our analysis of the therapy required to treat the worst episode of scleral inflammation supports the concept of a gradation of severity of anterior scleritis from diffuse to necrotizing disease, with a similar therapeutic response for both posterior and nodular scleritis. However, it is recognized that these types of data tend to be self-supporting, as mild disease (diffuse scleritis) was given mild treatment (NSAID) at presentation. We conclude from this study that the clinical diagnostic criteria provide valuable prognostic information for the management of scleritis. Our review of the incidence of ocular complications, the response of patients to treatment, and the incidence of an associated connective tissue disease confirm that diffuse anterior scleritis is usually a benign and self-limiting condition, whereas necrotizing scleritis is a severe disease that may be a manifestation of an underlying systemic disorder. The natural history of nodular scleritis suggests that it is a disease of intermediate severity and that these patients should be monitored for the development of scleral necrosis. The prognosis of posterior disease most closely approximates nodular disease, although it has a poor visual prognosis as a result of retinal and optic nerve involvement. Patients with posterior
scleritis probably form a heterogeneous population, because, even using B-scan ultrasonography, it is difficult to determine whether the underlying disease is diffuse, nodular, or necrotizing, although all three forms can be shown to exist.
REFERENCES 1. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976; 60:163-91. 2. Watson PG, Hazleman BL. The Sclera in Systemic Disorders. Philadelphia: Saunders, 1976; 90-1. 3. Watson P. Diseases of the sclera and episclera. In: Tasman W, Jaeger EA, eds. Duane's Clinical Ophthalmology, rev. ed. Philadelphia: J B Lippincott, 1989; vol. 4, chap 23. 4. Cabo M. Inflammation of the sclera. lnt Ophthalmol Clin 1983; 23(1): 159-71. 5. Meyer PA. Watson PG, Franks W, Dubord P. 'Pulsed' immunosuppressive therapy in the treatment of immunologically induced corneal and scleral disease. Eye 1987; 1:487-95. 6. Watson PG. Doyne Mernorial Lecture, 1982. The nature and the treatment of scleral inflammation. Trans Ophthalmol Soc UK 1982; 102: 257-81. 7. Siegel S, Castellan NJ Jr. Nonpararnetric Statistics for the Behavioural Sciences 2nd ed. New York: McGraw-Hill, 1988; 206-16. 8. Sevel D. Rheumatoid nodule of the sclera. (A type of necrogranulomatous scleritis.) Trans Ophthalmol Soc UK 1965; 85:357-67. 9. Sevel D. Necrogranulomatous scleritis: clinical and histologic features. Am J Ophthalmol 1967; 64:1125-34. 10. McGavin DDM, Williamson J, Forrester JV, et al. Episcleritis and scleritis: a study of their clinical manifestations and association with rheumatoid arthritis. Br.J Ophthalmol1976; 60:192-226. 11. Wilhelrnus KR, Watson PG, Vasavada AR. Uveitis associated with scleritis. Trans Ophthalrnol Soc UK 1981; 101 :351-6. 12. Benson WE. Posterior scleritis. Surv Ophthalrnol1988; 32:297-316. 13. Calthorpe CM, Watson PG, McCartney ACE. Posterior scleritis: a clinical and histological survey. Eye 1988; 2:267-77. 14. Fraunfelder FT, Watson PG. Evaluation of eyes enucleated for scleritis. Br J Ophthalrnol 1976; 60:227-30. 15. Cleary PE, Watson PG, McGill Jl, Hamilton AM. Visual loss due to posterior segrnent disease in scleritis. Trans Ophthalmol Soc UK 1975; 95:297-300. 16. Wilhelmus KR, Grierson I, Watson PG. Histopathologic and clinical associations of scleritis and glaucoma. Am J Ophthalmol 1981; 91: 697-705.
471
Abstract: The clinical features of 290 patients with scleral inflammation were reviewed to determine whether a classification based on the anatomical site and clinical appearance of the disease at presentation reflected its natural history. The authors' results confirm that the majority of patients remain in the same clinical category throughout the course of their disease. Of the 104 (35.9%) patients who experienced a recurrence of their disease, only 12 had progressed from diffuse to nodular disease, and 10 patients who originally had nodular disease developed scleral necrosis. Patients with necrotizing scleritis were older than patients in the other groups and more frequently had an associated systemic disease than patients with either diffuse or nodular disease; necrotizing scleritis was the most difficult disease to treat. Diffuse anterior scleritis had a lower incidence of visual loss (9%) than either nodular scleritis (26%) or necrotizing disease (74%), and, therefore, the authors consider nodular scleritis a disease of intermediate severity between diffuse scleritis and necrotizing disease. In this series, 12% of patients presented with posterior scleritis, and visual loss was most frequent in this group (84%). Ophthalmology 1991; 98:467-471
Scleritis is a granulomatous inflammation of the scleral coat of the eye. It may be recognized clinically by the associated scleral edema that displaces the overlying episcleral vessels, which are, in tum, congested. 1 The clinical presentation and prognosis of scleritis is clearly not identical in all patients, and classifications of the disease have been developed that take this into account. The most frequently used criterion for classification is the clinical appearance of the disease; 1•2 other classifications based on either the etiologic agent 3 or the presumed component of the sclera that is the target for the inflammatory process are less useful. 4 The classification proposed by Watson and Hayreh 1 was derived from observation of the anatomical site of the inflammatory process and the associated changes in the scleral vasculature (Table 1). Although it was found that there was a degree of overlap between the diagnostic groups, clinical experience suggested that patients could be assigned to a specific category at their initial examination and that the subgroups of disease usually remained separate. Inherent in this classification was the observation that diffuse anterior scleritis tended to be a benign variant Originally received: September 6, 1990. Revision accepted: December 11, 1990. From the Department of Clinical Ophthalmology, Moorfields Eye Hospital, London. Correspondence to Peter G. Watson, FRCS, Moorfields Eye Hospital, City Rd, London EC1V 2PD, England.
of the disease, whereas the majority of ocular complications occurred after necrotizing scleritis. We have compared the natural history of nodular, diffuse, and necrotizing scleritis to determine if patients maintain their initial diagnostic category during recurrences of disease, or whether variations in the clinical appearance reflect grades of severity in a single disease process.
PATIENTS AND METHODS All patients who attended the scleritis clinic of Moorfields Eye Hospital between January 1986 and January 1988 were reviewed, and the natural history of their disease was assessed. Particular attention was paid to the diagnosis made at presentation and the diagnosis at subsequent exacerbations of disease. A number of different observers saw the patients during the study period, but one of us (PGW) had observed all the patients from the time of presentation and had reviewed the diagnosis during the course of the disease. The same diagnostic categories proposed by Watson and Hayreh 1 were used throughout the study, and, wherever possible, the diagnosis recorded in the clinical notes was substantiated by review of color clinical photographs and anterior segment fluorescein angiograms. For the purposes of this study, posterior scleritis was defined as scleral inflammation primarily arising posterior to the equator when visualized by indirect ophthalmoscopy through a dilated pupil; this 467
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Table 1. Clinical Classification of Scleral and Episcleral Inflammation Episcleritis Simple Nodular Scleritis Anterior scleritis Diffuse scleritis Nodular scleritis Necrotizing scleritis: with inflammation without inflammation Posterior scleritis Table 2. Distribution of Patients with Scleritis by Disease Group First Attack (F:M) Worst Attack (F:M) Diffuse 123 (42%) Nodular 90 (31 %) Necrotizing 42 (15%) 35 (12%) Posterior
(1.1:1) (1.4:1) (1.6:1) (1.5:1)
105 (36%) 98 (34%) 55 (19%) 32 (11%)
290 patients
(1.1:1) (1.3:1) (1.7:1) (1.7:1)
Multiple (F:M) 30 (28%)* 53 (54%) 14 (25%) 7 (21%)
290 patients
(1.1:1) (1.4:1) (3.7:1) (1.3:1)
104 patients
* Expressed as percentage of the worst disease episode. Cumulative Relative Frequencies
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erythrocyte sedimentation rate, and investigation for syphilis serology, immunoglobulins, and autoantibodies had been performed on the majority of patients. A record was made of any coexisting disease. The treatment of these patients was based on the incremental use of therapeutic agents to obtain remission. Oral nonsteroidal anti-inflammatory drugs (NSAIDs)flurbiprofen, 100 mg, three times a day, or indomethacin, 25 mg, three times a day-were used for mild disease if there was no evidence of vascular closure. Oral steroids, starting with prednisolone, 60 to 120 mg per day for 2 to 3 days and then reducing, were prescribed if there was either a failure of the inflammation to resolve on nonsteroidal agents or if there was clinical evidence at presentation of stasis of the episcleral and scleral circulations. Oral immunosuppressive agents (cyclophosphamide, azathioprine, or cyclosporin) and pulsed intravenous steroid and immunosuppressives (methylprednisolone, 500 mg to 1 gm and cyclophosphamide, 500 mg) were reserved for the minority of patients who failed to resolve with oral steroids or for patients who presented with scleral necrosis.5·6 Topical steroid drops (prednisolone, 0.3%; dexamethasone, 0.1%) were used as supplementary therapy but not as primary treatment. Intraorbital, but never subconjunctival, steroids have been used in exceptional circumstances. Since the distribution of patient data within groups was not normally distributed, the Kruskal-Wallis test was used to detect the presence of differences between disease groups, using the mean rank with appropriate adjustments for the number of comparisons. 7 Comparisons between individual groups were then made using the Mann-Whitney Utest.
RESULTS 0
20
40
60
80
100
AGE
Fig 1. Cumulative relative frequency of the age of presentation in years for the clinical groups of scleritis. I = nodular scleritis, 2 = posterior scleritis, 3 = diffuse anterior scleritis, 4 = necrotizing scleritis.
diagnosis was usually confirmed by observing scleral thickening with ultrasonography. As a consequence, eyes in which there was a posterior extension of scleritis arising in the anterior segment have not been included in this definition. Necrotizing scleritis with and without inflammation has been considered to be one disease group in this investigation. The following features were recorded for each patient: visual acuity loss, defined as a permanent drop in Snellen acuity of two or more lines; raised intraocular pressure, which persisted after the control of ocular inflammation; anterior uveitis; corneal infiltration; corneal guttering; scleral translucency and frank loss of scleral tissue. Operations performed for complications of scleritis included cataract extraction, corneal or scleral grafting, and drainage procedures for glaucoma. A chest x-ray, blood count, 468
A total of 290 consecutive patients were reviewed, 74 (25.5%) of whom had bilateral disease. The mean observation period was 6.9 years (standard deviation, 5.1 years; range, 8 months to 22.5 years). The female to male ratio was 1.27 to 1. The mean age ofthe group was 51.5 years (standard deviation, 15.7 years), comprising 50.0 years (standard deviation, 15.8 years) for males and 52.6 years (standard deviation, 17.4 years) for females. The numbers and sex distribution of patients within each diagnostic category at presentation and after their most severe recurrence are presented in Table 2. The mean age of patients presenting with diffuse anterior scleritis (45.8 years) was lower than patients with nodular disease (52.9 years), which was in tum lower than necrotizing disease (66.3 years). These differences were statistically significant (P < 0.004 and P < 0.001) (Fig 1). Multiple attacks of scleritis were documented in 35.9% of patients and these most frequently occurred in patients with nodular disease (54%) (Table 2). There was no difference in the age of onset of disease between patients who had a single attack or who went on to have multiple attacks of scleritis, but multiple attacks of necrotizing
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Fig 2. Top left, 54-year-old man who presented in December 1981 with left-sided diffuse anterior scleritis. Top right, during reactivation of disease in August 1986, a small scleral nodule developed at the insertion of the lateral rectus muscle. Bottom left, anterior segment fluorescein angiography performed at the first episode shows rapid and diffuse filling of scleral vasculature (time = 22.0 seconds after injection). Bottom right, angiography at the second episode demonstrates localized diffuse leakage (arrows) not present during the first attack (time = 19.4 seconds after injection). The vascular bifurcation (V) can be identified on both the bottom photographs.
scleritis were more frequent in females than in males (3.66 to 1). During the course of multiple attacks, a different form of scleritis, typically a more severe form of the disease, developed in a few of the patients ( 12%) (Fig 2, Table 3). The number of patients who progressed from diffuse to nodular scleritis was similar to the number who progressed from nodular to necrotizing scleritis. Both events were more common in females (2 to 1 and 4 to 1 ratios, respectively). The ocular complications for each diagnostic group are presented in Table 4. A loss of visual acuity was most common in patients with posterior scleritis; however, when anterior scleral disease was considered in isolation, the incidence of visual loss increased through diffuse to nodular disease and was the highest after necrotizing disease. The proportion of patients with glaucoma and corneal infiltration after an attack of nodular or necrotizing disease was similar. By definition, scleral loss only occurred during the course of necrotizing disease. Although necrotizing scleritis accounted for 19% of the patients in the series, 17 scleral patch grafts were performed on these
Table 3. Number of Patients Changing Clinical Groups During Recurrence of Scleritis (1 04 Patients) No change Diffuse to nodular Nodular to necrotizing Posterior to nodular Posterior to diffuse Diffuse to necrotizing Nodular to ·diffuse Necrotizing to nodular Nodular to pseudotumor
66
12 10
4
3 3 2
2
2
patients, which accounted for 56% of the complications that required surgery. A total of 16.8% of all patients had a positive rheumatoid factor and 10.3% had clinical rheumatoid arthritis. A positive rheumatoid titer was most frequent in patients with necrotizing disease (21%) and least frequent with diffuse anterior scleritis ( 14% ). A positive titer to antinuclear 469
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Table 4. Complications of Scleritis
Diffuse Nodular Necrotizing Posterior
Visual Loss
Glaucoma
Corneal Infiltration
Corneal Gutter
Cataract
Scleral Thinning
10 (9%)* 26 (26%) 41 (74%) 27 (84%)
10 (9%) 14 (14%) 6 (11%) 6 (19%)
20 (19%) 46 (47%) 21 (38%) 2 (6%)
3 (3%) 13 (13%) 22 (40%) 1 (3%)
1 (1%) 5 (5%) 11 (20%) 1 (3%)
13 (12%) 48 (49%) 55 (100%) 4 (12%)
* Expressed as percentage of the worst disease episode.
Table 5. Associated Systemic Disease in Scleritis Patients Rheumatoid arthritis Wegener's granulomatosis Ulcerative and Grahn's colitis Relapsing polychondritis Systemic lupus erythematosis Systemic arteritis Polyarteritis nodosa Behcet's disease Polymyalgia rheumatica Herpes zoster Raynaud's disease Ankylosing spondylitis Gout Sarcoidosis Rosacea Psoriasis
30 11 6 6 3
2 2 2 2 2 2
1 1 1 1 1 73 (25.2%)
Table 6. Number of Patients with Associated Systemic Disease Diffuse scleritis Nodular scleritis Necrotizing scleritis Posterior scleritis
14(13%) 28 (28%) 25 (45%) 6 (19%)
factor of greater than 1 in 10 ( 11%) and other associated systemic diseases (45%) also were more common in patients with necrotizing scleritis (Tables 5 and 6). The treatment used during the most severe attack of scleritis is listed by disease groups in Table 7. It may be seen that whereas ocular inflammation in 61% of patients with diffuse anterior scleritis resolved with NSAIDs, the majority (66%) of patients with nodular disease required a course of oral steroids. In contrast, no patients with necrotizing disease settled with NSAIDs, 29% required oral prednisolone, and 67% required immunosuppression. Overall, 69% of all patients needed steroid treatment and 30% required other forms of immunosuppression. The response of posterior scleritis to treatment was similar to that of nodular disease. The duration of treatment required to produce a resolution of disease also varied between groups. Patients with diffuse anterior scleritis usually received treatment for the shortest period (mean, 3.8 months), while the mean duration of treatment for patients with nodular or posterior disease was similar ( 16.4 and 21.6 months, respectively). The mean period of treatment of patients with 470
necrotizing disease (54.6 months) was significantly longer, due in part to a small number of patients who required long-term maintenance treatment to prevent recurrence of their disease (maxim urn treatment, 21 years).
DISCUSSION The term scleritis covers a spectrum of ocular disease that extends from a trivial self-limiting episode of inflammation to a sight-threatening necrotizing process. A descriptive classification of scleritis has been formulated that is based on clinical observation, and, although this tells us little about the etiology of the disease, it acts as an indicator of severity and is, thus, a guide to therapy. Despite reports that a proportion of patients with scleral nodules develop localized scleral necrosis, 2 •8•9 we have confirmed that the majority of patients maintain their disease group after presentation. There is an unavoidable bias toward severe disease in any tertiary referral clinic. However, the proportion of patients within the scleritis subgroups in this study differed from previous large retrospective series. 1•10•11 In particular, there was a higher incidence of posterior scleritis. This probably reflects the diagnostic criteria for posterior scleritis that have been applied in this study as well as an increased awareness of the condition. 12•13 An underreporting of posterior scleritis as a cause of ocular inflammation is suggested by studies of enucleated eyes in which 43 to 62% had either primary posterior scleritis or a posterior extension of anterior disease. 14 •15 Ocular complications as a result of scleritis were common and occurred in all clinical groups. However, the proportion of patients who lost vision differed. After attacks of anterior scleral disease, visual acuity loss was least common in diffuse anterior scleritis, intermediate in nodular disease, and most frequent after necrotizing scleritis. Posterior scleritis had the highest incidence of visual acuity loss, primarily from edema of the overlying retina 15 and involvement of the optic nerve and its sheaths. Cataract formation, especially posterior subcapsular change, was most common after necrotizing scleritis and may result from either local inflammation, anterior segment ischemia, or the chronic use of corticosteroids. The origin of raised intraocular pressure in association with scleritis is believed to be the result of progressive damage to the trabecular meshwork from granulomatous infiltration associated with the scleritis, to which is often added an an-
TUFT AND WATSON
•
PROGRESSION OF SCLERAL DISEASE
Table 7. Maximum Treatment Required to Control Scleral Disease (290 Patients) Treatment Disease
Nil
Topical
NSAID
Diffuse Nodular Necrotizing Posterior
0 0 1* 0
4 (4%) 0 1* 0
64 (61%) 15(15%) 0 5 (16%)
5
84
Prednisolone 33 65 16 22
(31%) (66%) (29%) (69%)
136
Intravenous ME-Prednisolone and Immunosuppression 4 (4%) 18 (18%) 37 (67%) 5 (16%) 64
NSAID = nonsteroidal anti-inflammatory drug. * Scleral necrosis developed while patient was taking systemic steroid for rheumatoid arthritis.
terior uveitis and edema of the overlying sclera; 16 the incidence of glaucoma in this study (9 .1%) is comparable with the figures of 11.6% and 22% reported in other series.t,lO,t6 A recurrence of scleral inflammation occurred in 35.7% of patients during the course of their disease; most frequently in female patients with nodular scleritis. However, only a third of these patients were believed to have changed their clinical category during the course of their disease. There was a particularly strong tendency for women who were rheumatoid positive to progress to necrotizing disease. Scleritis has been linked with numerous connective tissue disorders, but, in the majority of cases, no underlying disease could be detected. 1·2 •10 Rheumatoid arthritis is the connective tissue disorder most commonly associated with scleral disease. A patient's age and sex also are related to the development of scleritis; patients presenting with necrotizing disease were significantly older than the other groups, which may be related to the onset of systemic vasculitis. Our analysis of the therapy required to treat the worst episode of scleral inflammation supports the concept of a gradation of severity of anterior scleritis from diffuse to necrotizing disease, with a similar therapeutic response for both posterior and nodular scleritis. However, it is recognized that these types of data tend to be self-supporting, as mild disease (diffuse scleritis) was given mild treatment (NSAID) at presentation. We conclude from this study that the clinical diagnostic criteria provide valuable prognostic information for the management of scleritis. Our review of the incidence of ocular complications, the response of patients to treatment, and the incidence of an associated connective tissue disease confirm that diffuse anterior scleritis is usually a benign and self-limiting condition, whereas necrotizing scleritis is a severe disease that may be a manifestation of an underlying systemic disorder. The natural history of nodular scleritis suggests that it is a disease of intermediate severity and that these patients should be monitored for the development of scleral necrosis. The prognosis of posterior disease most closely approximates nodular disease, although it has a poor visual prognosis as a result of retinal and optic nerve involvement. Patients with posterior
scleritis probably form a heterogeneous population, because, even using B-scan ultrasonography, it is difficult to determine whether the underlying disease is diffuse, nodular, or necrotizing, although all three forms can be shown to exist.
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