Diseases of the Sclera and Episclera
Peter Watson
The association of scleral disease and severe systemic disease was recognized in the earliest clinical description of scleritis in 1717 by Sir William Read, Royal Ophthalmologist to Queen Anne in England.1 He also recognized that scleral inflammation could be caused by infection as well as being part of a systemic disease involving the joints. Although scleral disease is uncommon, only presenting once in every 800 new patients to a clinic,2 it is this connection between scleritis and severe and often potentially fatal systemic disease that makes early and accurate diagnosis essential to prevent inadequate treatment of severe disease and overtreatment of benign conditions. The diagnosis depends primarily on accurate and careful clinical observation.
The relationship between joint and connective tissue disease can be understood once it is realized that the collagen makeup of joint and sclera are similar, and although the non-weight-bearing eyeball has no need of a synovial membrane, its blood supply is similarly indirect from the episclera and the underlying choroid. This means that the sclera and the joint react in a similar way to inflammatory stimuli. As with most connective tissue disorders, scleritis is polygenic and occurs in immunocompetent patients who are able to protect themselves against pathogens but react in an abnormal overexuberant manner to antigens. This response results in chronic, granulomatous, and destructive changes within the tissue.
ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
The function of the sclera is to provide a firm opaque protective coat for the intraocular contents. This coat is resilient enough to allow for variations in the intraocular pressure, yet firm enough to prevent severe distortion of the contents of the eye on movement or when pressed on by the muscles or external forces.3 This stability of structure, which is vital for clear vision, is made possible by the organization and viscoelastic properties of scleral connective tissue.
Microscopically distinct concentric layers can be identified. From the exterior, underlying the conjunctiva, are the Tenon capsule, the episclera, the scleral stroma proper, and finally, the lamina fusca, which melds into the underlying choroid. Two sites exhibit specialized structure and function: the perilimbal trabecular meshwork, through which aqueous filters into the Schlemm canal, and the lamina cribrosa, which permits axons of the optic nerve to exit the posterior sclera.
The episclera is a fibroelastic structure formed after the development of the sclera from a mesenchymal condensation of the areolar structures of the orbit, possibly in response to eye movement. A deep or visceral layer is closely applied to the sclera. The outer parietal layer combines with the muscle sheaths, fusing first with the visceral layer and then with conjunctiva near the limbus. The subconjunctival space is traversed by only a few fibers, which form very little barrier to edema; it is not a lymphatic space because it contains no endothelium. The parietal layer of the Tenon capsule is penetrated by the muscles, and by the anterior ciliary artery, veins, nerves, and aqueous veins. The two layers of the episclera are thinly joined together by connecting fibers, and each layer is supplied with its own vascular network derived from the anterior ciliary arteries.
Throughout, the sclera is densely collagenous, the stroma consisting of fibrils with various diameters combining into either interlacing fiber bundles or defined lamellae in outer zones. Scleral fibrils are heterotypic structures made of collagen types I and III, with small amounts of types V and VI also present. Scleral elastic fibers are especially abundant in lamina fusca and trabecular meshwork. The interfibrillar matrix is occupied by small leucine-rich proteoglycans, decorin, and biglycan, containing dermatan and dermatan/chondroitin sulfate glycosaminoglycans, together with a large proteoglycan, aggrecan, which also carries keratin sulfate side chains.
Decorin is closely associated with the collagen fibrils at specific binding sites situated close to the C-terminus of the collagen molecules.
Decorin is closely associated with the collagen fibrils at specific binding sites situated close to the C-terminus of the collagen molecules.
Proteoglycans influence hydration, solute diffusion, and fluid movement through the sclera, both from the uvea and via the trabecular meshwork. The collagen bundles are arranged to neutralize the external pressures imposed by the action of the muscles. These bundles vary in size from 10 to 15 µm in thickness and 100 to 150 µm in length, roughly parallel to the surface but interlacing among themselves.4 The somewhat irregular size and the crisscross pattern account, in part, for the opaqueness of the sclera. The sclera is also fully hydrated at all times. If the water content is reduced to 40% by drying, the sclera becomes translucent. This phenomenon, which is often observed during detachment surgery, is probably produced by concentration of the proteoglycan, thus changing its refractive index to one that is near that of collagen. As will be seen, a similar change occurs after certain types of scleral disease in which the sclera becomes translucent as a result of changes in collagen and proteoglycan.
Development
The shape of the sclera is determined during the formation of the inner layer of the optic cup, the retina, and the choroid. The sclera is derived from a condensation of neural crest, mesectoderm. The mesoderm itself contributes directly to only a small strip of temporal sclera and to the extraocular muscles, vascular endothelium, and ocular adnexa. The sclera develops outside the choroid relatively late in development (7 weeks) starting anteriorly. The organization of both sclera and choroid is in turn induced by the retinal pigment epithelium. Abnormalities of development at or before the 20-mm stage may lead to colobomas and in lesser degrees to progressive myopia. Development of sclera over the posterior pole is not complete until the end of the fifth month of fetal life. From then on, the shape of the sclera is modified by the effect of the intraocular pressure.5
After birth, the eye continues to grow; by maturity, its girth at the equator will have increased by 40% and its mass and volume will have trebled. Gene determination allows a programmed sequence of events to occur that decides in which direction changes happen, and the extent of that movement. The end point of development is determined by the rates of growth, structure, development, and function of the adjacent structures. Thus, scleral development is determined not only by the genetic signaling to the fibrocytes of the sclera, but by the concomitant development of lens, retina, and choroid and the production of aqueous by the ciliary body.
During this period of growth, the refractive elements in the eye must alter in order to acquire and then maintain a state of emmetropia. This is achieved by changes in the curvature of both cornea and lens and by an increase in the axial length of the eye. This increase in axial length occurs in two stages: an infantile phase that is up to 3 years of age and then a slower juvenile phase that is complete around the age of 13 years, by which time the eye is fully developed. The elastic fibers in the sclera can be stretched beyond their limit of elasticity when not supported by a fully developed collagenous structure. The whole globe can therefore be distended until 3 years after birth; the lamina cribrosa is the only scleral structure that can be stretched after this age.
Vascular Supply and Nutrition
Although the sclera has a low metabolic activity, it requires some nutrition, which it derives from the underlying choroid and overlying episclera, the sclera being entirely permeable to water, glucose, and proteins. The sclera transmits blood vessels, but retains a very scant supply for its own use. However, the sclera is supplied with nerves, particularly in the anterior segment near the muscles; damage to these nerves in destructive scleritis is undoubtedly the major cause of pain in this condition. The nerves also appear to be stimulated by distention of the sclera.
The episclera, or Tenon capsule, provides part of the nutrition of the sclera and for the cellular response to inflammation. In addition, the episcleral membranes also act like the synovial membrane to enable smooth movement of the eye and, together with the muscular sheaths to which they are fused, provide a check on excessive movement.
With the increasing use of fluorescein and indocyanine green (ICG) angiography in the early detection of severe necrotizing disease of the sclera, it is necessary to have an understanding of the normal anatomy of the vasculature of the anterior segment of the eye.6, 7 and 8 The blood supply to this region is enormous, being derived from the anterior ciliary arteries, but with extensive collateral arterial anastomoses to the posterior ciliary arteries at the root of the iris and the episcleral arterial circle adjacent to the limbus. The anterior system is readily visible with the slit lamp and by anterior segment fluorescein and ICG angiography, especially if the eye is inflamed.9, 10(pp22-24,103-108)
The recognition of the normal vascular anatomy is of vital importance in the differentiation of episcleral and scleral conditions. Clinically, the separation and displacement of these vascular layers give the most important clues to the site and, hence, the severity of the inflammation.
On slit-lamp examination, three layers of vessels are readily visible11:
The conjunctival plexus, which is the most superficial layer of vessels, can be moved over the underlying structures.
The superficial episcleral capillary plexus is a radially arranged series of vessels lying within the parietal layer of the Tenon capsule and moving freely with the episcleral tissue. The vessels in this layer anastomose at the limbus with the conjunctival vessels, with other members of the same plexus, and with the deep plexus.
The deep episcleral capillary network is closely applied to the sclera in the visceral layer of the Tenon capsule. These vessels anastomose freely with each other, forming a syncytium over the surface of the sclera.
That the conjunctival and superficial episcleral vessels can be blanched with 1:1,000 epinephrine or 10% phenylephrine but the deep vessels are only slightly constricted is of considerable assistance when attempting to differentiate between deep and superficial inflammation as the deep vascular layer can be readily observed when the superficial vessels have been constricted.
The large vessels to and from the anterior extension of the long posterior ciliary arteries and the intrascleral plexus traverse the episclera near the insertions of the muscles and through perforating channels midway between the muscle insertions and the limbus. There may be as many as 12 of these channels. There are thus two connecting sagittal and two coronal arterial circulations in the anterior segment of the eye.10(pp22-24,103-108) As a consequence of this artery-to-artery anastomosis, the blood flow throughout this circulation is not only slow but even oscillating.8 This means that substances leaking from the capillaries are not carried away fast. Coupled with the fact that the level of immunoglobulins is highest 2 mm from the limbus,12 this is the ideal situation for immunologic reactions to take place, and indeed the usual positions to find the start of scleral inflammation are in the upper and lower temporal and nasal quadrants where the circulation is the slowest.
CLINICAL EXAMINATION
There is no ocular disease that rewards careful clinical examination more than scleritis. Failure to take an adequate history or to undertake a gross examination away from the slit lamp can easily result in an incorrect or inadequate diagnosis. Failure to diagnose and treat scleritis early may result in blindness, as the destructive process can be extremely rapid and is irreversible.10(p342,Fig12.23) While conditions involving the episclera tend to be acute, transient, and of little importance, inflammation of the sclera is usually indolent, painful, and destructive, often representing a local manifestation of a generalized systemic condition. Therefore, it is of considerable importance to decide which tissue is involved from the onset of the disease.
History
Time taken in taking a careful history will be amply rewarded in patients with scleral disease. It is essential to inquire about the onset of the disorder, as there is often a prodromal stage before symptoms and signs develop.
The timing and the mode of onset of the scleritis may reveal the precipitating cause, be it infection, severe stress, or the onset of some systemic disease.
Both episcleral and scleral disease commence with redness and discomfort, but photophobia and lacrimation are most unusual. Their presence, particularly if combined with any change in the vision, indicates either an incorrect diagnosis or an intercurrent corneal or intraocular disease.
While episcleritis gives a feeling of heat, prickling, or irritation, pain is the prominent characteristic of scleral disease; it is often the pain, rather than the redness of the eye, that causes the patient to seek advice.
The pain of deep-seated scleral disease is exceptionally severe and boring in character. Unlike the pain of superficial conditions, which are localized to the eye, the pain in scleritis radiates to the forehead, brow, and jaw, characteristically waking the patient during the night but diminishing through the day.
Usually no underlying condition can be found in patients with episcleritis, but some give a history of recent viral disease, of allergy, hypersensitivity reactions, or contact with external irritants, particularly industrial solvents. If associated with migraine, then, treating the migraine will treat the episcleritis.
Scleral disease can be a manifestation of disease of any system of the body; therefore, a routine inquiry should be made concerning the cardiovascular system for evidence particularly of systemic arteritis or hypertension, the respiratory system for evidence of tuberculosis or sarcoidosis, and the genitourinary system for evidence of renal tuberculosis or venereal disease.
Skin disorders that accompany or precede the onset of scleral inflammation include herpes zoster, rosacea, psoriasis, and erythema nodosum or arteritis. No central nervous system disease appears to be associated with scleral disease.
Most importantly, a very strong relationship exists between skeletal and scleral disease, so an attempt should be made to determine whether there is any suggestion of connective tissue disease (e.g., a history of general malaise,
pains in multiple or single joints, pains in the back or in the neck, and the presence of morning stiffness).
pains in multiple or single joints, pains in the back or in the neck, and the presence of morning stiffness).
In general, the more rapid the onset of the condition, the more readily it is treatable, and, consequently, the better the prognosis. However, because most therapy for inflammatory scleral disease is administered systemically and is immunosuppressive in type, a history of gastric ulceration must be elicited. It is of major importance because its presence may affect the type and extent of the therapy that can be given.
Eye Examination
Failure of vision is often insidious, so the visual acuity must be measured at frequent intervals during the course of the disease. Even a small reduction in vision is always a serious sign.
The external examination of the eye in daylight must never be omitted, however inconvenient. This examination is essential to distinguish the deep discoloration, the increased transparency, and the area of maximum edema in deep scleral disease. No other method gives so much information; tungsten or fluorescent light is not as effective as daylight. Areas of deep inflammation and the extent of the progression of scleral disease, invisible when examined with the slit lamp, are often easy to detect in daylight.
The object of slit-lamp examination is to determine the depth and nature of scleral and episcleral conditions and the presence of corneal changes. The changes seen are drawn in the records, as, carefully done, they are more valuable than photographs in judging the progression or regression of disease.
With the use of diffuse light with a neutral-density filter, the vascular networks of both eyes are examined in detail to determine the layer in which the vessels show maximum congestion, and also to decide whether there is edema of sclera, episclera, or subconjunctival space, or infiltration of episcleral tissues. To determine this, it may be necessary to blanch the superficial tissues with epinephrine 1:1,000 or phenylephrine 10%.
The red-free (green) filter is also extremely valuable in confirming the areas of maximum congestion and whether any areas are totally avascular. Because this is an important physical sign and is easily missed, examination in red-free light should be routinely performed. The green light brings the vessels into very sharp contrast with the background and enables the position of maximum inflammation to be determined with certainty. It also enables the paths and configurations of the vessels to be followed and will show lymphocytic infiltration of the episcleral tissue as yellow spots; this often indicates that the inflammation is more extensive than previously supposed.
Slit-lamp examination is also used to ascertain the nature and depth of any corneal changes, the nature of any episcleral infiltration or mass, and the presence of cells in the anterior chamber or vitreous and posterior synechiae.
Transillumination of the sclera in which a strong beam of light is shone through the pupil can be helpful in distinguishing areas of thinning of scleral tissue.
Glaucoma often occurs secondary to scleral disease. Applanation readings should be undertaken at the first visit and subsequently at each visit during treatment, especially if corticosteroids in any form are used.
Ophthalmoscopy must be performed to exclude a posterior scleritis, which can be notoriously difficult to diagnose. Ophthalmoscopy is particularly important if cells are observed in the anterior or posterior chamber. Some patients with scleritis have granulomatous changes in the posterior segment that give rise to an exudative retinal detachment and choroidal folds. Scleral depression should be used with circumspection as the thin sclera can perforate.
Orbital changes are not uncommon: the orbital tissue not only being involved by the posterior scleritis, but also inflammation in the orbit may affect the posterior sclera. The extraocular muscles become involved in this process, and myositis seems to be a major cause of the discomfort and pain in posterior scleral inflammation.13 Proptosis and also limitation of ocular movements may be induced if the inflammation is severe. It is worth noting that posterior scleritis can occasionally be completely symptom-free even when the patient has developed a complete ophthalmoplegia.
INVESTIGATIONS
Because so many patients with scleral disease have systemic disease, a thorough physical examination is essential. This is probably best performed by a rheumatologist familiar with the joints, skin, cardiovascular, and respiratory disease.
Hematologic
The diagnosis of scleritis is clinical, but to determine whether there is an underlying etiology, the following routine investigations are performed:
Hemoglobin
White blood cell count: differential white cell count and platelets
Erythrocyte sedimentation rate or plasma viscosity
Acute phase protein; the C-reactive protein (CRP) is the best indicator of an active generalized inflammatory response.
If connective tissue disease is suspected, full immunologic investigations are undertaken, including levels of immunoglobulins and immunofluorescent studies for autoantibodies (including rheumatoid factor or anti-cyclic citrullinated peptide [anti-CCP], lupus erythematous cells, and antinuclear and anti-DNA antibodies). If a systemic vasculitis such as Wegener granulomatosis or periarteritis nodosa is possible, then antineutrophil cytoplasmic antibody (ANCA, cANCA, and pANCA) tests are essential investigations.
Serum uric acid
Serologic tests for syphilis
Imaging
Ultrasonography
B-scan ultrasonography should never be omitted from the examination of patients with scleritis. Now that highquality ultrasonography has become available, the extent and severity of the inflammation can be determined with great accuracy.10(pp118-125) Many patients who were formerly thought to have only anterior segment disease have been found to have extensive and sight-threatening posterior scleritis as well. It also has become known that many patients with posterior scleritis with few symptoms and signs have much more extensive disease than had previously been considered possible. B-mode images are extremely helpful for the diagnosis of posterior scleritis. Following treatment, the swelling may be slow to resolve, and if fibrosis occurs, it may never resolve. The use of these images in following the course of the disease must therefore be used with caution.
Angiography
Table 23-110(pp103-118)
The direction of flow, the distinction between arteries and veins, the patency of the vessels, the integrity of the circulation, and the presence or absence of localized
vasculitis can be determined only by the use of lowdose anterior segment fluorescein and ICG angiography (Table 23-1).7, 8 and 9 Because of the difference in size of the fluorescent molecules, they become visible at different times during the circulation. It is important, therefore, to be able to compare a color and red-free photograph of the area of interest with the angiograms.
vasculitis can be determined only by the use of lowdose anterior segment fluorescein and ICG angiography (Table 23-1).7, 8 and 9 Because of the difference in size of the fluorescent molecules, they become visible at different times during the circulation. It is important, therefore, to be able to compare a color and red-free photograph of the area of interest with the angiograms.
TABLE 23-1 Angiographic Findings in Scleral Disease | ||||||||||||||||||||||||||||||||||||
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The ICG and fluorescein angiography investigations are complementary. They can be performed sequentially at the same examination using the same cameras used for examination of the posterior segment of the eye. Sodium fluorescein 20% (0.6 mL) (125 mg) is used first, as this low concentration gives the optimum intravascular plasma fluorescence with minimum leakage. Most of the information is obtained within the first few seconds of transit with fluorescein. The ICG is then injected and the sequence followed for 20 minutes, as the most useful information comes from the late films.9
Arterial Phase
Anterior Episcleral Arterial Circle
The anterior ciliary arteries run radially toward the limbus within the Tenon capsule, giving few, if any, branches until they reach the anterior segment of the globe. Their positions are very variable, and they do not always follow the rectus muscles. They bifurcate 2 to 5 mm behind the limbus, and each division runs forward and circumferentially to anastomose with a branch from an adjacent artery. This results in an anterior episcleral arterial circle in which arterial blood may be static, oscillating, or flowing rapidly. The divisions of the anterior ciliary arteries are typically superficial at their origins, but run deeper at their anastomoses. They occasionally dip too deep to be seen in fluorescein angiograms, but remain visible on ICG angiography.
From the anterior episcleral arterial circle, four distinct circulations are supplied: episcleral, anterior conjunctival, limbal, and iris.
Episcleral Circulation
Immediately after their origin by bifurcation of the anterior ciliary arteries, the contributions to the anterior episcleral circle divide again to give recurrent branches that run posteriorly and subdivide to form a netlike episcleral plexus. The variability of the positioning of the anterior ciliary arteries inevitably leaves large areas of episclera far from such an arterial supply. These areas receive other posterior branches from the episcleral circle. Where the circle runs deep within the sclera, such branches appear as isolated perforating vessels. They fill very shortly after the episcleral circle, and they also divide repeatedly as they run posteriorly.
Anterior Conjunctival Circulation
Throughout their superficial course, the arteries of the episcleral circle give off fine loops that run forward into the limbal reflection of the conjunctiva before curving back radially and dividing to form the lacework of the anterior conjunctival capillary plexus. The delicate column of blood within the anterior conjunctival loops may be punctuated by a string of individual erythrocytes, suggesting that the lumen is approximately 12 µm in diameter.
Anterior conjunctival loops may also arise from perforating posterior branches of the episcleral circle.
The anterior conjunctival circulation, supplied by the anterior ciliary arteries, always fills before the posterior conjunctival circulation, which is derived from the posterior tarsal vessels. The watershed zone between these sources can fill very late. However, anterior conjunctival loops do sometimes anastomose with arteries of similar caliber derived from the posterior tarsal circulation.
Limbal Arcades
The limbal arcades are supplied through anterior branches of the episcleral arterial circle. Their origins are often shared with those of the anterior conjunctival loops, and, where the circle runs deep, they too are derived from the perforating posterior branches. They often fill very late during a normal angiogram.
The limbal capillary loops never leak fluorescein, even during high-dose angiograms, suggesting that their endothelial cells are united by tight junctions.
Iris Vessels
The first flush of fluorescein within the anterior episcleral arterial circle always coincides with filling of the radial arterioles of the iris. In some angiograms, the iris circulation appears to derive directly from the episcleral circle through the communication between the anterior and long posterior ciliary arteries.
Venous Phase
Anterior ciliary veins accompany the arteries, but there is no well-organized venous ring corresponding to the anterior episcleral arterial circle. The posterior episcleral branches of the arterial circle are paralleled by centripetal venules, and looping anterior conjunctival venules are interspersed between the arterioles. ICG angiography reveals these two venules accompanying each of the larger arterioles, which are almost invisible in the normal eye but dilate rapidly in the early stages of inflammation. Their obvious presence may be used as an indicator of disease activity. The posterior conjunctival vessels drain back into the tarsal circulation.
Capillary Phase
On fluorescein angiography, the episcleral capillary net of the episclera is often difficult to discern below the more prominent conjunctival circulation. It is most clearly seen when the conjunctival circulation fills late for anatomic or pathologic reasons. The determination of the true extent of the perfusion requires the use of ICG angiography.
The anterior conjunctival capillary plexus forms an interlacing network between the anterior conjunctival arterioles. Perfusion of the watershed zone that separates the territories supplied by the anterior ciliary and posterior tarsal systems may be delayed by as much as 15 seconds after first flush. However, this region is often crossed by arteriolar anastomoses between the two circulations, which can be detected in ICG angiography. The destination of venous blood is not affected by whether it originated from the anterior ciliary or posterior ciliary or tarsal circulations.
Other Imaging Techniques
Optical Coherence Tomography
The advent of spectral-domain optical coherence tomography (OCT) has enabled very high definition of the anterior sclera up to the insertion of the rectus muscles. At 830 nm, an axial resolution of 5 µm can be obtained so that the structures of the anterior segment can be easily distinguished. Furthermore, when separation of the collagen fibers by edema and infiltration and destruction of tissue occur, this can be seen in great detail. Examination of these images has not only helped in the diagnosis and following of patients with scleral disease, it has also confirmed the classification of disease into diffuse, nodular, and necrotizing. It also helps to distinguish between the various varieties of necrotizing disease essential to the early treatment of the most severe forms of the condition.10(pp124-129)
Posterior segment OCT is particularly valuable in posterior scleritis and detecting the resultant edema in the region of the macula and its response to treatment.
High-frequency Ultrasonography Biomicroscopy
High-frequency ultrasonography biomicroscopy (UBM) is less useful than anterior segment spectral-domain OCT, but sometimes reveals, in addition, extensive involvement or destruction of the deep scleral tissue around the ora and the ciliary body, indicating the need for urgent and intensive use of immunosuppressive therapy.
If biopsy seems to be indicated, anterior segment spectral-domain OCT and UBM images of scleral nodules may be able to show whether they are solid or full of fluid. However, because of the echo characteristics of different fluids with UBM, this may not represent the true situation if this technique is used alone, so these findings need to be treated with caution.
Radiography
If they are clinically indicated, radiologic investigations should include a chest radiograph and a radiograph of the sacroiliac joints. Physical examination may not reveal sacroiliitis of the rheumatoid type. Radiographs of other joints are taken if a particular disease process such as rheumatoid arthritis, gout, or sarcoidosis is suspected.
Computed Tomography and Magnetic Resonance Imaging
If orbital extension of disease is thought to have occurred, then computed tomography or magnetic resonance imaging should be performed. However, these investigations, although sometimes very useful, are not obligatory, as scleral inflammation can usually be detected more readily and accurately by B-mode ultrasound imaging. If vision is threatened because of a lesion close to the optic nerve, then the extent of the lesion and its response to treatment can be monitored.
Other Investigations
Prick and patch testing of the skin has been universally unrewarding even when there is a known sensitizer. Local challenge has been attempted, but the results are inconclusive.
Electroretinography and electro-oculography are of assistance only in the presence of cataract or severe necrotizing or posterior scleritis. There is sometimes a dramatic fall in the electric response at the onset of disease and an equally dramatic rise when the disease is suppressed, provided destructive changes have not occurred.
Scleral Biopsy
Scleral biopsy should be used only if no other method of diagnosis exists, as in some infections. Biopsies should be performed with extreme caution, as many nodules contain nothing but fluid. If left alone, these will heal with scar tissue; if removed, the sclera will not recover and the underlying tissue will be exposed.
IMMUNOLOGY-INDUCED SCLERAL DISEASE
Episcleritis
Episcleritis is an inflammation of the episclera and overlying Tenon capsule, characterized by a dilatation and transudation of fluid from their vessels.
Episcleritis is almost always a benign inflammatory condition occurring in young adults, with a marked tendency to recur. The condition, which is frequently bilateral, may be divided on clinical grounds into simple episcleritis and nodular episcleritis.
Clinical Manifestations
The onset is usually acute; the eye may become red and painful in as short a time as half an hour. The patient’s main complaint is redness of the eye, which is often sectorial and may be accompanied by a feeling of hotness, pricking, and mild discomfort. There is no discharge, although the eye waters occasionally.
Pain may be absent, but the discomfort may be so severe that patients cannot pursue their normal occupation. The pain or discomfort is localized to the eye, rarely radiating to the forehead and never producing the severe boring pain that is so commonly described in scleritis. In a severe attack, the lids may become swollen, but this is a rare occurrence. If photophobia is present, an accompanying corneal condition should be suspected.
Although simple and nodular episcleritis differ in their clinical courses, the edema and infiltration remain entirely within the episcleral tissues. The sclera is not involved. The maximum congestion is in the superficial episcleral network, with some slight congestion of the overlying conjunctival vessels and deep episcleral vessels.10(Fig3.12) The intraocular structures are not involved in either variety, nor is the visual acuity affected.
Anterior segment angiography reveals a normal vascular pattern but a very rapid flow rate, with the whole transit of the dye being completed within 2 or 3 seconds. In episcleritis associated with migraine, fluorescein/ICG angiography reveals vaso-nonperfusion of some arterioles.
The redness of simple episcleritis may be intense, varying from a fiery red or a brick red discoloration to a mild red flush, but it does not have the bluish tinge that is seen in scleritis. The distribution is usually sectorial but can involve the whole anterior segment of the globe. The episcleral vessels are engorged, but retain their normal radial position and architecture. In simple episcleritis, there is a diffuse edema of the episcleral tissues. These tissues are sometimes infiltrated with gray deposits that appear yellow in red-free light. Surprisingly, the eye is rarely tender to the touch.
In contrast to simple episcleritis, the infiltration and edema of nodular episcleritis are localized to one part of the globe, forming a nodule and some surrounding congestion. The nodule can be moved over the underlying sclera, which is not edematous. The scleral plexus of vessels can be distinguished deep to the nodule, lying flat on the sclera and slightly congested but otherwise normal in color and configuration. Episcleral nodules may be single or multiple, but do not undergo necrosis. After multiple attacks of nodular episcleritis in the same location, the superficial lamellae of the sclera and, occasionally, the adjacent cornea show some alteration: the sclera becoming slightly more transparent and the corneal stroma hazy in this one area.
Etiology
As episcleritis is almost always an inconvenience and not a visually threatening disease, investigation is not necessary. Of those attending tertiary referral centers with episcleritis (almost by definition those with the most serious and intractable problems), 30% of patients can be found to have some associated general conditions,14, 15 but the rest defy all attempts to discover an etiology. Although some patients have a strong family history of atopy, results of investigations have been uniformly negative. Of those in whom an etiology was found, several had attacks associated with migraine, but only 5% showed any association with connective tissue disease, 7% had an association with herpes zoster, 3% each had an association with gout or syphilis; the rest had associated conditions such as erythema nodosum, Schönlein-Henoch purpura, IgA nephropathy, erythema multiforme, contact with industrial solvents, or penicillin sensitivity, indicating an immune basis for the condition.
Sometimes an attack of episcleritis coincides with an attack of migraine. Fluorescein and ICG angiography shows a spasm of some arterioles in the area of episcleritis. The vessel reperfuses after a delay and antimigraine therapy, but the inflammation may continue for several days.
Episcleral Biopsy
Episcleral biopsy has neither contributed to the understanding of the disorder nor has it been of value in the diagnosis of lymphomatous infiltration.
Pathology
Microscopic and electron microscopic studies of biopsy specimens from patients with simple and nodular episcleritis have been totally noncontributory in elucidating the etiology of this condition. The inflamed area is packed with lymphocytes and a few other inflammatory cells, but there are no mast cells, plasma cells, or eosinophils.
Treatment
Even without therapy, simple episcleritis improves considerably within the first week and resolves within 3 weeks. Provided the eye is not too uncomfortable, most patients can be persuaded to leave the eye untreated, because the condition will resolve spontaneously. Cold artificial tear
drops (4°C) will give symptomatic relief. However, if it is believed that some therapy is essential, topical corticosteroids or locally applied nonsteroidal anti-inflammatory drugs (NSAIDs) will reduce the inflammatory response and speed resolution slightly.16
drops (4°C) will give symptomatic relief. However, if it is believed that some therapy is essential, topical corticosteroids or locally applied nonsteroidal anti-inflammatory drugs (NSAIDs) will reduce the inflammatory response and speed resolution slightly.16
The use of corticosteroid drops must be continued for several days after the inflammation has subsided to prevent the exacerbation of the condition that occurs if they are stopped suddenly. Prednisolone, betamethasone, or dexamethasone drops may be administered hourly until redness disappears, and then three times daily for 4 to 5 days. Under no circumstances should topical steroids be administered continually for more than a few weeks at a time because of the very real danger of inducing steroid glaucoma and cataract.
If the condition fails to respond immediately, other treatment regimens should be sought. Ocular NSAIDs can be administered four times daily until redness disappears. Glaucoma and cataract have not been observed after prolonged use, but many patients become intolerant to the use of the ointment or complain of stinging and irritation.
If the cause of the episcleritis is thought to be migrainous, treatment of the migraine may relieve the spasm of the arterioles.
Whereas simple episcleritis resolves rapidly without therapy, the resolution of nodular episcleritis is much slower. Local therapy is consequently of much more value; the same regimen of treatment is followed.
In the few patients in whom episcleritis becomes indolent, or in whom recurrences are so numerous that the patient becomes incapacitated, it is reasonable to consider systemic therapy with NSAIDs such as flurbiprofen (Froben), 100 mg three times daily, which usually gives immediate and prolonged relief of symptoms and signs. It is important to note that not all of the NSAIDs work in this condition, and individual patients are more responsive to one preparation than another. Treatment with NSAIDs may be terminated abruptly when the condition comes under control.
The complications of episcleritis are minor and are not responsible for any decrease in visual acuity.
Course and Prognosis
Whether treated or not, simple episcleritis will resolve in 10 to 21 days. It will usually reappear at irregular intervals and then eventually disappear.
In nodular episcleritis, the nodule initially increases rapidly in size, sometimes reaching the size of a split pea. Thereafter, it gradually regresses over a variable period and eventually disappears, although this may take up to 2 months without treatment.
Recurrences occur in nodular episcleritis also, but the two varieties are not mutually exclusive (a simple episcleritis may recur as a nodular episcleritis and vice versa). However, episcleritis never develops into scleritis in the same attack, although edema of the episclera invariably accompanies scleritis.
Episcleritis is an entirely benign condition, although it may be a great nuisance to the patient. It may recur over a period of many years, but it rarely leaves any residual ocular changes except for some areas of scleral transparency or localized stromal keratitis in those patients who have had severe attacks of nodular disease occurring always at the same site. Of 180 patients initially diagnosed as having episcleritis, only four developed scleral involvement and only 2% had a decrease in visual acuity of two lines or more within a year of the onset, and in every case this was from increasing involutional cataract.17, 18 and 19
Scleritis
Scleritis, unlike episcleritis, is a severe destructive disease, sometimes leading to the loss of an eye from deteriorating vision, severe pain, or even perforation of the globe. Such changes, when they occur, are rapid, so early diagnosis and effective treatment is essential. Scleral disease can be diagnosed when the patient is first seen. Whereas episcleritis rarely, if ever, involves the scleral tissue, in scleritis the episclera is always involved. Therefore, attention must be diverted from the superficial episclera to the underlying sclera to detect the early changes of scleral edema or necrosis.
The onset of scleritis is usually gradual, building up over several days. By the time patients seek advice, the clinical types can be distinguished as anterior or posterior, or sometimes both. Anterior scleritis may be further subdivided into diffuse, nodular, or necrotizing. Necrotizing scleritis may be further subdivided into vaso-occlusive (including scleromalacia perforans, in which there are no signs of inflammation) and granulomatous, which includes both vasculitic and surgically induced scleritis (SINS). These subdivisions have been confirmed through examination of images obtained by anterior segment spectral-domain OCT. Similar changes occur if the posterior segment is involved, but are less easy to diagnose as the imaging is less efficient.
Long-term follow-up of patients with scleral disease showed that only 8% of patients changed from one type of disease to another during the course of this disease, so although differentiation into the various clinical types does not necessarily indicate an etiology, it does have a direct bearing on the prognosis and the type of treatment to be used.17
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