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A thorough ophthalmic examination is critical for both diagnosis and assessing response to therapy.
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Use of standardized grading scales for assessing intraocular inflammation can improve patient management.
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Standard grading scales are available for anterior chamber cells and flare and vitreous cells and haze.
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A detailed examination of the peripheral retina can reveal pars plana exudates, signs of retinal vasculitis, Delen–Fuchs nodules, or other lesions suggesting active inflammation or infection.
The ocular examination of patients with uveitis is important not only to diagnose the disease correctly but also to determine the appropriate therapy. The examination will provide information that enables the examiner to generate a differential diagnosis and will allow the patient’s subjective complaints to be placed into the framework of objective clinical findings. In addition, the baseline examination becomes an important yardstick against which treatment success or failure will be measured. Many inflammatory diseases are chronic and require potentially toxic therapy. Therefore, it is critical to accurately assess whether a patient is benefiting from treatment. This includes a thorough review of the patient’s previous medical records and accurate assessment of the disease at each clinic visit. A complete review of the patient’s medical records provides important information for planning new therapeutic approaches and guards against repeating therapies that were unsatisfactory in the past. Because a patient’s medical record is valuable in assessing response to therapy, it is important to accurately record the presence or absence of important physical findings in a reproducible and standardized manner. Furthermore, because many of the ophthalmic findings in inflammatory disease, such as vitreous cells and haze, are evaluated only by subjective means, the examiner should strive to maintain internal consistency in grading the severity of the observations and to standardize these observations whenever possible. Importantly, standard grading scales should be used whenever possible. The use of standard scales provides consistency when different ophthalmologists are involved in the care of the patient over time. This also allows comparison of patients with those reported in the literature.
Visual acuity
Several factors can lead to reduced visual acuity in patients with uveitis or retinitis. A combination of corneal opacity, anterior chamber inflammation, cataract, and vitreous haze may exacerbate a disturbance in retinal function caused by retinal edema, necrosis, or scarring. In addition, optic nerve function may be compromised after inflammation or glaucoma. It is important for the clinician to determine the cause of diminished vision because the therapeutic approach will differ according to the cause. For example, it would be inappropriate to increase a patient’s dose of prednisone to treat worsening vision that is due to a progressive posterior subcapsular cataract. Whatever type of visual acuity measurement is used, it must be performed under the same lighting conditions each time, otherwise the fluctuations induced by the testing environment will mask changes in vision caused by worsening disease or response to therapy. A best-corrected visual acuity measurement should be obtained either by refraction or at the very least with the use of a pinhole occluder. Near-vision measurement is also helpful because we have observed that an improvement in near vision can precede an improvement in distance vision by several weeks in patients with chronic macular edema.
The most common method to measure visual acuity is the Snellen eye chart. Like all eye charts, the Snellen chart tests a patient’s ability to resolve high-contrast letters and is satisfactory if their vision is good. Unfortunately, the chart does not have enough sensitivity for patients with poor vision. There are no lines between 20/100 and 20/200 or between 20/200 and 20/400. In addition, there are too few letters on the lines above 20/100. Although an improvement in visual acuity from 20/200 to 20/125 may not be significant to the patient, the ability to measure this improvement is an important indicator that the current therapeutic approach is working. Because many patients with macular edema have a visual acuity of less than 20/80, initial improvement might be missed with use of a standard Snellen chart.
For these reasons, we have used the ETDRS chart initially developed for the evaluation of patients in the Early Treatment for Diabetic Retinopathy Study (ETDRS) ( Fig. 3-1 ). This chart has five letters per line starting with the 20/200 line, and every three lines represent a doubling of the visual angle. Therefore, improving from 20/40 to 20/20 represents the same level of improvement in visual function as 20/80 to 20/40. If patients cannot read the 20/200 line while sitting 4 m from the chart, they are moved to 1 m from the chart and the acuities are recorded as 5 over the appropriate denominator, that is, 5/200. Because each line has five letters, the acuity can be expressed as the total number of letters read. The 1 and 4 m scales can be made continuous by adding 30 letters to the number read at 4 m. The scale of visual acuity is then linear and continuous from 5/200 (five letters) to 20/12.5 (95 letters).
A computerized method for testing visual acuity for clinical research has been developed as an alternative to the standard ETDRS testing protocol. A multicenter study comparing this elctronic visual acuity testing algorithm (E-ETDRS) was compared to the standard testing protocol and showed high test–retest reliability and good concordance with the standard ETDRS testing. This new method allows electronic capture of the data, eliminates computational errors, reduces testing time, and may help reduce technician bias.
External examination
As stated earlier, a detailed examination of the skin can provide useful diagnostic clues for the astute clinician. Not only should the skin of the lids be closely examined, but also the entire skin should be evaluated for presence of rashes, nodules, or vitiligo. We have diagnosed sarcoidosis on the basis of the presence of lid granulomas and of lesions on the extremities and chest, and we have diagnosed Kaposi’s sarcoma based on characteristic vascular lesions on the upper eyelid. If any skin findings are noted, a consultation with a dermatologist and a skin biopsy should be considered.
Pupils and extraocular muscles
Evaluation of the pupils is frequently difficult in the patient with uveitis because of synechiae or chronic cycloplegic therapy. The inflamed pupil, even without synechiae, may not move well as a result of iris atrophy. When examination is possible, the status of the optic nerve can be assessed with the standard swinging flashlight test to detect an afferent pupillary defect.
Involvement of the extraocular muscles in intraocular inflammatory disease is unusual. Esotropia or exotropia resulting from long-standing visual loss may develop as a result of cataract, retinal, or optic nerve disease. The finding of a new vertical tropia or internuclear ophthalmoplegia should alert the physician to underlying diseases of the central nervous system that may be associated with causes of uveitis, such as multiple sclerosis, sarcoidosis, or non-Hodgkin’s lymphoma.
Intraocular pressure measurement
Either elevated intraocular pressure or hypotony can occur as a result of intraocular inflammation. Goldmann applanation tonometry is usually sufficient to measure the intraocular pressure in patients with uveitis; however, fluorescein should not be instilled until the slit-lamp examination and ophthalmoscopy are completed, because fluorescein enters the eye and prevents an accurate assessment of the amount of flare in the anterior chamber. In addition, fluorescein may obscure the view of the posterior segment if the pupil is small, and may persist in the eye for more than 24 hours, especially in eyes with hypotonia and reduced aqueous flow. Therefore, applanation tonometry should either be performed under anesthetic without fluorescein, done with a pneumotonometer, or preferably, performed at the end of the examination.
Slit-lamp biomicroscopy
Conjunctiva
Conjunctival hyperemia is a common sign of acute anterior inflammation but is rare in chronic posterior segment disease. Usually conjunctival injection is uniform in the perilimbal region and represents ciliary body inflammation. The conjunctival injection of uveitis can be differentiated from conjunctivitis by the lack of involvement of the fornix and palpebral conjunctiva. Scleritis and episcleritis may occur in conjunction with some types of intraocular inflammation. Injected deep scleral vessels, a purple scleral hue, and severe pain distinguish true scleritis from more superficial inflammation. Scleritis associated with uveitis is often nodular and confined to a section of the globe, whereas ciliary body injection tends to involve the globe more diffusely. Some confusion may arise when a patient with intraocular inflammation develops an allergic reaction to topical medication. The eye becomes more painful and red during treatment, and this may be misinterpreted as worsening disease and failure of treatment. However, patients with a superimposed allergic reaction often develop itching, dermatitis, and significant conjunctival injection affecting the palpebral conjunctiva.
Cornea
Keratic Precipitates
Keratic precipitates (KPs) are the most commonly reported corneal finding in uveitis ( Fig. 3-2 ). They are small aggregates of inflammatory cells that accumulate on the endothelial surface of the cornea. The presence of these deposits on the endothelium of the cornea can provide useful diagnostic information and indicates the current level of inflammatory activity. Also, in an eye without active anterior segment inflammation manifested by cells and flare, the presence of KPs tells the practitioner that the eye was previously inflamed.
KPs usually accumulate on the lower half of the cornea, often in a base-down triangle configuration; however, in some disorders, such as Fuchs’ iridocyclitis, KPs may be present superiorly. The precipitates vary in size from flecks the size of cornea guttata to 1 mm in diameter. Because cornea guttata may be present in patients with uveitis, very fine small KPs can be distinguished by an inferior corneal location and slightly elongated shape. KPs can be easily seen with the slit lamp and direct or retroillumination. The small aggregates have been conventionally referred to as ‘nongranulomatous,’ whereas the larger, more greasy-appearing ones have been termed ‘mutton-fat’ or ‘granulomatous.’ These terms may be misleading because they imply a pathologic correlation that is rarely known. There is no objective way of defining granulomatous versus nongranulomatous KPs. The extreme instances are clear, but one may see both types coexisting in one patient at the same time, or see variations during the course of the disease or therapy. In general, the larger granulomatous aggregates are composed of macrophages and giant cells and occur in chronic inflammation, whereas the smaller nongranulomatous ones occur in acute inflammation and are more likely to be composed of neutrophils and lymphocytes. Nevertheless, there are a number of diseases typically associated with granulomatous KPs (see Box 4-3 ), and the presence of these precipitates can help in developing a differential diagnosis. In most inflammatory reactions, the neutrophil is the first cell present, and the transformed macrophages (epithelioid cells) and lymphocytes accumulate as the inflammation becomes more chronic. KPs therefore mimic the course of the inflammation in the tissue. For example, patients with documented pulmonary sarcoidosis may have acute anterior inflammatory episodes with small nongranulomatous KPs. If the inflammatory disease becomes chronic, the KP aggregates may become larger and more granulomatous. After the resolution of active inflammation, the KP aggregates may disappear completely or become smaller, translucent, or pigmented. KPs may also be washed away during intraocular surgery.
Other Corneal Findings
Other corneal findings can provide clues to the correct diagnosis. For example, corneal dendrites may be seen with uveitis as a result of herpes simplex virus infection. Interstitial keratitis may be associated with syphilis or Cogan’s syndrome; the clinician should examine the cornea carefully because the presence of stromal ghost vessels extending more than several millimeters from the limbus may easily be overlooked. We have noted similar findings in the inferior cornea in patients with sarcoidosis. Finally, we have seen several patients with corneal grafts who were referred with conditions diagnosed as idiopathic uveitis. In a number of these the uveitis was actually caused by early allograft rejection.
Anterior chamber
The anterior chamber is easily examined with the slit lamp for signs of ocular inflammation. Because inflammatory cells do not arise in the aqueous, the presence of cells or increased protein (flare) in the anterior chamber is evidence of spillover from the inflamed iris or ciliary body. Not infrequently, a patient with recurrent iritis will come to the ophthalmologist complaining of pain, but because of a lack of cells or flare on examination will be told that there is no uveitis and that no therapy is needed. To the practitioner’s dismay, the patient returns the next day with full-blown iritis. The explanation for this is that the inflammation begins in the iris and ciliary body, and only when sufficient inflammatory cells accumulate within these tissues do the cells begin to enter the aqueous and become visible to the clinician. Therefore, anterior chamber inflammation is a convenient but somewhat indirect measure of the inflammatory reaction in the iris and ciliary body.
Anterior chamber cells are primarily lymphocytes in most episodes of anterior uveitis, but a significant number of neutrophils may be present early in the course of disease. Anterior chamber cells are best seen by directing the slit-lamp beam obliquely across the eye and focusing posterior to the cornea. There is considerable variation among physicians on the grading of the number of cells. Because the cells represent an index of activity but not a direct measure of the active inflammation, we do not believe that the grading system must discriminate between small increments of disease. Table 3-1 summarizes the system proposed by Hogan and colleagues, the system proposed by Schlaegel that uses a wide beam with a narrow slit, and our preferred system that uses a 1 × 1 mm slit beam. The smaller slit allows some resolution for more severe inflammation and less resolution at the milder end of the spectrum. We are most interested in quantifying anterior chamber cells during the early stages of acute inflammation when a change in cellularity may signal an early response to therapy, and when a lack of response might dictate a change in therapy. The problem with most classification systems is that it is impossible for clinicians to remember how many cells are associated with a trace grade of trace, occasional, or rare cells. Therefore we have modified our grading system: for grades of trace cells (1–5) and 1+ cells (6–15 cells), I will put the exact number of cells counted in parentheses after the grade, for example 1+ (11) or trace (3). The grading scale we used was adopted at the First International Workshop discussing the standardization of uveitis nomenclature and published in 2005. In many chronically inflamed eyes it may be impossible to eliminate every last cell, and these rare cells may not require treatment. Nevertheless, persistence of more than a rare cell may place the patient at increased risk for inflammatory complications and worsen the prognosis after cataract extraction.
It is also our experience that the size of the individual cells in the anterior chamber will decrease as the inflammation begins to resolve. This may occur before the number of cells actually decreases. A change from large activated lymphocytes to smaller cells may account for this clinical observation. It is important to differentiate inflammatory cells from other types of cell in the anterior chamber. Red blood cells, iris pigment cells, and malignant cells may be mistaken for inflammatory cells. The differentiation is especially difficult if a lymphoid malignancy is present: monoclonal antibody staining of cells obtained by paracentesis may be critical in identifying the type of cell.
Increased protein content in the anterior chamber is a manifestation of a breakdown of the blood–ocular barrier. When the slit beam is obliquely aimed across the anterior chamber, the ability to visualize the path of the beam is termed flare. There are approximately 7 g of protein/100 mL of blood, but only 11 mg of protein/100 mL of aqueous. A faint amount of flare is normal if a bright light is used. The amount of light scattering is proportional to the concentration of protein in a solution, and hence more flare indicates increased protein in the anterior chamber fluid. Flare can be clinically graded on a scale of 0–4+ using a grading scale published by Hogan and colleagues in 1959 ( Table 3-2 ). This scale was adopted by the SUN Working Group with slight modification. We have reserved the 4+ grade for leakage of protein so extensive that a fibrin clot is present. In addition to the subjective grading of flare, it is possible to more accurately measure the degree of light scattering and quantify the amount of protein. A technique described by Herman and colleagues uses the principle that fluorescein in the anterior chamber will bind to albumin, and the amount of bound fluorescein will alter the polarization of fluorescein as measured by fluorophotometry. This method is able to quantify alterations in blood–ocular barrier leakage of albumin. A newer technique of objectively assessing aqueous flare measures the scattering of a laser beam projected across the anterior chamber. This laser flare meter is more fully described in Chapter 5 .
Some disagreement exists as to whether the presence of flare by itself, without cells or other signs of active inflammation, should be treated. In our opinion, without objective quantification of a change in the leakage across the blood–ocular barrier, chronic flare alone is not a sign of active inflammation. Damaged blood vessels may be leaky for a long time after the active inflammation has resolved. Continued treatment with drugs such as corticosteroids may do little to alter the repair of these vessels in the absence of active inflammation. There is no evidence that small amounts of increased protein in the anterior chamber are detrimental to the eye, and there appears to be no reason for continued therapy in this situation. Specifically, children with juvenile rheumatoid arthritis with flare but no cells should not be treated with topical corticosteroids. Therefore, flare should be considered a marker of inflammation but not necessarily a pathognomonic finding of active inflammation.
A hypopyon ( Fig. 3-3 ) is a collection of leukocytes that settles in the lower angle of the anterior chamber. The cause of a hypopyon is unclear and is not related solely to the number of cells in the anterior chamber. It is also related to the presence of sufficient fibrin to cause the cells to clump and settle. Hypopyon is a dramatic but short-lived finding in ocular inflammation that has been associated with Behçet’s disease, endophthalmitis, and rifabutin toxicity in patients with AIDS. A hypopyon may also occur sporadically in severe acute inflammation associated with many other types of uveitis. Of course, a hypopyon frequently develops in patients with endophthalmitis, and infection should always be considered as a potential etiology. This is especially true in patients who have had recent intraocular surgery. However, a sterile hypopyon can also occur after intraocular surgery. Severe exacerbation of uveitis can occur after ocular surgery in patients with uveitis, especially if appropriate anti-inflammatory therapy is not given. Retained lens fragments can also precipitate severe intraocular inflammation and hypopyon. A pseudohypopyon, composed of tumor cells or hemorrhagic debris, can occur in some of the masquerade syndromes (see Chapter 30 ) after vitreous hemorrhage. Finally, a hyphema can occur in eyes with uveitis, often due to neovascularization of the iris. Interestingly, a case of a pink hypopyon was noted in a patient with Serratia marcescens endophthalmitis. Cytologic examination revealed no erythrocytes, and the pink color was due to the bacteria.
