Background wo cases of acute anterior (AAU) are presented; one involving a 24-year-old T Caucasian female, and the other affecting a 48-year-old Hispanic female. These cases cover one of the most common forms of ‘’ that prompts patients to seek eye care urgently, and illustrate the clinical decision-making process arriving at the diagnosis and ap- propriate management. The condition is relatively common, with many third- Anterior Uveitis: and fourth-year optometry interns en- countering it at least once during their clinical rotations. Thorough case histo- Teaching Case Reports ry, careful slit lamp biomicroscopy and complete posterior segment examina- Len V. Hua, PhD, OD, FAAO tion are essential to correctly diagnose Lorne B Yudcovitch, OD, MS, FAAO and treat this ocular condition. In addi- tion, lab testing, imaging and referral to an internist and/or rheumatologist are called for in some cases. AAU is an acute intraocular inflamma- tion of the and due to a breakdown in the blood-aqueous bar- rier, leading to presence of “cells and flare” in the anterior chamber 1 (AC). Abstract The diagnosis of AAU is relatively Acute anterior uveitis (AAU) is the most common form of intraocular inflam- simple due to the plethora of clinical mation seen by eye care professionals that affects relatively younger patients, with symptoms, such as photobia and pain- ful eye, and signs, such as limbal flush, significant distress and potentially long-lasting sight-threatening complications. posterior synechiae, and AC cells and The diagnosis of AAU is relatively simple for clinicians because of multiple pre- flare observed on slit lamp biomicros- senting signs and symptoms; however, the etiology is often much more difficult copy. In contrast, the challenge is in to elucidate. Therefore, it is critical for interns and practicing clinicians to have determining the etiology because AAU an extensive understanding of the pathogenesis of AAU. Judicious yet effective could be a result of trauma or iatrogenic dosage of topical and cycloplegic agents are the mainstay of AAU sources, an infectious agent, medica- treatment. Depending on the presentation and cause, other medications, lab tions, a systemic autoimmune condi- tests and tertiary procedures may be necessary. Finally, coordination with other tion or idiopathic cause. Consequently, specialists (i.e., ophthalmologists, rheumatologists) may be critical in diagnosis the differentials for the etiology of AAU and treatment. Eye care providers play a key role in the interdisciplinary man- can be lengthy, and a thoughtful list of questions is important in narrowing the agement of the patient with AAU. causative suspects. For instance, ques- Key Words: Anterior uveitis, iritis, iridocyclitis, cells and flare, HLA-B27, tions related to recent soft contact , cycloplegics wear, injury or ocular surgery can rule out their corresponding association. Whereas age-related macular degenera- tion and tend to affect older patients, AAU is a condition that affects Dr. Hua is an Assistant Professor at Pacific University College of Optometry and Chief of Medical relatively younger patients more fre- Eyecare. He teaches pharmacology, biochemistry and ocular emergencies in addition to being an attending for primary care and ocular disease clinics. quently, with significant distress and po- tentially long-lasting sight-threatening Dr. Yudcovitch is an Associate Professor at Pacific University College of Optometry and served for complications.2 Therefore, it is critical several years as Clinic Director of the college’s Northeast and Southeast Eye Centers. He instructs in ocular disease, therapeutics and patient care courses as well as in several clinic areas. for interns and practicing clinicians to have an extensive understanding of the pathogenesis of AAU and its prompt and appropriate treatment, including

Optometric Education 92 Volume 36, Number 2 / Winter/Spring 2011 interdisciplinary co-management as in- dicated. Figure 1A (Case 1) Anterior uveitis OD with fibrous deposits on the lens Student Discussion Guide Case 1 description A 24-year-old Caucasian female pre- sented to the University Eye Clinic on June 16, 2010 with a complaint of a red, watery and painful right eye for about a day. She also mentioned that this was the third episode she had experienced on an annual basis over the past three years, with the past two episodes lasting approximately 40 days with treatment. Her medical history was unremarkable, without any ocular injury or surgery. In addition, she had denied any joint pain or bowel disease when questioned. She reported that her sister has an ‘eye turn’ and had been treated with an eye patch, and that her maternal uncle was recently Figure 1B (Case 1) diagnosed with glaucoma. She currently High magnification (40X) shows cells (representative takes multivitamins and an oral contra- arrows) in the AC OD ceptive. Her last eye exam two months ago revealed normal exam findings. At the current visit, her distance visual acuity (VA) without correction was 20/20-1 OD and 20/20+1 OS. Both eyes showed smooth, accurate, full and equal extraocular muscle movements in all fields of gaze. No pupillary de- fect was observed, and no notable pho- tophobia was reported in either eye. Finger counting confrontation visual fields were full OD and OS. Anterior segment findings, as observed with bio- microscopy, demonstrated 1+ circum- limbal flush with trace cells and flare OD (Figures 1A and 1B). Goldmann applanation tonometry was 13 mmHg OD and 14 mmHg OS at 10:48 a.m. Dilated fundus examination showed a normal with healthy maculae was recurrent, she was also referred for She was referred to a local rheumatol- and vasculature and cup-to- blood workup, human leukocyte anti- ogist-ophthalmologist for further con- disc ratios of 0.45H /O.40V OU, with gen (HLA) testing and spinal X-ray to sultation. Her recent spinal X-ray and healthy optic nerve head rims and dis- explore a possible systemic cause. A re- blood workup were normal, with the tinct disc margins in both eyes. view of her chart records revealed that exception that she was HLA-B27 posi- The patient was diagnosed with recur- her blood workup two years ago was tive. The specialist concluded that the rent, but mild, acute anterior uveitis of normal. inflammation has affected only the -pa her right eye and educated about her Follow-up # 1: June 23, 2010 tient’s eye so far, but in the future she findings, prognosis and treatment op- will have a higher risk for arthritis, and tions. She was treated with Pred Forte A week later, the patient felt that her that long-term nonsteroidal anti-in- (PF; acetate 1% ophthal- eye condition was slightly worse, al- flammatory drug (NSAID) treatment mic suspension) igt q2h and homatro- though her VA was still 20/20-1 OD may be beneficial. and 20/20+1 OS. Moderate circumlim- pine 5% (H) ophthalmic solution igt qhs Case 2 description OD. She was recommended to return bal injection, 2+ cells and 2+ flare, was to clinic a week later, or sooner if her seen in the AC. The PF was increased to A 48-year-old Hispanic female pre- symptoms get worse. Since the uveitis igt q1h OD and the H to igt bid OD. sented to the University Eye Clinic on Feb 2, 2010 with a chief complaint of

Optometric Education 93 Volume 36, Number 2 / Winter/Spring 2011 painful red eye, severe and tearing OD for the past few days. Figure 2A (Case 2) She had tried an over-the-counter anti- Anterior uveitis OD with fibrous membrane and allergy drop, but it did not help. Medi- posterior synechiae cal history was positive for depression and hand tremors, for which she had been taking oral vitamin B6 and Flex- eril (cyclobenzaprine), respectively. She reported no joint/back pain and no pain on urination or bowel movement. Her last eye exam was many years ago, and she reported no history of ocular injury or surgery. Family medical his- tory was negative for diabetes, hyper- tension, glaucoma or blindness. At the current visit, her uncorrected distance VA was 20/150 OD and 20/150 OS, with pinhole improvement to 20/60-2 OD and 20/60+1 OS. Both eyes showed smooth, accurate, full and equal extraocular muscle movements in all fields of gaze. No afferent pupillary Figure 2B (Case 2) defect was observed; however, the pa- tient was photophobic in her right eye. Anterior uveitis OD. Fibrous membrane resolved with Finger counting confrontation visual topical steroid treatment fields were full OD and OS. Anterior segment findings, as observed with bio- microscopy, demonstrated 2+ circum- limbal injection and 2+ cells in the AC in the right eye. No vitreal cells or haze were seen in either eye. Posterior poles appeared normal OU with healthy mac- ulae, vasculature, and cup-to-disc ratios of O.30H/0.30V both eyes. Goldmann applanation tonometry was 16 mmHg OD and 15 mmHg OS at 5:46 p.m. Acute anterior uveitis with posterior synechiae OD was diagnosed, and the patient was educated about her find- ings, prognosis and treatment options. She was treated with a prescription regi- men of PF igt q1h OD and H bid OD. The patient was recommended to return to clinic the next day for follow-up. contact tonometry was 10 mmHg OD and a rheumatological consult was also Follow-up # 1: Feb 03, 2010 and 12 mmHg OS at 9:47 a.m. One recommended. The patient reported slight improve- drop of phenylephrine 10% and one Follow-up # 2: Feb 05, 2010 ment in her comfort after taking the drop of atropine 1% were instilled in- The patient appreciated further im- drops as prescribed, but she was still office to attempt to break the posterior provement over the next two days, al- tearing and photophobic in her right synechiae. As before, no vitreal cells or though she still felt some discomfort eye. Her uncorrected VA was worse at haze were seen OU. Posterior poles also and tearing. Her VA had improved to 20/400 OD and the same at 20/150 were normal OU with healthy macu- 20/80-1 (pinhole 20/40+1) OD and OS, but pinhole improved the VAs to lae, vasculature, and cup-to-disc ratios was unchanged OS (20/150; pinhole 20/100- OD, 20/60 OS. Anterior seg- of O.30H/0.30V both eyes. 20/60). Anterior segment findings, as ment findings, as observed with biomi- The patient was instructed to continue observed with biomicroscopy, demon- croscopy, demonstrated 2+ circumlim- the PF igt q1h OD and H igt bid OD strated mild circumlimbal injection, 1+ bal injection, 2+ cells and 3+ flare in and to return to clinic in two days. A cells and 1+ flare in the AC with poste- the AC with posterior synechiae and fi- letter with request for a blood workup rior synechiae at 7 o’clock, and resolv- brin membrane OD (Figure 2A). Non- was sent to her primary care provider, ing fibrin membrane OD (Figure 2B).

Optometric Education 94 Volume 36, Number 2 / Winter/Spring 2011 Noncontact tonometry was 12 mmHg had not filled her spectacle prescription and demographics OD and 14 mmHg OS at 3:16 p.m. from the prior visit, and her VA was 6. Discuss the importance of the The patient was instructed to continue still 20/80 (pinhole 20/40-1) OD and presence of HLA-B27 20/100 (pinhole 20/50) OS. She was the PF igt q2h OD for two days and 7. Discuss systemic inflammatory then taper to igt q4h OD for the sub- educated on her recent uveitis condi- tion and warned that it might recur in diseases that have high associa- sequent three days, continue H igt bid tion with AAU OD, and to return to the clinic in five the future. days with her blood workup results. Key concepts 8. Describe the mechanisms of ac- tion of drugs used in manage- Follow-up # 3: Feb 10, 2010 1. Common etiologies of acute ante- ment of AAU rior uveitis Five days later, the patient felt that her 9. Discuss the potential side-effects symptoms were worse, with more pain 2. Thorough case history for patients of steroid use and photophobia. Her VA was reduced with acute anterior uveitis at 20/150 (pinhole 20/50) OD and B. Generating questions, hypothesis, 3. The use of epidemiology in differ- and diagnosis 20/200 (pinhole 20/60) OS. Anterior entiating possible causes segment findings, as observed with bio- 1. What are important questions microscopy, demonstrated moderate 4. Clinical findings in differential di- relevant to AAU? circumlimbal injection, 2+ cells and 1+ agnosis of acute anterior uveitis 2. How is AAU diagnosed? flare in the AC with posterior synechiae 5. Treatment of acute anterior uveitis at 7 o’clock OD. Noncontact tonom- 3. What age group does AAU 4. The importance of patient educa- etry was 10 mmHg OD and 15 mmHg tend to affect? tion and regular follow-up OS at 9:59 a.m. 4. What are the potential differ- 5. The essentials of appropriate- sys The patient was advised to increase the ential diagnoses? temic workup and specialist con- PF to igt q2h OD and H bid OD. In sultations 5. Why is dilation neces- addition, she was prescribed oral pred- sary? nisone (60mg/day for one week). She Learning objectives was also promptly referred to see a lo- 6. What laboratory tests are help- 1. To ask intelligent questions in help- ful in identifying the etiology? cal rheumatologist. Her blood workup ing with differential diagnoses there showed high white blood cell and 7. Is the diagnosis valid? 2. To understand the signs and symp- platelet counts, low hematocrit and C. Management positive presence of HLA-B27. toms of ocular inflammation 1. What are the different topical Follow-up # 4: Feb 17, 2010 3. To relate patient demographics to known epidemiology of the AAU corticosteroids available for A week after the combined topical and ocular inflammation? How are oral steroid treatment, the patient felt 4. To rule out posterior segment in- they ranked in terms of po- much better, with only mild discom- volvement of ocular inflammation tency? fort. Her VA was 20/80 (pinhole 20/40- 5. To provide appropriate patient ed- 2. Why are cycloplegics needed? ) OD and 20/150 (pinhole 20/50) OS. ucation and optimal medical man- Refraction was performed, giving -3.00 agement 3. Should oral NSAIDs be used? -1.00 x 164 to 20/25- OD and -2.50 6. To collaborate with other health 4. When is laboratory workup -1.25 x 021 to 20/25 OS with near ad- care professionals in management advised? dition of +1.50 OU. Anterior segment of possible systemic cause 5. What is the follow-up sched- findings, as observed with biomicros- ule? copy, demonstrated mild circumlimbal Discussion questions injection, with no cells and trace flare A. Knowledge, concepts, facts, infor- 6. What course of action is neces- in the AC OD. mation required for critical review sary when symptoms get worse with treatment? The rheumatologist concluded that she of the cases has HLA-B27-associated uveitis, and 1. Describe the signs and symptoms 7. When should the patient be maintained her on oral steroid as pre- of anterior uveitis vs. other in- referred to a specialist? scribed. She was recommended to taper flammation/injury 8. What specialists are indicated? off her oral and topical steroid gradu- 2. Describe the different types of ally over the next two weeks and to dis- 9. Why is it necessary to taper the uveitis based on anatomy continue the homatropine. steroid? 3. Discuss the cause of cells and Follow-up # 5: Mar 03, 2010 D. Critically assessing implications, flare in the anterior chamber patient management and psycho- At this visit (almost three weeks later), 4. Discuss the risk factors for social issues the patient was off all prescribed uveitis uveitis medication, and she felt that her eye 1. What are the implications of condition had completely resolved. She 5. Determine causality based on standard treatment vs. modi- patient case history, risk factors fied/no treatment? Consider Optometric Education 95 Volume 36, Number 2 / Winter/Spring 2011 cost, time, side-effects, con- venience effect and quality of Table 1 life. Standardization of Uveitis Nomenclature (SUN) grading 2. What are the consequences as- system for AC cell and flare severity.2 The presence or sociated with noncompliance absence of a should be noted separately in to the treatment plan? addition to the AC cellular activity grade. 3. What pertinent information should be used to educate the Grade AC Cells (1 mm x 1 mm beam) AC Flare patient about the condition? 0 None None

4. Discuss ways to respond to the 0.5+ 1-5 cells - anxiety of the patient towards future recurrence and progno- 1+ 6-15 cells Faint sis with respect to the patient 2+ 16-25 cells Moderate (clear iris & lens) and the patient’s family mem- bers. 3+ 26-50 cells Marked (hazy iris & lens) 4+ >50 cells Intense (fibrin or plasmoid Educator’s Guide aqueous) The educator’s guide includes the nec- essary information to discuss the case. of the population.4 HLA-B27, a Class obvious. Ocular signs include anterior Literature review I major histocompatibility complex chamber cells that slowly drift in the The breakdown of blood-aqueous bar- (MHC), is a strong risk factor and as- aqueous humor. These anterior chamber rier in the iris and ciliary body leads to sociated with up to half of all cases of cells should be differentiated regionally clinical signs and symptoms of acute AAU.5 HLA-B27-positive AAU tends from cells in the vitreous, which would anterior uveitis. It is the most common to be more severe in presentation and indicate an intermediate or posterior form of intraocular inflammation seen earlier in onset than HLA-B27-negative uveitis. The clinician may often use by eye care professionals.1 The leak- uveitis, affecting primarily younger pa- high magnification with a relatively age of vascular contents into the ante- tients between 20 and 40 years of age.3 bright illumination upon biomicros- rior chamber can be seen as “cells” and In addition, males are affected 2.5 times copy to visualize cells. The appearance “flare” via slit lamp biomicroscopy. A more frequently than females in HLA- of cells in the AC is similar to seeing a grading system was established by the B27-positive uveitis. The prevalence of few to numerous dust particles floating Standardization of Uveitis Nomencla- the HLA-B27 gene varies among popu- and moving in empty space. Similarly, ture (SUN) for clinical use (Table 1).2 lations, as high as 8% in Caucasians, bright illumination and magnification Cells are predominantly white blood and as low as 0.5% in Japan.1,3 is often necessary to visualize flare, cells (leukocytes) released in response A number of systemic inflammatory with conical beam illumination reveal- to inflammation. Flare is comprised of diseases, such as ankylosing spondylitis ing a Tyndall effect (light scattering) serum proteins: pro-inflammatory -cy (AS), Reiter’s syndrome and psoriatic from the suspended protein particles. tokines and chemokines that selectively arthritis, have been known for decades Severe flare and inflammatory media- recruit inflammatory white blood cells. to associate with HLA-B27 and AAU. tors released into the anterior chamber Furthermore, flare can coalesce to form Particularly, 90% of patients with AS can rarely lead to a viscous ‘plasmoid’ fibrin, while white blood cells can pre- possess the HLA-B27 antigen.2, 6 aqueous and hypopyon. The corneal cipitate in the corneal endothelium in endothelium may show adherent cells certain forms of uveitis to form keratic Clinical features (both white blood cells and, less often, precipitates (KPs). Therefore, the di- Acute anterior uveitis typically presents iris melanocytes) that predispose the in- agnosis of AAU is relatively simple for with the patient experiencing hallmark ferior aspect of the (Arlt’s trian- clinicians because of multiple present- symptoms of recent onset eye pain (of- gle). Although the eye can appear white ing signs and symptoms. However, the ten dull, aching pain) and photophobia. with uveitis, circumlimbal injection is etiology is often much more difficult to Secondary symptoms include blurred a notable sign and, less often, a more elucidate. vision, a watery/tearing eye, redness generalized conjunctival inflammation. The annual incidence of uveitis has been and headache. One or both eyes may Posterior synechiae (iris adhesions, usu- estimated to be about 35 per 100,000 be affected. Visual acuities may or may ally at the pupillary ruff, to the anterior in the general population with a preva- not be reduced depending on severity lens capsule) are not uncommon with lence of 0.5%.1 Of the uveitides catego- of the uveitis. Pupillary testing may anterior uveitis; one study found pos- rized by anatomical location (anterior, show a sluggish pupillary constriction terior synechiae in half of 119 patients response to light, usually due to iris in- with acute anterior uveitis, regardless if intermediate, posterior, panuveitis) an- 7 terior uveitis accounts for most of the flammation and/or iris synechial adhe- it was HLA-B27 positive or negative. cases seen clinically.3 The lifetime inci- sions. A direct and consensual eye pain A corectopia (irregularly shaped pupil) dence of AAU may be as high as 0.2 % to light is highly specific to anterior can result from posterior synechiae, as uveitis, even when other signs are not as well as later adhesion of pigment to the Optometric Education 96 Volume 36, Number 2 / Winter/Spring 2011 anterior lens capsule in a circular pat- tern corresponding to pupillary ruff Table 2 pigment (Vossius ring). A fibrin mem- Differential diagnoses for anterior segment brane on the anterior lens capsule can inflammation often remain from longstanding syn- echiae. Extensive posterior synechiae AAU (iritis, iridocyclitis) (infective, traumatic/toxic, contact lens can lead to circumferential adhesion to acute red eye) the anterior lens capsule, leading to pu- / pillary block, a bowing forward of the Lens-related (phacolysis/phacoanaphylaxis) iris (iris bombé) from posterior aque- Acute angle closure glaucoma Posterior segment disease (tumor, panuveitis) ous entrapment, and highly-elevated (IOP). Peripheral (post operation, endogenous) anterior synechiae (PAS), whereby the peripheral iris tissue near the ciliary body adheres to the anterior chamber angle structures, is less common. Best the . Photophobia, eye pain ) from arc-weld flash- observed via gonioscopy, these adhe- and reduced vision are usually very es or high altitude reflection sun/ sions can block the trabecular mesh- severe, with poorer prognosis for snow exposure, chemical insult, or work, impeding aqueous outflow and long-term vision. from immune conditions (i.e., Thy- potentially elevating the IOP. • Endophthalmitis, a true eye emer- geson’s superficial punctuate kerati- tis). Infective keratitis may be bac- Differential diagnoses gency involving inflammation of the vitreous and aqueous humor, terial, viral, fungal, acanthamoebic, The common differential diagnoses for may present with symptoms of or chlamydial/parasitic. Light sen- AAU are summarized in Table 2, and blurred vision, eye pain and red- sitivity, redness, pain, and reduced some of the more serious conditions are ness and light sensitivity, simi- vision with any of these forms of discussed. lar to AAU. However, history is keratitis can mimic AAU. It is also • Intermediate/posterior/panuveitis an important differential, as en- possible that an anterior uveitic are conditions whereby uveal in- dophthalmitis can be a rare endog- response is seen accompanying an flammation has progressed beyond enous (causative source is within infective keratitis, so treatment of the iris tissue. The sign of cells and/ eye) complication from ocular both conditions may be warranted. or inflammatory exudates in the infection after surgical procedures Treatment of the non-infective ker- vitreous is a key finding with these such as extraction and vit- atitis may be similar to treatment uveitides, and vitreal haze is often reoretinal surgeries.9,10 Exogenous of AAU (i.e., topical steroid and present. Because constant fluid ex- (source is from outside the eye) en- cycloplegic agents). With infective change in the vitreous does not oc- dophthalmitis may result from in- keratitis, however, care must be tak- cur as it does in the aqueous, the fection spread from another source en to determine the specific caus- cells and inflammatory byproducts (i.e., endocarditis). Endophthalmi- ative organism, as topical steroids persist and move with gravity to tis may also occur from penetrating have the potential reduce wound settle in the inferior retina (called or ocular surgery and, in healing and the body’s immune re- ‘snowbanking’) along the pars pla- very rare instances, be due to un- sponse to fight the infection. This is na. This condition of intermediate known causes or present as a sterile especially true of herpetic epithelial uveitis is called pars planitis, and is inflammation from retained lens keratitis, where topical steroid use more common in younger individ- material after an operation or from may worsen the condition. Patients uals, with a mean age of 30.7 years toxic agents.11 Usually along with with herpetic keratitis (particularly (± 15.1 years). Over two-thirds of similar symptoms, a layer of white herpes zoster infection) may pres- cases are idio- blood cells may be seen settled in ent with acute pain, redness and pathic, with , multiple the inferior anterior chamber (hy- light sensitivity, and the clinician sclerosis (MS) and popyon). Immediate referral for must look closely for signs of den- being the relatively less common a vitreal tap and culturing/sensi- dritic lesions, pustules and rashes causes.8 Posterior uveitis may pres- tivities is indicated for endophthal- that may identify herpetic infec- ent with , chorioret- mitis, with subsequent tion. sodium and rose inal inflammation, retinal vasculi- vitrectomy and fortified topical, Bengal stain assessment are critical tis and edema. Vitreal intravitreal and systemic antibiotic to ruling-out herpetic lesions on haze may also accompany posterior treatment.12,13 the cornea. Fluorescein staining uveitis. While photophobia may be may also reveal epithelial defects, • Keratitis can present with similar infiltrates and ulcers due to other reduced in posterior uveitis (due to symptoms to AAU, and the causes less inflammation of the irides), vi- organisms. The presence of mu- of keratitis may be non-infective or copurulent discharge is a diagnostic sual blur is usually more severe and infective in etiology. Non-infective prognosis of visual recovery poorer. sign of bacterial or chlamydial in- keratitis may be due to external fection. While untreated bacterial Panuveitis involves all regions of sources such as light (i.e., Optometric Education 97 Volume 36, Number 2 / Winter/Spring 2011 and chlamydial corneal infections usually worsen over several hours to Table 3 a few days, fungal and certain acan- Cycloplegic agents, their concentrations, maximal effect thamoebic infections may progress and duration of action in healthy eyes more slowly, with progression over a week or more after initial inocu- Cycloplegic Agent Maximal Effect (min) Duration of Action lation not uncommon. History of Tropicamide 0.5, 1% 20-30 3 hours soft contact lens wear, old makeup Cyclopentolate 1, 2% 20-45 1 day use, water-based activities (i.e., swimming, hot tub) and vegeta- Homatropine 2, 5% 20-90 2-3 days tive injury are important in deter- Scopolamine 0.25% 20-45 4-7 days mining the diagnosis. Treatment of Atropine 0.5, 1, 2% 30-40 1-2 week(s) infective keratitis is dependent on the causative organism, and typi- cally involves topical antibiotics Figure 3 (bacterial), oral antibiotics (chla- The cellular inflammatory pathway (enzymes labeled mydial), topical and oral antivirals in bold), with points of inhibition by corticosteroids and (herpetic), antimycotics (fungal) or NSAIDs (nonsteroidal anti-inflammatory drugs) shown antiamoebics (acanthamoeba). (adapted from Samiy N et al., 1996)14 • Patients with acute angle closure can present similar symptoms to AAU, including pain, blurred vision, ha- los vision, frontal headache, nausea and vomiting. Circumlimbal flush and corneal edema is often seen. Intraocular pressure (IOP) spike is an important sign to differenti- ate acute angle closure from AAU; however, the patient may have an IOP spike secondary to iris bombé caused by AAU. The main approach to management of acute angle clo- sure is to reduce the IOP as quickly as possible with topical, and often stabilizing the blood-aqueous bar- (alpha receptor) agonist used for oral, glaucoma medications. rier by decreasing the iris surface assisting with the dilation of the area (preventing further cellular and pupil. It is used in-office with a cy- Treatment options for acute anterior exudative leakage). The main - cy cloplegic agent for breaking recal- uveitis cloplegic agents (listed from short- citrant posterior synechiae. Usually Management of AAU is focused on 1) est maximal effect time/duration to only one or two drops are instilled reducing the inflammation and any as- longest) are listed in Table 3. The in the affected eye to facilitate di- sociated pain, redness, photophobia most popular agents used in AAU lation. The drug also assists in fa- and visual blur; and 2) determining the treatment are homatropine 5% cilitating view of the vitreous and etiology. The first step is achieved by (trade name: Isopto-Homatropine retina, to determine if there is any several treatments: 5%; typical dosage igt q12hr) and posterior segment inflammation. • Sun protection scopolamine 0.25% (trade name: • Corticosteroids Isopto-Hyoscine; typical dosage igt The patient with AAU has usu- q6hr). Atropine (trade name: Isop- Corticosteroids are critical in the ally determined that avoidance of to-Atropine 1%; typical dosage igt treatment of uveitides, including bright light is to their immediate q12hr) is used in more severe cases. AAU. They reduce pain (includ- benefit. Encouragement of sun- Even though a cycloplegic’s dura- ing photophobia), inflammation glasses, a brimmed hat, staying in- tion of action is relatively long in (of most ocular tissues) and redness doors more frequently and lowered healthy eyes, the duration of action (of , episclera, limbus). lighting levels are good behavioral may be much shorter in uveitis due Corticosteroids block the enzyme modifications during the acute to the presence of increased esteras- phospholipase A2 (which converts symptomatic stage. es in the AC of a uveitic eye; hence cell membrane phospholipids into • Cycloplegics more frequent dosing is needed. inflammatory mediators such as leu- kotrienes and prostaglandins). This Cycloplegic agents are important • Mydriatics inflammatory pathway is seen in Fig- for relaxing the iris (for comfort), Phenylephrine 2.5% or 10% (trade ure 3.14 Topical ophthalmic steroid breaking posterior synechiae, and name: AK-Dilate) is an adrenergic drops can be divided into 3 main cat-

Optometric Education 98 Volume 36, Number 2 / Winter/Spring 2011 egories, based on clinical potency: tion with one or more antibiotics) • Osteoporosis Minimally effective: are also available for evening use. • Growth suppression • Reduced immunity (infec- • dexamethasone sodium Risks of topical corticosteroids in- clude posterior subcapsular cataract tions) phosphate 0.05% oint- • Hypothalamus-Pituitary-Ad- ment (PSC) formation and elevated IOP. Usually these risks are minimal due renal (H-P-A) axis suppression • loteprednol 0.2% (trade • Menstruation problems name: Alrex) to the short-term use of steroids in AAU treatment. Prednisolone Because of these risks, the use of Moderately effective: acetate has a higher propensity to oral steroids should be weighed • prednisolone phosphate elevate IOP. Studies have shown with the potential side-effects. 0.125%, 0.5%, 1% solu- lotoprednol 0.5% (Lotemax) to be • NSAIDs tions comparable to prednisolone acetate • fluorometholone 0.1% 1% in effectively reducing ante- Both oral and topical ophthalmic (trade name: FML Mild), rior uveitis, yet not elevating IOP non-steroidal anti-inflammatory 0.25% (trade name: FML as much as prednisolone acetate.18 drugs (NSAIDs) have limited ef- Forte) Other risks of topical steroid use fectiveness in treating active AAU, • rimexolone 1% ( trade include reduced host immunity, as their mechanism of action in- name: Vexol) stromal melt, scleral thinning and hibits the enzyme cyclo-oxygenase herpetic epithelial infection spread. (which produces prostaglandins) Maximally effective: but not the enzyme phospholipase In certain recalcitrant uveitis cases, • loteprednol 0.5% (trade A2 (which produces leukotrienes, or when the patient is unable to name: Lotemax; combined responsible for attracting white properly instill eyedrops or oint- with tobramycin in Zylet) blood cells into the anterior cham- ment, injectable steroids may be • dexamethasone 0.1% ber via chemotaxis). However, one indicated. These include regional (combined with tobramy- study showed a 66.8% reduction subconjunctival or sub-Tenons in- cin in TobraDex) in recurrences of HLA-B27-asso- jections of triamcinolone or dex- • 1% prednisolone acetate ciated uveitis over a 3-year period amethasone, as well as intravitreal 20 (trade name: Pred Forte) with chronic oral NSAID use. injections of each drug (Triesence; • difluprednate 0.05% Alcon Laboratories) or implants • Immunomodulators emulsion (trade name: (Ozurdex; Allergan Inc.), respec- Durezol) In cases of non-infectious AAU tively. Fluocinolone acetate intra- that is recalcitrant or non-respon- All topical ophthalmic steroid eye vitreal implant (Retisert; Bausch + sive to steroid treatment, immuno- drops (except for the solution pred- Lomb) is also an option in recurrent modulation may be necessary. The nisolone phosphate and emulsion uveitides unresponsive to other ste- effectiveness of these medications diflurprednate) are formulated as roid treatments. Unfortunately, the with uveitis has been demonstrated suspensions. As such, the patient risk of elevated IOP and cataract in several cases.21,22 These consist of must shake the bottle vigorously with these routes of administration immunosuppressants and biolog- before instilling the drop onto the is much higher.21 ics. The three main immunosup- eye, to provide a homogenous sus- • Oral steroids such as prednisone pressant drug categories are: pension of medication. The most (Orasone, Deltasone, Meticorten, popular steroid prescribed for AAU • Antimetabolites (methotrex- Sterapred, other trade names) and is Pred Forte (prednisolone 1%; igt ate, mycophenolate, azathio- methylprednisone (Medrol, other q2hr); its generic version has been prine) trade names) are indicated when found to be less homogenous in • T-cell suppressors, aka calcineu- an AAU is severe or when posterior formulation, with more shakes re- rin inhibitors (cyclosporine, ocular involvement is seen. Typi- quired for the drug to go into sus- voclosporin, tacrolimus) cal adult dosage is 1mg/kg body pension.15, 16 A more recent steroid • Cytotoxic agents, aka alkylat- weight, with taper upon improve- on the market, difluprednate (Du- ing agents (cyclophosphamide, ment and dependent on duration rezol) was shown to be as effective chlorambucil) of treatment (longer tapers with as Pred Forte, yet with only half the Biologics, a relatively newer class longer treatments). Along with dosage of Pred Forte.17 All steroids of drugs, are comprised of recom- increased IOP and posterior sub- used over the course of a week or binant cytokines and monoclonal capsular cataract risk, several other more are usually tapered gradually antibodies directed against selected potential side-effects include, but upon improvement of signs and cell-surface markers.23 The main are not limited to: symptoms, and then discontinued. biologics are: • Hypertension If symptoms recur, the steroid’s • Tumor necrosis factor-alpha • Hyperglycemia original dosage (or more frequent inhibitors (infliximab, adali- • Psychosis dosage) is re-initiated. Several ste- mumab) • Edema (Cushing’s Syndrome) roid ointments (most in combina- • Anti-lymphocyte drugs (ritux-

Optometric Education 99 Volume 36, Number 2 / Winter/Spring 2011 imab, alemtuzumab) • Interleukin-2 receptor blocker Table 4 (daclizumab) Common causes of acute and chronic anterior uveitis • Recombinant interferon-alpha (adapted from McCannel et al., 1996)4 Both immunosuppressants and biolog- ics often take several weeks to achieve Acute Anterior Uveitis Chronic Anterior Uveitis efficacy. HLA-B27 positive (uveitis only) Juvenile idiopathic arthritis (JIA) Ankylosing spondylitis Fuch’s heterochromic iridocyclitis • Surgery Reactive arthritis (Reiter’s) Idiopathic Psoriatic arthropathy Sarcoidosis Surgical treatment for AAU is rare HLA-B27 negative (idiopathic) Syphilis and only indicated in severe cases Sarcoidosis Lupus Behcet’s disease Herpes (zoster/simplex) where secondary complications Posner-Schlossmann Syndrome arise. Permanent structural changes Crystalline lens-associated from uveitis that may require sur- Syphilis Lupus gical management include cataract Trauma formation, secondary glaucoma due to pupillary block or angle clo- sure, and . Sur- Table 5 gical indications include restoring Review of systems via history with uveitis-associated visual clarity, diagnostic biopsy, or diseases (adapted from Cheng et al., 2005 and removing media opacities to moni- Gutteridge et al., 2007)3,27 tor the posterior segment. Surgi- cal procedures include, but are System Diseases not limited to: extracapsular pha- Dermatological Psoriasis, syphilis, sarcoidosis, lupus, herpes simplex/zoster, coemulsification/cataract extrac- Behcet’s disease tion, iridotomy/iridectomy, filter- Gastrointestinal Inflammatory bowel disease ing surgeries, vitrectomy and other Genito-urinary Reiter’s syndrome, Behcet’s disease, syphillis corneal and retinal procedures. Respiratory Sarcoidosis, tuberculosis Discussion Rheumatological Spondyloarthropathies (eg., alkylosing spondylitis) Uveitis is an inflammatory disease of the eye, potentially responsible for up Table 6 to 20% of all blindness.24 The Intern- Systemic diseases with uveitis association and tational Uveitis Study Group (IUSG) corresponding lab tests (adapted from Cheng et al., 2005)3 and Standardization of Uveitis nomen- clature (SUN) Working Group have Diseases Clinical Features Laboratory tests adopted a classification of uveitis ac- HLA-B27 positive Uveitis only HLA-B27 cording to anatomical location: ante- rior (anterior chamber), intermediate Ankylosing spondylitis Lower back pain, worse in a.m. HLA-B27, ESR, spinal X-ray Reiter’s syndrome Triad: arthritis, urethritis and HLA-B27, ESR, ANA (ciliary body, vireous), and posterior (retina, ), with panuveitis in- Arthritis, psoriasis joint pain, skin inflammation HLA-B27, joint X-rays volving all locations.25,26 Acute anterior uveitis (AAU) is an ocular presenta- Inflammatory bowel disease Bloody diarrhea & abdominal cramp HLA-B27, endoscopy tion that has many potential etiologies. Behcet’s disease Aphthous mouth/genital ulcers HLA-B5 Identification of the key clinical find- , CNS plaques Cranial MRI, HLA-DR2 ings of AAU – cells and flare – along Sarcoidosis African ethnicity, shortness of breath, ACE, lysozyme, chest X-ray, with the accompanying symptoms of skin nodules gallium scan, biopsy pain and photophobia - has been docu- mented in the literature for over half a century.27 While the most common spondylitis and other connective tissue tion. Less common potential infective etiology of anterior uveitis is idiopathic disorders, questions regarding joint and etiologies include syphilis, tuberculosis, (38-70%), the next most-common eti- back problems, pain on urination or toxoplasmosis and Lyme disease.4 Table ology is HLA-B27-positive, particu- stomach irritation, arthritis, or other 4 summarizes the common causes of larly with acute-onset forms.4 HLA- autoimmune diseases (i.e., Reiter’s syn- acute and chronic anterior uveitis. B27 is present in 1.4-8% of the general drome, inflammatory bowel disease, psoriatic arthritis, and post-infectious The management of uveitis is strongly population; however, it can be present achieved through an evidence-based in between 50-60% of patients with arthritis) should be asked in the his- 3 tory, along with the patient’s current approach. No standard laboratory AAU. Since HLA-B27-positive re- evaluation for uveitis exists, except for sults are strongly related to ankylosing medication list. Other causes of AAU may include trauma and herpetic infec- determining syphilis and possibly sar- Optometric Education 100 Volume 36, Number 2 / Winter/Spring 2011 coidosis-based etiologies. In addition, B-27 2. Bloch-Michel E, Nussenblatt RB. many laboratory tests have false-neg- Some lab tests, such as complete blood International Uveitis Study Group ative or false-positive results that may count (CBC), erythrocyte sedimenta- recommendations for the evalu- potentially confuse the clinical picture tion rate (ESR), and rheumatoid fac- ation of intraocular inflamma- and/or contribute to erroneous diag- tor (Rf), have been regarded as too tory disease. Am J Ophthalmol. noses, along with an additional cost 1987;103:234-235. 28 non-specific for diagnostic purposes in burden. Careful history and physical anterior uveitis, and only play only an 3. Chang JH, McCluskey PJ, Wake- examination related to the review of adjunct role in certain cases.32 The clini- field D. Acute anterior uveitis systems (i.e., dermatologic, hemato- cian must balance the diagnostic value and HLA-B27. Surv Ophthalmol. logic, respiratory, circulatory, neuro- with cost-effectiveness when ordering 2005;50:364–388. logical, ear/nose/throat, constitutional, laboratory tests (Table 6). etc.) often is more valuable to deter- 4. McCannel CA, Holland GN, Helm mining the cause of the uveitis (Table Conclusion CJ, Cornell PJ, Winston JV, Rim- 5).29 Physical signs such as the presence mer TG. Causes of uveitis in the or absence of granulomatous nodules This article highlights two cases of acute general practice of . or keratic precipitates (KPs) also assist anterior uveitis (AAU), their clinical UCLA Community-Based Uveitis in discriminating autoimmune (i.e., management and course. While the Study Group. Am J Ophthalmol. sarcoid, systemic lupus erythematosis) hallmark signs and symptoms of AAU 1996;121:35–46. from non-autoimmune-based uveitis.30 are highly diagnostic, the pathogenesis 5. Chang JH, McCluskey P, Wakefield and etiology may be elusive. A careful When AAU is severe, unresponsive to D. Expression of toll-like receptor evidence-based methodology, including 4 and its associated lipopolysaccha- treatment, persists or recurs, labora- detailed case history and review of sys- tory testing may be necessary (Table 6). ride receptor complex by resident tems, physical examination and poten- antigen-presenting cells in the hu- Minimum lab tests (with key identifi- tial laboratory testing, is necessary for able disease examples in brackets) may man uvea. Invest Ophthalmol Vis effective diagnosis and management. Sci. 2004;45:1871–1878. include: HLA-B27 (ankylosing spon- Treatment is initially focused on reduc- dylitis), urinalysis (psoriatic arthritis), ing the inflammatory findings, with the 6. Brewerton DA, Hart FD, Nicholls A, angiotensin converting enzyme (ACE) goals of improving patient comfort and Caffrey M, James DC, Sturrock RD. (sarcoidosis), venereal disease research visual function. Once a more detailed Ankylosing spondylitis and HLA- laboratory aka VDRL and fluorescent etiology of the AAU is determined, B27. Lancet. 1973;1:904–907. treponemal antibody aka FTA-ABS treatment is then also geared towards 7. Linssen A, Meenken C Outcomes of (syphilis) and chest X-ray (tuberculosis, the cause. HLA-B27-positive and HLA-B27- sarcoidosis). In certain cases, anterior negative acute anterior uveitis. Am chamber or vitreal taps, culture swabs Throughout the care of the patient J Ophthalmol. 1995;120(3):351- or tissue biopsies may be indicated. One with AAU, it is important to educate 61. clinical study made evidence-based rec- the patient thoroughly regarding his/ ommendations for appropriate tests in her condition, the possible causes and 8. Rodriguez A et al. Referral pat- four anterior uveitis situations:31 prognosis. Following this, discussion of terns of uveitis in a tertiary eye the various treatment options and ini- care center. Arch Ophthalmol. • Non-granulomatous anterior tiation of treatment should begin im- 1996;114(5):593-9. uveitis in an adult: HLA-B27 mediately, with close monitoring (i.e., 9. Taban M, Behrens A, Newcomb o If recurrent or chronic: chest daily or every few days, depending on RL. Acute endophthalmitis follow- X-ray, VDRL and FTA-ABS the severity of the presentation). Judi- ing : a systematic • Granulomatous anterior uveitis in cious yet effective dosage of topical cor- ticosteroid and cycloplegic agents are review of the literature. Arch Oph- an adult: chest X-ray, purified pro- thalmol. 2005;123(5):613-20. tein derivative (PPD) tuberculin the mainstay of AAU treatment. De- 10. Lundstrom M, Wejde G, Stenevi testing, serum ACE levels, VDRL pending on the presentation and cause, U, Thorburn W, Montan P. En- and FTA-ABS other medications, lab tests and tertiary procedures may be necessary. Finally, dophthalmitis after cataract sur- • Granulomatous anterior uveitis, coordination with other specialists (i.e., gery: a nationwide prospective suspected sarcoidosis, in an adult ophthalmologists, rheumatologists) study evaluating incidence in rela- or child: chest X-ray, ACE may be critical in diagnosis and treat- tion to incision type and location. o If suspicion is high despite ment. Eye care providers play a key role Ophthalmology. 2007;114(5):866- these tests normal: High-reso- in the interdisciplinary management of 70. lution computerized tomogra- the patient with AAU. 11. Zhang Y, Zhang MN, Jiang CH, phy (HRCT) scan of the chest Yao Y, Zhang K. Endophthalmitis or whole body gallium scan References following open injury. Br J with or without biopsy 1. Chang JH, Wakefield D. Uveitis: a Ophthalmol. 2010;94:111-114. • Anterior uveitis in a child: Anti- global perspective. Ocular Immu- 12. Ng JQ, Morlet N, Pearman JW, nuclear antibody (ANA), HLA nol Inflamm. 2002;10:263–279. Constable IJ, McAllister IL, Kenne-

Optometric Education 101 Volume 36, Number 2 / Winter/Spring 2011 dy CJ. Management and outcomes 21. Walton RC, Nussenblatt RB, Whit- uveitis investigation by Canadian of postoperative endophthalmitis cup SM. Cyclosporine therapy for ophthalmologists. Can J Ophthal. since the endophthalmitis vitrec- severe sight-threatening uveitis in 2008;43(6):652-657. tomy study: the Endophthalmitis children and adolescents. Ophthal- Population Study of Western Aus- mology. 1998;105(11):2028-34. tralia (EPSWA)’s fifth report. Oph- 22. Huang JJ. Alternatives for long- thalmology. 2005; 112(7):1199- term immunomodulation. Glau- 206. coma Today. 2010;8(12):46-48. 13. Endophthalmitis Vitrectomy Study 23. Imrie FR, Dick AD. Biologics in Group. Results of the Endophthal- the treatment of uveitis. Curr Opin mitis Vitrectomy Study. A random- Ophthalmol. 2007;18(6):481-6. ized trial of immediate vitrectomy and of intravenous antibiotics for 24. Suttorp-Schulten MS, Rothova A. the treatment of postoperative bac- The possible impact of uveitis in terial endophthalmitis. Arch Oph- blindness: a literature survey. Br thalmol. 1995;113(12):1479-96. J Ophthalmol. 1996;80(9):844- 848. 14. Samiy N, Foster CS. The role of non-steroidal anti-inflammatory 25. Jabs DA, Nussenblatt RB, Rosen- drugs in ocular inflammation. Int baum JT. Standardization of Uveitis Ophthalmol Clin. 1996;36:195- Nomenclature (SUN) Working 206. Group. Standardization of uveitis nomenclature for reporting clinical 15. Fiscella, R.G., Jensen, M. & Van data. Results of the First Interna- Dyck, G. Generic prednisolone tional Workshop. Am J Ophthal- suspension substitution. Arch mol. 2005;140:509-516. Ophthal. 1998;116:703. 26. Robert H Janigian Jr, MD Uveitis, 16. Calvin W. Roberts, Peter L. Nelson. Evaluation and Treatment. Web ar- Comparative analysis of predniso- ticle. www.emedicine. lone acetate suspensions. J Ocular com. Accessed on Feb 10, 2010. Pharm Ther. 2007;23(2):182-187. 27. Hogan MR, Kimura SJ, Thygeson 17. DaVanzo RJ. Durezol™ compared P. Signs and symptoms of uveitis: to Pred Forte® in the treatment of I. Anterior uveitis. Am J Ophthal- endogenous anterior uveitis. Poster mol. 1959;47:162-3. D1106, program 2697. ARVO Annual Meeting; May 4, 2009; 28. Sandler G. The importance of the Ft.Lauderdale,FL. history in the medical clinic and the cost of unnecessary tests. Am 18. Controlled evaluation of lotepred- Heart J. 1980;100(6 Pt 1):928-31. nol etabonate and prednisolone ac- etate in the treatment of acute ante- 29. Gutteridge IF and Hall AJ. Acute rior uveitis. Loteprednol Etabonate anterior uveitis in primary care. US Uveitis Study Group. Am J Clin Exp Optom. 2007; 90(2):70- Ophthalmol. 1999;127(5):597-9. 82. 19. Goldstein DA, Godfrey DG, Hall 30. Sinha R, Naithani P, Satpal G. A, Callanan DG, Jaffe GJ, Pearson Newer investigations and manage- PA, Usner DW, Comstock TL. In- ment guidelines in uveitis. Indian J traocular pressure in patients with Ophthalmol. 2010; 58(1):88–91. uveitis treated with fluocinolone 31. Forooghian F, Gupta R, Wong DT; acetonide implants. Arch Ophthal- Derzko-Dzulynsky L. Anterior mol. 2009;127(1):115-6. uveitis investigation by Canadian 20. Teasley LA, Ahmed M, Androudi ophthalmologists: insights from the S, et al. Oral non-steroidal anti-in- Canadian National Uveitis Survey. flammatory drug therapy for HLA- Can J Ophthal. 2006;41(5):576- B27 positive patients with chronic 83. non-infectious uveitis. ARVO; 32. Noble J, Hollands H, Forooghian May 1-5, 2005; Fort Lauderdale, F, Yazdani A, Sharma S, Wong DT, Florida. Abstract 2831. Derzko-Dzulynsky L. Evaluating the cost-effectiveness of anterior

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