2011-2012 Basic and Clinical Science Course, Section 9: Intraocular Inflammation and Uveitis (Basic & Clinical Science Course)

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Intraocular Inflammation and Uveitis

Intraocular Inflammation and Uveitis Section 9

2011-2012

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AMERICAN ACADEMY

\..:J OF OPHTHALMOLOGY TI,~

Ey" M .I). Association

L I HLONG tt:>UCATION ""'"." OrHTHAlMOLOGIS ~

The Basic and Clini cal Science COllrse (BCSC) is one component of the Lifelong Education for the Ophthalmologist (LEO) fram ework, which assists members in planning their continu ing medical education. LEO includes an array of clinical education produ cts that members may select" to form indivi dualized, self-directed leolrning plans fo r updating their clinical knowledge. Active membe rs or fellows who use LEO com ponent s moly accumulate sufficie nt CME credit s to earn the LEO Awa rd. Contact the Academy's Cli nica l Education Division for furt her information on LEO. The American Academy of Opht halmology is accredited by the Acc reditation Council for Continuing Medical Educat ion to provide conti nui ng medical education for physicians. The American Academy of O phthalmology deSignates this end uri ng material for a maximum of 10 AMA PRA Category 1 Credits TM. Physicians should clai m on ly cred it commensurate with the exte nt of their participation in the activity.

The BCSC is deSigned to increase the physic ian's ophthalm ic knowl edge th rou gh study and review. Users of this act ivity are encouraged to read the text and then answer the study questions prOVid ed at the back of the book. To claim AMA PRA Category 1 Credits™ upon 'completion of this activit)', learners must demonst rate appropriate knowledge and participation in the ac tivity by taking the posttest for Sect ion 9 and achieving a score of 80% or higher. For further details, please see the instructions for requesting C M E cred it at the back of the book. The Academy provides this material for educational purposes only. It is not intended to represent the only or best method or procedure in every case, nor to replace a physician's own jud gment or give speci fi c ad vice for case management. Lncluding all ind ications, contraind ications, side effects, a nd alternat ive agen ts for each drug or treatment is beyond the scope of this material. All information and recommendations should be verified , prior to use, with current information included in the manufacturers' package inserts or ot her independent sources, and considered in light of th e patient 's condition and history. Reference to certain drugs, instrum ents, and ot her products in this course is made for ill ustrati ve purposes only and is not intended to constitute an endorsemen t of such. Some material may include information on applications that are nOI considered community standard, that reflect indicat ions not included in approved FDA labeling, or that are approved fo r use only in restricted research settings. The FDA has stated that it is the responsibility of the physician to d etermine the FDA statu s of each drug or device he or she wishes to use, and to use them with appropriate, informed patient consent in compliance with applicabl e law. The Acadel11), specifically disclaims an)' and all liability for inj ury or ot her damages of any kind, from negligence or otherwise, fo r any and all claims thaI may arise from the use of any recommendation s or other information contained herein. Cover im age courtesy ofE. Mitchel Opremcak, MD.

Copyri ght © 20 II Ameri can Academy of O phthal mo logy All rights rese rved Prin ted in Singapore

Basic and Clinical Science Course Gregory L. Skuta, MD, Oklaho ma City, Oklaho ma, Sen ior Secretary for

Clinical Education Louis B. Cantor, MD, India napolis, Indiana, Secretary for Ophthallllic Knowledge Jayne S. Weiss, MD, Detroit, Michigan, BCSC Course Chair

Section 9 Faculty Responsible for This Edition Ramana S. Moorthy. MD, Chair, Indianapolis. Indiana P. Kumar Rao, MD, St. Louis, Missouri Russell W. Read, MD, PhD, Birmingham, Alabama Russell N. Van Gelder, MD, PhD, Seattle, Was hington Albert T. Vitale, M 0, Salt Lake City, Utah Bahram Bodaghi, MD, PhD, COl1Sultant, Paris, France Carrie M. Parrish, MD, ashville, Tennessee

Practici/lg Ophthalmologists Advisory Committee for Education T he Academy wishes to ackn owledge Mary Lou Jackson, MD, Vision Rehabilitation Committee. for her review of this edition. The Academy wishes to acknowledge the American Uveitis Society for recommending fac ul ty members to the BCSC Section 9 committee.

Financial Disclosures T he following Academy staff members state that they have no significant financial interest o r other relat ionsh ip with the man ufacturer of any commercial product discussed in this co urse o r with the manufacturer of any compe tin g commercia l product: Christi ne Arturo, Steve Huebner, Stephanie Tanaka, and Brian Veen. The auth ors state the folloWing fina ncial relat ionships: Dr Bodaghi: Allerga n, consultant; Bausch & Lomb Surgical, consultant; Lux Biosciences, grant reci pientj Nova rtis Pharmaceuticals, gra nt rec ipi ent

Dr Rao: National Eye Insti tute, gra nt recipient; Ge nentech, grant recipient Dr Read: Alcon Laboratories, consultant; EyeSight Foundatio n of Alabama, grant recipient; GlaxoS mith Kline, consultant; Intern ati onal Retinal Research Foundation, grant recipient; Research to Prevent Blindness, grant recipient; Lux Biosciences. consultant

Dr Van Gelder: Alcon Laboratories, consultant, grant recipient; Novartis Pharmaceuticals, consultant; Photoswitch Therapeut ics, grant recipient

Dr Vitale: Bausch & Lomb Surgical, consu ltant; Aciont, consultant The other authors state that they have no significant fina ncial interest or other relation ship with the manufacturer of any commercial product discussed in the chapters that they contributed to this course or with the manufacturer of any competing commercial product.

Recent Past Faculty Janet Davis, M D C. Stephen Foster, MD Careen Yen Lowder, M D, Ph D alini S. Bora, PhD In addition, the Academy gratefully acknowledges the contribution of numerous past facu lty and advisory committee members who have played an impo rtant role in th e devel opment of previous editions of the Basic and Clinical Science Course.

American Academy of Ophthalmology Staff Richard A. Zorab, Vice President, Ophthalmic Knowledge Hal Straus, Director, Publications Department Christin e Arturo, AcquisitiOflS Mauager Stephanie Tanaka, Publications Manager D. Jean Ray, ProductiOlI Manager Brian Veen, Medical Editor Steven Huebner, Adm;'lislrative Coordinator

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JIA '" juvenile idiopathic arthritis; ANA = antinuclear anti bodies; NA = not applicable. Recommendations for follow-up continue through childhood and adolescence. Reprinted with permission from Cassidy J, Kivlin J, Li ndsley C, Nocton J; Section on Rheumatology; Section on Ophthalmology. Ophthalmologic examinations in children with juvenile rheumatoid arthritis.

Pediatrics. 2006;117(5):1844.

studies have shown that this treatment regimen can effectively control the uveitis, is gen· erally well tolerated, and can spare patients the complications oflong·term corticosteroid use. In addition, newer studies have revealed benefit from TNF inhibitors and other bio· logic agents in the treatment of /lA, with a reduction in ocular inflammation, a decrease in topical and systemic corticosteroid use, and fewer recurrences.

Treatment of cataracts in patients with JIA remains a challenge, and the use of IOLs remains controversial. Children who are left aphakic may develop amblyopia. There is a high complication rate following cataract surgery in patients with JIA·associated iridocy· clitis, due to the difficulty in controlling the more aggressive inflammatory response seen in these children. Lensectomy and vitrectomy via the pars plana have been advocated. However, there have been reports of more successful cataract surgery with IOL im· plants in patients with JIA. BenEzra and Cohen studied 5 children with JIA who received IOL implants. Although the vision initially improved in 4 of 5 eyes, it later decreased due to the development of retrolental membranes. Lam and colleagues reported good results following cataract extraction and IOL implants in 5 children with JIA. The major differ· ence between the 2 studies was the more aggressive, long· term preoperative and postop· erative use of IMT in the latter. The following guidelines must be followed when selecting patients with JIA for cataract surgery with IOL implants: • The patient's intraocular inflammation must be well controlled for at least 3 months before surgery with systemic IMT and must not require frequent instillation of top· ical corticosteroids.

Only acrylic lenses should be implanted. Patients must be followed up very frequently after cataract surgery to detect any inflammation, and inflammation that occurs must be aggressively treated . • IMT must be used preoperatively and postoperatively, not just peri operatively.

132 • Intraocular Inflammation and Uveitis o

o

Because long-term results are not available, patients must be strongly advised about the need for careful, regular, lifelong follow-up to detect late complications that may lead to loss of the eye. The ophthalmologist must have a low threshold for IOL explantation in patients who have persistent postoperative inflammation and recurrent cyclitic membranes.

Patients with band keratopathy should be treated (eg, scraping or chelation with sodium ethylenediaminetetraacetic acid IEDTA]) and allowed to heal well before cataract surgery is attempted. See also Chapter 10 and BCSC Section 6, Pediatric Ophthalmology and Strabismus, Chapter 21. Glaucoma should be treated with medical therapy initially, although surgical intervention is often necessary in severe cases. Standard filtering procedures are usually unsuccessful, and the use of anti fibrotic agents or aqueous drainage devices is usually required for successful control of the glaucoma. BenEzra D. Cohen E. Cataract surgery in children with chronic uveitis. Ophthalmology. 2000;

107(7): 1255- 1260. Cunningham ET Jr. Uveitis in children. Ocullmmunollnflamm. 2000;8(4):251-261. Ducos de Lahitte G, Terrada C, Tran TH. et a1. Maculopathy in uveitis of juvenile idiopathic arthritis: an optical coherence tomography study. Br JOphthalmol. 2008;92(1):64-69. Holland GN, Denove CSt Yu F. Chronic anterior uve itis in children: clinical characteristics and

complications. Am J Ophthalmol. 2009,147(4):667-678. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol. 1990;34(4):253 - 267. Lam L, Lowder CY. Baerveldt G. Smith SD. Trabou lsi EL Surgical management of cataracts in children with juvenile rheumato id arthritis -associated uveitis. Am I Ophthalmol.

2003,135(6):772- 778. Paroli MP. Spinucci G, Fabiani C. Pivetti-Pezzi P. Retinal complications of juvenile idiopathic arthritis-related uveitis: a microper imetry and optical coherence tom ography study. Owl

ImmunollnJlamm.20IO,18(1):54 - 59. Probst LE, Holland EJ. Intraocular lens implantation in patients with juvenile rheumatoid ar-

thritis. Am J Ophthalmol. 1996,122(2):161 - 170. Rajaraman RT, Kimura y, Li S, Haines K, Ch u DS. Retrospective case review of pediatric patients with uveitis treated with infliximab. Ophthalmology. 2006;113(2):308- 3 14. Sen HN , Levy-Clarke G. Faia LJ. et al. High-dose daclizumab for the treatment o f juvenile idiopathic arthritis-associated active anterior uve itis. Am I Ophthalmol. 2009; 148(5):696-703. Tynjala p. Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford). 2008;47(3):339-344.

Fuchs heterochromic iridocyclitis Fuchs heterochromic iridocyclitis, or Fuchs uveitis syndrome, is an entity that is frequently overlooked. Between 2% and 3% of patients referred to uveitis clinics have Fuchs heterochromic iridocyclitis. This condition is usually unilateral, and its symptoms vary from none to mild blurring and discomfort. Signs include o

o

diffuse iris stromal atrophy with variable pigment epithelial layer atrophy (Fig 6-14) small white stellate KPs scattered diffusely over the entire endothelium (Fig 6-15); diffusely distributed KPs also occur with herpetic keratouveitis cells presenting in the anterior chamber as well as the anterior vitreous

CHAPTER 6: Noninfectious(Autoimmune)Ocular InflammatorvDisease . 133

in Fuchsheterochromiciridocyclitis. Figure6-14 Heterochromia A, Righteye. B. LeJteye. Note the lighter iris color and stromalatrophy("moth-eatenappearance")in the lelt eye, which was the affecled eye. lcoudesv of Davrd Forster, MD)

Figure6-15 Diffuselydistrbuted keraticprecioltatesin a oatientw th Fuchsheterochromic iridocvclltis.(Cauftesv Forste. MD) of David

Synechiaealmost never form, but glaucomaand cataractsoccur frequently.Generally, funduslesionsareabsent,but fundusscarsand retinalperiphlebitishavebeenreportedon rareoccasions. Macularedemaseldomoccurs, The diagnosisis basedon the distributionofKPs,lackofsynechiae,lackof symptoms, and heterochromia.Heterochromiamay be subtlein a brown-eyedpatientand one must look carefullyfor signsof iris stromalatrophy.Often, the inflammationis discoveredon a routine examination,suchas when a unilateralcataractdevelops.Usually,but not invariably,a lighter-colorediris indicatesthe involvedeye(Fig 6- l6). In blue-eyedpersons, however,the affectedeyemay becomedarkeras the stromalatrophyprogresses and the darkeriris pigmentepitheliumshowsthrough.

Figure6-16 Heterochromla in Fuchshetero chromlcirldocycitis in a brown-eyedpatient.

134 • Intraocular Inflammation and Uveitis

The etiology of Fuchs heterochromic iridocyclitis remains unclear. Associations with ocular toxoplasmosis. herpes simplex vi rus. and CMV infection have been suggested. de Groot- Mijnes and colleagues recently reported the association of rubella vi rus in patients with Fuchs heterochromic iridocyclitis; 13 of 14 patients with the disease demonstrated intraocular immunoglobulin G (lgG) production against rubella virus. whereas none had antibodies agai nst herpes simplex virus. herpes zoster virus. or Toxoplasma gondii. Patients generally do well with cataract surgery. and IOLs can usually be implanted successfully. However. some patients may suffer significant visual disability as a result of extensive vitreous opacification. even after uncomplicated cataract surgery with IOL implantation in the capsular bag. Pars plana vitrectomy should be carefully considered in such patients. Glaucoma cont rol can be d ifficu lt. Abnormal vessels may bridge the angle on gonioscopy. These vessels may bleed during surgery. resulting in postoperative hyphema. Few cases of Fuchs heterochromic iridocyclitis require therapy. The prognosis is good in most cases even though the inflammation persists for decades. Because topical corticosteroids can lessen the inflammation but typically do not resolve it. aggressive treatment to eradicate the cellular reaction is not indicated. Cycloplegia is seldom necessary. Histologi cal examination shows plasma cells in the ci liary body. indicating that true inflammation occu rs. Birnbaum AD, Tessler HH , Schu ltz KL, et al. Epidemiologic relationship between Fuchs het· erochromic iridocyclitis and the United States rubella vacc ination program. Am J Ophthal. mol. 2007;144(3):424 - 428. de Groot·Mijnes 10, de Visser L. Rothova A. Schull er M. van Loon AM , Weersink AJ. Rubella virus is associated with Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2006; 141 (1 ): 212-2 14.

Idiopathic iridocyclitis In many patients with chronic iridocyclitis. the cause is unknown. Therapy. includi ng cycloplegia. may be necessary before a specific diagnosiS is possible. In some cases initially labeled as idiopathic. repeat diagnostic testing at a later date may reveal an underlying systemic condition.

Intermediate Uveitis The Standardization of Uveitis Nomenclature (SUN) Working Group defines intermediate uveitis as the subset in which the major site of inflammation is in the vitreous; it accounts for up to 15% of all cases of uveitis. It is characterized by ocular inflammation concentrated in the ante rior vitreous and the vitreous base overlying the ciliary body and peripheral retina- pars plana complex. Inflammatory cells may aggregate in the vitreous ("snowballs"). where some coalesce. In some patients. inflammatory exudative accumulation on the inferior pars plana ("snowbanking") seems to correlate with a more severe disease process. There may be associated reti nal phlebitis. Anterior chamber reaction may occur. but in adults it is usually mild and attributed to spillover from the vitreous.

cHAprER 6: Noninfectious(Autoimmune)Ocular InflammatoryDisease. 135 Intermediate uveitis is associatedwith various conditions, including sarcoidosis,mul tiple sclerosis(MS), Lyme disease,peripheraltoxocariasis,s)?hilis, tuberculosis,primary Sj90mm Hg) elevatedblood ureanitrogen positivehepalitisB serologl abnormalarteriographicfindings demonstrationofneutrophilson biopsyspecimens ofsmallor medium sizedarteries

The presenceof antineutrophilcltoplasmicantibody(ANCA) further suggests the di (see agnosis the discussionofWegenergranulomatosis in the followingsection).The 5-year mortality rateof untreatedPAN is 90%.Althoughsystemiccorticosteroidusemay reduce this rateto 50%,appropriatetreatmentmandatescombinationtherapywithimmunomodulatory medicationssuchascyclophosphamide, which improvesS-yearsurvivalto 8070and mayinducelong-termremissionofthe disease. It is thereforeimportantto considerPAN in the differentialdiagnosisofretinal vasculitispresentingin patientswith multiplesystemic complaintsin whom an underlyingnecrotizingvasculitisis suspected; appropriatediagnosisandmanagement canbe life-saving.Tissuebiopsyconfirmsthe diagnosis. Akova YA, fabburNS,FosterCS.Ocularpresentationofpolyarteritis nodosa.Clinicalcourseand managementwith steroid and cltotoxic therapy.Ophthalmology.1993;100(12):r 775 178t. Gayraud M, Gtrillevin L, Cohen R et al, and the French Cooperative Study Group for Vasculitides.Treatment of good prognosis polyarteritis nodosa and Churg-Strausssyndrome: comparisonofsteroids and oral or pulse cyclophosphamidein 25 pattents.Br I Rheumatol. 1997:36(12):1290-1297 .

CHAPTER 6:

Noninfectious (Autoimmune) Ocular Inflammatory Disease.

145

Perez VL, Chavala SH, Ahmed M, et al. Ocular manifestations and concepts of systemic vascu-

litides. Surv Ophthalmol. 2004;49(4}:399- 418.

Wegener granulomatosis Wegener granulomatosis is a multisystem autoimmune disorder characterized by the classic triad of necrotizing granulomatous vasculitis of the upper and lower respiratory tract, focal segmental glomerulonephritis, and necrotizing vasculitis of small arteries and veins. Involvement of the paranasal sinuses is the most characteristic clinical feature of this disorder, followed by pulmonary and renal disease. Renal involvement mayor may not be evident at presentation, but its early detection is important, as up to 85% of patients develop glomerulonephritis during the course of the disease, which, ifleft untreated, carries significant mortality. A limited form of this disease has also been described, consisting of granulomatous inflammation involving the respiratory tract without overt involvement of the kidneys; however, subclinical renal disease may be present on tissue biopsy. Patients may present with constitutional symptoms, sinusitis associated with bloody nasal discharge, pulmonary symptomatology, and arthritis. Dermatologic involvement is seen in approximately one-half of patie nls, with purpura involving the lower extremities occurring most frequently; less common are ulcers and subcutaneous nodules. Nervous

system involvement may be seen in approximately one-third of patients with peripheral neuropathies, the most common being mononeuritis multiplex; less frequently observed are cranial neuropathies. seizures, stroke syndromes. and cerebral vasculitis.

Ocular or orbital involvement is seen in 15% of patients at presentation and in up to 50% of patients during the course of the disease. Orbital involvement, one of the most frequently reported ocular findings , is usually secondary to contiguous extension of the granulomatous inflammatory process from the paranasal sinuses into the orbit. Orbital pseudotumor, distinct from the sinus inflammation; orbital cellulitis; and dacryocystitis may arise from the involved and secondarily infected nasal mucosa. Scleritis of any type, particularly diffuse anterior or necrotizing disease, with or without peripheral ulcerative keratitis, affects up to 40% of patients. Posterior scleritis has also been reported. ApproXimately 10% of patients with Wegener granulomatosis and ocular involvement have been reported to have an associated nonspecific unilateral or bilateral anterior, intermediate, or posterior uveitis) with varying degrees of vitritis. Retinal involvement is rela-

tively uncommon, occurring in up to 10% of patients. Retinal vascular manifestations range from relatively benign cotton-wool spots, with or without associated intraretinal hemorrhages, to more severe vasa-occlusive disease, including branch or central retinal artery

or vein occlusion. Retinitis has been reported in up to 20% of patients; those with accompanying retinal vasculitis may develop retinal neovascularization, vitreous hemorrhage, and neovascular glaucoma (Fig 6-22). Optic nerve involvement, especially ischemic optic neuropathy, is not uncommon. Vision loss in Wegener granulomatosis may occur in up to 40% of patients, especially among those with long-standing or inadequately treated disease. Tissue biopsy establishes the histologic diagnosis; chest x-ray may disclose nodular, diffuse. or cavitary lesions; and laboratory evaluation may note proteinuria or hematuria.

elevated ESR, and the presence of C-reactive protein and ANCAs. ANCAs are antibodies directed against cytoplasmic azurophilic granules of neutrophils and monocytes, which are specific markers for a group of related systemic vasculitides

146 . IntraocularInflammationand Uveitis

FiguJe 6-22 Wegener granulomatosis: retinitis. (Couttesy of E. MitchelOprcmcak, MD )

that include Wegenergranulomatosis,PAN, microscopicpolyarteritisnodosa,ChurgStrausssyndrome,and pauci-immunoglomerulonephritis. Two main classesof ANCA havebeendescribedbasedon the immunofluorescence stainingpatternon ethanol-fixed neutrophilsand the main target antigen.The cytoplasmicpattern,or c-ANCA, is both sensitiveand specificfor Wegenergranulomatosis and is presentin up to 95%ofpatients; proteinase3 is the most common target antigen.The perinuclearpattern,or P-ANCA, is associatedwith PAN, microscopicpolyarteritisnodosa,relapsingpolychondritis,and renal vasculitis.Myeloperoxidaseis the most common antigenictarget.In contrastto the resultsfound in Wegenergranulomatosis, the diagnosticsensitivitiesof C-ANCAand p-ANCA for PAN areonly 5% and 157o,respectively; in patientswith microscopicpolyarteritis nodosa,p-ANCA (myeloperoxidase) positivityis more common (507o-80%), with a smallerpercentage(4070)havingthe c-ANCA (proteinase3) marker As with PAN, appropriatetreatmentmandatescombinationtherapywith oral corticosteroidsand IMI specificallycyclophosphamide. Without therapy,the l -yearmortality rateis 80%.However,937o ofpatientstreatedwith cyclophosphamide and corticosteroids successfullyachieveremissionwith resolutionof ocular manifestations.As with pAN, ophthalmologistsmustbe intimatelyfamiliarwith Wegenergranulomatosis, asocularinflammatorymanifestations arefrequentlypresent,andtimely diagnosisandtreatmentare essentialin reducingnot only ocular morbidity but overallpatientmortaliry Hoffman GS, Kerr GS, Leavitt RY,et al. Wegenert granulomatosis:an analysisof 158patients. Ann Interfl Med. 1992;ll6(6):488-498. Pakrou N, Selva D, Leibovitch I. Wegenert granulomatosis: ophthalmic manifestations and management. Semifl Arthritis Rheum. 2006;35(5\284-292.

SusacSyndrome Susacsyndrome(alsoknown asSICRETsyndrome,for smallinfarctionsofcochlear,retinal, and encephalictissue)is a rareentity,initially reportedin 1979by Susacet al andconsistingofthe clinicallyobservedtriad of encephalopathy, hearingloss,and retinal artery branchocclusions.It occursmostly in youngwomenbut hasbeennotedin patientsaged

(Autoimmune) CHAPTER 6: Noninfectious OcularInflammatorv Disease. 147 16 to 58 years.Differentialdiagnosisat presentationincludesMS, herpeticencephalitis, acutedisseminatedencephalomyelitis, and Behqetdisease.Howeve! ocular findings are highly specificandallowpromptdiagnosticconfirmationwith subsequent therapeuticadjustments.Ophthalmoscopyshowsdiffuseor localizednarrowingof retinal arterieswith a "boxcar" segmentationof the blood column at the level of peripheralretinal arteries. Vitreoushazeor cellsare absent.RetinalFA disclosesfocalnonperfusedretinal arterioles with hyperfluorescent walls(Fig6-23).Thereis usuallyno evidenceof embolicmaterialor inflammatoryreactionsaroundthevessels. Magneticresonance imaging(MRI) is another usefuldiagnostictool and showsmultifocalsupratentorialwhite matter lesions;the corpus callosummay be involved.Treatmentremainscontroversialand includeshigh-dose intravenouscorticosteroids,anticoagulants, and IMT. The courseof Susacslmdromeis not alwaysself-limitingand isolatedretinal arteriolarinvolvementmay occur as a very latemanifestation. Aubart Cohen E Klein I, Alexandra JF,et al. Long term outcome in Susacs}a]drome.Medirire (Baltimore). 2007:86(2\93 102. SusacJO, Hardman JM, Selhorst lB. Microangiopathy of the brain and. rclina. Neurology. 1 9 7 9 r 2 9 i 3 ) : 33 11 36 .

InflammatoryGhorioretinopathies of UnknownEtiology The inflammatory chorioretinopathies, or white dot syndromes,are a heterogeneous group of inflammatory disorderswith overlappingclinical featuresthat sharein common the presenceof discrete,multiple, well-circumscribed,yellow-whitelesionsat the level of the retina,outer retina,RPE,choriocapillaris,and choroid during somephaseof their course.The white dot syndromesconsistofthe predominantlynoninfectiousocular s)'ndromeslisted in Table6-3. Their differentialdiagnosisincludessystemicand ocular infectiousentitiessuchasslphilis, diffuseunilateralsubacuteneuroretinitis(DUSN),and ocularhistoplasmosis syndrome(OHS),aswell asnoninfectiousentitiessuchassarcoidosis,sympatheticophthalmia,VKH syndrome,and intraocularlymphoma (Table6-4). Common presentingsymptomsinclude photopsias,blurred vision, nyctalopia,floaters,

Figure6-23 Susacsyndrome.A, Co or fundus photographdiscloslngan area of intraretlnal whiteningcorresponding to a supratemporal brancharteryocclusionin the left eye. B, F uoresceinangiogramshowinga supratemporal brancharteryocclusionwith multipleareasof segmentalstalningwell away from sites of bifurcatlon.lcourtesy afAlbertT Vtate, MD)

Table 6-3

Inflammatory Chorioretinopathies Birdshot

APMPPE

Serpiginous Choroiditis

MCP

Age

O lder (30-70)

Young (20-50)

Young, middleage (20-60)

Young (9-69)

Se.

hM

M=F

M=F

F 13,11

Laterality

Bilateral

Bilateral

Bilateral,

Bilateral

Bilateral

SFU

MEWDS

ARPE

AZOOR

Young (18-40)

Young (14-34)

Young (10-47 )

Young (16-40)

Voung (13-63)

F I90%)

F (100%1

F (3:1)

M",F

F (3: 1)

Asymmetric

Unilateral

Unilateral

Un ilateral (24%1, bilateral (76% )

PIC

asymmetric

Systemic associations

80%-98% HLA-A29+. lymph ocyte proliferation to retinal S-antigen

Pathogenesis Autoimmune?

Viral prodrome, HLA-B7 cerebrovasculi tis, CSf

(75%)

None

None

None

Viral prodrome

None

Systemic autoimmune disease 128%)

150%)

abnormalit ies Viral?

Autoimmune?

Viral?

Variant o f MCP? limited myopic degeneration?

Autoimmune

Viral? Common non-diseasespecific genetics?

Vi ral?

Viral vs autoimmune

Infectious (herpes)? Onset

Insidious

Acute

Variable

Insidious

Acute

Insidious

Acute

Acute

Insidious

Course

Chronic, recurrent

Self-limited

Chronic, recurrent

Chronic, recurrent

Self-limited

Chronic, recurrent

Self-limited

Self-limited

Chronic, re cu rr ent (31%)

Symptom s

Blurred viSion, floaters, photopsias. disturbed night and color vision

Blurred vision, scotomata, photopsias

Blurred vis ion, scotomata

Blurred vision, float ers, photopsias, metamorphopsia , scotomata

Paracentra l scotomata, photopsias, metamorphopsia

Blurred vision, decreased vision

Blurred or decreased vision, scotomata, photopsias

Central metamorphopsia, scotomata

Photopsias

Examination

Vitritis; ovoid, creamy, whiteyellow, postequatorial lesions (50-1500 IJm), do not pigment

Mu ltifocal, fla t, grayw hite lesions, 1- 2 disc areas, outer retina/RPE with evolving pigmentation

Geographic, yellow-gray, peripapillary, macular chorioretinal lesions with centripedal extension; activity at leading, peripheral edge with APE/choriocapillaris atrophy in its wake

Myopia, iridocyclitis (50%), vit ritis (100%), active whiteyellow chorioret inal lesions (50-200 IJm ) evolving to punched -out sca rs

Myopia, vitritis absent, w hiteyellow chorioretinal lesions

Moderate vitritis, 50500lJm yellow-white lesions posterior pole to midperiphery, APE, hypertrophy, atrophy, large stellate zones of subretinal fibrosis

Myopia; mild iridocyclitis; vitrit is; small white-orange, evanescent, perifoveal dots (100-200 IJm) outer retinal APE; macular granularity

Small, hyperpigmented lesions with yellow ha lo (100-200 jJm), unassociated vitritis

Initially normal to subtle APE changes, late pigment m igration, focal perivenous sheathing

Structural compli cations

Aetinal vasculitis, disc edema, CME, CNVM (6%)

Disc edema

CNVM (25%), RPE mottling, scarring, loss of choriocapillaris

Optic disc edema, peripapillary pigment changes. CME (14%-44%). CNVM (33%)

CNVM (17%-40%). serous detachment over confluent lesions

Neurosensory retinal detachment, CME. CNVM

Disc edema, venous sheathing

None

APE mottling, occasional CM E

Fluorescein angiography

Early hypofluorescence vs silence, subtle late stain; leakage fro m d isc, vessels, CME; delayed retinal circulation time

Acu te lesions: early blockage. late staining; late window defects

Early hypofluorescence, late stain ing/leak of active border, leakage in presence of CNVM

Early blockage, late staining of lesions, leakage from CME, CNVM

Early hyperfluorescence, variable late leakage/ staining acute lesions, leakage in presence of CME, CNVM

Multiple areas of alternating hypo- and hyperfluorescence; early, late staining

Early punctate hyperfluorescence, wreathlike configuration, late staining of lesions. o ptic nerve

Early hyperfluorescence with surrounding halo of hyperlluorescence and late staining

In acute stage, normal with increased retinal circulation time; in late stage, diffuse hyperfluorescence, RPE atrophy

IFA)

(Continued)

Table 6-3

(con tin ued)

Indocyanine green

Birdshot

APMPPE

Corresponding

Hypofluorescent spots cor-

hypo fl uores cent lesions more numerous than

angiography (leG I

on exam, FA

responding

to those seen on exam, FA

Serpiginous Choroid itis Early hypofluorescence, late staining, more widespread

extent than seen on exam, FA

MCP

PIC

SFU

Multiple hypo- Multiple hypofluorescent,

fluorescent lesions, conflu ence around optic

ne rve, more numerous than on exam,

MEWDS

ARPE

AZDDR

ERG : diminished a wave. early recepto r potentia ls (re versible); VF: enla rged blind spot. paracentral scotomata

ERG: no(-

ERG, mfERG: abnormal ; VF: temporal . superior defects. enlarged bl ind spot

Multiple hypo-

fluor escent spots,

peripapillary, posterior pole lesions, co rresponding to those seen on exam, FA

more numerous than on exam, FA

FA ERG: ab normal rod and cone responses

Electrophysi· ology. visual fields (V FI

EOG: variably abnormal

ERG : no rmal

ER G: abnormal. extinguished responses

ERG : normal VF: enlargement of blind spot

VF, ERG. and EOG markedly attenuated

~ 41 %)

mal EOG: abnormal

Visual pr ognosis

Guarded without treatment

Good

Guarded

Guarded

Good i n absence ofCNVM

Guarded

Excellent

Excellent

Guarded

Treatment

System ic corticosteroids,IMT

Observation; systemic corticosteroids with CNS involvement

System ic corticosteroids. IMT. laser for CNVM

Systemic corticosteroids. IMT, laser for

Observation; systern ie/periocular corticosteroids, laser for CNVM

Corticosteroids for CME . IMT of equivocal effiC8CY long term

Observatio n

None

Corticosteroids. IMT, antivirals of equivocal efficacy

CNV M

APMPPE .. ac ute posterior mu lt ifoca l p lacoid pigment epitheliopathy. ARPE

:=

acute reti na l pigmen t epitheliitis, AZOO R

=- acute zona l occu lt o uter

ret inopathy, CN VM '"

choroida l neovasc ular memb rane, IMT = im munom odu latory thera py, M CP = mu lt ifoca l cho r o id it is and pan uveit is syndrom e, M EWDS '" m Ulti pl e evanescent white dot syndro m e. PIC

= pu nctate inne r cho roid iti s, SFU :: su bretina l fibrosis and uveit is synd rom e.

CHAPTER 6:

Noninfectious (Autoimmune) Ocular Inflammatory Disease.

151

Table 6-4 Differential Diagnaisis far Chariaretinapathies Syphilis Diffuse unilateral subacute neuroretinitis (DUSN) Ocular histoplasmosis syndrome (OHS) Tuberculosis Toxoplasmosis Pneumocystis choroidopathy Candidiasis Acute retinal necrosis (ARN) Ophthalmomyasis Sarcoidosis Sympathetic ophthalmia Vogt-Koyanagi -Harada (VKH) syndrome Intraocular lymphoma

and visual field loss contiguous with a blind spot. In many cases, a prodromal viral syndrome can be identified. Bilateral involvement, albeit asymmetrically (with the exception of multiple evanescent white dot syndrome [MEWDSJ), is the rule. Other than patients with birdshot retinochoroidopathy or serpiginous choroiditis, the majority of individuals are younger than age 50. A female predominance is observed in patients with MEWDS, birds hot retinochoroidopathy, multifocal choroiditis and panuveitis, punctate inner choroiditis (PIC), and acute zonal occult outer retinopathy. The etiology of the white dot syndromes is unknown. Some investigators have postulated an infectious cause; others have suggested an autoimmune/inflammatory pathogenesis arising in individuals with common non- disease-specific genetics, triggered by some exogenous agent. An increased prevalence of systemic autoimmunity in both patients with white dot syndromes and their first- and second-degree relatives suggests that inflammatory chorioretinopathies may occur in families with inherited immune dysregulation that predisposes to autoimmunity. Whether the white dot syndromes represent a clinical spectrum of a Single disease entity or are each discrete diseases awaits identification of the underlying mechanisms. Although they have similarities, the white dot syndromes can be differentiated clinically based on their variable lesion morphology and evolution, distinct natural histories, and angiographic behavior. This has important implications with respect to disease-specific treatments and predictions of the ultimate visual prognosis. Gass ID. Are acute zonal occult outer retinopathy and the white dot syndromes (AZOOR com plex) specific autoimmune diseases? Am J Ophthalmol. 2003;13 5(3 ):380-381. lampol LM, Becker KG. White spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol. 2003;135(3): 376-379. Quillen DA, Davis IB, Gottlieb JL, et al. The white dot syndromes. Am 137(3),538-550.

J Ophthalmol.

2004;

Pearlman RB, Golchet PR, Feldmann MG, et al. Increased prevalence of autoimmunity in patients with white spot syndromes and their family members. Arch Ophthalmol. 2009;127(7 ): 869- 874.

152 o lntraocularInflammationand Uveitis

Bitdshot rctinochotoi dopathy (vitiliginouschorioretinitis) pre is an uncommondisease Birdshotretinochoroidopathy pastthefourthde in whitewomenofnorthernEuropean descent sentingpredominantly cadeoflife. While no consistentsystemicdiseaseassociationhasbeenidentified,birdshot retinochoroidopathyis highly correlatedwith the HLA-A29 haplotype,with a sensitivity of 960/oand a specificityof 93%.The presenceof the haplotypeconfersconsiderableincreasedrelativerisk (224-fold)for the developmentof this disease.HLA-A29 is confirmatory rather than diagnostic,as 7% of the generalpopulation carriesthis haplotlpe, and in the absenceof characteristicclinical features,an alternativediagnosisshouldbe considered.Retinalautoimmunityis thought to play an important role in the pathogenas is suggested by the similaritiesbetweenit and esisof birdshot retinochoroidopathy, experimentalautoimmuneuveitisand by the demonstrationof lymphoclte proliferation to retinal S-antigen.Alternatively,it hasbeenhypothesizedthat an infectiousagentmay enhancethe expression,by the HLA-A29 molecule,of self-peptidesto T lymphocltes. Both T and B lymphocytes,but no organisms,havebeenseenon histologicexamination ofthe chorioretinallesionsfrom autopsyeyeswith birdshotretinochoroidopathy. Presentingsymptomsincludeblurred vision,floaters,nyctalopia,and disturbanceof color vision.Anterior segmentinflammationmay be minimal or lacking;however,varying degreesofvitritis arecommonlynoted.Funduscopyrevealscharacteristicmultifocal, hlpopigmented,ovoid, cream-coloredlesions(50-1500pm) at the level of the choroid and RPE in the postequatorialfundus;tlpically theseshow a nasaland radial distribution, emanatingfrom the optic nerve,and frequentlytheyfollow the underlyingchoroidal by vessels(Fig 6-24).They do not becomepigmentedover time and arebestappreciated indirectophthalmoscopy. Retinalvasculitis,CME, andoptic nerveheadinflammationare importantcomponentsofactivedisease. Latecomplicationsincludeoptic atrophy,epireti(ERM) nal membrane formation,and,rarely,CNV FA revealsinconsistentfindings dependingon age,lesions,and phaseof study.Al with subtlelatestaining, though earlybirdshotlesionsmay showinitial hlpofluorescence in general,FA doesnot typically highlight the birdshot lesionsthemselvesbut rather is

Figure 6-24 Birdshot retinochoroidopathy with multiple postequatorial, cream-colored S.Maafthy, MD) ovold lesions.Gourtesy af Ramana

) c u l a rl n f l a m m a t o r V c H A p r E6B: N o n i n f e c t i o u(sA u t o i m m u n eO D i s e a s e. 1 5 3 useful in identifying more subtle indices of active lnflammation such as retinal vasculitis, CME, and optic nerve head leakage (Figs 6-25, 6-26). Late hlpopigmented lesions t)?ically do not show transmission defects,implying loss of pigment concurrent with loss of choriocapillaris. Indocyanine green (lCG) angiography discloses multiple hlpofluorescent spots,which are tlpically more numerous than those seen on clinical examination or on FA (Fig 6-27). Fundus autofluorescence(FAF) imaging revealshlpoautofluorescence in areasof RPE atrophy that are [rore numerous and not uniformly correspondent with the birdshot leslons, suggestingthat the choroid and RPE may be affected independently. Placoid macular hlpoautofluorescence may be an important predictor of central vision loss(Fig 6-28). Important differential diagnostic considerations include pars planltis, VKH syndrome, sympathetic ophthalmia, OHS, and especiallysarcoidosis,which may present with chorioretinal lesions of similar morphology and distribution as those seen in birdshot retinochoroidopathy. Progressivevisual field loss and abnormal electroretinogram (ERG) results are commonly seenwith extendedfollow-up, suggestingthat a more diffuse retinal dysfunction not fully explained by the presenceof CME or other structural abnormalities contributes to visual loss.For this reasonfull-field ERGs (with attention to the 30-Hz flicker implicit time and scotopic b wave amplitudes) and both Goldmann and automated visual fields (30 2 with attention to the mean deviation) are more useful parametersin following diseasecourse and responseto therapy than changesin funduscopic examination resultsor visual acuity.

Figure6-25 Fluorescein angiograrnshowing diifuse ret na phlebits in a patlentwlth birdshot retinochorodopalhy. lcourtesy of E Mitchel

Figure6-26 Fluorescein angiogramshowing cystoidretina edemd in a patlentwlth blfdshot ret nochorodopalhy. tcourtesy of E Mitchel

1 5 4 . I n t r a o c u l aIrn f l a m m a t i o na n d U v e i t i s

greenanFigure6-27 Blrdshotretlnochoroldopathy. Fundusphotograph(A) and lndocyanine giogram(B) showing numerousmidphasehypofluorescent spots corresponding to lundus leSiOns. /Couftesyol,4 lbert T Vitate.MD )

Figure6-28 Birdshotretinochoroidopathy. A, Color fundus photographshowing multifocal hypopigmenled spotswith n the maculaand outsidethe arcades.B, Autof uorescencephotographshowingplacoidhypoautofluorescence in the cenlralmacua (arrow).C, Opticalcoherence tomographyimage showlng f oveaI thlnning. /Fepr;nred w th petmisstan framKoizuni H,pazzani MC, Spaide BF Funclusautofluarcscence n bidshat choriaretinopathy. Ophlha malagy 20A8: 115lA:e 17. Epub Apr 18.)

Although it has been reported that 2070 of patients may have selfJimiting disease, the course is generally marked by multiple exacerbations and rernissions, with few patients maintaining good vision without treatment. It was recently reported that among patients with diseaseduration longer than 30 months, more than two thirds had visual

CHAPTER 6:

Noninfectious (Autoimmune) Ocular Inflammatory Disease. 155

acuity worse than 20/50 and one-third worse than 20/200. The overall 5-year cumulative incidence of visual acuity of 20/ 200 or worse was 20%. Treatment consists of the initial administration of systemic corticosteroids, with early introduction of corticosteroid-sparing IMT, because birdshot retinochoroidopathy is typically incompletely responsive to corticosteroids alone and extended treatment is anticipated in most patients. Corticosteroid-sparing immunomodulators include low-dose cyclosporine (2-5 mg/kg/day), mycophenolate mofetil, azathioprine, methotrexate, daclizumab, and intravenous polyclonal immunoglobulin. Periocular corticosteroid injections are useful as adjunctive therapy in managing CME and inflammatory recurrences. This approach is effective in reducing intraocular inflammation, inflammatory recurrences, and the risk of developing CME, as well as preserving visual acuity. The intravitreal fluocinolone acetonide implant is an option for patients who cannot tolerate systemic therapy. Gordon LK. Monnet D. Holland GN. Brezin AP. Yu F. Levinson RD. Longitudinal cohort study of patients with birdshot chorioretinopathy. IV. Visual field results at baseline. Am IOphthalmol. 2007;144(6):829- 837. Holder GE. Robson AG. Pavesio C. Graham EM. Electrophysiological characteri sation and monitoring in the management of birdshot chori oreti nopathy. Br I Ophthalmol. 2005;89 (6):709- 7 18.

Kiss 5, Ahmed M, Letko E, Foster CS. Long-term follow-up of patie nts with birdshot retinochoroidopathy treated with corticosteroid -sparing systemi c immunomodulatory therapy. Ophthalmology. 2005;11 2(6):1066- 1071. Koizumi H, POlloni MC, Spaide RF. Fundus autofluorescence in birdshot chorioretinopathy. Ophthalmology. 2008;11 5(5):e I5- e20. Epub Apr 18. Levinson RD, Gonzales CR. Birdshot retinochoroidopathy: immunopathogenesis. evaluation , and treatment . Ophthalmol e lin North Am. 2002 ;15(3) :343-350. Oh KT. Christmas NJ. Folk Jc. Birdshot retinochoroiditis: long term follow-up of a chronically progressive di sease. Am J Ophthalmol. 2002;133(5):622- 629. Thorn e JE, Jabs DA , Peters GB, Hair D. Dunn lP, Kempen lH . Birdshot retin ochoroidopathy: ocular complications and visual impairment. Am I OphtlJafmof. 2005; 140(1 ):45-51.

Acute posterior mu!tifoc81 pl8coid pigment epitheliopathy Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), an uncommon condition presenting in otherwise healthy young adults, typically occurs with an influenza-like illness (50%) and affects men and women equally. A genetic predisposition may be present given the association ofHLA-B7 and HLA-OR2 with the development of this entity. A number of noninfectious systemic conditions have been reported in connection with APMPPE, including erythema nodosum, Wegener granulomatosis, PAN, cerebral vasculitis, scleritis and episcleritis, sarcoidosis. and ulcerative colitis. Infectious

conditions including group A streptococcal and adenovirus type 5 infections, tuberculosis, Lyme disease, and mumps have also been associated with APMPPE, as has hepatitis B vaccination. These diverse disease associations reinforce the concept that APMPPE is an immune-driven vascular alteration.

Patients typically present with a sudden onset of bilateral, asymmetric visual loss associated with central and paracentral scotomata, with the fellow eye becoming involved within days to weeks. Photopsias may precede visual loss. There is minimal anterior segment inflammation , but vitritis of a mild to moderate degree is present in 50% of patients.

1 5 6o I n t r a o c u l a I nr f l a m m a t i oann dU v e i t i s Funduscopicfindingsincludemultiple,large,flat, yellow white placoidlesionsat the level of the RPE,varying in sizefrom I to 2 disc areas,locatedthroughoutthe posteriorpole to the equator(Fig 6-29).New peripherallesionsmay appearin a linear or radial array overthe next 3 weeks.Papillitismay be observed,but CME is uncommon.Atlpical findings include retinal vasculitis,retinal vascularocclusivedisease,retinal neovascularization, and exudativeretinal detachment.The lesionsresolveover a period of 2 to 6 weeks, leavinga permanent,ivell-definedalterationin the RPEconsistingof alternatingareasof depigmentation and pjgmentclumping. The diagnosisof APMPPEis basedon the characteristic clinicalpresentationand FA (blockage)lesions findings during the acutephaseofthe disease:earlyh)?ofluorescence correspondingto but t)?ically more numerousthan thoseseenon funduscopyand late hyperfluorescentstaining (Fig 6-30). Subacutelesionsmay show increasedcentralhyperfluorescence with late staining;with resolution,transmissiondefectsare t)?ically observed.ICG angiographyrevealschoroidalhlpofluorescencewith h)?ervisualizationof the underlyingchoroidalvesselsin both the acuteand inactivestagesofthe disease, with theselesionsbecomingsmallerin the inactivestages(Fig 6-31).Whether the lesionsof APMPPEthemselves aredueprimarily to involvementofthe RPEor representchoroidal/ choriocapillaryperfusion abnormalitieswith secondaryinvolvementof the RPE and

Figure6-29 Acute posteriormultifoca plac(APMPPE). oid pigmentepitheliopathy Mu tlfocal,placoidlesionsin the macula.rcadesyof Albei I Vitale, MD )

Figure6-30 Fluorescein anglogramin a pat ent wlth APMPPE.A, Earlyb ockageof choroidal circuation.B, Late-phase stainlng.(Caunesy of Atben T vttate, MD.)

C H A P T6Ei R N o n i n f e c t i o ulsA u t o i m m u n e )O c u l a rl n f l a m m a t o r vD i s e a s e. 1 5 7

Figure6-31 lndocyaninegreen angiogram t t h A P M P P Es h o w l n gm u l tp l e in a patienw m dphase hypofluorescent spots. /Courlesy of Albett T. Vnale,MD.)

photoreceptors remains controversial; however, taken together, the FA, ICG, and FAF imaging findings suggestthe latter. Choroidal perfusion abnormalities seen early on FA and ICG angiography are more numerous than the overlying placoid lesions; abnormalities noted on FAF imaging lag the appearanceof these lesions, are fewer in number, and lack the perfusion changesseen during angiography; and RPE alterations seen during recovery appearwell after the choroid is affected.All ofthese implicate a primary choroidal process. In addition to choroidalmetastasis, viral retinitis,toxoplasmicretinochoroiditis,and pneumocystischoroiditis,an important differentialdiagnosticconsiderationis serpiginous choroiditis.APMPPE is an acute,usuallynonrecurringdisease,whereasserpiginous choroiditis is insidious and relentlesslyprogressive. An uncommon variant termed relentlessplacoid chorioretinitis that has features of both serpiginouschoroiditis and APMPPE has been reported.Men or women between the second and sixth decade of life present with floaters, photopsia, paracentral scotomata, and decreasedvision with a variabledegreeof both anterior segmentinflammation and vitritis. The acuteretinal lesionsare similar to those of APMPPE or serpiginous choroiditis both clinically and angiographically,but the clinical course is aq?ical for both entities. Patients have numerous posterior and peripheral lesions predating or occurring simultaneously with macular involvement. Acute lesions heal over a period ofweeks with resultant chorioretinal atrophy. OIder pigmented areas are observed together with new active white placoid lesions that are not necessarilyextensionsofprevious areasofactivity. Prolongedperiods of diseaseactivity with the appearanceof numerous (>50) multifocal Iesions scatteredthroughout the fundus are seen. Relapsesare common, with the appearance of new lesions and the growth of subacute lesions for up to 2 years after the initial presentation. FA demonstrates early hypofluorescence and late staining of these lesions. Although rnacular involvement can result in vision loss, metamorphopsia, or scotomata, visual acuity is preservedin most patientsupon healingof the lesions(Fig 6-32). Although visual acuity returns to 20/40 or better within 6 months in the majority of patients with APMPPE, 2070are left with residual visual dysfunction. Risk factors for visual loss include foveal involvement at presentation, older age at presentation, unilateral disease,a longer interval between initial and fellow eye involvement, and recurrence. There are no convincing data to suggestthat treatment with systemic corticosteroids is beneficial in altering the visual outcome, altl.rough some authorities advocate their use in patients presenting with extensive macular involvement, in an effort to limit subsequent RPE derangement of the foveal center, and in individuals with an associated

158 . Intraocularlnflammation and Uveitis

Figurs6-32 RelentlessplacoidchorioretinF tis. Retinalpigmenteplthelialhyperpigmentation andalrophvir the cenrralnacula in areas of previousinf ammation,with new, yellowwhite foci of activediseasetemporaland in{erior to the optic nerve (arrows).rcauftesy af Albeft f. Vitale.MD.)

CNS vasculitis.Similarly,the preciserole of systemicsteroids,antiviral agents,and IMT for the treatmentofrelentlessplacoidchorioretinitisis incompletelyunderstood.Systemic steroidsarecommonlyemployed,but the diseasemay recurdespitetheir use. Fiore T, Iaccheri B, Androudi S, et al. Acute posterior multifocal placoid pigment epitheliopathy. Outcome and visual prognosis.Retira. 2009;29(7)994 100I. JonesBE, Jampol LM, Yannuzzi LA, et al. Relentlessplacoid chorioretinitisi a new entity or an unusual variant ofserpiginous chorioretiniris?Arch Ophthalmol.2000;l l8(7):931-938. Pagliarini S, Piguet B, Ffpche Tf, Bird AC. Fovealinvolvement and lack ofvisual recoveryin APMPPE associatedwith uncommon features.Eye.1995i9(ptl)t42-47. SpaideRF Autofluorescenceimaging of acute posterior multifocal placoid pigment epitheli, opathy. Retina. 2006;26(4):479 -482. StangaPE, Lim JI, Hamilton P Indocyanine greenangiographyin chorioretinal diseases:indi, cationsand interpretation: an evidence-basedupdate.Ophthalmology.2003;ll0(I\15-21. Wolf MD, Folk lC, PanknenCA, coeken NE. HLA-B7 and HLA-DR2 antigensand acutepostelior multifocal placoid pigment epitheliopathy.Arch OphthalmoL1990;108(5):698-700.

Sery igi nous chotoi d itis Serpiginouschoroiditis,also known as geographicor helicoidchoroidopathy, is an uncommon,chronic,progressiveinflammatorycondition affectingadult men and women equallyin the secondto seventhdecadesoflife. Its etiologyis unknown,but it is thought to representan immune-mediatedocclusivevasculitis,as suggestedby the finding of lymphocltesin the choroidalinfiltratesof patientswith this diseaseaswell asby the increasedfrequencyof HLA-87 and retinal S-antigenassociations. An infectiousetiology is suggested by the demonstrationof elevatedantibacterialantibodies,suchasantistreptolysinO antibodies,and the associationofviral meningitisin patientswith this disease. A possibleassociationwith herpesviruses has alsobeenpostulatedbut not conclusively demonstrated. Serpiginouschoroiditishasbeenreportedto occur in patientswith Crohn disease, sarcoidosis, and PAN, but no consistentsystemicdiseaseassociations havebeen identified.Although serpiginouschoroiditis may occur more frequentlyin individuals with positivePPD skin test resultsand tuberculouschoroiditismay be indistinguishable from serpiginouschoroiditis,treatmentwith antituberculousagentsdoesnot ameliorate the courseof the latter.

CHAPTER 6: Noninfectious(Autoimmune)Ocular InflammatoryDisease. 159 Patientspresent with painless,unilateral, paracentral scotomata and decreasedvision with minimal vitreous involvement and a quiet anterior chamber. Classically,funduscopy reveals asymmetric bilateral diseasewith characteristic gray white lesions at the level of the RPE projecting in a pseudopodial or geographic manner from the optic nerve in the posterior fundus (Fig 6 33). Far less commonly, macular or peripheral lesions may present without peripapillary involvement. Diseaseactivity is typically confined to the leading edge of the advancing lesion and may be associatedwith shallow subretinal fluid. Occa sionally, vascular sheathing has been reported along with RPE detachment and neovascularization of the disc. Late findings include atrophy of the choriocapillaris, RPE, and retina, with extensive RPE h)?erpigmentation and subretinal fibrosis, and CNV occurring at the border ofthe old scar in up to 2570ofpatients. The disease course is marked by progressive centrifugal extension, with marked asymmetry between the 2 eyes.New leslons and recurrent attacks are typical, with up to 38o/oof patients reaching a final visual acuity of between 201200and counting fingers in the affected eye. FA shows blockage of the choroidal flush in the early phase of the study and staining ofthe active edge ofthe lesion in the later stageofthe angiogram (Fig 6-3a). In contrast, early h)'perfluorescencewith late leakageis indicative ofthe presenceof CNV

Figure6-33 Serpiginouschorolditis.lco{r/resy o f A l b e f tM t a l e , M D . )

Figure6-34 Fluorescein anglogramin a patientwith serpiginous choroiditis.A, Earlyblocked f uorescence(arrow).B, Latestainng and eakageat the act ve marginof the leston(arrcw). (Cauftesyof Albert T. VtIale,MD.)

160 . Intraocular Inflammation and Uveitis ICG angiographyrevealshypofluorescence throughoutall phasesof the study for both acuteand old lesions;it may revealmore extensiveinvolvementthan FA or clinical examinationand may be usefulin distinguishingactivenew serpiginouslesions,which are hl2ofluorescent,from CNV which may appearas localizedareasof hyperfluorescence during the middle to latephasesofthe study.FAFimagingmaybe an exquisitelysensitive modalityin detectingdamageto the RPEand in rnonitoringthe clinicalcourseofpatients with serpiginouschoroiditis, with characteristichlpoautofluorescence corresponding closelyto areasof regressed diseaseactivity and hlperfluorescence highlightingareasof activedisease(Fig 6-35). Giventhe small numberofpatientswith serpiginouschoroiditis,thereis no consensusregardingthe optimaltreatmentregimenor its efficacy.Systemic, periocular,andeven intravitreal corticosteroidsmay be used in the treatmentof activelesions,particularly

Figure6-35 A, Fundusphotographshowinginactivesefpiginouschoroiditis with peripapilary chorioretinal atrophyextendingintothe macua beneathfovea.B, Corresponding fundusauto fluorescence(FAF)imageshowlng hypoautofluorescence corresponding to the chorioretinal atrophy.C, Fundusphotographshowing discoloration of relinalpigment epitheliumdurlng exacerbation of diseaseactivity(arrow).D, Ca(espondinghyperautofuorescentsignalon FAF larrowl- (Bepinted with permission frcm YehS, Forooghian E Wang W et at. Fundus autoflrorescence imaEng of the white dat syndrames.Atcn Aph]tr,a-rlol.2A10;128(1):51.)

CHAPTER 6:

Noninfectious (Autoimmune) Ocular Inflammatory Disease. 161

those threatening the fovea. The addition of systemic IMT at the outset has been suggested as corticosteroids alone are ineffective and patients require prolonged anti-inflammatory therapy. Cyclosporine monotherapy has been effectively used in small numbers of patients, as has triple therapy with prednisone, cyclosporine, and azathioprine. Although this approach may induce rapid remission of acute disease, prolonged therapy is required and disease recurrence is frequently observed as these agents are tapered. Cytotoxic therapy with cyclophosphamide or chlorambucil has been shown to induce long drug-free remissions. The intravitreal fluocinolone acetonide implant may be used in patients intolerant of systemic therapy. Intravitreal anti-VEGF agents, focal laser photocoagulation, and photodynamic therapy are important therapeutic modalities for the treatment of associated CNV. Akpek EK, Jabs DA, Tessler HH , Joondeph BC, Foster CS. Successful treatment of serpiginous choroiditis with alkylati ng agents. Ophthalmology. 2002;109(8): 1506- 15 13. Christmas NJ, Oh KT. Oh OM, Folk Je. Long·term follow· up of patients with serpiginous choroiditis. Retina. 2002;22(5):550-556. Gupta V. Gupta A. Arora S, Bambery P, Dogra AR. Agarwal A. Presumed tubercular serpiginous like choroiditis: clinical presentati ons and management. Ophthalmology. 2003; 110(9): 1744-1 749. Hooper PL, Kaplan HJ. Triple agent immunosuppression in serpiginous choroiditis. Ophthal~ mology. 199 1;98(6):944-951. Lim WK, Buggage RR, Nussenblatt RB. Serpiginous choroiditis. Surll Ophtlzalmol. 2005;50(3): 23 1- 244. Piccolino F, Grosso A, Savini E. Fundus autofluorescence in serpiginous choroiditis. Graefes Arch Ciin Exp Ophthalmol. 2009;247(2): 179-1 85. Priya K. Madhavan HN, Reiser BJ. et al. Association of herpesviruses in the aqueous humor of patients with serpiginous choroiditis: a polymerase chain reaction-based study. Ocullm· munollnjlamm . 2002;10(4) :253- 26 1.

Multifocal choroiditis and panuvBitis Multifocal choroiditis and panuveitis (MCP), PIC, and the subretinal fibrosis and uveitis syndrome represent a subset of the white dot syndromes; some authorities regard them as discrete entities while others view them as a single disease with a variable severity continuum. MCP, although classified as a pan uveitis, is presented here among the white dot syndromes, given its characteristic funduscopic appearance and the predominance of posterior pole involvement.

MCP is an idiopathic inflammatory disorder of unknown etiology affecting the choroid, retina, and vitreous that presents asymmetrically, most often in young myopic women with photopsias, enlargement of the physiologic blind spot, and decreased vision. In contrast to patients with OHS, those with MCP and CNV are less likely to have the HLA-DR2, HLA-B7, or HLA-DRI haplotypes. The ophthalmoscopic hallmarks include the presence of punched-out white-yellow dots (50-200 ~m) in a peripapillary, midperipheral, and anterior equatorial distribution (Fig 6-36). Varying degrees of anterior segment inflammation and an associated vitritis are uniformly present, effectively excluding a diagnOSis of OHS or PIC. The lesions are smaller than those seen in birdshot retinochoroidopathyor APMPPE and evol ve into atrophiC scars with varying degrees of hyperpigmentation. They are larger and more pigmented than those seen in patients with PIC.

1 6 2 o I n l l s e s r ; r r ; n f l a m m a t i o na n d U v e i t i s

Figure6-36 Multifocal choroidit s and panuve tls \MCP). Eourtesv of aamana s Moafthy, MD)

New lesionsmay appear,and peripheralchorioretinalstreaksand peripapillarypigment changessimilar to thoseseenin OHS havebeenobserved.Subretinalfibrosiswith RPE clumping is much more common in MCP than OHS. Structuralconplicationsnoted at presentation, includingcataract(32%),CME (14%),ERM (570),andCNV (282o), aswell asthosethat developoverthe chroniccourseofthis disease, arefrequentcausesofvisual impairment. FA showsearly hlpofluorescencewith late stainingof acuteactivelesions,whereas atrophiclesionsbehaveastransmissiondefects(earlyhlperfluorescence that fadesin the latephasesofthe angiogram).Earlyhlperfluorescence andlateleakageareobservedin the presenceof macularedemaand CNV (Fig 6 37). As with birdshot retinochoroidopathy,

Figure6-37 Multlfocalchoroiditisand panuveitis:fluoresceinangiogram.A, Eary blocked fluotescence (arrows).B, Lale stalningof lesions (arrows). (Caurtesy af Bamana S.Maarthy, MD)

e )c u l a Irn f l a m m a t o D . 163 C H A P T6E : NRo n i n f e c t i o (uAsu t o i m m u n O r yi s e a s e ICG angiographyshowsmultiple midphasehypofluorescent Iesionscompatiblewith active choroiditisthat are more numerousthan thoseseenon clinical examinationor FA, frequentlyclusteredaroundthe optic nerve.This finding may correlatewith the enlarged blind spot revealedby visualfield testing.The hypofluorescent spotsmay fadewith treatment and resolutionof the intraocularinflammation.The most common finding on FAF imagingis punctateh)?oautofluorescent spots(> 125pm) correspondingto multipleareas of chorioretinalatrophy;however,smaller(