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SUPPLEMENT TO APRIL 2012

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 The Clinical Utility of Fundus Autofluorescence Imaging By Jeffry D. Gerson, O.D., F.A.A.O.

 The Role of the Vitreous in Retinal Disease By Carolyn E. Majcher, O.D., Andrew S. Gurwood, O.D., F.A.A.O., Dipl., and Julie K. Hutchinson, O.D.

 Earn 1 CE Credit: A Case of Late-Onset Leber’s Hereditary By Carol Aune, B.S., O.D., and James Walters Ph.D., O.D.

 A Case of Suspected Retinal Melanocytoma

By W. Lee Ball, O.D., F.A.A.O.

001_ro0412 RetinaGuide.indd 1 4/12/12 9:41 AM FUNDUS AUTOFLUORESCENCE

The Clinical Utility of Fundus Autofluorescence Imaging By Jeffry D. Gerson, O.D., F.A.A.O.

THE HISTORIC STANDARD for the doc- umentation of posterior segment findings has been fundus photog- raphy. Generally, the need for fun- dus photography is substantiated by the detection of a clinical find- ing that warrants documentation for future reference. However, we are now learning that there is more to be seen than what conventional can capture. Although there have been refer- ences to fundus autofluorescence (FAF) in the medical literature for more than 35 years, this approach is only now becoming a more mainstream imaging technique.1 Not only can FAF be an ideal tool for documentation, but also it will Normal fundus autofluorescence (FAF) image of a patient’s posterior pole. often serve as a diagnostic modal- ity because the device can elucidate hypo-FAF secondary to xantho- dystrophies and Stargardt’s many conditions that are not vis- phyll pigment absorbing the signal. disease, to age-related macular ible through traditional means of Areas of hyper-autofluorescence degeneration and other condi- examination or other technologies. or hypo-autofluorescence may be tions that involve impaired RPE Additionally, FAF can be used to indicative of an abnormality in cell function. Lipofuscin builds detect structural abnormalities and RPE activity that is either active up through incomplete degrada- predict functional deficits.2,3 These or has already occurred. These tion of photoreceptor outer seg- abilities go beyond what optical changes in fluorescence are visu- ments and incomplete release of coherence tomography (OCT), ally reminiscent of those found in degraded material.6 (FA), elec- FA (although they are caused by FAF, however, is not an “all- trophysiology and other imaging different fundamentals). More spe- telling” diagnostic modality. In technologies can provide. cifically, while FA reveals vascular some cases of blinding pathol- leakage, FAF actually shows meta- ogy, the FAF appearance may How does FAF Work? bolic activity. be perfectly normal—even if the FAF provides an objective, non- From a technical standpoint, RPE-photoreceptor complex is invasive measurement of the reti- FAF permits topographic mapping unaffected. nal pigment epithelium’s (RPE’s) of lipofuscin distribution in the metabolic activity. A measurement RPE as well as other fluorophores Clinical Applications of FAF of FAF is decreased by a loss of that occur in the outer and There are several areas of prac- photoreceptor cell integrity and is the sub-neurosensory space.4 This tical interest where FAF has the increased by abnormal RPE behav- is important, because accumulation potential to change how we diag- ior and/or function. of lipofuscin is a significant marker nose and/or treat patients: Autofluorescence of the retina for aging of metabolically active • Early macular disease detec- and macula typically will appear cells, particularly those comprising tion. Understanding the extent of a uniform gray color, with darker the RPE.5 RPE defects of the posterior pole vasculature due to blood absorp- Excess lipofuscin has been as well as other macular diseases tion and a darker head indicted in a variety of retinal may be accomplished via periph- due to a lack of RPE. In the fovea, disorders—from inherited dis- eral FAF imaging, as evidenced there is reduced FAF, or mild eases, such as macular pattern in multiple clinical trials.7 In fact,

APRIL 2012 REVIEW OF OPTOMETRY 3

001_ro0412 RetinaGuide.indd 3 4/12/12 9:41 AM FUNDUS AUTOFLUORESCENCE

This patient presented with Stargardt’s macular dystrophy (FAF left, color fundus right). The FAF image illustrates the extent of macular disease more clearly.

peripheral changes may pre-date an early diagnosis, but rather the it may help educate a patient on macular changes in AMD, central detection of an already advanced the chronic and diffuse nature of serous chorioretinopathy (CSCR) disease state.9 this condition. and many other diseases thought We also know that macular tox- • AMD and GA. The extent and to be specific to the macula. Using icity is more common than once progression of AMD can be closely peripheral FAF as a screening believed, partially due to previous monitored with FAF. Further, FAF tool for such macular conditions techniques not being accurate may potentially indicate which may help to predict their future enough to detect mild pathologic patients are at an increased risk onset and permit early initiation of changes. The updated guidelines for the development of geographic disease-modifying treatments. For call for objective testing, which is to atrophy (GA).12 FAF also may help instance, if peripheral changes are include FAF, spectral domain OCT evaluate the potential effectiveness indicative of early macular degen- and/or multi-focal electroretino- of various treatment modalities— eration, then lifestyle modification gram testing.8 This updated screen- especially if the patient has GA. can be instituted to prevent visu- ing protocol is particularly signifi- Currently, several pharmaceuti- ally significant changes associated cant because of the sheer number of cal companies are using FAF to with AMD. patients who use Plaquenil. evaluate the treatment efficacy of • Plaquenil . In • CSCR. When we see patients several developmental drugs for 2011, the screening guidelines for with CSCR, we often wonder if GA (oral, injectable and topical Plaquenil (hydroxychloroquine, it is a first occurrence or a recur- medications). This is an important Sanofi-Aventis) toxicity were rence, how much global RPE dam- consideration, because several updated in an article published age there is, and what their visual studies have shown that changes in Ophthalmology.8 Screening for outcome will be. FAF can help us documented on FAF imaging often Plaquenil retinopathy is more answer these questions, and even precede GA or its expansion.13,14 accurately performed through FAF address the concern of whether Areas of new GA expansion initial- than conventional funduscopic the patient has CSCR.10 If the ly may appear bright on FAF imag- observation.9 Historically, clinical individual has CSCR, FAF may be ing, and then subsequently exhibit observation and visual fields were used to help guide our follow-up a dark or “dead” appearance on thought to be adequate for timely schedule and/or referral for treat- various areas of the RPE. diagnosis of macular toxicity sec- ment. Studies have shown that FAF Although we believe AMD to be ondary to Plaquenil use. However, appearance can be a predictor of a macular disease that only occurs we now know that these screen- visual outcome and function in in the posterior pole, results from ing techniques will not facilitate patients with CSCR.11 Additionally, the Reykjavik Study show that

4 REVIEW OF OPTOMETRY APRIL 2012

001_ro0412 RetinaGuide.indd 4 4/12/12 9:41 AM peripheral and posterior pole pathologies regularly coexist and are often signs of each other.15 Additionally, there are advantages to having FAF documentation for patients with neovascular AMD, because the technology may help predict visual outcome—especially in patients who have developed choroidal with- in six months or less of diagnosis.16 We diagnosed this patient with pigmentosa (O.D. left, O.S. right). A Glance at Current FAF Devices Fortunately, it is now possible widefield imaging platform in a on a referral basis for colleagues. He is (and practical) to include this tabletop design that offer unprec- a fellow of both the American Academy technology in your practice. The edented views of peripheral chang- of Optometry and the Optometric two primary companies that read- es.17 Additionally, this device exhib- Retina Society. ily offer devices with FAF imag- its strong sensitivity in the detec- 1. Miller SA. Fluorescence in Best’s Viteliform dystrophy, lipofuscin ing capabilities are Heidelberg tion of macular-specific diseases, and fundus flaimaculatus. Br J Ophthalmol. 1978 Apr;62(4):256- Engineering and Optos. providing results that are in close 60. 2. Querques L, Querques G, Forte R, Souied EH. Microperimetric • Spectralis (Heidelberg agreement to those obtained via Correlations of Autofluorescence and Optical Coherence 17 Tomography Imaging in Dry Age-Related . Engineering) offers BluePeak blue traditional fundus photography. Am J Ophthalmol. 2012 Feb 7. [Epub ahead of print] laser autofluorescence technology 3. Seidensticker F, Neubauer AS, Wasfy T, et al. Wide-field fundus autofluorescence corresponds to visual fields in that is being used in several clinical Whether your practice currently patients. Clin Ophthalmol. 2011;5:1667-71. trials. In particular, the company has access to FAF imaging, this tech- 4. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina. 2008 is using BluePeak to evaluate the nology soon will become even more Mar;28(3):385-409. 5. Terman A, Brunk UT. Oxidative stress, accumulation of bio- potential efficacy of drugs that pre- essential to the proper care and logical garbage, and aging. Antioxid Redox Signal. 2006 Jan- vent the onset or enlargement of will be able to provide our patients Feb;8(1-2):197-204 6. Wing GL, Blanchard GC, Weiter JJ. The topography and age rela- GA in patients with AMD. with the most accurate information tionship of lipofuscin concentration in the RPE. Invest Ophthalmol Vis Sci. 1978 Jul;17(7):601-7. • Daytona (Optos) was first about their conditions as well as rec- 7. Lois N. Fundus Autofluorescence in Stargardt macular dystrophy- unveiled at the 2011 American ommend the best treatment options fundus flavimaculatus. Am J Ophthalmol. 2004 Jul;138(1):55-63. ■ 8. Marmor MF, Kellner U, Lai TY, et al. Revised recommendations Academy of Optometry meeting in available. on screening for chloroquine andhydroxychloroquine retinopathy. Boston. This device incorporates Dr. Gerson is in private practice in Ophthalmology. 2011 Feb;118(2):415-22. 9. Marmor M. Comparison of screening procedures in hydroxy- FAF technology into its existing Shawnee, Kans. He also sees patients chloroquine toxicity. Arch Ophthalmol. 2011 Dec 22. [Epub ahead of print] 10. Lindner E, Weinberger A, Kirschkamp T, et al. Near-infrared autofluorescence and indocyanine green angiography in central serous chorioretinopathy. Ophthalmologica. 2012;227(1):34-8. 11. Imamura Y, Fujiwara T, Spaide RF. Fundus autofluores- cence and visual acuity in central serous chorioretinopathy. Ophthalmology. 2011 Apr;118(4):700-5. 12. Csutak A, Lengyel I, Jonasson F, et al. Agreement between image grading of conventional (45°) and ultra wide-angle (200°) digital images in the macula in the Reykjavik eye study. Eye (Lond). 2010 Oct;24(10):1568-75. 13. Holz FG, Bellman C, Staudt S, et al. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001 Apr;42(5):1051-6. 14. Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, et al. Correlation between the area of increased autofluorescences- urrounding geographic atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2648-54. 15. Lengyel I. AMD-like pathologies at the peripheral fundus: Reykjavik Eye Study: An ultra-wide angle (200°) and auto- fluorescence digital image grading study. Abstract presented at Association for Research in Vision and Ophthalmology 2009. 16. Dandeker SS, Jenkins SA, Peto T, et al. Autofluorescence imaging of choroidal neovascularizationdue to age-related macular degeneration. Arch Ophthalmol. 2005 Nov;123(11):1507-13. 17. Csutak A. Agreement between image grading of conventional (45°) and ultra wide-angle (200°) digital images in the macula in We confirmed the presence of chronic central serous chorioretinopathy with FAF imaging. the Reykjavik Eye Study. Eye (Lond). 2010 Oct;24(10):1568-75.

APRIL 2012 REVIEW OF OPTOMETRY 5

001_ro0412 RetinaGuide.indd 5 4/12/12 9:41 AM HYDROXYCHLOROQUINETHE VITREOUS HUMOR TOXICITY

The Role of the Vitreous in Retinal Disease By Carolyn E. Majcher, O.D., Andrew S. Gurwood, O.D., F.A.A.O., Dipl., and Julie K. Hutchinson, O.D.

THE VITREOUS is an extracellular (cortical vitreous).2 development.5 The primary vitre- matrix that forms a transpar- The cortical vitreous is a thin ous is the innermost segment that ent hydrophilic gel. It is princi- layer (100μm to 300μm) that lies is derived from surface ectoderm. pally composed of water (98% to adjacent to the , It provides support for the devel- 99.7%).1,2 The vitreous functions and zonules anteriorly, and adja- oping eye and serves as the pri- as a pathway for nutrients to cent to the retina posteriorly.1,2 mordial vascular supply. It reaches reach the lens and retina; provides The cortical vitreous encircles the its most vascular stage near the structural support that stabilizes nuclear vitreous. ninth week of gestation. Shortly the volume of the ; and may The posterior vitreous cortex afterwards, these vessels begin to regulate eye growth and shape consists of densely packed type II atrophy and are replaced by the during development.1-3 collagen fibrils and contains the clear, avascular, secondary adult In order to maintain transpar- highest vitreal concentration of vitreous that originates from neu- ency, it functions as a barrier to hyaluronic acid (HA).6 It is absent roectoderm and mesoderm. Lastly, cellular invasion and diffusion of over the optic nerve head and the tertiary vitreous forms the lens macromolecules from surrounding thins over the macular region.2 zonules. It is mainly derived from intraocular tissues.2 In the gel state, Here, the collagen fibrils run paral- neuroectoderm.5 the vitreous lowers oxygen tension lel to the retina and do not insert Attachments of the vitreous to in the retina and the lens.2,4 This directly into the internal limiting the retina occur in areas where the becomes evident when for- membrane (ILM).2 ILM is the thinnest. Attachment mation is hastened following pars The condensation of peripheral locations include: the vitreous base; plana (PPV). When the cortical collagen fibrils forms a false the margins of the (when vitreous is removed, a sharp spike anatomic membrane. Anteriorly, it this area detaches, it produces in lens oxygenation fuels lenticular is termed the anterior hyaloid mem- the classic circular Weiss or Vogt opacification.2,4 brane (AHM). The AHM runs adja- rings); the back of the crystalline Here, we’ll examine the vitreous cent to the lens zonules adjacent lens in contact with the hyaloideo- humor’s role in the development to the posterior surface of the lens capsular ligament of Wieger; the and severity of several sight-threat- and anterior to the ora serrata. The 500μm-diameter foveola; along ening retinal conditions, includ- false anatomic membrane located large retinal vessels; and at sites of ing posterior vitreous detach- posterior to the ora serrata is abnormal vitreoretinal adhesion, ment (PVD), age-related macular termed the posterior hyaloid mem- such as lattice margins.1,5,7 denegation (AMD), retinal vein brane (PHM). It runs adjacent to The strongest attachment occurs occlusion, diabetic the retina.1,5 The AHM is in direct at the vitreous base, which is (DME) and vitreomacular traction contact with the aqueous humor located 3mm to 4mm across the ora (VMT) syndrome. and thus behaves like a membrane, serrata and pars plana.1 Here, there separating these two ocular com- is a high concentration of collagen Vitreal Anatomy partments.2,5 fibrils oriented perpendicular to the The vitreous comprises about Cloquet’s canal (or the hyaloid base that insert into the pars plana 80% of the total globe volume. It canal) is a remnant of the embry- and the anterior retina through can be divided into two parts: the onic hyaloid system. It runs from defects in the ILM.2 central nucleus and the posterior the posterior pole of the lens to the A false ligament, the hyaloideo- cortex.1,5 The central nucleus is a optic nerve head.1,5 This canal wid- capsular ligament of Wieger, is a true biological gel with a lower col- ens anteriorly to form the patellar circular attachment between the lagen fibril density than the cortex.1 fossa and posteriorly to form the margin of the patellar fossa and the Collagen fibrils in this region gener- Area of Martegiani over the optic posterior surface of the lens.1 It was ally run in an anterior-to-posterior disc.5 The space formed between previously believed that the poste- direction. Anteriorly, the fibrils the lens and the patellar fossa is rior vitreous collagen fibrils directly blend with those of the basal vitre- known as Berger’s space.5 inserted into the ILM; but, recent ous; posteriorly, they insert into the The vitreous is segregated into findings suggest that an extracel- surrounding vitreous cortex shell three distinct stages during lular matrix composed of laminin,

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001_ro0412 RetinaGuide.indd 6 4/12/12 9:41 AM fibronectin and sulfated proteo- compressive forces.2 glycans that interface and act as a The cortical vitre- “molecular glue.”6,8 The posterior ous contains a small vitreous adherence is more diffuse in amount of organelles- nature than focal attachments at the containing hyalocytes disc, fovea and retinal blood vessels.8 that are thought to synthesize and secrete Vitreal Composition HA.5 While minimal In addition to water, the vitreous microfibrils of fibril- contains inorganic salts, ascorbic lin have been isolated acid and two major macromolecules: from the vitreous, they collagen and glycosaminoglycans represent the major (GAGs).5,8 Essentially, the vitreous structural component Pertinent anatomy of the human vitreous. gel is formed by a dilute meshwork of the lens zonules.2 of collagen fibrils, which provides a • Syneresis is described as a col- scaffold-like structure that is “inflat- Essentials of Vitreous Degeneration lapse of the vitreous, with an aggre- ed” by HA.8 The vitreous contains Postmortem studies of the vitre- gation of collagen fibrils into macro- a low concentration of collagen ous structure confirm two primary scopic bundles of parallel fibrils.1,8,11 (300mg/ml) that is stable through- degeneration states: liquefaction When both synchysis and syneresis out life.2 Most of the collagen is pres- (synchysis) and aggregation of colla- are present, clinical observation ent in the form of thin and uniform gen fibrils (syneresis).8 shows collagen aggregates moving fibrils that contain mixed amounts of • Synchysis refers to liquefac- freely in the vitreous upon ocular collagen types (II, hybrid V/XI, VI, tion of the vitreous, and is typically movement.1 The shadows cast on the type IX).2,7,9,10 a senile process that is accelerated retina create the symptoms of flashes Vitreal type II collagen is a fibril- by , inflammation, trauma, and . forming substance that provides the hereditary vitreoretinal syndromes vitreous with its tensile strength and (such as Stickler and Marfan Posterior Vitreous Detachment supportive structure.2,5 The long, syndromes), retinal vascular dis- Posterior vitreous detachment unbranched vitreous collagen fibrils eases, and vitreous hemor- (PVD) refers to the separation of the have a uniform diameter of 10nm to rhage.1,7,13,14 Synchysis is the most cortical vitreous from the ILM, and 20nm, and are arranged in parallel common degenerative change in the may be located anywhere posterior bundles that form an interconnected vitreous and is present as early as age to the vitreous base.1,16 It may be network.2,11 Chondroitin sulfate four; liquefied vitreous may account localized, partial or complete.2 A chains of type IX collagen on the for approximately 20% of the vitre- complete PVD occurs when the pos- surface of a fibril bridge adjacent col- ous volume by age 14 to 18 years.1,2 terior cortical vitreous is detached lagen fibrils in a ladder-like configu- There is a steady increase in synchy- from the entire retina—including its ration, connecting them and spacing sis after age 40. In fact, more than attachment to the optic nerve up them apart.8,9 This spacing is impor- half of the vitreous body is liquid by to the posterior border of the vitre- tant to prevent light scatter.8 Type V the age of 80.2,8 ous base.2 At age 50, the incidence collagen likely plays a role in linking Senile synchysis may be caused by of PVD in phakic is greater HA with collagen fibrils.2,12 aggregation and redistribution of than 50%, increasing to approxi- GAGs are charged carbohydrates the collagen fibrils. This phenom- mately 75% by age 65.17 There is an that attract counterions and water.2 enon yields pockets of liquefaction increased risk for PVD in aphakic or HA is the chief GAG present in the known as lacunae, which are devoid pseudophakic eyes, myopes and eyes vitreous. HA is found in the great- of collagen fibrils.2,9,15 These lacunae with a history of trauma or intra- est concentration in the posterior initially develop centrally; however, ocular inflammation.17 Additionally, vitreous cortex.2 By filling the spaces they enlarge and coalesce.2 Lacunae women are prone to PVD at a between collagen fibrils, GAGs cre- are evident on slit-lamp biomicros- younger age secondary to reduced ate a swelling pressure to inflate the copy as pockets of optically empty HA synthesis (reduced HA synthesis gel, separate and cross-link the paral- space that lack the normal, fine has been associated with decreased lel fibrils, and provide resistance to fibrillar structure.1 postmenopausal estrogen levels).7,16

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Biomicroscopic examination ing grading system for age-related tomography (OCT).24 Deflection reveals an optically clear space filled PVD:19 of the posterior hyaloid or vitreous with liquefied vitreous between the • Stage 1. Incomplete perifoveal strands often can be observed at detached posterior hyaloid and the PVD in up to three quadrants. that site.24 retina.1 The pathognomic sign of a • Stage 2. Incomplete perifo- Complications of anomalous PVD PVD is the presence of a clinically veal PVD in all quadrants, with result from static, anteriorly directed observable fibrous annulus of tis- residual attachment to the fovea tension induced by vitreous degen- sue that overlies the optic disc.17 A and optic disc. eration as well as dynamic traction patient with an acute PVD may com- • Stage 3. Incomplete PVD over associated with ocular movements.7 plain of newly visible floating spots the posterior pole, with residual Ocular movements localize traction that follow eye movement and con- attachment to the optic disc. to areas of firm vitreoretinal adhe- tinue to travel even after termination • Stage 4. Complete PVD. sion.7 Most early-stage anomalous of ocular movement.17 Photopsia is This research showed that even PVD complications occur insidiously, another common symptom, which young, healthy eyes have incomplete and are located in the posterior pole. is perceived as peripheral arcs or or partial PVD beginning as early Late-stage complications of complete flashes of light, that is produced by as the fourth decade of life, which anomalous PVD typically cause acute mechanical retinal stimulation as the may progress slowly for years before symptoms and usually occur in the vitreous articulates with the area that becoming a complete PVD.7,19 periphery. Late-stage complications the retina remains attached.17 of anomalous PVD include: retinal The process of PVD begins with Anomalous Posterior Vitreous or optic disc hemorrhage, vitre- synchysis of the vitreous and weaken- Detachment ous hemorrhage, retinal break or ing of posterior vitreoretinal adhe- An anomalous PVD results when tear, and rhegmatogenous retinal sion.8 Enlargement of formed lacu- synchysis occurs without sufficient detachment.7 nae cause the posterior vitreal corti- detachment from the ILM. This cal wall that overlies the involved results in tractional effects at the The Role of the Vitreous area to become thinned.7,18 In gen- interface.8 Individuals with genetic in Retinal Disease eral, as the vitreoretinal adhesion dis- collagen diseases, such as Marfan’s, Tractional stress (force per unit solves, it forms discontinuities within Ehlers-Danlos and Stickler’s syn- area) seems to be inversely propor- the posterior hyaloid (either via dromes, have a higher incidence of tional to the size of vitreoretinal fissure evolution or a microbreak in anomalous PVD. These maladies also adhesion zones (as the size of the the thin cortical vitreous layer).7,8,16 increase the risk of retinal complica- vitreoretinal adhesion zone decreas- This allows synchytic vitreous to tions at an early age.8,13,20 Anomalous es, the tractional forces increase).7 enter the subhyaloid space, which PVD may result in vitreoschisis, a Smaller diameters of vitreous attach- dissects the posterior hyaloid from splitting of the posterior vitreous ment seem to play a more significant the ILM of the retina.8 cortex and forward displacement role in macular dehiscence/hole for- PVDs typically begin in a single of the vitreous body, which leaves mation and localized cystoid foveal quadrant of the perifovea (most remnants of the outer layer firmly thickening.7 Larger diameters of often superior). Persistent attach- attached to the retina.21,22 vitreous attachment typically result ments to the ILM remain at the Vitreoschisis is thought to play a in diffuse macular thickening, trac- fovea and optic nerve head.19 Over role in the pathogenesis of macular tional macular detachment or exac- time, the perifoveal detachment pucker, macular holes and prolifera- erbation of already existing macular enlarges to completely surround the tive diabetic vitreoretinopathy.21-23 pathology.7 persistent attachment at the fovea.19 A common consequence of anom- One study classified vitreoretinal Finally, detachment of the vitreous alous PVD is the development of complications of early-stage anoma- from the remaining foveal region vitreoretinal traction. Vitreoretinal lous PVD according to the size and produces a funnel-shaped configura- traction, as opposed to vitreoretinal location of the vitreomacular adhe- tion with attachments at the optic adherence without traction, is char- sion zone:7 disc and vitreous base. When the acterized as a vitreous attachment • Complications associated with PVD releases from the optic nerve, to the retina with associated tissue adhesion sizes of less than or equal the process is complete.17,19 elevation, thickening and deformity to 500μm (approximately 1/3 disc One study outlined the follow- that is visible on optical coherence diameter) included macular

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001_ro0412 RetinaGuide.indd 8 4/12/12 9:41 AM microhole (50μm to 150μm), idio- may confine pro-angiogenic cyto- of complete PVD in eyes with non- pathic macular hole, inner lamellar kines, such as vascular endothelial exudative AMD or no AMD ranged macular hole and tractional cystoid growth factor (VEGF) and free radi- from 61% to 72%.25 However, the macular edema (CME). cals, within the macula, which fosters rate of complete PVD in eyes with • Adhesion zones of 1,500μm the development of choroidal neo- exudative AMD ranged from just (1 disc diameter) or greater, com- vascularization (CNV).7,28,29 21% to 34%.25,29 These results suggest monly resulted in vitreomacular A third suggestion indicates that that PVD may be protective against traction (VMT) syndrome, traction- VMT may compromise the junc- the development of wet AMD.25,29 al diabetic macular edema (DME), tional proteins that are necessary A similar disparity was seen in myopic traction maculopathy and for the barrier integrity of the RPE, subjects with end-stage AMD, where neovascular age-related macular which promotes CNV genesis.29 A a lower incidence of complete PVD degeneration (AMD). fourth proposal suggests that a thick- was detected in eyes with geographic When peripapillary adhesion ened posterior vitreous cortex and atrophy (70%) compared to eyes occurred, vitreopapillary traction abnormal tissue at the vitreomacular with fibrotic (disciform) scarring syndrome often resulted.7 The interface may prevent oxygen and (40%).29 Furthermore, partial PVD researchers postulated that epiretinal nutrients from diffusing from the cil- (central vitreoretinal adhesion sur- membranes (ERM) were the result of iary body into the macula, disrupting rounded by shallow detachment of Müller, glial and astrocyte prolifera- the choroidal supply of oxygen and the posterior vitreous cortex) has tion through compromised regions nutrients that normally diffuse from been more frequently documented of the ILM, and were associated with the choriocapillaris to the macular in eyes with exudative AMD (30%), various vitreomacular adhesion sites photoreceptors.29,30 than eyes with nonexudative AMD of differing sizes.7 One final theory is that mechani- (12.3%) or no AMD (5.4%).25 cal stress may cause both static and Interestingly, PVD is more com- Age-related Macular Degeneration dynamic forces to induce secretion monly found in eyes with end-stage Many etiologic factors have been of signaling factors by Müller cells, AMD that exhibit disciform scarring proposed for the development of which ignites a cascade of inflamma- than in eyes with active exudative AMD.25,26 These include oxidative tory factors and local vascular chang- AMD.29 This suggests that the devel- stress, ischemia, inflammation, genet- es.28,31 A recent study indicated that opment of PVD either promotes ic factors and aging of the retinal vacuum-induced pulsatile stretching CNV regression or that macular pigment epithelium.25,26 Recent inves- of cultured rat RPE cells triggered disciform scarring may facilitate vit- tigations suggest that mechanical and the production and secretion of reoretinal dehiscence by altering the biochemical influences of the vitre- VEGF when compared to control integrity of the ILM.29 ous also may play an important role cultures that were not subjected to Using OCT imaging, one research in AMD pathogenesis.25,27-31 Whether mechanical stress.31 group described posterior vitreo- VMT is a cause or a result of AMD In general, it is believed that trac- macular adhesion/traction to be remains unclear.27 Local inflamma- tional forces generated by the vitre- approximately three to eight times tion, scarring and disruption of the ous are transmitted to the RPE via a more common in eyes with exuda- photoreceptor-RPE interface induced physical bridge with the sensory ret- tive AMD (36% to 38%) than in eyes by AMD may activate Müller cells ina.31 Then, a stretch-induced VEGF with nonexudative AMD (7% to and possibly astrocytes, causing focal secretion contributes to increased 10%) or no sign of AMD (11%).25,27,29 corresponding vitreous adhesions.28 levels of the growth factor, which Drawing from these results, the These connections induce tractional provokes angiogenesis and break- authors concluded that chronic VMT forces on the retina.28 down of the blood-retinal barrier.31 also may be a risk factor for the Investigators have proposed sev- Several studies seem to confirm development of exudative AMD. eral theories to explain the patho- the aforementioned hypothesis In subsequent studies that exam- genesis of VMT in AMD.28-31 One regarding VEGF secretion.25,29 These ined this evidence, CNV was pres- hypothesis suggests that persistent investigations indicate that eyes with ent in far more eyes with AMD vitreomacular adhesion may induce AMD and complete PVD have a con- and vitreomacular adhesion than chronic, low-grade inflammation.28 siderably lower incidence of CNV eyes without vitreomacular adhe- Another postulation implies that an compared to eyes with no or incom- sion.25,27,29 Likewise, vitreomacular adherent posterior vitreous cortex plete PVD. In one report, the rate adhesion seemed to be more fre-

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quently observed in eyes with disci- research may redefine the role ties.24,39 It likely begins as intracy- form scarring (20%) compared to of PPV as an important option in toplasmic swelling of Müller cells eyes with geographic atrophy (0%).29 the management of CNV that is that is incited by intrinsic metabolic In one report, a lower incidence of poorly responsive to aggressive agents, including VEGF and inter- vitreomacular adhesion was discov- anti-VEGF therapy.28 leukin-6 (IL-6), that are released ered in eyes with disciform scars One study indicated that traction- following any retinal ischemic (20%) compared to eyes with active al forces may reduce the effect of event.36,38 Elevated levels of both exudative AMD (38%), which sup- anti-VEGF treatment, causing phar- metabolic factors have been found ports the theory that the release of macological resistance in a subpopu- in the aqueous humor and vitreous adhesion may promote regression of lation of patients.28 Likewise, another fluid of eyes with central retinal vein active disease.29 Additionally, results study showed a potential benefit of occlusion (CRVO) that exhibit mac- from these studies suggested that combining vitrectomy with subreti- ular edema.36 Theories speculate vitreomacular adhesion was almost nal surgery in eyes with recurrent that the vitreous may act as a reser- always found above the CNV area— CNV following repeated sessions of voir, storing these agents and keep- regardless of its location—further photo-dynamic therapy.35 ing them in constant contact with illustrating the relationship between The surgeons who investigated the neurosensory retina wherever vitreomacular adhesion and exuda- the role of PPV in exudative AMD vitreomacular adhesion is present.38 tive AMD.25,27,28 observed only mild liquefaction of Recent research, however, points A research team at Duke the vitreous gel with remarkably firm to the potential for vascular insult University Medical Center in attachments at the macula.34,35 The to promote accelerated vitreous Durham, N.C., examined the varia- surgeons theorized that reduction liquefaction located proximal to the tions in dynamic mechanical forces of tangential retinal traction would retinal area that is affected by vein both during and after eye motion. allow intraretinal macular edema occlusion before adequate weaken- They documented that, during nor- (ME) to be absorbed.34 Moreover, an ing of the vitreoretinal adhesion mal eye movement, the RPE was increase in partial oxygen pressure ensues.24 This process then causes under continuous shear stress when within the vitreous cavity might have increased vitreous traction in the forces were physically transmitted to contributed to decreased rates of area of the affected major vein, the the underlying RPE by the vitreous. CNV.33,34 adjoining vasculature or the optic This traction, especially at the edges nerve margin.24 These forces are also of RPE junctions, resulted in detect- Retinal Vein Occlusion transmitted to macular Müller cells, able RPE tears upon clinical exami- ME is one of the most frequent causing them to swell with simultane- nation that were confirmed with causes of in ous release of capillary fluid, which fluorescein angiography (FA).32 patients who experience retinal vein yields CME.38 Consistent with these findings, occlusion.36,37 It occurs as a result of Other reports have revealed that the Duke researchers suggested that increased venous pressure, which the incidence of partial PVD is sig- artificial induction of PVD via surgi- damages the capillary endothelium nificantly greater in eyes with branch cal or pharmacologic methods may and breaks down the inner blood- retinal vein occlusion (BRVO) than provide prophylactic or therapeutic retinal barrier.37 Recent studies have in unaffected eyes.24,39,40,41 In eyes benefit against both CNV and inade- focused on the role of the vitreous with ME secondary to vein occlu- quate retinal oxygenation.33 Further, in persistent ME secondary to retinal sion, 41% had associated vitreous several other case studies that evalu- vein occlusion.24,36,38-42 The research traction with a similar incidence in ated eyes with exudative AMD and indicated that the vitreous contrib- both CRVO or BRVO eyes, suggest- vitreomacular adherence have shown utes to ME, both by containing meta- ing that vitreous traction influences CNV regression, decrease in foveal bolic agents that increase vascular the evolution of chronic macular thickness and improvement in vision permeability and by exerting vitreo- edema.24,40 In these cases, the loca- following PPV with artificial detach- macular traction.24,36,38-42 tion of the traction was often extra- ment of the posterior hyaloid.28,34 Cystic ME is characterized by foveal, adjacent to the occlusion Vitrectomy was shown to be of OCT as round, intraretinal, hypo- site, and less frequently foveal or particular benefit in eyes with rela- reflective lacunae with well-defined papillary.24,39 The researchers found tively small CNV lesions (less than boundaries and hyper-reflective that retinal edema and serous retinal 0.5 optic disc diameter).34 This septa that separate the small cavi- detachment that impacted the

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001_ro0412 RetinaGuide.indd 10 4/12/12 9:41 AM traction site was almost always in suggests that removal of VEGF via ILM peeling and artificial detach- contact with the central macula, the procedure plays an important ment/removal of the posterior producing diffuse ME or combined role in edema resolution.36 In these hyaloid in eyes with ME secondary diffuse ME and serous macular studies, PPV was often combined to retinal vein occlusion.36,38,44,47,48 In detachment.24,39 Diffuse ME in these with ILM peeling to reduce the risk these cases, ME resulting from either studies was identified via OCT as an of ERM formation as well as ME CRVO or hemiretinal vein occlusion ill-defined, widespread, hyporeflec- recurrence.44 (HVO) was significantly reduced as tive retinal thickness that resembled Investigators theorize that PPV was central foveal thickness in all a porous sponge.39 Further, current with ILM peeling “unroofs” the PPV eyes, with a documented main- evidence suggests that eyes with vit- inner retina and allows the retained/ tained effect of at least five years.44 reoretinal traction are more likely compartmentalized intraretinal These results were associated with to develop diffuse ME, while eyes blood and extracellular fluid to improved corrected vision in eyes without traction are more likely to drain out of the retina.44 In addi- with non-ischemic CRVO (less than develop CME.39 tion, the peeling of a thickened 10 disc areas of non-perfusion noted In one report, researchers noted a ILM may improve retinal plasticity, on FA and HVO, but not in eyes subsequent resolution of ME and an facilitating fluid diffusion out of with ischemic CRVO).44 improvement in visual acuity follow- the retina.44 Further, the increase in Such findings suggested that most ing spontaneous extrafoveal traction oxygen tension within the vitreous vision loss in eyes with ischemic release associated with central ME cavity and retina following vitrec- CRVO was likely secondary to macu- and macular detachment in an eye tomy likely reduces ischemia.34,38,45 lar ischemia, not ME. Similar findings affected by BRVO.24 Another study Finally, the benefit of PPV in cases of were reported following PPV and suggested that ischemic CRVO may recalcitrant ME following grid laser ILM peeling in eyes with chronic actually promote the development of or repeated intravitreal injections CME secondary to BRVO, with a papillary vitreous traction (disc eleva- of anti-VEGF agents is thought to mean decrease in central macular tion associated with either incom- release mechanical vitreous traction, thickness of 62% and associated plete PVD or vitreopapillary fibrous which acts as a natural obstacle to mean improvement in visual acuity membrane) with secondary peripap- anatomic improvement.39 from 20/100 at baseline to 20/40 at illary retinal traction and localized Today, identifying pre-existing the seven-month follow-up.48 macular or .42 vitreoretinal traction may be an Given these outcomes and the important step when considering Diabetic Macular Edema discovery of the possible pathophysi- intravitreal treatments, because its DME influences the vitreous in ologic advantages of 3-port PPV, presence may increase the likelihood three possible ways:49 the benefits of the procedure may of both tractional retinal detachment • Accumulation of angiogenic now outweigh the risks. It has been and ME progression.39,46 Mounting factors in the premacular vitreous extrapolated that removal of angio- data also seems to indicate that gel, which increases vascular perme- genic cytokines, such as VEGF and vitrectomy serves a protective role ability. IL-6, contained in the preoperative against the formation of retinal or • Abnormal glycation and cross- vitreous may help stabilize retinal disc neovascularization (NV) in eyes linking of vitreal collagen, which vascular permeability and therefore with CRVO.38 This theory is sub- causes vitreous destabilization and decrease ME formation.36 stantiated by the observation that increased macular traction. This hypothesis is supported by eyes with BRVO and complete PVD • Increased reports in patients who experienced rarely develop pre-retinal neovascu- formation. partial vitrectomy. In cases where larization.40 Likewise, the risk of vit- Focal DME is defined by dis- vitrectomy was repeated, vitreous reous hemorrhage following BRVO crete areas of leakage on FA. It is levels of VEGF were lower at the is greatest in patients with partial produced by microaneurysms and time of the second procedure.43 PVD, suggesting the increased risk of typically is responsive to focal laser Additionally, other surgical investiga- developing pre-retinal NV is aggra- photocoagulation.50 Diffuse DME is tors have shown that high vitreous vated by vitreous tractional effects characterized by generalized areas VEGF levels at the time of PPV have on these new, fragile vessels.40 of leakage and is associated with vit- been associated with a greater post- Numerous studies have reported reomacular traction, vitreoretinal or operative improvement in ME. This beneficial results following PPV with vitreopapillary vitreous traction, and

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epiretinal membrane formation.50 without PVD) who were treated with ERM removal.62 A greater reduction Diffuse DME is less responsive to pan-retinal photocoagulation (PRP) in central retinal thickness occurred grid photocoagulation, which often exhibited retinopathy that improved in eyes with worse baseline acuity, yields merely temporary benefits.50,51 or remained unchanged at six-month greater preoperative retinal thick- One report indicated that diabetes follow-up.56 However, in eyes with ness, removal of ILM at time of PPV patients without ME (55%) have a complete PVD, 93% remained stable and OCT evidence of vitreoretinal significantly higher rate of complete or improved.56 In contrast, the abnormalities.62 But again, vision was PVD than those with ME (20%), sug- PDR worsened in 57% of eyes with not substantially improved.62 The gesting that a complete PVD maybe partial PVD.56 The study suggested research team concluded that, while protective against edema forma- that complete PVD or the absence preoperative presence of vitreoreti- tion.52 Moreover, approximately half of PVD reduces levels of vitreous nal abnormalities appeared to be of eyes with diffuse or focal DME traction and protects against the most amenable to surgical interven- involving the center of the macula progression of PDR.56 The suspected tion, the functional outcomes were have some sort of vitreoretinal trac- mechanism is elimination of the col- not always improved.62 tion located outside the fovea, either lagenous network of the cortical vit- Other studies have added to the at the optic nerve head or in the pos- reous, which the new vessels require controversy.63,64 One paper sug- terior pole.50 While vitreous trac- as a scaffold for growth.2 gested that PPV with separation tion at the fovea is less common, Even in non-tractional cases, vit- of the posterior hyaloid was best it is present in approximately 20% rectomy seems to improve DME for improving visual prognosis of eyes with DME and is accom- by increasing retinal oxygenation and encouraging resolution of panied by additional areas of trac- and removing growth factors edema.63 Another commented that tion outside of the fovea about that increase vascular permeabil- functional/surgical success was half of the time.50 ity.34,49,53,57 As seen in vein occlusion, significantly better in eyes that Vitreofoveal traction has the vitrectomy for DME is often coupled had not undergone preoperative potential to induce focal ME with a with ILM peeling. This theory is macular laser treatment.64 peaked center, and is typically asso- supported by the fact that ILM There is conflicting evidence as to ciated with a significantly greater in patients with DME have been the benefit of PPV in cases of DME macular thickness than that observed found to be significantly thicker without vitreous traction.57,58,65 One in eyes with extrafoveal or vitreo- than those in eyes without DME.58,59 study reported that PPV with artifi- papillary traction.50,53 Furthermore, Additionally, peeling of the ILM cial induction of PVD with or with- researchers suggest that extrafo- may activate Müller cell repair out ILM peeling improved vision in veal vitreous traction is present in mechanisms.58,60 ILM peeling also only half of cases.57 Further, vision approximately 35% of eyes with facilitates a more complete removal was stabilized in only one third of DME and commonly occurs at vari- of the vitreous.58,61 486 eyes with diffuse non-tractional ous vitreoretinal and/or papillary A large study conducted by DME at six years post-op.57 Another sites.50 Additionally, vitreoretinal the Retinopathy Clinical Research study suggested that standard PPV traction may cause localized serous Network included 241 eyes with without peeling of the ILM provided retinal detachment or schisis-like DME involving the center of the little visual benefit compared to mac- clefts at the point of traction.53,54 macula that was associated with ular photocoagulation in eyes with Approximately one quarter of VMT (vitreomacular interface central clinically significant ME that eyes with DME and vitreoretinal abnormality or traction in 71%) or persisted for more than a year. traction have identifiable ERM was unresponsive to injection or While there is unclear protocol, a without PVD.50 By contrast, ERM laser treatment.62 Eyes were treated body of evidence is being generated in non-diabetes patients is strongly with PPV and removal of the poste- that suggests while surgical induc- associated with posterior vitreous rior hyaloid, with or without ERM tion of PVD alone improves macular detachment.50,55 or ILM peeling. 62 At six months, edema, it is markedly less effective It seems that partial PVD with vit- median central macular thickness than surgical induction of PVD reoretinal traction is a major risk fac- decreased by one-third in eyes, but with ILM removal.58 Moreover, ILM tor for progression of proliferative visual acuity remained unchanged.62 delamination appears to be benefi- (PDR).56 In one The best results occurred in eyes cial for chronic DME, even in eyes study, 80% of patients with PDR (but with worse baseline acuity following with pre-existing PVD.58

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001_ro0412 RetinaGuide.indd 12 4/12/12 9:41 AM Vitreomacular Traction and Macular reomacular adhesions can reverse retinopathy and macular holes.8,76,77 Hole Formation early VMT-associated structural Dispase—a relatively non-specific As the vitreous body changes changes to the macula, thus restor- agent with proteolytic activity against overtime, liquefaction and collapse ing normal visual function.66,71,73 type IV collagen and fibronectin— occurs.66-72 At times, the result- Pharmacologically assisted vitreolysis has been linked to retinal toxicity in ing posterior vitreous detachment may be an option worth consider- human eyes, which suggests the need remains incomplete.66-72 The residual ing to assist in breaking these vit- for more specific agents that spare stubborn adhesions between the reoretinal adhesions, allowing for retinal tissue.8,78 posterior hyaloid and the underlying the normal macular anatomy to be Specific molecules that have been neurosensory retina create VMT. 66-72 restored before later-stage macular tested in FDA human clinical trials The tractional force—thought to be hole pathogenesis.66,69-71 Otherwise, include chondroitinase and hyal- either tangential or anteroposterior— surgical intervention via PPV has uronidase.8,79 While hyaluronidase exerted by the hyaloid face of the been the mainstay of treatment for induces vitreous liquefaction, it usu- vitreous on the highly organized neu- these cases.70,71 ally does not simultaneously induce roretinal macular tissue can cause adequate vitreoretinal adhesion sepa- significant structural and functional Treatment Options ration.8 This is most likely the reason changes.66 VMT can lead to a constel- With respect to macular edema, that phase III trials investigating the lation of macular pathologies. vitrectomy traditionally is reserved use of hyaluronidase to clear vitre- Macular holes, first described by J. for recalcitrant disease, because the ous hemorrhage in eyes of patients Donald M. Gass, M.D., traditionally procedure can cause significant side with type I and type II diabetes were have been graded on a scale, depend- effects, including rhegmatogenous found to be unsuccessful.8,79 Future ing on the foveal appearance and retinal detachment, cataract develop- investigations that focus on a com- the extent of tissue involved.22,66-68 ment, hypotony, choroidal effusion bination of specific molecules likely With the advent of OCT and spectral and .74,75 Recent will afford better results with fewer domain OCT, even greater anatomi- research has fueled interest in devel- retinal side effects.8 Inevitably, there cal detail can now be appreciated. oping injectable pharmaceutical is hope that these investigations will The presence of VMT is often con- agents that could induce PVD in a produce an agent that will eventually sidered the earliest event of macular less invasive and benign manner. decrease the necessity of vitrectomy. hole formation.22,66,68-72 Pharmacologic vitreolysis refers Recent research suggested that to the use of exogenous agents to It is clear that the vitreous humor, eyes exhibiting small, focal macular alter the biochemical and biophysical with its complex anatomic structure adhesions with peripapillary attach- states of the macromolecules that are and network of neurosensory retinal ments have a likelihood of macular responsible for maintaining vitreous adhesions, plays a vital role in the hole formation.64 Another study indi- structure and vitreoretinal adhesion.8 homeostasis of retinal tissue. The cated that, as the vitreous begins to Most pharmacologic agents are enzy- majority of new retinal research detach, liquefied vitreal gel escapes matic and include both substrate- concerning vitreoretinal pathology through any acquired small break specific and non-specific agents as supports an association of more in the posterior hyaloid face.66 The well as broad-acting agents that are severe sequelae in cases exhibiting most frequently documented site of designed to simultaneously liquefy enhanced vitreoretinal adhesions. escape is in the region of the glial the vitreous while achieving dehis- Further, the discovery of reduced ring over the optic disc.66 The lique- cence of all vitreoretinal adhesions.8 pathology in cases of both naturally fied material enters the subhyaloid Non-specific agents include plasmin, occurring and induced (pharma- space and exerts pressure on the vit- microplasmin (i.e., Ocriplasmin cological or surgical) vitreoretinal reous cortex, causing it to move ante- [ThromboGenics]) and dispase, separation has fueled novel ideas for riorally.66 The traction exerted on while specific agents encompass managing recalcitrant ME secondary the retina by the vitreous, which has chondroitinase, hyaluronidase and to intraretinal, subretinal and prereti- attachments located at the macula matrix metalloproteinases.8 nal pathologies. Continuing research and adjacent to the optic nerve head, Plasmin, typically acquired from may permit the development of less begins the processes that induce the patient’s own serum, has been invasive techniques for dissolving macular hole formation.66,67,73 tested mainly as an adjunct to vitrec- pathological vitreoretinal relation- Spontaneous release of the vit- tomy in cases of advanced diabetic ships in favor of reduced anatomic

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25. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular macular edema. Retina. 2010 Nov-Dec;30(10):1638-45. dysfunction and improved visual adhesion: A potential risk factor for exudative age-related macular 52. Nasrallah FP, Jalkh AE, Van Coppenolle F. The role of the vitreous in outcomes. ■ degeneration? Am J Ophthalmol. 2007 May;144(5):741-6. diabetic macular edema. Ophthalmology. 1988 Oct;95(10):1335-9. 26. Spaide RF, Armstrong D, Browne R. Continuing medical education 53. Ophir A, Trevino A. Extrafoveal vitreous traction associated with dia- Dr. Majcher is a primary care resident review: choroidal neovascularization in age-related macular degenera- betic diffuse macular oedema. Eye (Lond). 2010 Feb;24(2):347-53. tion—what is the cause? Retina. 2003 Oct;23(5):595-614. 54. Karatas M, Ramirez JA, Ophir A. Diabetic vitreopapillary traction and at the Eye Institute at Salus University in 27. Lee SJ, Lee CS, Koh HJ. Posterior vitreomacular adhesion and risk macular oedema. Eye (Lond). 2005 Jun;19(6):676-82. Elkins Park, Pa. Dr. Gurwood is professor of exudative age-related macular degeneration: paired eye study. Am J 55. Appiah AP, Hirose T, Kado M. A review of 324 cases of idiopathic Ophthalmol. 2009 Apr;147(4):621-6. premacular gliosis. Am J Ophthalmol. 1988 Nov 15;106(5):533-5. of clinical sciences at the Eye Institute at 28. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreo- 56. Jalkh A, Takahashi M, Topilow HW, et al. Prognostic value of Salus University. Dr. Hutchinson practices macular adhesion in age-related macular degeneration: Spectral optical vitreous findings in diabetic retinopathy. Arch Ophthalmol. 1982 coherence tomography and surgical results. Am J Ophthalmol. 2008 Mar;100(3):432-4. in St. Louis and is an adjunct faculty mem- Aug;146(2):218-227. 57. Kumagai K, Furukawa M, Ogino N, et al. Long-term follow up of 29. Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion vitrectomy for diffuse nontractional diabetic macular edema. Retina. ber at the University of Missouri-St. Louis in active and end-stage age-related macular degeneration. Am J 2009 Apr;29(4):464-72. College of Optometry. Ophthalmol. 2009 Jan;148(1):79-82. 58. Hoerauf H, Brüggemann A, Muecke M, et al. Pars plana vitrectomy 30. Schulze S, Hoerle S, Mennel S, Kroll P. Vitreomacular traction and for diabetic macular edema. Internal limiting membrane delamination vs exudative age-related macular degeneration. Acta Ophthalmol. 2008 posterior hyaloid removal. A prospective randomized trial. Graefes Arch 1. Khurana AK. Comprehensive Ophthalmology. New Age International: Aug;86(5):470-81. Clin Exp Ophthalmol. 2011 Jul;249(7):997-1008 Delhi, India; 2007:243-8. 31. Seko Y, Seko Y, Fujikura H, et al. Induction of vascular endothelial 59. Matsunaga N, Ozeki H, Hirabayashi Y, et al. Histopathologic evalua- 2. Le Goff MM, Bishop PN. Adult vitreous structure and postnatal growth factor after application of mechanical stress to retinal pig- tion of the internal limiting membrane surgically excised from eyes with changes. Eye (Lond). 2008 Oct;22(10):1214-22. ment epithelium of the rat in vitro. Invest Ophthalmol Vis Sci. 1999 diabetic maculopathy. Retina. 2005 Apr-May;25(3):311-6. 3. Halfter W, Winzen U, Bishop PN, et al. Regulation of eye size by the Dec;40(13):3287-91. 60. Uckermann O, Uhlmann S, Pannicke T, et al. Ischemia-reperfusion retinal basement membrane and vitreous body. Invest Ophthalmol Vis 32. Meyer CH, Toth CA. Retinal pigment epithelial tear with vitreo- causes exudative detachment of the rabbit retina. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3586-94. macular attachment: a novel pathogenic feature. Graefes Arch Clin Exp Sci. 2005 Jul;46(7):2592-600. 4. Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases Ophthalmol. 2001 Jun;239(5):325-33. 61. Sonada KH, Sakamoto T, Enaida H, et al. 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J Biol Chem. 2004 Dec 40. Trempe CL, Takahashi M, Topilow HW. Vitreous changes in retinal 68. Huang LL, Levinson DH, Levine JP et al. Optical coherence 17;279(51):53331-7. branch vein occlusion. Ophthalmology. 1981 Jul;88(7):681-7. tomography findings in idiopathic macular holes. J Ophthalmol. 13. Maumenee IH. Vitreoretinal degeneration as a sign of general- 41. Murakami K, Ho PC, Trempe CL, et al. Tractional detachment of the 2011;2011:928205. ized connective tissue diseases. Am J Ophthalmol. 1979 Sep;88(3 Pt macula following branch retinal vein occlusion. Ann Ophthalmol. 1983 69. Schneider EW, Johnson MW. Emerging nonsurgical methods for 1):432-49. Aug;15(8):760-5. the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 14. Sebag J. Pathology of the vitreous. In: Sebag J. The vitreous: 42. Rumelt S. Optic disc traction syndrome associated with central reti- 2011;5:1151-65. structure, function, and pathobiology. New York: Springer-Verlag; nal vein occlusion. Arch Ophthalmol. 2003 Aug;121(8):1093-7. 70. Kumar N, Kandari JA, Sabti KA, et al. Partial-thickness macular 1989:97-147. 43. Noma H, Funatsu H, Mimura T, et al. Changes of vascular endothe- hole in vitreomacular traction syndrome: a case report and review of the 15. Bishop PN. Age-related changes on the surface of vitreous collagen lial growth factor after vitrectomy for macular edema secondary to retinal literature. J Med Case Reports. 2010 Jan 13;4:7. fibrils. Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1041-6. vein occlusion. Eur J Ophthalmol. 2008 Nov-Dec;18(6):1017-9. 71. Shechtman DL, Dunbar MT. The expanding spectrum of vitreomacu- 16. Sebag J. Development and aging of the vitreous. In: Sebag J. The 44. Park DH, Kim IT. Long-term effects of vitrectomy and internal lar traction. Optometry 2009 Dec;80(12):681-687. vitreous: structure, function, and pathobiology. New York: Springer- limiting membrane peeling for macular edema secondary to central 72. Odrobina D, Michalewska Z, Michalewski J, et al. Long-term evalu- Verlag; 1989:73-92. retinal vein occlusion and hemiretinal vein occlusion. Retina. 2010 ation of vitreomacular traction disorder in spectral-domain optical coher- 17. Tiedeman J, Mittra R, Han D, et al. Vitreous and retinal detach- Jan;30(1):117-24. ence tomography. Retina. 2011 Feb;31(2):324-31. ments. In: Regillo C, Brown G, Flynn H. Vitreoretinal disease: the essen- 45. Stefansson E, Novack RI, Hatchell DL. Vitrectomy prevents retinal 73. Reese AB, Jones IS, Cooper WC. Macular changes secondary to tials. New York: Thieme; 1999:65-86. hypoxia in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 1990 vitreous traction. Trans Am Ophthalmol Soc. 1966;64:123-34. 18. Kishi S, Hagimura N, Shimizu K. The role of the premacular liquefied Feb;31(2):284-9. 74. Akçay B. Outcomes of 23-gauge pars plana vitrectomy in vitreoreti- pocket and premacular vitreous cortex in idiopathic macular hole devel- 46. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment nal diseases. Clin Ophthalmol. 2011;5:1771-6. opment. Am J Ophthalmol. 1996 Nov;122(5):622-8. following intravitreal bevacizumab (Avastin) in patients with severe prolif- 75. Schoenberger SD, Miller DM, Riemann CD, et al. Outcomes of 19. Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous erative diabetic retinopathy. Br J Ophthalmol. 2008 Feb;92(2):213-6. 25-gauge pars plana vitrectomy in the surgical management of pro- detachment in healthy eyes of older persons evaluated byoptical coher- 47. Raszewska-Steglinska M, Gozdek P, Cisiecki S, et al. Pars plana liferative diabetic retinopathy. Ophthalmic Surg Lasers Imaging. 2011 ence tomography. Arch Ophthalmol. 2001 Oct;119(10):1475-9. vitrectomy with ILM peeling for macular edema secondary to retinal vein Nov-Dec;42(6):474-80. 20. Snead MP, Yates JR. Clinical and molecular genetics of Stickler occlusion. Eur J Ophthalmol. 2009 Nov-Dec;19(6):1055-62. 76. Trese MT, Williams GA, Hartzer MK. A new approach to stage 3 syndrome. J Med Genet. 1999 May;36(5):353-9. 48. Ma J, Yao K, Zhang Z, Tang X. 25-gauge vitrectomy and triamcino- macular holes. Ophthalmology. 2000 Aug;107(8):1607-11. 21. Sebag J. Classifying posterior vitreous detachment: a new way to lone acetonide-assisted internal limiting membrane peeling for chronic 77. Williams JG, Trese MT, Williams GA, et al. Autologous plas- look at the invisible. Br J Ophthalmol. 1997 Jul;81(7):521. cystoid macular edema associated with branch retinal vein occlusion. min enzyme in the surgical management of diabetic retinopathy. 22. Sebag J, Gupta P, Rosen RR, et al. Macular holes and macular Retina. 2008 Jul-Aug;28(7):947-56. Ophthalmology. 2001 Oct;108(10):1902-5; discussion 1905-6. pucker: the role of vitreoschisis as imaged by optical coherence tomog- 49. Diabetic Retinopathy Clinical Research Network Writing Committee. 78. Jorge R, Oyamaguchi EK, Cardillo JA, et al. Intravitreal injection of raphy/scanning laser . Trans Am Ophthalmol Soc. Vitrectomy outcomes in eyes with diabetic macular edema and vitreo- dispase causes retinal hemorrhages in rabbit and human eyes. Curr 2007;105:121-9; discusion 129-31. macular traction. Ophthalmology. 2010 Jun;117(6):1087-1093. Eye Res. 2003 Feb;26(2):107-12. 23. Sebag J. Diabetic vitreopathy. Ophthalmology. 1996 Feb;103(2): 50. Ophir A, Martinez MR, Mosqueda P, et al. Vitreous traction and 79. Bhavsar AR, Grillone LR, McNamara TR, et al. Vitrase for Vitreous 205-6. epiretinal membranes in diabetic macular oedema using spectral-doma- Hemorrhage Study Groups. Predicting response of vitreous hemor- 24. Martinez MR, Ophir A. Extrafoveal traction in retinal vein occlusion inoptical coherence tomography. Eye (Lond). 2010 Oct;24(10):1545-53. rhage after intravitreous injection of highly purified ovine hyaluronidase using spectral domain optical coherence tomography. Graefes Arch Clin 51. Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/ (Vitrase) in patients with diabetes. Invest Ophthalmol Vis Sci. 2008 Exp Ophthalmol. 2011 Jun;249(6):811-20. or macular photocoagulation as a primary treatment for diffusediabetic Oct;49(10):4219-25.

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001_ro0412 RetinaGuide.indd 14 4/12/12 9:41 AM LEBER’S HEREDITARY OPTIC NEUROPATHY

A Case of Late-Onset Leber’s Hereditary Optic Neuropathy By Carol Aune, B.S., O.D., and James Walters Ph.D., O.D.

LEBER’S HEREDITARY OPTIC plained bilateral vision loss, where NEUROPATHY (LHON) is a maternally the diagnosis remains in doubt. inherited mitochondrial disorder that is characterized by painless, Patient History subacute, bilateral vision loss. A 51-year-old black male was The condition occurs primarily in referred for electrodiagnostic young, adult males. The average testing by his ophthalmologist as age of onset ranges between 18 a result of unexplained bilateral and 35 years; however, delayed vision loss. His chief complaint onset has been reported in included loss of central vision Release Date patients as old as 73 years of age. in both eyes (O.S. > O.D.) and April 2012 When examining a patient decreased color vision O.U. with LHON, the fundus exami- The patient stated that the Expiration Date nation may appear normal at vision in his right eye became March 1, 2015 the onset of vision loss although blurred three months earlier, fol- Goal Statement the clinician may observe optic lowed by pronounced vision loss This article reviews the case of nerve and nerve fiber layer in his left eye one month later. a 51-year-old man with Leber’s (NFL) swelling on optical coher- He informed us that his vision Hereditary Optic Neuroparthy ence tomography; vascular tor- gradually worsened over a two- (LHON). In addition, it discusses tuosity; arteriolar dilation; and month period and then stabilized. the role of genetic testing in LHON peripapillary telangiectasias. His blurred vision was constant, patients, where the diagnosis may The atrophic phase demon- and affected all viewing distances. be difficult to confirm. strates bilateral, temporal optic The patient denied pain while Faculty/Editorial Board pallor that often progresses to chewing, scalp tenderness or joint Carol Aune, B.S., O.D., and James complete optic atrophy. Cell ache. He also denied any family Walters, Ph.D., O.D. death is limited to the retinal gan- history of vision loss. Credit Statement glion cells and is hypothesized to Recently, the patient was diag- This course is COPE-approved for be a result of apoptosis secondary nosed with type 2 diabetes melli- 1 hour of CE credit. COPE ID is to oxidative stress caused by mito- tus and hypertension. His current 33938-PS. Please check your chondrial mutations. medications included metformin, state licensing board to see if this LHON is largely a diagnosis quinapril and verapamil. approval counts toward your CE of exclusion, and other causes At the most recent visit to his requirement for relicensure. There of optic neuropathy (i.e., toxic/ ophthalmologist one month ear- is a $20 fee to take this course. nutritional, compressive, isch- lier, he was diagnosed with unex- Joint Sponsorship Statement emic, etc.) must be ruled out. plained vision loss O.U.; complete This continuing education course is Regardless of age, genetic testing O.U.; mild, non- joint-sponsored by the Pennsylvania in any individual suspected of proliferative diabetic retinopathy College of Optometry. LHON should be performed to with no clinically significant macu- Disclosure Statement confirm the diagnosis. lar edema O.S.; and temporal pal- Drs. Aune and Walters have no There is no available treatment lor of the optic nerve heads O.U. relationships to disclose. for LHON, but low vision aids The patient was referred for and counseling should be recom- MRI scans of the brain and orbits mended. Also, you should advise (with and without contrast), which LHON carriers to moderate their were unremarkable. The patient smoking and alcohol intake. reported discontinuing all alcohol Here, we will examine the case intake four months prior, but he of a 51-year-old man with LHON. used to consume three to four Additionally, we will discuss the beers per day. He denied any role of genetic testing in LHON tobacco and/or illicit drug use. patients who present with unex- The patient was a truck driver for

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001_ro0412 RetinaGuide.indd 16 4/12/12 9:41 AM 27 years, but was on medical leave Instead, he went to a different testing or refraction. Preliminary because of his reduced vision. ophthalmologist who diagnosed testing included pupillary him with bilateral primary open- response, ocular motility and Diagnostic Data angle ; prescribed topi- biomicroscopy, which were unre- The patient’s uncorrected cal bimatoprost; and referred him markable. Humphrey 24-2 visual entering visual acuity measured to a neuro-ophthalmologist. field threshold testing revealed a 20/400 O.D and 10/400 O.S., A review of the patient’s significant secocentral in with no improvement upon records indicated that the neuro- both eyes (O.D. > O.S.). We also pinhole testing or refraction. ophthalmologist suspected nutri- documented an inferior arcuate Confrontation fields revealed tional and ordered defect of the right eye and a supe- defects in the inferior quadrants a complete blood count. The rior arcuate defect of the left eye. of the right eye and all regions of results revealed a slight decrease NFL analysis on optical coher- the left eye except the superior in hematocrit, hemoglobin, red ence tomography revealed thin-

temporal quadrant. Other pre- blood cells and B1 levels (for ning of the inferior and superior liminary testing, includ- temporal quadrants O.U. ing pupillary response, A high-definition scan of ocular motility and bio- the macula showed loss of microscopy, were unre- the papillomacular NFL markable. bundle O.U., with no His intraocular pres- other macular pathology. sure measured 22mm Hg The pattern VER O.D. and 17mm Hg O.S. remained severely Fundus photography depressed, and the 2Hz indicated thinning of the and 8Hz flash VERs were temporal rim of the right repeated. The results optic nerve and supe- indicated that the left eye Initial presentation of our patient indicated mild temporal optic nerve pallor in rior rim of the left optic both eyes. was now more respon- nerve. We observed a sive than the right eye. wedge defect in the infe- Fundus photography rior NFL of the left eye documented increased as well as mild temporal temporal optic nerve pal- optic nerve pallor in lor in both eyes as well as both eyes. We performed increased thinning of the visually evoked response superior temporal rim (VER) and documented of the left optic nerve. no significant pattern. The patient refused However, a flash VER at optical aids, although 2Hz and 8Hz showed a we observed a positive moderately strong out- Nine months later: Increased temporal optic nerve pallor in both eyes. response to magnifica- come in the right eye and tion. The patient was a severely compromised outcome which the patient was started on counseled on a probable diagno-

in the left eye. B1 oral supplements). However, sis of LHON, because the genetic We believed that the patient routine chemistries, liver func- testing results for the three prima- had bilateral optic atrophy, with a tion studies, protein electropho- ry mutations were still pending.

suspected hereditary component. resis, lead, B12 and folate levels Two months later, the genetic We told him to return to his oph- were all normal ruling out nutri- testing results revealed a G>A thalmologist, and recommended tional amblyopia. At that time, nucleotide substitution at mito- genetic testing for LHON. the neuro-ophthalmologist sug- chondrial position 11778 in the The patient returned nine gested that LHON was the top patient’s DNA. This finding was months later for a low vision differential diagnosis. consistent with a definitive diag- evaluation. He stated that his At the low vision evaluation, nosis of LHON. vision remained unchanged and the patient’s uncorrected enter- reported that he had not returned ing visual acuity measured 10/80 Discussion to the original referring ophthal- O.D. and 10/60 O.S., with no LHON is one of the most com- mologist for additional testing. improvement upon pinhole mon hereditary optic neuropa-

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have been reported.2,4 LHON was the first mitochon- drial disease to be discovered, and three primary mutations of the mitochondrial DNA (m.3460G>A, m.11778G>A, m.14484T>C) have been found in 90% of all LHON patients.1-3,8,11,12 These mutations affect the first site of the mito- chondrial respiratory chain.2,11 It is important to note that these primary mutations are more com- mon in patients with a family his- tory of multigenerational vision loss, whereas patients with no known family history often do not have a primary mutation.11 In recent years, 45 other muta- Humphrey 24-2 visual field threshold testing revealed a significant secocentral scotoma (O.D. > O.S.) and arcuate defects in both eyes. tions in mtDNA also have been associated with LHON.13 Just thies.1 Vision loss usually occurs atrophy.2,7,8,10 Optical coherence 50% of males and 10% of females in one eye first, and may occur tomography frequently reveals with the genetic defect develop either suddenly or progressively preferential involvement of the optic neuropathy.4,12 Due to this over two to three months.3 Vision papillomacular bundle and/or incomplete penetrance, it is likely loss in the fellow eye typically early involvement of the infe- that other factors are involved in occurs nine months later, with rior NFL.8 disease expression. Smoking and two months being the mean inter- Final visual acuities usually high alcohol intake have been val between vision loss in each are worse than 20/200; how- identified as triggers for visual eye.3 Simultaneous onset may ever, reports of mild, spon- loss in individuals carrying a present in approximately 25% taneous recovery have been known Leber’s mutation.12 Other to 50% of occurences.2,3 Patients documented.2,3 As with all factors, such as poor nutrition, often have no family history of optic neuropathies, color vision stress, exposure to toxins and vision loss, with 40% of cases defects, especially red/green trauma, have been reported in occurring in just one family mem- anomalies, may be observed. VER clinical practice.12 ber.2 Males are four times more amplitudes often are found to The optic nerve is rich in likely to be affected than females.2 be reduced or flat. Vision loss mitochondria, and neurons are The worldwide prevalence of usually is the only symptom of dependent on mitochondria for LHON is estimated to be one in LHON; but, associated neurologi- survival. Defects in the respiratory 50,000.3 cal complications, such as periph- chain of the mitochondria lead to LHON carriers typically are eral neuropathy, postural tremor, increased free radical prolifera- asymptomatic until the onset of movement disorders, multiple tion and decreased ATP produc- the acute phase, which causes sclerosis and cardiac anomalies, tion, which cause oxidative stress.4 central vision blurring as well as a central or secocentral scotoma A high-definition 2,7 optical coher- on field testing. During the ence tomogra- pre-symptomatic phase, carriers phy (OCT) scan of the macula may present with temporal NFL documented swelling and peripapillary telangi- loss of the 2,8 papillomacular ectasic vessels. During the acute nerve fiber layer phase, fundus examination may bundle in both 2 eyes, with no be normal in 20% of patients. other macular The atrophic phase demon- pathology. strates bilateral, symmetrical, temporal optic pallor that often progresses to complete optic

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001_ro0412 RetinaGuide.indd 18 4/12/12 9:41 AM Fundus photography of our patient’s left eye at initial presentation. We located a wedge defect in the inferior nerve fiber layer. The posterior pole of the right eye was unremarkable.

The wedge defect in the inferior nerve fiber layer was more evident on red-free photography. Nerve fiber layer analysis on OCT revealed thinning of the inferior and superior temporal quadrants O.U.

It is theorized that neuronal in improving vision or prevent- clinical electrophysiology and a special degeneration is a result of oxida- ing vision loss.2,3,7,14 Currently, interest in retinal pathology. tive damage caused by associated antioxidant gene therapy is under 4 13 1. Abu-Amero K, Bosley T. Mitochondrial Abnormalities in oxidation. investigation. Patients with LHON-like Optic Neuropathies. Invest Ophthalmol Cell death is limited to the LHON is largely a diagnosis of Vis Sci. 2006 Oct;47(10):4211-20. 2. Yu-Wai-Man P, Chinnery P. Leber Hereditary Optic retinal ganglion cells, and is exclusion, and diagnostic confu- Neuropathy. In: GeneReviews at GeneTests: Medical Genetics Information Resource. Available at: www.ncbi.nlm.nih.gov/books/ hypothesized to be a result of sion may occur with compressive, NBK1174/ (accessed January 25, 2012). apoptosis secondary to oxidative toxic, nutritional, ischemic or 3. Orssaud C. Leber’s hereditary optic neuropathy. Orphanet Encyclopedia. Available at: www.orpha.net/data/patho/GB/uk- stress (although it is unknown other hereditary optic neuropa- LHON.pdf (accessed January 25, 2012). 4. Kumar M, Tanwar M, Saxena R, et al. Identification of novel why only the ganglion cell thies. All patients suspected of mitochondrial mutations in Leber’s hereditary optic neuropathy. layer is affected or why healthy LHON should undergo MRI, Mol Vis. 2010 Apr 30;16:782-92. 5. Shah V, Randhawa S, Mizen T et al. You’re too old for that. individuals suddenly develop VER and complete blood testing Surv Ophthalmol. 2008 Jul-Aug;53(4):403-10. symptoms).2,13 The preferential to rule out other etiologies. 6. Ajax ET, Kardon R. Late-onset Leber’s hereditary optic neu- ropathy. J Neuroophthalmol. 1998 Mar;18(1):30-1. involvement of the papillomacu- Ultimately, all LHON suspects 7. Newman N. Progression of visual field defects in leber heredi- tary optic neuropathy: experience of the LHON treatment trial. lar bundle is thought to occur should be considered for genetic Am J Ophthalmol. 2006 Jun;141(6):1061-7. because of its small axons.8 testing to confirm the diagnosis. 8. Barboni P, Carbonelli M, Savini G, et al. Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of Remember, however, absence of the retinal nerve fiber layer by optical coherence tomography. As previously mentioned, there the mutation does not rule out Ophthalmology. 2010 Mar;117(3):623-7. 9. Borruat F, Green W, Graham E. Late onset Leber’s optic are no known treatments for LHON, because all the mutations neuropathy: a case confused with ischemic optic neuropathy. Br J Ophthalmol. 1992 Sep;76(9):571-3. LHON. The LHON Treatment attributed to the disease have not 10. Trobe J, Glaser J, Cassady J. Optic Atrophy: Optic atro- Trial attempted to use topical bri- yet been identified. ■ phy. Differential diagnosis by fundus observation alone. Arch Ophthalmol. 1980 Jun;98(6):1040-5. monidine prophylatically to pre- Dr. Aune is an optometrist practicing 11. Ramos C, Bellusci C, Savini G, et al. Association of optic disc size with development and prognosis of Leber’s hereditary optic vent vision loss in patients’ unaf- in Raleigh and Eastern N.C., where she neuropathy. Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1666-74. fected eyes.7 Brimonidine was focuses on ocular pathology, low vision 12. Kirkman M, Yu-Wai-Man P, Korsten A, et al. Gene- environment interactions in Leber hereditary optic neuropathy. used because of its antiapoptic and specialty contact lenses. Dr. Walters Brain. 2009 Sep;132(Pt 9):2317-26. properties; however, it was unsuc- is an associate professor at the University 13. Qi X, Sun L, Hauswirth W, et al. Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary cessful. Other studies have shown of Houston College of Optometry and optic neuropathy-causing mutation. Arch Ophthalmol. 2007 Feb;125(2):268-72. that idebenone, minocycline, clinical director of the Ocular Diagnostic 14. Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do infrared light and multivitamin and Medical Clinic at the University idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J supplementation, were ineffective Eye Institute. He has a background in Neuroophthalmol. 2000 Sep;20(3):166-70.

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Questions Examination Answer Sheet 1. Which statement regarding the inheritance pattern of Leber’s Valid for credit through March 1, 2015 hereditary optic neuropathy (LHON) is true? a. It is an X-linked recessive disorder. b. It is a paternally inherited mitochondrial disorder. A Case of Late-Onset Leber’s Hereditary Optic Neuropathy c. It is a maternally inherited mitochondrial disorder. Directions: Select one answer for each question in the exam and completely darken d. Males can transmit this condition to their daughters only in very rare the appropriate circle. A minimum score of 70% is required to earn credit. There is a instances. $20 fee to take this course 2. Which symptoms characterize a classic presentation of LHON? Mail to: Optometric CE, PO Box 488, Canal Street Station, New York, NY 10013 a. Painless, acute, unilateral vision loss that is seen primarily in the elderly. COPE-approved for 1 hour of CE Credit. COPE ID: 33938-PS. b. Painless, subacute, bilateral vision loss that is seen primarily in young adult males. There is an eight-to-ten week processing time for this exam. c. Slowly progressive, unilateral or bilateral vision loss that is often accom- A B C D panied by headaches. 1. 11. The goal statement was achieved: d. Severely impaired vision as an infant that is often accompanied by jerk- Very Well Adequately Poorly ing, involuntary eye movements. 2. A B C D 12. The information presented was: 3. What clinical findings may be observed upon initial presentation? 3. A B C D Very Useful Useful Not Very Useful a. A normal fundus. b. Peripapillary telangiectasias. c. Leakage on fluorescein angiography. 4. A B C D 13. The difficulty of the course was: d. Both a and b. Complex Appropriate Basic 5. A B C D 4. What is an effective treatment option for LHON? 14. Your knowledge of the subject was increased: a. No known treatments currently are available. b. Topical brimonidine. 6. A B C D Greatly Somewhat Hardly c. Antioxidant gene therapy. d. Nutritional supplements. 7. A B C D 15. The quality of the course was: Excellent Fair Poor 5. What is the appropriate management for a patient diagnosed with 8. A B C D How long did it take to complete this course? LHON?

a. Counsel patient on condition; recommend fish oil and a diet rich in red meat. 9. A B C D Comments on this course: b. Counsel patient on condition; prescribe high-dose vitamin A; and refer for low vision devices. 10. A B C D Topics you would like in the future CE articles: c. Counsel patient on condition; recommend moderate smoking and alcohol intake; and refer for low vision devices. d. Counsel patient on condition; inform him or her of probable resolution within three months. Please retain a copy for your records. Please print clearly. 6. Which condition should be ruled out when considering a diagno- You must choose and complete one of the following three identifier types: sis of LHON? a. Toxic or nutritional optic neuropathies. 1 SS # - - b. Compressive optic neuropathy. Last 4 digits of your SS # and date of birth State Code and License #: (Example: NY12345678) c. Ischemic optic neuropathy. d. All of the above. 2 - 3

7. Which test can provide a definitive diagnosis of LHON? First Name a. Genetic testing for known LHON mutations. b. Optical coherence tomography (OCT). Last Name c. Magnetic resonance imaging (MRI). d. All of the above. E-Mail The following is your: Home Address Business Address 8. Why is OCT a useful tool when gathering data to support a diag- nosis of LHON? Business Name a. During the acute phase, nerve fiber layer (NFL) swelling may be observed. Address b. Preferential involvement of the papillomacular bundle may be observed. c. Early involvement of the inferior NFL may be observed. City State d. All of the above. ZIP

9. What is a known trigger for the expression of LHON? Telephone # - - a. Minocylcine use. b. Smoking and high alcohol intake. Fax # - - c. Ultra violet light exposure. d. All of the above. By submitting this answer sheet, I certify that I have read the lesson in its entirety and completed the self-assessment exam personally based on the material presented. I have not obtained the answers 10. What is the proposed mechanism of action in LHON? to this exam by any fraudulent or improper means. a. Defects in the mitochondrial respiratory chain lead to oxidative stress, neuronal damage and apoptosis of the retinal ganglion cells. b. Defects in the retinal vessels due to arteriosclerosis and vascular disease lead to an ischemic event that affects the short posterior ciliary artery that Signature Date supplies the optic nerve. c. Focal regions of breakdown in the choriocapillaris vasculature lead to degeneration of the retinal pigment epithelium, resulting in photoreceptor loss. Lesson 108143 RO-0412-2 d. Spontaneous apoptosis of the retinal ganglion cells occurs via a mecha- nism that is not well understood.

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001_ro0412 RetinaGuide.indd 20 4/12/12 9:41 AM RETINAL MELANOCYTOMA DIABETES

A Case of Suspected Retinal Melanocytoma By W. Lee Ball, O.D., F.A.A.O.

MELANOCYTOMA is a neoplasm or Diagnostic Data hamartoma that is composed of Best-corrected visual acuity mea- melanocytes.1,2 Most commonly sured 20/20 O.U. at distance and found on the optic nerve, melano- near. Amsler grid was remarkable cytomas usually are asymptomatic.2 for mild paracentral metamor- However, in certain instances, they phopsia O.D. On Ishihara pseudo- cause blurry vision. Here, we review isochromatic testing, color vision a case report of a suspected presen- was normal in both eyes. Pupillary tation of retinal melanocytoma. responses were equal, round and reactive to light, with no afferent History defect O.U. Extraocular muscle A 23-year-old white female pre- movements were full and unre- 1. Fundus image of a patient’s right eye revealed sented to the Beth Israel Deaconess stricted in all positions of gaze O.U. the presence of a darkly pigmented lesion. Medical Center’s Division of Cover testing revealed orthophoria Ophthalmology in Boston on at distance and four prisms of exo- corneal staining O.U. November 11, 2010. Her chief phoria at near. Confrontation fields Her intraocular pressure mea- complaint was of a gray spot in her were full to careful finger counting sured 15mm Hg O.U. at 2:15 vision O.D. that had been evident in each eye. p.m. The patient was dilated at for the past five years. Most recent- Both gross inspection of the face 2:20 p.m. with one drop of 2.5% ly, she noticed that the spot had and anterior segment evaluation of phenylephrine hydrochloride and increased in size. We noted no asso- the lids were negative for lumps, Tropicamide (tropicamide 1%, ciated redness, itching or discharge. bumps or other abnormalities. Her Bausch + Lomb) O.U. She denied the presence of flashes, were clear, with no scar- A dilated posterior segment eval- floaters, transient visual obscura- ring, edema, neovascularization, uation of each eye revealed clear tions or headache. infiltrates or dendrites. The bul- crystalline lenses without opacifica- Excluding annual vision evalua- bar and palpebral conjunctivae tion or . No red tions by her primary care physician, were clear without evidence of or white cells were found in the this was our patient’s first compre- injection, chemosis, melanosis, vitreous of either eye, and there was hensive eye care examination. Her papillae or follicles. The anterior no evidence of posterior vitreous ocular and medical histories were chambers were deep and quiet, detachment or syneresis. negative for trauma or systemic dis- with no trace of cells or flare, The optic nerve measured ease. Additionally, her family medi- or hypopyon. 0.5mm in the horizontal and verti- cal and ocular histories were nega- The irides were brown in color; cal meridians and was pink, well tive for systemic disease, glaucoma, flat; and without transillumina- perfused and round, with distinct retinal detachments, age-related tion defects or other signs of margins O.U. No notching, bean- macular degeneration or other atrophy, tears, nodules or neo- podding, Drance hemorrhage or hereditary retinal disorders. vascularization. We detected no retinal nerve fiber layer loss was Further, the patient’s social his- posterior synechiae. noted in either eye. The disc had a tory was noncontributory. She is a was not performed. normal appearance without tilting, graduate student at a local universi- However, using Van Herick’s crescents or peripapillary atrophy ty and denied a history of smoking, method, we estimated her anterior O.U. The retinal vasculature in illicit drug use or ethanol consump- chamber angles to be grade 4—both each eye had a normal course and tion. The patient took no medica- nasally and temporally O.U. caliber, with an arteriole-to-venule tions and reported a drug allergy Both corneas were anesthetized ratio of 2:3. There were no signs to penicillin (rash). Although she with one drop of 0.5% propara- of arteriovenous nicking or venous was concerned about the change caine hydrochloride at 3:10 p.m. beeding O.U. in vision, the patient was oriented We also placed one strip of 0.6mg There were no signs of retinal to time, place and person, and had fluorescein sodium on the lower neovascularization, retinitis or a generally pleasant demeanor. fornix of each eye. We noted no underlying choroidal processes

APRIL 2012 REVIEW OF OPTOMETRY 21

001_ro0412 RetinaGuide.indd 21 4/12/12 9:41 AM RETINAL MELANOCYTOMA

mal. The lesions vary in Discussion size from pinpoint to Melanocytomas are rare. In several disc diameters, multiple published case studies, and may be found any- melanocytomas represented just where in the retina.3 five of 907 pigmented intraocular • Choroidal mela- tumors examined.6 Such darkly pig- noma. These lesions mented lesions are usually located almost always appear at the optic nerve head, but may elevated and are not as be found throughout the fundus.2,6 uniformly pigmented or Reflectivity on A-scan ultrasonog- 2. Optical coherence tomography scan revealed a superficial lesion O.D. as sharply demarcated raphy generally is high, with no sig- as CHRPE.3 Also, cho- nificant vascularization.4 These find- O.U. There were no retinal holes, roidal melanomas usually exhibit ings are significantly different from tears or detachments, and we growth. On A-scan ultrasonogra- melanoma, making differentiation obtained clear views to the ora ser- phy, the regular structure and low- relatively easy. rata at 360°. to-medium reflectivity are indicative We noted a darkly pigmented, of the characteristic homogenous This case illustrates the funda- well-defined lesion located nasal to cellular structure.4 mental importance of patient his- the macula and along the superior • Choroidal nevus. Choroidal tory, clinical observation and OCT arcade O.D. (figure 1). The left nevi are located deep to the RPE. studies in the diagnosis of retinal macula was unremarkable, and we They appear flat, and may range melanocytoma. OCT supported noted a positive foveal reflex O.U. from light to dark brown in color. the clinical impression that the We performed color fundus The borders are less well defined jet-black lesion with sharp borders photography O.D. Additionally, than CHRPE, and often have a was superficial, as seen with retinal we ordered an optical coherence feathery appearance (because shadowing. No vascularization was tomography (OCT) scan, which nevus cells extend along larger present. Given the clinical find- revealed a superficial lesion with choroidal vessels). and pig- ings, we believed that an A-scan retinal shadowing O.D. (figure 2). mentary modeling are often seen was not warranted. Following the OCT scan, we called on the surface of nevi, which sug- Again, there is no treatment for for a chair-side consultation with an gests chronicity.3 retinal melanocytoma. But, in any in-office retinal specialist. He exam- • Melanocytoma. These enti- suspected case, be certain to sched- ined the patient and agreed with ties have a similar appearance to ule the patient for regular checkups the working diagnosis of retinal that of nevi, save a jet-black color. to monitor progression. ■ melanocytoma. Melanocytoma may be found in Dr. Ball is a graduate of the University We recommended observation the , on the optic nerve, or of Houston College of Optometry and and informed the patient that throughout the fundus.3 a Fellow of the American Academy of the lesion was benign in nature— Optometry. He completed an optometric although it could grow slowly with Diagnosis residency at the University of Miami time. We did not provide the patient The final assessment of the Bascom Palmer Eye Institute. After resi- with a new spectacle prescription. patient is retinal melanocytoma. dency, Dr. Ball joined the staff at Beth Israel Deaconess Medical Center, a teach- Differential Diagnoses Treatment and Follow-up ing hospital of Harvard Medical School. The differential diagnoses con- Remember, there are no avail- He is also the associate director of medical sidered in this case include: able treatments for retinal mela- affairs for Vistakon, a division of Johnson • Congenital hypertrophy of nocytoma. Appropriate follow-up & Johnson Vision Care.

the retinal pigment epithelium includes yearly observation to 1. Dorland WN. Dorland’s Illustrated Medical Dictionary, 28th edi- (CHRPE). The typical fundus monitor for disease progression. tion. Philadelphia: Elsevier; 1994. 2. Zou Y, Ni C. Clinical and histopathological studies of melanocy- lesion is a solitary, round, flat, Almost all cases of melanocytoma toma of the optic disc. Yan Ke Xue Bao. 2000 Jun;16(2):112-5. 3. Schachat AP, Murphy RP, Patz AP. Retina Basic Science and hyperpigmented lesion that is well are benign with transformation Inherited Retinal Disease. St. Louis: The CV Mosby Company; 1989. demarcated from normal-appearing into malignant melanoma occur- 4. Hodes BL, Choromokos E. Standardized A-scan echographic 2,5 diagnosis of choroidal malignant melanomas. Arch Ophthalmol. retinal pigment epithelium (RPE). ring in only 1% to 2% of cases. 1977 Apr;95(4):593-7. 5. Murray TG. Bascom Palmer Eye Institute. Ocular Oncology: The color ranges from light brown If malignant transformation does Melanocytoma. Available at: www.eyecancermd.org/eye_cancers. to black. Clinically, the overlying occur, enucleation of the eye may html#melanocytoma (accessed March 26, 2012). 5 6. Howard GM, Forrest AW. Incidence and location of melanocyto- retina and vasculature appears nor- be considered. mas. Arch Ophthalmol. 1967 Jan;77(1):61-6.

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