# **Ophthalmology: Current and Future Developments** *Diagnostic Atlas of Retinal*

*Diseases*

*(Volume 1)*

# **Editors**

# **Mitzy E. Torres Soriano**

*Unidad Oftalmológica "Dr. Torres López". Centro Médico Cagua, Aragua, Venezuela*

# **Gerardo García Aguirre**

*Retina Department, Asociación para Evitar la Ceguera en Mexico, Mexico City, Mexico*

# **Co-Editors**

# **Maximiliano Gordon**

*Centro de la Visión Gordon Manavella, Rosario, Santa Fe, Argentina*

# **Veronica Kon Graversen**

*University of North Carolina at Chapel Hill, Chapel Hill, NC, USA*

### **Ophthalmology: Current and Future Developments**

*Volume # 1* 

*Diagnostic Atlas of Retinal Diseases* 

Editors: Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica

Kon Graversen

ISSN (Print): 2468-7162

eISSN (Online): 2468-7170

eISBN (Online): 978-1-68108-357-5

ISBN (Print): 978-1-68108-358-2

Published by Bentham Science Publishers – Sharjah, UAE.

© 201 by the Editor / Authors. Chapters in this eBook are Open Access and distributed under the Creative Commons Attribution (CC BY 4.0) license, which allows users to download, copy and build upon published chapters, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book taken as a whole is © 201 Bentham Science Publishers under the terms and conditions of the Creative Commons license CC BY-NC-ND.






# **FOREWORD**

Drs. Torres, García, Gordon and Kon deliver a very useful and practical work that contains, in this volume, a collection of images of retinal vascular diseases and macular diseases. The editors have recruited a vast array of retina specialists from four continents to write the different chapters that constitute this volume. The chapters are structured in such a way that the reader may easily find pearls about the diagnosis, differential and treatment, accompanied by beautiful pictures using different imaging modalities. Our subspecialty has had tremendous advances in recent years regarding diagnostic imaging, and I'm sure ophthalmologists and residents will find this compilation really useful and enjoyable.

### **Dr. Hugo Quiroz-Mercado**

Retina Department Asociación para evitar la Ceguera en Mexico Mexico City Mexico E-mail: hugoquiroz@yahoo.com

# **PREFACE**

We are honored to contribute to the information and education of ophthalmology students around the world. We have attempted to distill the current knowledge of medical practice and basic science retina research into a diagnostic atlas of retinal diseases. This is a quickreference atlas eBook of the retina, edited by specialists in the field, essential to any practicing ophthalmologist or resident who has more than a passing interest in diseases and treatment of the retina.

This e-book includes contributors from Mexico, Venezuela, Argentina, Brazil, United States, Denmark, Spain, Italy, Costa Rica and Peru. It is divided into three volumes: Volume I, retinal vascular diseases, choroidal neovascularization related diseases, vitreomacular interface, and other macular disorders; Volume II, traumatic retinopathies, diseases of vitreous, peripheral degenerations, retinal detachment, pediatric retinal diseases, and retinal dystrophies; and Volume III, posterior uveitis, tumors of the retina, and choroid.

This diagnostic atlas eBook of retinal diseases contains full-color, high quality images of the most frequent retinal pathologies with a brief and comprehensive review of retinal diseases. Each chapter includes essentials of diagnosis, differential diagnosis and treatment. The format is concise, well organized, and didactic, without being exhaustive.

We hope and expect that our atlas of retina will facilitate in providing patients with the best possible care.

### **ACKNOWLEDGEMENTS**

We would like to express our gratitude to Judy Soriano, who provided support with english composition and edition.

To our friends and colleagues without whose contribution would not have been possible to realize this project.

We also want to thank the staff of Bentham Science for their help and support and give us the opportunity to publish this eBook.

### **DEDICATION**

This e-book is specially dedicated to Guillermo Manuel Gordon, MD. He inspired us to always work hard and try our best. He was a friend and a recognized ophthalmologist of Rosario-Argentina, who died on May 2nd, 2015.

### **Dr. Mitzy E. Torres Soriano**

Unidad Oftalmológica "Dr. Torres López", Centro Médico Cagua, Aragua, Venezuela

### **Dr. Gerardo García Aguirre**

Retina Department, Asociación para Evitar la Ceguera en Mexico, Mexico City, Mexico

### **Dr. Maximiliano Gordon**

Centro de la Visión Gordon Manavella, Rosario, Santa Fe, Argentina

### **Dr. Veronica Kon Graversen**

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

# **List of Contributors**




*vi*

**CHAPTER 1**

# **Non-Proliferative Diabetic Retinopathy**

**Luis Felipe Rivero1,2,\*** and **Maximiliano Gordon<sup>3</sup>**

*1 Centro Clínico de Ojos Maracay, Maracay, Venezuela*

*2 Centro Oftalmológico Regional Aragua "Filippo Sindoni", Maracay, Venezuela*

*3 Centro de la Visión Gordon-Manavella, Rosario, Santa Fe, Argentina*

Diabetic retinopathy (DR) is the most frequent ocular complication in patients with diabetes mellitus. Its early and moderate stages are called non-proliferative diabetic retinopathy (NPDR). It is characterized clinically by the presence of one or more of the following signs: microaneurysms, intraretinal hemorrhages, intraretinal microvascular anomalies (IRMA), cotton-wool spots (CWS), hard exudates, and venous beading.

### **ESSENTIALS OF DIAGNOSIS**

The hallmark of DR is the development of microaneurysms, which are small dilations of the capillaries due to weakening of their walls and the loss of pericytes [1]. They appear clinically as tiny red dots in the retinal stroma, predominantly in and around the posterior pole. Eventually they may break, leading to the formation of intraretinal hemorrhages. When the broken microaneurysms are located in the most superficial layers of the retina, the hemorrhage will take a flame or splinter-like appearance, oriented along the nerve fiber layer. When they are located in the deeper layers, the hemorrhage will look like a red dot or blot. Clinically, microaneurysms and dot hemorrhages are indistinguishable (Fig. **1**), so they are referred to as hemorrhages and/or microaneurysms (H/Ma). Unless clotted, microaneurysms will show as hyperfluorescent points in a fluorescein angiogram (FA). They may or may not

<sup>\*</sup> **Corresponding author Luis Felipe Rivero:** Centro Clínico de Ojos Maracay, Av. José María Vargas N° 18, Maracay 2101, Edo. Aragua, Venezuela; Tel: +58(243) 241-8324/5243; E-mail: luife2020@hotmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

### **4** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*

leak dye depending on the integrity of their walls (Fig. **2**). In an optic coherence tomography (OCT), they appear as hyperreflective rings usually located in the middle retinal layers [2] (Fig. **3**). The smaller intraretinal hemorrhages will hardly show in the FA, while the larger ones block the dye (Fig. **4**). The largest intraretinal hemorrhages may be seen in an OCT as moderately hyperreflective masses located in the inner retinal layers.

**Fig. (1).** Intraretinal hemorrhages and microaneurysms. **Left**: Both deep intraretinal hemorrhages and microaneurysms (H/Ma) appear as small red points and dots. Some of them are pointed with arrows. **Right**: Superficial intraretinal hemorrhages have a splinter or flame shape (some of them are pointed with arrows). Note that superficial hemorrhages as well as CWS follow the striations of the nerve fiber layer.

Capillary wall damage will lead to leakage of fluids and macromolecules. These will accumulate in the retinal stroma producing macular edema, which can be observed as areas of thickening of the retina. Lipoproteins diffusing from microaneurysms or weakened capillaries will be trapped at the outer plexiform layer forming the so-called hard exudates. They are irregularly shaped yellowwhite spots located slightly deeper in the retina and may coalesce with each other, forming streaks, clusters or a circinate pattern centered on the leaking structure (Fig. **5**). They may accumulate in the center of the fovea forming a dense plaque, which carries a very bad visual prognosis [3]. They are not usually seen on a FA, except when they are extremely dense, causing minimum blockage of the dye. On the OCT they appear as markedly hyperreflective and irregular interstitial images with posterior shadowing (Fig. **6**).

*Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **5**

**Fig. (2).** Fluorescein angiogram showing microaneurysms. They can be observed as well-defined hyperfluorescent (white) dots, appearing in the early phases of the study. Non-leaking microaneurysms will remain as well-defined dots throughout the angiogram (some are circled in red). Leaking microaneurysms develop a hazy area around them that increases along the study (some are circled in yellow).

As diabetic retinopathy progresses, there will be further damage to the arterioles and capillaries, leading to progressive ischemia. Focal ischemia in the inner layers will result in the arrest of the axoplasmic flow with the subsequent dilation of the axons, constituting the so-called CWS [4]. Clinically they present as small superficial grey-white fluffy spots with feathery borders (Fig. **7**). They are usually located near the temporal arcades and near the disc in the nasal retina. They look hypofluorescent in the FA (Fig. **4**). In an OCT they appear as more or less pronounced focal thickenings of the nerve fiber layer with enhanced hyperreflectivity (Fig. **8**). Over some 6 to 12 months CWS will eventually fade, leaving almost no signs of their former presence but relative scotomata [5] and nicks in the inner retinal layers [6].

**6** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*

**Fig. (3).** OCT showing microaneurysms. Top: a large microaneurysm (white arrow) in the setting of a severe (center involving) macular edema. Bottom: note that normal vessels (yellow arrows) look very similar to microaneurysms (white arrows). However, normal vessels are usually found in the inner retinal layers (nerve fiber layer or ganglion cell layer), while microaneurysms are usually located in the middle retinal layers. In this case, they are all seen in the inner nuclear layer. The only way to positively differentiate one from the other is to see where the B scan passes in comparison with the fundus image.

**Fig. (4).** Fluorescein angiogram of both CWS and flame hemorrhages. Note that both produce blockage of the dye, although the hemorrhage does so more intensely.

**Fig. (5).** Hard exudates. Note that they usually form circinate patterns surrounding a group of microaneurysms and that they tend to coalesce.

*Fig. 6 contd.....*

*Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **7**

**8** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*

**Fig. (6). a**) In an OCT, hard exudates (black arrows) appear as highly hyperreflective and irregular images with posterior shadowing, usually located by the outer plexiform layer; **b**) In some cases they form streaks, especially around the fovea, in what constitutes a macular star (arrow shows one such streak); **c**) Hard exudates may migrate and accumulate in the center of the fovea, forming plaques. This case shows early migration of the lipids; **d**) These plaques may initiate an inflammatory response, leading to a retinal epithelial detachment with subjacent fibrosis (red arrow), which carries a very poor visual prognosis.

*Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **9**

**Fig. (7).** Cotton wool spots (arrows). Note their feathery borders and their distribution along the nerve fiber layer bundle.

**Fig. (8).** OCT of CWS. Note the severe thickening and reflectivity enhancement of the nerve fiber layer. Some vessels are seen passing through them. **Top**: Three adjacent CWS. **Bottom**: A single large CWS. They are typically located in the perifoveal area.

### **10** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*

In some cases, very small tortuous vessels may develop in the proximity of prior CWS or in other ischemic areas. These are called IRMA, and are very difficult to see clinically (Fig. **9**). It is not clear what their nature is, but they are probably intraretinal new vessels or perhaps intraretinal shunts bypassing non perfused areas [7].

**Fig. (9).** IRMAs appear clinically as very small, tortuous and hard to see thread-like vessels. This patient has multiple IRMAs in the inferior and nasal quadrants. Some of them are pointed with arrows.

The last sign of NPDR is venous beading, which is a succession of constrictions and thickenings of the vein walls and translates significant ischemia (Fig. **10**). This is the feature most strongly associated with progression to proliferative diabetic retinopathy [8]. As the capillary dropout increases it induces progressive venous dilatation followed by the appearance of small bumps on the veins, and finally, strictures will develop. Venous loops and sheathing may also appear.

### *Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **11**

**Fig. (10). Left**: Moderate, but significant venous beading. Arrows point to several constrictions. Center: Severe venous beading with several successive constrictions and dilations of the vein walls. **Right**: Very severe venous beading.

**Fig. (11).** Mild NPDR. Note that only a few microaneurysms can be seen in all four quadrants.

**Fig. (12).** Moderate NPDR. H/Ma, CWS, venous beading and hard exudates may be present, but do not meet severity criteria. Note that all four quadrants must be examined to establish the degree of severity.

## **Classification**

A simplified classification, the International Clinical Diabetic Retinopathy Disease Severity Scale, was published in 2003 to facilitate the staging in the clinical setting [9]. The part of the scale pertaining NPDR is shown in the following table (Table **1**).

*Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **13**

**Table 1. International clinical diabetic retinopathy disease severity scale.**


Proposed by the Global Diabetic Retinopathy Project Group [9].

**Fig. (13).** Severe NPDR. In this case, more than 20 H/Ma can be counted in each of the four quadrants, along with several CWS and some hard exudates.

### **DIFFERENTIAL DIAGNOSIS**

Most ischemic diseases may mimic diabetic retinopathy. Especially important are those pathologies that frequently concur with it, such as vein occlusions [10] **14** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*

(Fig. **14**), hypertensive retinopathy [11], ocular ischemic syndrome [12] and subretinal neovascular membranes [13].

**Fig. (14).** Central vein occlusion simulating a severe NPDR in a diabetic patient. Venous tortuosity and asymmetry with the other eye helped determine the right diagnosis.

Other diseases that should be considered include retinal macro aneurysms, macular telangiectasias [14], radiation retinopathy [15], autoimmune retinopathies (such as systemic lupus erythematosus and antiphospholipid syndrome) [16], neoplasms (leukemia, lymphomas), HIV retinopathy, sickle cell disease [17], Eales disease and CMV retinitis [18]. Usually the differential diagnosis is straightforward when the patient is not diabetic or it is based on an examination of the patient's past medical history.

*Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **15**

## **MANAGEMENT**

The most important measure to prevent the appearance or to slow down the progression of diabetic retinopathy is to optimize the metabolic control of the patient [19 - 21]. This includes keeping both fasting and postprandial glycemic levels within normal limits, hemoglobin A1c below 7%, normal serum lipids, and a good, though not necessarily strict [22] control of blood pressure. Frequent exercise, a healthy diet, a normal body mass index and avoiding tobacco may also aid in maintaining a good metabolic control [23, 24]. Fenofibrate at 200 mg/d has been shown to slow the progression of DR and should be considered to treat it [22, 25].

Periodic controls are warranted to assess the evolution of the disease and to determine the development of macular edema or proliferative retinopathy, which would require treatment. Mild NPDR should be followed once a year, moderate every six to 12 months, and severe quarterly [26].

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

## **REFERENCES**


### **16** *Ophthalmology: Current and Future Developments, Vol. 1 Rivero and Gordon*


### *Non-Proliferative Diabetic Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **17**


[http://dx.doi.org/10.1016/S0140-6736(98)07019-6] [PMID: 9742976]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 2**

# **Proliferative Diabetic Retinopathy (PDR)**

**Maria H. Berrocal1,\*** and **Luis A. Acabá<sup>2</sup>**

*1 Berrocal & Asociados, San Juan, Puerto Rico*

*2 Sidney Kimmel College of Medicine, Philadelphia, PA, USA*

### **ESSENTIALS OF DIAGNOSIS**

Proliferative diabetic retinopathy (PDR) occurs as a progression of severe diabetic vascular damage and includes intraretinal capillary closure with resultant ischemia and the formation of new vessels (Figs. **1**-**3**). Severe non-proliferative diabetic retinopathy is the precursor of PDR. It includes diffuse intraretinal hemorrhages in 4 quadrants, venous beading in 2 quadrants or more and intra-retinal microvascular abnormalities (IRMA) in 1 quadrant. The chance of progression to PDR in 1 year is between 15% and 45% [1, 2].

Severe NPDR can be confused with PDR. Fluorescein angiography is the best way to differentiate IRMA from neovascularization as the latter shows significant leakage throughout the study. The evolution of new vessels starts with fine vessels with minimal fibrosis, then an increase in vessel size and fibrous tissue, and then the end stage of PDR which includes regressed vessels and significant fibrovascular proliferation on the posterior hyaloid. Vitreous hemorrhage and subhyaloid hemorrhage can result from PDR.

### **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis includes NPDR particularly when many IRMAs are present, other retinovascular diseases like vein occlusions, sickle cell retinopathy,

<sup>\*</sup> **Corresponding author Maria H. Berrocal:** 150 Ave De Diego Ste 404, San Juan, 00907, Puerto Rico; Tel: (787) 725-9315; E-mail: mariahberrocal@hotmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

### *Proliferative Diabetic Retinopathy (PDR) Ophthalmology: Current and Future Developments, Vol. 1* **19**

leukemic retinopathy, hypertensive retinopathy, radiation retinopathy, retinal vasculitis, sarcoidosis, and ocular ischemic syndrome. Differences in the clinical picture and fluorescein angiographic appearance are usually sufficient to discriminate bet-ween these entities.

**Fig. (1). A**. Red-free image of the right eye of a 35 year-old male with prominent neovascularization in the posterior pole; **B**. Red-free image of the left eye in the same patient, showing neovascularization and exudates.

**Fig. (2-I).** 66-year-old male with type 1 diabetes mellitus and proliferative diabetic retinopathy. **A**. Early fluorescein angiography (FA) of the right eye showing multiple areas of capillary dropout and ischemia, including the foveal area with enlarged foveal avascular zone. One area of NVE is present in the superotemporal arcade; **B**. FA of the nasal retina with severe ischemia and capillary leakage; **C**. Late FA of the same eye, showing diffused leakage in the posterior pole; **D**. OCT of retinal area near neovascularization showing areas of localized tractional retinal detachment.

**Fig. (2-II). E**. Image of the left eye, with prominent neovascularization in the disc; **F**. Early FA showing intense staining of the neovascularization in the disc; **G**. FA of the temporal retina, showing severe capillary dropout throughout the retina with diffused staining and microaneurysms; **H**. OCT of the fovea showing macular edema with a large cyst.

**Fig. (3).** 35-year-old female with type 1 diabetes mellitus. **A**. Fundus photograph showing very prominent neovascularization throughout the posterior pole; **B**. Same eye one week after 1.25 mg intravitreal bevacizumab, with marked regression of neovascularization.

*Proliferative Diabetic Retinopathy (PDR) Ophthalmology: Current and Future Developments, Vol. 1* **23**

## **MANAGEMENT**

Medical management includes optimizing diabetic control to prevent progression. Conditions that can cause worsening of PDR include hypertension, anemia, pregnancy and renal disease [1 - 4]. The Diabetes Control and Complications trial (DCCT) showed that intensive glycemic control reduces the progression of PDR [2].

The mainstay of treatment for high-risk PDR is scatter laser photocoagulation in a pan retinal distribution (Figs. **4** and **5**). This results in regression of neovascular vessels and prevents progression of the disease [5, 6]. High risk PDR includes any of these: 1. -mild neovascularization of the disc (NVD) with vitreous hemorrhage (VH); 2. -moderate to severe NVD with or without hemorrhage; 3. -moderate (1/2 disc area) neovascularization elsewhere (NVE) with VH. Another definition of high risk includes any three of: 1.-vitreous or pre-retinal hemorrhage; 2.- presence of new vessels; 3.- new vessels on or near optic nerve (ON); 4.-moderate or severe neovascularization.

**Fig. (4A).** 40-year-old female with tractional retinal detachment. **A**. Preoperative image showing fibrovascular tissue throughout the arcades.

**24** *Ophthalmology: Current and Future Developments, Vol. 1 Berrocal and Acabá*

**Fig. (4B).** Postoperative image showing flattened retina, laser photocoagulation scars in the periphery and residual hemorrhage in the inferior arcade.

**Fig. (5).** 27 year-old female with type 1 diabetes mellitus. **A**. Fundus photograph of the right eye showing neovascularization in the superotemporal arcade, hard exudates and microaneurysms in the posterior pole; **B**. FA showing neovascularization with leakage, venous beading and capillary dropout; **C**. Fundus photograph of the same eye 8 months later, after panretinal photocoagulation was applied, with some fibrosis in the superotemporal arcade; **D**. FA showing increased neovascularization, venous beading and capillary closure.

*Proliferative Diabetic Retinopathy (PDR) Ophthalmology: Current and Future Developments, Vol. 1* **25**

**Fig. (5). E**. Fundus photograph of the same eye 11 months after photocoagulation, with a tractional retinal detachment and massive neovascularization throughout the posterior pole; **F**. Nasal view of the same eye; **G**. Fundus photograph 3 months after vitrectomy with preoperative bevacizumab.

Full PRP is defined as 1,200 or more 500µm spots separated by 1/2 burn width and 0.1s duration. This can be performed in 1 or 2 sessions.

### **26** *Ophthalmology: Current and Future Developments, Vol. 1 Berrocal and Acabá*

Surgical management of PDR is performed when there is persistent or severe VH and or traction retinal detachment threatening the fovea. The Diabetic Retinopathy Vitrectomy Study (DRVS) results showed a greater benefit of early vitrectomy in VH eyes in type 1 diabetics, and in very severe PDR (Figs. **4**-**7**) [7].

The advent of VEGF inhibitor therapy for many conditions has made its use appealing in the treatment of diabetic retinopathy (Fig. **3**). Although the benefit of these agents has been validated for the treatment of diabetic macular edema, panretinal photocoagulation remains the mainstay of treatment of PDR.

**Fig. (6).** Tabletop neovascular fibrovascular proliferation in an eye with a tractional retinal detachment.

*Proliferative Diabetic Retinopathy (PDR) Ophthalmology: Current and Future Developments, Vol. 1* **27**

**Fig. (7).** 36-year-old with type 1 diabetes mellitus and no prior laser photocoagulation. **A**. Massive fibrovascular proliferation causing circumferential traction and a combined rhegmatogenous-tractional retinal detachment: **B**. Peripheral view of fibrovascular sheet with very large neovascular vessels.

**28** *Ophthalmology: Current and Future Developments, Vol. 1 Berrocal and Acabá*

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Diabetic Macular Edema**

**Maximiliano Gordon1,2,\*** and **Mitzy E. Torres Soriano1,2,3**

*1 Centro de la Visión Gordon-Manavella, Rosario, Santa Fe, Argentina*

*2 Retina Department, Ophthalmology Service, Hospital Provincial del Centenario, Rosario, Santa Fe, Argentina*

*3 Unidad Oftalmológica "Dr Torres López", Centro Médico Cagua, Aragua, Venezuela*

Diabetic macular edema (DME) is the main cause of visual loss in diabetic patients. It may present at every stage of diabetic retinopathy.

The systemic risk factors identified for DME are hyperglycemia, arterial hypertension, hyperlipidemia, kidney failure and anemia [1, 2].

### **ESSENTIALS OF DIAGNOSIS**

Diabetic macular edema is diagnosed with a detailed bio-microscopic examination with the slit lamp and indirect ophthalmoscopy.

The Early Treatment Diabetic Retinopathy Study (ETDRS) described DME as retinal thickening or hard exudates (consisting of lipoproteins) within 1 disk diameter of the center of the macula (Figs. **1**, **2**, **4a**, **5a-b**, **6a**, **8**, **11a**).

The term clinically significant macular edema (CSME) indicates the severity of macular edema and is used for treatment guidelines. CSME is characterized by: 1) thickening of the retina within 500 µm of the macular center; 2) hard exudates at the center of the retina or within 500 µm with thickening of adjacent retina; and 3) one or more disc diameters of retinal thickening, part of which is within one disc diameter of the center of the macula [3].

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Maximiliano Gordon:** Centro de la Vision Gordon - Manavella, Montevideo 763, CP 2000, Rosario - Santa Fe, Argentina; Tel: +54 (0341) 4 400 239; E-mail: maximilianogordon19@gmail.com

**30** *Ophthalmology: Current and Future Developments, Vol. 1 Gordon and Torres Soriano*

**Fig. (1).** Fundus photograph of CSME in both eyes. Microaneurysms, hard exudates and retinal hemorrhages are shown.

**Fig. (2).** Fundus photograph of severe and clinically significant diabetic macular edema in both eyes.

In 2002, the American Academy of Ophthalmology proposed an international classification of DME (Table **1**): DME absent: absence of retinal thickening or hard exudates in the posterior pole. DME present: some retinal thickening or hard exudates in the posterior pole.



Program and abstracts of the American Academy of Ophthalmology 2002 [4].

### *Diabetic Macular Edema Ophthalmology: Current and Future Developments, Vol. 1* **31**

Classically, three different types of DME can be observed in fluorescein angiography (FA): 1) focal leakage: well-defined focal area of leakage from micro-aneurysms or dilated capillaries (Figs. **3**-**6**); 2) diffuse leakage: widespread leakage from IRMA, retinal capillary bed (Fig. **7**); and 3) diffuse cystoid leakage: diffuse leakage and pooling of dye in the cystic spaces of the macula in the late phase of the angiogram [5]. However, one of the most important utilities of the angiography is to roll out macular ischemia (Fig. **7**). It has long been considered that ischemic changes and microvascular pathologies are key in the development of DME. In diabetic retinopathy, peripheral ischemia leads to an increased production of vascular endothelial growth factor (VEGF), which can result in the breakdown of blood-retinal barriers, thus increasing retinal vessel permeability and causing DME. These areas can be detected using ultra-wide field fluorescein angiography [6].

**Fig. (3).** FA of the same patient as shown in Fig. (**1**). (**a-b**) Multiple hyperfluorescent points due to mycroaneurisms with mild leakage in late phases (**c-d**).

**Fig. (4).** Fundus photograph (**a-b**) and FA (**c-d**) of focal diabetic macular edema. OCT showing focal increased macular thickness and cystoid macular edema (**e-f**).

**Fig. (5).** (**a-b**) CSME with abundant and confluent hard exudates involving fovea. (**c-d**) FA shows multiple hyperfluorescent points due to microaneurysms with mild leakage in late phases (**e-f**).

### **34** *Ophthalmology: Current and Future Developments, Vol. 1 Gordon and Torres Soriano*

**Fig. (6).** (**a**) Fundus photograph of DME in right eye. (**b-d**) FA shows hyperfluorescent points with mild leakage in late phases.

**Fig. (7).** (**a**) Fundus photograph reveals retinal round hemorrhages and hard exudates in a diabetic female patient. (**b-c**) FA shows hypofluorescence from capillary dropout, typical of ischemic diabetic maculopathy and (**d**) late hyperfluorescence due to diffuse perivascular leakage.

OCT has shown four important changes in neurosensory retinal structure: cystoid macular edema (CME) (Figs. **4e-f**, **8** and **10**), swelling of the retina (Figs. **9** and **10**), serous retinal detachment (Fig. **11b**), and retinal traction (Fig. **12**) [5].

**Fig. (8).** Cystoid diabetic macular edema with a significant amount of hypereflective foci that correspond to hard exudates.

**Fig. (9).** 59 year-old male patient with insulin dependent diabetes mellitus and diabetic retinopathy. Spectral domain-optical coherence tomography showing (**a**) focal cystoid diabetic macular edema in his right eye; and (**b**) diffuse diabetic macular edema showing retinal swelling and cystoid spaces in his left eye. Visual Acuity: OD 20/25 OS 20/200.

*Diabetic Macular Edema Ophthalmology: Current and Future Developments, Vol. 1* **37**

**Fig. (10).** Spectral domain-optical coherence tomography showing diffuse diabetic macular edema, intraretinal dense hard exudates with posterior shadow and hypo-reflective outer retinal layers.

### **38** *Ophthalmology: Current and Future Developments, Vol. 1 Gordon and Torres Soriano*

**Fig. (11).** (**a**) Fundus photograph of CSME; (**b**) OCT shows small and medium cystoid intraretinal spaces and subretinal serous detachment.

**Fig. (12).** Spectral domain-optical coherence tomography showing diabetic macular edema with vitreoretinal traction component.

## **DIFFERENTIAL DIAGNOSIS**

Other causes of macular edema may be hypertensive retinopathy (it can coexist), vein occlusion (central vein or branch), pseudophakic macular edema, uveitis (anterior or posterior), radiation retinopathy, and active choroidal neovascularization.

## **MANAGEMENT**

Of the utmost necessity is the strict control of diabetes, hypertension, and hypercholesterolemia.

Diabetic macular edema is usually a chronic disease. Although sometimes spontaneous recovery is possible, patients that do not receive treatment will experience a moderate visual loss (15 or more letters on the ETDRS chart) within 3 years in 24% of CSME cases and in 33% of center-involving CSME cases [7 - 9].

Laser Photocoagulation: In the ETDRS, grid laser treatment in diffuse macular edema revealed that treated eyes showed improved visual acuity in 16% of cases, remained unchanged in 77% of cases, and worsened in 7% of cases, while these results changed to 11%, 73%, and 16%, respectively, after 2 years of follow-up [3]. Therefore, these results did not show substantial benefit in treated eyes [10]. However, in patients with focal DME, a focal laser pattern is used for the treatment of leaking micro-aneurysms revealed by the FA.

Steroids: Some reports suggest the beneficial effects of subtenon or peribulbar steroid injection therapy for DM [11, 12]. Intravitreal injection of triamcinolone acetonide is a treatment option for patients with DME who do not respond to laser photocoagulation. The most frequent ocular adverse effects associated to corticosteroids are glaucoma and cataract. Actually, some fluocinolone acetonide implants and dexamethasone long standing delivered intravitreal implants were approved for DME treatment [5, 10, 13, 14].

Anti-VEGF therapy: Blockage of VEGF has shown to reduce vascular permeability [5]. Intra-vitreous injection of anti-VEGF agents has been proven to be a relatively safe treatment option for diabetic edema (Fig. **13**) and more effective than laser photocoagulation of the macula. The most commonly used VEGF inhibitors are aflibercept (Eylea, Regeneron Pharmaceuticals), ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) [15]. The first two are approved for intraocular use by the FDA. Bevacizumab is not approved for intraocular treatment, but it is used as an off-label therapy.

### *Diabetic Macular Edema Ophthalmology: Current and Future Developments, Vol. 1* **41**

**Fig. (13).** 60 year-old male patient with diabetic retinopathy. Spectral domain-optical coherence tomography showing (**a**) diabetic macular edema; and (**b**) resolution after repeated intravitreal bevacizumab in his right eye. Retinal thickness is significantly decreased.

Micro-pulse laser is a treatment option for DME [16 - 18] that produces multiple short exposure burns localized to the apical portion of the RPE, with minimal effects to the surrounding structures [5].

Pars plana vitrectomy may be used to remove vitreomacular traction, which can reduce the concentration of DME-promoting factors and also improve the fluid currents and thus the inner retinal oxygenation [5].

The management of DME remains complex, so a combined treatment approach is often necessary in order to address the persistence of fluid within the macular region.

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### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


trial. J Ophthalmic Vis Res 2014; 9(4): 453-60. [http://dx.doi.org/10.4103/2008-322X.150818] [PMID: 25709771]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Central Retinal Vein Occlusion**

**Nelson Segovia Rodríguez\***

*Retina Department, Grupo de Clínicas IDB, Centro Profesional Arca, Barquisimeto, Venezuela*

Central retinal vein occlusion (CRVO), a member of the group of vascular retinal diseases, is a sight-threatening condition that needs to be correctly diagnosed and treated in order to diminish its consequences, which can lead to painful blindness if neovascular glaucoma (NVG) develops. CRVO occurs predominantly in adults of 65 years old and over [1]; the prevalence does not differ by gender [2], and it is predominantly unilateral [3]. Some described systemic risk factors are end-organ damage from hypertension or diabetes, a hypercoagulable state, and a diagnosis of stroke or obstructive sleep apnea [4, 5]. The most described ocular risk factor is glaucoma. Patients with CRVO also show an increased (almost two-fold) incidence in cerebrovascular accidents compared with age and sex-matched controls in a US population [6].

### **ESSENTIALS OF DIAGNOSIS**

Fortunately, this is a relatively easy condition to diagnose based mostly on its clinical features. CRVO commonly presents as a sudden and painless loss of vision. Occasionally, the vision loss occurs gradually, mostly happens at night time in the recumbent position probably by low blood pressure and/or high central venous pressure. The typical fundoscopic features appear in all the four quadrants of the fundus: venous tortuosity and dilation, retinal hemorrhages (scattered superficial and deep), and cotton wool spots (Figs. **1**-**3**). Macular edema and optic disc swelling are also present. All these features are present in varying degrees depending on the severity of the occlusion. Long-standing CRVO should be

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Nelson Segovia Rodríguez:** Retina Department, Grupo de Clínicas IDB, Centro Profesional Arca, Barquisimeto, Venezuela; Tel: +57(315)5929618; Email: nelsegovia@yahoo.com

*Central Retinal Vein Occlusion Ophthalmology: Current and Future Developments, Vol. 1* **45**

suspected if occluded or sheathed retinal veins are observed, or if vascular anastomoses (known as optociliary collaterals) at the optic disc are detected (Fig. **4**).

**Fig. (1).** Central Retinal Vein Occlusion. Fundus photograph shows tortuosity and dilatation of all branches of the central retinal vein, dot and flame-shaped hemorrhages, macular edema and optic nerve head cupping is noted. (Courtesy of Mitzy E. Torres Soriano).

**Fig. (2).** Fundus photograph showing massive intraretinal hemorrhages, venular tortuosity, cotton wool spots and macular edema, corresponding to an ischemic CRVO.

**Fig. (3).** Red-free photograph shows the typical features of CRVO, corresponding to a non-ischemic CRVO.

**Fig. (4).** Eye fundus of a patient with long standing CRVO demonstrating optociliary shunts vessels (optociliary collaterals) in the optic nerve head, and panretinal photocoagulation.

CRVO can be divided into 2 clinical types, ischemic and non-ischemic. Nonischemic CRVO (Figs. **3**, **5**, **6**) is the most common type, accounting for about 75% CRVO cases. Non-ischemic CRVO is characterized by mild to moderate loss of acuity, usually 20/200 or better, and an absent or mild relative afferent pupillary defect. Conversion to ischemic CRVO occurs in 15% of cases within 4

### **46** *Ophthalmology: Current and Future Developments, Vol. 1 Nelson Segovia Rodríguez*

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months and 34% within 3 years. Ischemic CRVO (Figs. **2**, **7**, **8**) is characterized by severe visual loss (20/200 or worse), a marked afferent pupillary defect, extensive typical fundoscopic features (Fig. **7**), poor perfusion to retina, and presence of severe electroretinographic changes [7].

In addition to the general clinical assessment made by the patient's physician, including a complete blood count, renal function (serum levels of urea and creatinine), fasting serum lipids and fasting serum levels of glucose and glycated hemoglobin, a complete evaluation should include:

**Fig. (5).** Non-ischemic CRVO. Fundoscopy shows tortuosity and dilatation of all branches of the central retinal vein, dot/blot and flame-shaped hemorrhages, throughout all four quadrants. (Courtesy of Mitzy E. Torres Soriano).

**Fluorescein Angiography (FA):** Fluorescein angiography (FA) reveals marked delay in arteriovenous transit time, which is longer than 20 seconds, masking by retinal hemorrhages, vessel wall staining, leakage and perfusion status (greater than 10 disc areas of retinal capillary non-perfusion is the ischemic form) [7, 8] (Figs. **6**, **8**-**11**).

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**Fig. (6).** Fluorescein angiography of (Fig. **5**). It reveals delay in arteriovenous transit time, blockage from retinal hemorrhages, vessel wall staining; in late phases cystoid macular edema (petalloid appearance) and optic nerve staining. (Courtesy of Mitzy E. Torres Soriano).

**Fig. (7).** Ischemic CRVO. Fundoscopy showing extensive hemorrhages in the posterior pole and giving the "blood and thunder appearance". (Courtesy of Mitzy E. Torres Soriano).

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**Fig. (8).** Fluorescein angiography of the eye showing in Fig. (**7**), showing hypofluorescence due to blockage from hemorrhages in the retina, capillary non perfusion and areas of capillary leakage. (Courtesy of Mitzy E. Torres Soriano).

**Fig. (9).** Fluorescein angiography (FA) image showing optic nerve head swelling, engorged venules, hypofluorescence by blockage and capillary non-perfusion.

**Fig. (10).** FA image shows closely the capillary dilation in the optic nerve head and vessel wall staining.

**Fig. (11).** FA of the mid-periphery showing zones of non-perfusion and capillary abnormalities.

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**Optical Coherence Tomography (OCT):** Optical Coherence Tomography (OCT) images reveal that the increased retinal thickness is caused mostly by large cystoid spaces in the inner nerve layer of the foveal region and diffuse intraretinal edema of the foveal and perifoveal areas [7, 9] (Figs. **12**, **13**).

**Fig. (12).** Optical coherence tomography (OCT) of a patient with CRVO and associated macular edema showing a central field retinal thickness of 794 microns.

**Fig. (13).** OCT report of the same patient of Fig. (**12**) shows some clinical features of CRVO like intra retinal hemorrhages and venous tortuosity. In the OCT image, increased retinal thickness, intra retinal cystoid spaces of different sizes and neurosensory retina detached from retinal pigment epithelium can be observed (serous retinal detachment or subretinal fluid).

**Electroretinogram (ERG):** Electroretinogram (ERG) shows reduced scotopic and photopic b-wave amplitude in the ischemic form. Another important predictor of neovascularization is a delayed implicit time in the photopic 30Hz flicker ERG.

## **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis of CRVO is not a difficult task. Other pathologies such as diabetic retinopathy, hypertensive retinopathy, and hyperviscosity syndromes occur bilaterally. If CRVO occurs bilaterally, a careful clinical systemic examination should be done. Other entities that should be ruled out are anterior ischemic neuropathy and ocular ischemia with venous stasis retinopathy [10] caused by severe carotid artery obstructive disease. Most difficulties in the differential diagnosis are encountered with early, mild non-ischemic CRVO and late forms and complications that can mimic other conditions.

## **MANAGEMENT**

Treatment of CRVO is mainly focused on macular edema and also on NVG. Many treatment options have been tried through the years from systemic, local (ocular medication) to surgical ones. The objective of this chapter is only to name a few of them, focusing on the actual trends.

Panretinal photocoagulation (PRP) (Fig. **4**) is indicated in the case of iris or angle neovascularization. In the case of optic disc neovascularization or neovascularization elsewhere, PRP also should be performed in order to avoid anterior segment neovascularization and the consequent NVG. It has been fully established in the CVOS Study that prophylactic treatment does not prevent iris and angle neovascularization. Furthermore, regression of iris and angle neovascularization in response to PRP is more likely to occur in eyes that have not been treated previously [11]. The main treatments for macular edema are intravitreal injections of ranibizumab, aflibercept, dexamethasone intravitreal implant, and off-label use of bevacizumab and triamcinolone. Ranibizumab showed to be effective, improving the best corrected visual acuity (BCVA) by 15 letters compared to placebo injections at six months [12, 13]. This improvement was also true with the use of bevacizumab [14]. Aflibercept also showed an improvement of BCVA, and this result was largely maintained between 6 to 12 months [15]. This evidence, based on randomized clinical trials, shows the important role of anti-vascular endothelial grow factor (anti-VEGF) in the treatment of CRVO (Fig. **14**). Dexamethasone intravitreal implants improved

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**Fig. (14).** Response to anti-VEGF treatment for macular edema secondary to CRVO. Top: OCT of an eye with non-ischemic CRVO, showing accumulation of intraretinal fluid and a subfoveal serous retinal detachment. Visual acuity was 20/40 Bottom: OCT of the same eye, after four doses of 1.25 mg intravitreal bevacizumab, showing resolution of intra and subretinal fluid. Visual acuity improved to 20/20. (Images courtesy of Gerardo Garcia-Aguirre, MD).

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mean BCVA at 1, 2 and 3 months, but not at six months compared to placebo [16]. With the use of triamcinolone, the percentage of patients with a gain of BCVA of 15 letters or more was 26.5%, 25.6% and 6.8% for triamcinolone 1 mg, 4 mg and placebo, respectively. Both triamcinolone concentrations stabilized visual acuity at month 12 [17]. By comparing the issues of secondary effects between the use of anti-VEGF drugs and steroids, it has been observed that in the latter group the rise in intraocular pressure and rate of cataract progression were higher than in control groups [16, 17]. A study from the European Vitreoretinal Society also suggests that vitrectomy with internal limiting membrane peeling may be a good treatment for macular edema due to CRVO. In this study, the improvement of vision was better than other therapies at every time point in time [18]. In future, randomized clinical trials are needed to verify these results and establish a standard of care for the treatment of macular edema secondary to CRVO.

**Follow up:** Patients with CRVO should be seen monthly for 6 months to detect the onset of anterior segment neovascularization and to establish prompt treatment.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


### **56** *Ophthalmology: Current and Future Developments, Vol. 1 Nelson Segovia Rodríguez*

[PMID: 11190017]


2010; 117(6): 1134-1146.e3. [http://dx.doi.org/10.1016/j.ophtha.2010.03.032] [PMID: 20417567]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 5**

# **Branch Retinal Vein Occlusion**

**Liriany Arrieta Ruiz<sup>1</sup>** and **Gerardo García Aguirre2,\***

*1 Unidad Popular de Ojos (UPO), Maracay, Venezuela*

*2 Retina Department, Asociación para Evitar la Ceguera en Mexico, Mexico City, Mexico*

Branch Retinal Vein Occlusion (BRVO) is a common retinal vascular disease caused by the occlusion of one of the branches of the central retinal vein, affecting only a portion, typically a quadrant, of the posterior pole [1]. It is three times more common than the central retinal vein occlusion, and onset usually occurs in the elderly. There are some risks factors for its development: hypertension, cardiovascular disease, obesity and open angle glaucoma.

### **ESSENTIALS OF DIAGNOSIS**

Patients usually complain of a sudden onset of blurred vision or central visual field defect.

Upon ophthalmologic examination, typical findings include superficial hemorrhages, which are usually flame-shaped, retinal edema, and cotton-wool spots in a sector of retina drained by the affected vein (Figs. **1**-**3**). The horizontal raphe is respected.

In the chronic stage (Fig. **4**), hemorrhages may be absent and macular edema with telangiectatic vessels can be observed, extending across the horizontal raphe. The quadrant most commonly affected is the superotemporal (63%) [2].

<sup>\*</sup> **Corresponding author Gerardo García Aguirre:** Retina Department, Asociación para Evitar la Ceguera en Mexico, Vicente García Torres 46, San Lucas Coyoacan, Mexico City 04030, Mexico; Tel: +52 (55) 10841400; Email: jerry\_gar\_md@yahoo.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

**Fig. (1).** Flamed-shaped hemorrhages and retinal edema in superior macular area. (Courtesy of Gerardo Garcia Aguirre (Mexico)).

**Fig. (2).** Retinal hemorrhages, cotton-wool spots and sclerotic vessels in inferotemporal BRVO. (Courtesy of Gerardo Garcia Aguirre (Mexico)).

**Fig. (3).** Intraretinal hemorrhages in the superotemporal area and macular edema. (Courtesy of Gerardo Garcia Aguirre (Mexico)).

**Fig. (4).** Left eye: Chronic superior temporal branch retinal vein occlusion, sclerotic vessels and neovascularization. Courtesy of Luis Miguel Suarez Tata MD (Venezuela).

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BRVO can be subdivided as ischemic or non-ischemic; the non-ischemic type is associated with a more favorable prognosis. This classification is based on findings observed in a fluorescein angiogram (FA). Non-ischemic BRVO is defined as the absence of retinal neovascularization and areas of capillary non-perfusion that amount to less than 5 disc areas. Ischemic BRVO is characterized by 5 or more disc areas of capillary non-perfusion and/or the presence of retinal neovascularization. Retinal neovascularization may lead to vitreous hemorrhage.

FA and optical coherence tomography (OCT) are helpful diagnostic tools. Findings in FA include delayed venous filling, hypofluorescence caused by hemorrhages and capillary non-perfusion, dilation and tortuosity of veins, leakage in case of neovascularization and macular edema (Figs. **5**-**8**). OCT is used as a rapid and noninvasive way of monitoring macular edema (Fig. **9**). Eyes may present cystoid macular edema and serous retinal detachment extending into the fovea.

**Fig. (5).** FA shows hypofluorescence caused by hemorrhages and areas of capillary non-perfusion (\*Courtesy by Claudia Arrieta).

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**Fig. (6).** FA shows areas of capillary non-perfusion, dilatation of veins, retinal telangiectasias and neovascularization. Courtesy of Gerardo Garcia Aguirre (Mexico).

**Fig. (7).** FA: Ischemic BRVO. Hypoflourescence caused by hemorrhages, capillary non perfusion and delayed venous filling, dilatation and tortuosity of veins. Areas of non-perfusion exceed 5 disc areas (\*Courtesy by Claudia Arrieta).

**Fig. (8).** Secondary retinal telangiectasias in an eye with history of inferotemporal BRVO (\*Courtesy by Claudia Arrieta).

**Fig. (9).** OCT: Cystoid macular edema and serous retinal detachment secondary to BRVO (\*Courtesy by Claudia Arrieta). (\*) FA and OCT were performed by Claudia Arrieta MD (Venezuela).

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## **DIFFERENTIAL DIAGNOSIS**

The principal differential diagnoses are diabetic retinopathy and hypertensive retinopathy.

## **MANAGEMENT**

Management is directed towards the most significant complications of BRVO: macular edema and retinal neovascularization [3].

Macular edema may be managed expectantly for a short period of time (usually up to 30 days), since some cases may regress spontaneously. The BVOS study demonstrated that macular grid laser photocoagulation was helpful for eyes with vision of 20/40 or worse [4, 5]. The current gold-standard for treatment, however, is the injection of intravitreal anti-VEGF agents. All three available agents (ranibizumab [6, 7], aflibercept [8] and bevacizumab [9]) have proven to be safe and effective for the treatment of macular edema, with significant reduction of macular thickness and improvement in visual acuity (Fig. **10**). Intravitreal steroids such as triamcinolone [10] or dexamethasone [11] have also proven to reduce macular edema secondary to BRVO, although results are not as favorable as the ones obtained with anti-VEGF agents, with the additional concern of side effects such as cataract or intraocular pressure elevation.

Eyes with retinal neovascularization should be treated with retinal laser photocoagulation directed toward areas of capillary non-perfusion observed in FA, to decrease the risk of vitreous hemorrhage and tractional retinal detachment [5].

Pars-plana vitrectomy should be considered in eyes with persistent vitreous hemorrhage, tractional retinal detachment or epiretinal membrane.

**Fig. (10).** Response to anti-VEGF treatment for macular edema secondary to an inferotemporal BRVO. Top: OCT of an eye with non-ischemic BRVO, showing accumulation of intraretinal fluid and a subfoveal serous retinal detachment Note the sparing of the superior macula (right side of the image). Visual acuity was 20/60 Bottom: OCT of the same eye, after three doses of 1.25 mg intravitreal aflibercept, showing resolution of intra and subretinal fluid. Visual acuity improved to 20/20 (Images courtesy of Gerardo Garcia-Aguirre, MD).

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[http://dx.doi.org/10.1016/j.ophtha.2009.07.017] [PMID: 20022117]

[3] Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol 2010; 4: 809-16.

[http://dx.doi.org/10.2147/OPTH.S7631] [PMID: 20689798]


[http://dx.doi.org/10.1016/j.ophtha.2011.05.014] [PMID: 21764136]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **A Three-Dimensional Look into Hypertensive Retinopathy**

### **Rafael Muci Mendoza\***

*Universidad Central de Venezuela, Unidad de Neurooftalmología, Hospital Vargas de Caracas, Venezuela*

### **ESSENTIALS OF DIAGNOSIS**

The amount of arteriolar damage signals the individual prognosis of a hypertensive subject; therefore, any information about its severity will be extremely helpful in a practical way. Arteriolosclerosis is the hardening and narrowing of the arterioles secondary to systemic arterial hypertension [1]. Fundoscopic changes reflect the duration, severity, and the right way to control hypertension, so monitoring the changes in the retina, the choroid, and the optic nerve will help the physician determine the best course of care of the hypertensive patient. "Essential" or "primary" hypertension is a pathological condition characterized by endothelial dysfunction that affects vessel structure and tone, thus causing constriction of blood vessels and narrowing of small arteries and arterioles in the peripheral vascular bed. It is a silent disease and its injurious effect begins many years before organic damage becomes clinically apparent [2, 3]. Arteriosclerosis follows chronic arterial hypertension like a shadow [4]. The amount of arteriolar damage is the essential piece of information that signals the individual prognosis of a hypertensive subject [5, 6]. Retinal arterioles share similar anatomical, physiological and embryological characteristics with cerebral, coronary and renal arterioles. Thus, the ocular fundus and the retina are like doors open to medical curiosity that enable noninvasive, *in vivo* testing of circulation,

<sup>\*</sup> **Corresponding author Rafael Muci Mendoza:** Universidad Central de Venezuela, Unidad de Neurooftalmología, Hospital Vargas de Caracas, Venezuela; Email: rafalemuci@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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since a direct fundoscopy allows for easy and bedside observation of the arterioles. This can lead to extremely important data when the resulting information is applied to other arterial territories [2].

When considered individually, the fundoscopic technique gains more importance than a blood pressure check. The reason is that it provides first-hand knowledge to the trained eye about past and future events in the disease natural history, thus providing a *three dimensional look into hypertensive patients*: 1) The acute or insidious damage to the arteries in the past, since the chronic form causes progressive arteriolosclerotic changes, unlike recently diagnosed hypertension; 2) "*Here and now*": the current situation of arteriolar and retinal damage, manifestation of the process activity, probable diastolic blood pressure readings, and, especially, which phase of the evolution process the patient is going through: incorrectly called benign hypertension *vs.* accelerated-malignant hypertension; 3) The possibility of differentiating "secondary" forms of hypertension and primary hypertension, and even the possibility of going deeper into the etiologic diagnosis; 4) Prognosis of the disease in untreated patients; and 5) Objective assessment of the response to different invasive and noninvasive treatments [4].

We consider the following fundoscopic changes of hypertension, which depend on diastolic blood pressure readings:

● Arteriolar signs typical of chronic hypertension. 1) Diffuse constriction that is difficult to observe if it is not in youthful vessels with normal auto regulation (pregnancy toxemia, acute diffuse glomerulonephritis). It is reversible. 2) Focal or localized constriction: apparent notches along the arterioles where caliber narrows and axial reflex is less bright. They are easily visible and constitute morphological wall changes that cannot be reversed with treatment. A significant number of them suggest left ventricular hypertrophy (Fig. **1**). 3) Irreversible generalized arteriolosclerosis: This means long-standing hypertension. It manifests as exaggerated axial reflex over arterioles, copper wiring and silver wiring of arterioles, sheathing of arterioles, and arteriolovenous crossing changes in its four grades of progressive severity: concealment, tapering, deflection with depression and compression (Figs. **1**-**8**).

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**Fig. (1).** Hypertensive arteriolosclerosis – time function: Arteriolar narrowing and focal narrowing.

**Fig. (2).** (**A**) Chronic hypertensive arteriolosclerosis: Copper wiring of arteriole. Abnormal arteriolovenous crossing of higher grade. Notice that the end that is distal from the crossing is wider than the proximal end, which denotes compression. A thin layer of collateral vessels can be seen adjacent to the optic disc. (**B**) Abnormal crossing (scanning microscopy).

**Fig. (3).** Chronic arterial hypertension: copper wiring of arterioles and arteriolovenous crossing of higher grade.

**Fig. (4).** Chronic arterial hypertension: copper wiring of arterioles and abnormal arteriolovenous crossings; venous collateral network and deep hemorrhages (manifestation of retinal ischemia); Silver wiring of one segment of the arteriole.

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**Fig. (5).** Chronic arterial hypertension: copper wiring of arterioles and abnormal arteriolovenous crossings; Arteriolovenous communication.

**Fig. (6).** Advanced retinal arteriolosclerosis: Copper wiring, segmental constriction, arteriolovenous crossings of higher grade; arteriolovenous and venoule-arteriolar –similarity with a Japanese bridge; Systemic correlation of left ventricular hypertrophy.

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**Fig. (7).** (**A**) Old occlusion of superior temporal artery –silver wiring of arteriole– with superfluous collateral vessels; (**B**) Acute myocardial infarction in evolution; (**C**) Basilar artery atherosclerosis.

**Fig. (8).** (**A**) Chronic hypertensive arteriolosclerosis; (**B**) Embolic occlusion of the central retinal artery and its branch arterioles.

● Retinal signs are typical of accelerated-malignant retinopathy. It is associated with the presence of fibrinoid necrosis in the kidney and includes retinal edema, cotton wool spots (accumulation of axoplasmic material) that are characteristic of this acute phase and are an invaluable sign of alarm because it is the way the retina "complains" when diastolic pressure exceeds 130 mmHg.

Light microscopy reveals the presence of so-called "cytoid bodies" because of its similarity with cells; hard exudates in the deeper retinal layers. Its pathogenesis combines alteration of the retinal capillary network and changes in the choriocapillaris of the choroid. When they are located in the macular area, they

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arrange in a star-shaped pattern around the fovea (macular star or stellar retinopathy); optic disc edema (a manifestation of hypertensive optic neuropathy) [2] (Figs. **9**-**18**).

**Fig. (9).** (**A**) Accelerated-malignant hypertension: cotton wool spots – axoplasmic material accumulations – a typical sign of alarm that indicates the severity of the disease; (**B**) Chronic malignant hypertension: hard exudates in the shape of small dots with waxy appearance.

## **Complications of Hypertensive Retinopathy**

Chronic hypertension, because of concomitant arteriolosclerosis, is responsible for vascular occlusions, whether arteriolar or venous. Arteriolar obstructions are associated with thrombotic occlusion or atheromatous embolism. On the other hand, vein occlusions, central or peripheral branch, the latter related to abnormal arteriolovenous crossing of higher grade, make it compulsory to carry out an assessment of the patient's coronary status. For its part, accelerated-malignant hypertension can be associated with exudative retinal detachment due to the presence of fibrinoid necrosis of the choroid (Figs. **19**-**25**).

## **Classification**

We favor Lip and collaborator's classification system (1994) [5] because it is simple and it allows the classification of hypertension quickly on different phases of evolution. Grade I: Non accelerated-malignant; and Grade II: Acceleratedmalignant (Fig. **26**).

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### **DIFFERENTIAL DIAGNOSIS**

The differential diagnosis for hypertensive retinopathy with diffuse retinal hemorrhage, cotton wool spots, and hard exudates includes most notably diabetic retinopathy. Diabetic retinopathy can be distinguished from hypertensive retinopathy by evaluation for the individual systemic diseases. Other conditions with diffuse retinal hemorrhage that can resemble hypertensive retinopathy include radiation retinopathy, anemia and other blood dyscrasias, ocular ischemic syndrome, and retinal vein occlusion.

**Fig. (10).** Chronic secondary accelerated hypertension. (**A**) 58-year-old male patient; and (**B**) 60-year-old male patient. Signs of chronic hypertensive arteriolosclerosis, plus cotton wool spots, which are manifestations of acceleration-malignancy.

**Fig. (11).** Accelerated-malignant hypertension. 18-year-old male patient. Rapidly progressive glomerulonephritis. (**A**) Multiple cotton wool spots and macular star. (**B**) Hyperfluorescence in the optic disc and around cotton wool spots that put pressure in the retina and capillary closure, and perilesional leakage due to blood-ocular barrier breakdown. No fluorescence on hard exudates.

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**Fig. (12).** A partial image of the retina showing (**A**) arteriolosclerotic changes that are typical of longstanding hypertension: Copper wiring of arteriole with bright axial reflex, irregular caliber and an arteriolovenous crossing of higher grade; and (**B**) involutional cotton wool spot and the presence of scattered hard exudates (a manifestation of acceleration-malignancy).

**Fig. (13).** Renovascular hypertension in a 59-year-old male patient. (**A**) Chronic secondary accelerated hypertension: multiple cotton wool spots; (**B**) After treatment, retinal signs tend to disappear, leaving hard exudates in the central area but without modifying arteriolosclerosis (arteriolar wall changes that cannot be reversed).

**Fig. (14).** Accelerated-malignant hypertension in a 48-year-old male patient with chronic secondary malignant hypertension: Macular hard exudates due to retinal edema.

**76** *Ophthalmology: Current and Future Developments, Vol. 1 Rafael Muci Mendoza*

**Fig. (15).** Accelerated-malignant hypertension in a 62-year-old male patient with atherosclerotic stenosis of both renal arteries.

**Fig. (16).** Asymmetric accelerated-malignant hypertension in a 22-year-old female patient with pheochromocytoma.

**Fig. (17).** (**A**) Accelerated-malignant hypertension, optic disc edema; fluorescein angiography: hyperfluorescence in the optic disc and choroidal scars; (**B**) Left ventricular hypertrophy; (**C**) Left renal atrophy.

*Hypertensive Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **77**

**Fig. (18).** Typical condition of accelerated-malignant hypertension: Optic disc congestion, cotton wool spots – accumulations of axoplasmic material – macular star image in a 20-year-old patient with rapidly progressive glomerulonephritis.

**Fig. (19).** Accelerated-malignant hypertension. (**A**) Bilateral optic disc edema; (**B**) Subhyaloid hemorrhage.

**Fig. (20).** (**A**) Accelerated-malignant hypertension and papilledema. (**B**) Hypertensive intracerebral

### **78** *Ophthalmology: Current and Future Developments, Vol. 1 Rafael Muci Mendoza*

hematoma. Such development of disc edema is unusual.

**Fig. (21).** (**A** and **B**) Eclampsia: 22-year-old patient with bilateral serous retinal detachment and macular edema; Choroidal infarctions (acute Elschnig spots); (**C**) Fluorescein angiography: Choroidal hyperfluorescence in patches and macular edema; (**D**) Two months later: Scattered hypofluorescent spots: related to choroidal infarctions (chronic Elschnig spots).

**Fig. (22).** Chronic arterial hypertension. (**A** and **B**) Superior temporal branch vein occlusion: retinography and fluorescein angiography: Triangular pattern of deep and superficial hemorrhages and cotton wool spots; (**C**) Scheme of abnormal arteriolovenous crossings of higher grade.

*Hypertensive Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **79**

**Fig. (23).** (**A**) Non-arteritic anterior ischemic optic neuropathy; (**B**) Left disc at risk.

**Fig. (24).** Examples of venous occlusions in hypertensive patients. (**A**) Superior temporal branch occlusion; (**B**) Hemispheric occlusion; (**C**) Ischemic occlusion of the central retinal vein.

**Fig. (25).** Chronic hypertension. (**A**) Systemic atheromatous embolism (Hollenhorst plaques) at two arteriolar bifurcations; (**B**) Histological appearance in posterior capsule of an eye. Visually empty space that was occupied by cholesterol emboli before tissue dehydration (\*). A dreadful clinical sign that anticipates a vascular catastrophe (myocardial infarction, stroke, aortic dissection or rapidly progressive renal failure).

**Fig. (26).** Lip's classification – recommended due to its simplicity.

## **MANAGEMENT**

The treatment for hypertensive retinopathy is primarily focused on reducing blood pressure.

Antihypertensive medication may reverse hypertensive retinopathy signs, with clinical case series [6, 7] showing regression of some retinopathy signs (*e.g.*, hemorrhages, cotton wool spots) with control of blood pressure.

If complications have occurred, surgery or laser may be required to help heal a hemorrhage or other resulting condition.

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

## **REFERENCES**

[1] Blandeiner C. Patología cardiovascular adquirida de las principales enfermedades en nuestro medio. Colección estudios: Universidad central de Venezuel. Consejo de Desarrollo Científico y Humanístico 1998.

### *Hypertensive Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **81**


[http://dx.doi.org/10.3109/08037059209065122] [PMID: 1345141]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Central Retinal Artery Occlusion**

**Silvia Mendoza<sup>1</sup> , Sandra Zambrano<sup>2</sup> , Diego Fernando Mojica<sup>2</sup>** and **Mitzy E. Torres Soriano3,\***

*1 Retina Department, Centro Oftalmológico de Valencia (CEOVAL), Valencia, Venezuela*

*2 Centro Oftalmológico de Valencia (CEOVAL), Valencia, Venezuela*

*3 Centro de la Visión Gordon-Manavella, Rosario-Santa Fe, Argentina*

Central retinal artery occlusion is a vaso-occlusive ischemic disease that causes a sudden painless loss of vision usually irreversible and unilateral. Incidence is 1 to 15 cases per 10,000 it generally occurs in the elderly, and is usually accompanied by an afferent pupillary defect [1 - 3].

The most frequent causes of obstruction of blood flow are:


Risk factors: Hypertension, hypercholesterolemia, blood dyscrasias, vasculitis.

<sup>\*</sup> **Corresponding author Mitzy E. Torres Soriano:** Centro de la Visión Gordon-Manavella, Montevideo 763, CP 2000, Rosario - Santa Fe, Argentina; Tel: +54 (0341) 4400239; E-mail: mitzytorres@yahoo.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

## **ESSENTIALS OF DIAGNOSIS**

## **Symptoms**


### **Fundus Findings**

● Whitish discoloration of the retina, due to edema of the inner retinal layers, especially at the posterior pole where the nerve fiber layer and ganglion cell layer are thickest (Figs. **1**-**4**) [1 - 6].

**Fig. (1).** Central retinal artery occlusion: Note pale retina, narrowed arterioles and "cherry red spot" in macula.

### **84** *Ophthalmology: Current and Future Developments, Vol. 1 Mendoza et al.*


## **Complementary Exams**

● Fluorescein angiography: to assess if the arterial obstruction is complete or partial and to determine if there is reperfusion (Figs. **2**, **4**).

**Fig. (2). A**. Fundus photograph showing retinal pallor and a cherry-red spot. **B** and **C**. Early to mid stages of the fluorescein angiogram showing significant delay in the vascular filling. There is a small area adjacent to the optic disc that is still perfused by a cilioretinal artery. **D**. Late Phase of the Angiogram.

● Optical coherence tomography may show increased inner retinal layer thickness (Fig. **3B**) in the acute stage of CRAO, due to retinal edema and optic nerve swelling [5].

**Fig. (3). A**. Color photograph of the left fundus showing diffuse retinal whitening with a classic cherry-red spot. This patient has an area of perfused retina supplied by a cilioretinal artery located just temporal to the disc. **B**. Optical coherence tomography shows hyperreflectance of inner retinal layers. (Courtesy of Manuel Torres MD, Cagua, Venezuela).

### **86** *Ophthalmology: Current and Future Developments, Vol. 1 Mendoza et al.*

**Fig. (4). A**. Central retinal artery occlusion in a patient with diabetic retinopathy, **B**. Fundus autofluorescence. **C-F**. FA shows non-perfusion of the retinal vasculature from early to late phases. (Courtesy of Manuel Torres MD, Cagua, Venezuela).


*Central Retinal Artery Occlusion Ophthalmology: Current and Future Developments, Vol. 1* **87**

**Fig. (5).** Electroretinogram of the same patient of Fig. (**2**). There is a reduction in the b-wave amplitude in cone and rod response of right eye (left side of the image) due to a CRAO.

### **DIFFERENTIAL DIAGNOSIS**

Although the cherry-red spot is a fairly specific clinical sign, it is not pathognomonic, since it may also be observed in traumatic *commotio retinae*, and in metabolic diseases such as Niemann-Pick disease, Farber disease, Tay-Sach disease, and Sandhoff disease among others.

**88** *Ophthalmology: Current and Future Developments, Vol. 1 Mendoza et al.*

## **MANAGEMENT**

Once it ensues, there is no proven treatment for this disease. Retinal tissue can survive for up to 240 minutes without oxygen before damage is permanent and irreversible. Therefore the aim of treatment is to restore retinal circulation as soon as possible.

Treatment strategies include:


Other therapeutic options are:


All these therapeutic measures have to be attempted within the first six hours of the occlusion, and have a very low success rate.

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[http://dx.doi.org/10.1016/S0896-1549(05)70080-8]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Branch Retinal Artery Occlusion and Cilioretinal Artery Occlusion**

### **Raul Velez-Montoya\***

*Retina Department, Asociación para Evitar la Ceguera en México, IAP. Mexico City, Mexico*

Branch retinal artery occlusion (BRAO) is an arterial occlusive disease in which the obstruction of blood flow is located after the bifurcation of the central retinal artery in its major branches. The severity of the clinical manifestations will depend on the exact localization of the obstruction which can be found anywhere from the emergence of the major temporal or nasal arcades to the small capillary arterioles [1, 2].

BRAOs are thought to represent 38% of all acute retinal artery obstructions [3]. It is classified according to its visual outcome in *transient* and *permanent* BRAO [2, 4, 5]. Diabetes mellitus, arterial hypertension, ischemic heart disease, and transient ischemic attacks/cerebrovascular accidents are more prevalent in patients with BRAO than the matched US population (p<0.001) [2]. Smoking prevalence in female patients with BRAO is higher; although this association has not been proven in male patients. When comparing BRAO with central retinal artery occlusion (CRAO), only diabetes mellitus has a slightly higher prevalence among patients with CRAO [2].

Embolism is the most common cause of BRAO [5, 7]. There are three main types or retinal emboli: calcific (10.5%), cholesterol (74%), and platelet-fibrin (15.5%) [6, 7]. The most common sources of emboli are the carotid artery (plaque) and the heart (valvular lesions, atrial fibrillation, patent foramen ovale, tumors in left

<sup>\*</sup> **Corresponding author Raul Velez-Montoya:** Retina Department, Asociación para Evitar la Ceguera en México, Vicente García Torres, 46. San Lucas Coyoacán, México DF.04030; México; Tel: +52.55.10841400; Fax: +52.55.10841404; Email: rvelezmx@yahoo.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

atrium and myxoma) [8]. Due to the fact that microemboli are responsible for most BRAO, and the major source of microemboli is an arterial plaque, the absence of an abnormal carotid doppler does not rule out the carotid artery as the source of microemboli [7, 9].

### **ESSENTIALS OF DIAGNOSIS**

Conversely to CRAO patients, in which visual loss can be severe (light perception) at presentation, more than 70% of patients with *permanent* BRAO, seen within 7 days of onset, will have 20/40 or better at the initial visit especially if the affected vessel is the inferior temporal artery. Furthermore, 80% of patients with decreased visual acuity (VA) at presentation (worse than 20/40) will experience an improvement of VA within 1 week after onset. Final VA of 20/40 or better is seen in 89% of patients, and only 3% of eyes experience a worsening of VA during follow-up. The most frequently reported visual field defects are a central scotoma (20%) and inferior central altitudinal defect (13%), which tend to improve in 47% of the cases within 1 week of onset. In patients with *transient* BRAO, VA at presentation of 20/40 or better is seen in more than 90% of cases. The central and peripheral visual field remains normal. Final VA tends to be 20/40 or better in virtually all cases, regardless of VA at onset (even if it was worse than 20/40) [1, 5].

During the acute phase of the disease, an area of retinal pallor corresponding to the area of compromised blood flow and oncotic damage (swelling) can be identified on fundus examination (Figs. **1**, **2**) [10 - 12]. However, the initial pallor is replaced by the normal sheen of the fundus in long-standing cases, making it more difficult to diagnose [10]. If there is enough ischemia, cotton-wool spots will develop 6 to 18 hours after onset, especially if the affected vessel is large enough and close to the posterior pole where the nerve fiber layer is thicker [13, 14]. A retinal emboli is seen in 47% of cases. However, its absence does not rule out an embolic case because it may have disintegrated, migrated and disappeared by the time the eye is examined [15, 16].

**92** *Ophthalmology: Current and Future Developments, Vol. 1 Raul Velez-Montoya*

**Fig. (1).** BRAO on a diabetic patient after pars plana vitrectomy and silicon oil. **A**) Color photograph shows whitening of the posterior pole with normal color of the papillomacular bundle. **B**) Red-free photograph shows more clearly the territory supplied by the cilioretinal artery on the same patient.

**Fig. (2).** Acute phase of inferotemporal BRAO. **A**) Fundus photograph shows retinal pallor in inferior macular area. **B** and **C**) FA shows a delay on the vessel filling and transit time. **D**) Cattle trucking and staining of the vessels walls (Courtesy of Natalia Pecce MD, Argentina).

*Branch Retinal Artery Occlusion Ophthalmology: Current and Future Developments, Vol. 1* **93**

Fluorescein angiogram (FA) may show delayed filling, reduced arterial caliber, "cattle trucking" of the arterial blood column (Figs. **2**, **3**), and increased transit time on the affected vessels as well as capillary dropout and collateral vessels development on the area of the retina affected by compromised blood flow (Fig. **4**) [4, 17, 18]. Optical coherence tomography (OCT) of the ischemic areas will show marked thickening and hyper-reflectivity of the inner retina during the acute phase (Fig. **5**) [10, 13, 19]. A decrease in retinal thickness may be noticed after resolution [10, 13]. Fundus autofluorescence of the area supplied by the occluded retinal artery will show decreased autofluorescence due to blockage of the normal autofluorescence of the retinal pigment epithelium by the thickened retina with normal autofluorescence over the rest of the retina [10, 12]. After resolution, an increase in autofluorescence due to a very thin retina may also be visualized [10].

**Cilioretinal Artery Occlusion (CLRAO):** The cilioretinal artery originates from the short posterior ciliary arteries or from the choroid, and emerges directly from the optic disc or disc margins, and not from the central retinal artery [5, 16]. It is usually present in 49.5% of the eyes and supplies the papillomacular bundle [4, 20]. Clinically evident CLRAO is a rare event, since it only comprises between 5.3 to 7.1% of all cases or retinal artery occlusions [16]. It occurs in three clinical settings: as non-arteritic CLRAO alone; as an arteritic CLRAO associated with giant cell arteritis; and as CLRAO associated with central/hemicentral retinal vein occlusions [2, 5]. The clinical presentation at onset will depend on the clinical setting in which CLRAO occurred. Patients with non-arteritic CLRAO can have decreased VA (20/40 or worse) and central visual field defects (mostly central and centrocecal scotomas) which tend to improve during the follow-up [5]. Such presentations are due to the high variability in size of the cilioretinal artery and the area it supplies [1]. Translucent, pale gray swelling of the papillomacular bundle is typically present [21, 22]. The presence of a CLRAO with a white optic disc edema, posterior ciliary artery occlusion on fluorescein angiography, headache and jaw claudication in a patient of 50 years of age or older might signify an association with giant cell arteritis [2, 5]. In this scenario, prompt treatment should begin to prevent severe bilateral visual loss [22]. When associated with central or hemicentral retinal vein occlusion, VA at onset as well as VA improve-

# **94** *Ophthalmology: Current and Future Developments, Vol. 1 Raul Velez-Montoya* ment during follow-up will depend on the type of vein occlusion (ischemic or no

**Fig. (3). A**) BRAO of the superotemporal arcade on a patient with diabetic retinopathy, previously treated with panretinal photocoagulation. Color photographs shows a severe decrease in the caliber of the vessels. **B**) FA shows a delay on the transit time and a thinner dye column inside the affected vessels.

**Fig. (4). A**) BRAO of the superotemporal arcade. **B** to **D**) FA show a filling defect with extensive capillary dropout and collateral vessel formations.

ischemic), macular ischemia due to the CLRAO, and the existence of macular edema [5, 21]. Central visual field defects are usually due to CLRAO [5]. On fundus examination, CLRAO is accompanied by superficial and intraretinal hemorrhages [16].

**Fig. (5).** Spectral domain OCT in a patient with acute BRAO. There is an increase in the thickness of the inner retinal and increased reflectivity (area between arrow heads).

## **DIFFERENTIAL DIAGNOSIS**

Although diagnosis of BRAO is mostly clinical and straightforward during the acute phases, it can prove to be difficult on long-standing cases. Differential must be done with other entities causing whitening of the retina like commotion retina, persistence of myelinated nerve fiber layer, central/hemicentral retinal artery occlusion, and shallow retinal detachment, among others. There are multiple anecdotal associations of BRAO with various diseases including systemic lupus erythematosus, polyarteritis nodosa, dengue fever, West Nile virus, AIDS, toxoplasmosis, herpes zoster, sickle cell disease, Takayasu's arteritis, postsmallpox vaccination, Churg-Strauss syndrome, ocular Behçet's disease, Fabry's disease, head injury, and migraine [5].

Susac´s syndrome is a pathology characterized by the clinical triad of encephalopathy, hearing loss, and BRAO, mostly in young women, and is thought to be due to microangiopathy [24].

## **MANAGEMENT**

A wise man once said, "A disease without treatment has many treatments." This is the case of the arterial occlusive disease [25]. Although most of BRAO cases with impaired VA or visual field defects will improve regardless of whether it is

### **96** *Ophthalmology: Current and Future Developments, Vol. 1 Raul Velez-Montoya*

transient, permanent, or level of VA at onset, it is nearly impossible to identify which will improve and which will not, based on purely clinical evidence at presentation. Current options include the standard non-invasive therapies: the use of vasodilator to increase blood oxygen content and dilate arteries (sublingual isosorbide, systemic pentoxifylline, inhalation of carbogen and hyperbaric oxygen); ocular massage to attempt to dislodge the emboli [4]; lowering of intraocular pressure to increase retinal artery perfusion pressure (intravenous acetazolamide and mannitol, anterior chamber paracentesis) [4]; methylprednisolone [4]; oral acetylsalicylic acid [26]; and the combination of some or all of the above in a multimodal stepwise approach. None of these therapies has been shown to be better than a placebo in clinical trials in the treatment of BRAO. More invasive therapies include isovolemic hemodilution, anticoagulation with heparin, and local intra-arterial fibrinolysis with tissue plasminogen activator (*t*PA). However, the latter has proven to be of doubtful utility since major randomized clinical trials had found no greater benefit than non-invasive standard treatments but with higher rate of adverse reactions [26]. There are reports of the successful destruction of the emboli using an Nd:YAG laser. Nevertheless, there is still concern about the safety and efficacy of the treatment [27, 28]. In cases of CLRAO associated with giant cell arteritis, intensive corticosteroid therapy can prevent further visual loss [23].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**



### **98** *Ophthalmology: Current and Future Developments, Vol. 1 Raul Velez-Montoya*


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

**CHAPTER 9**

# **Retinal Arterial Macroaneurysm**

**Rodrigo Lechuga Perezanta<sup>1</sup>** and **Virgilio Morales Cantón2,\***

*1 Asociación para Evitar la Ceguera en Mexico, Mexico City, Mexico*

*2 Retina Department, Asociación para Evitar la Ceguera en Mexico, Mexico City, Mexico*

The term macroaneurysm was first coined by Robertson, in 1973 making reference to arterial retinal lesions with saccular or fusiform swelling, localized on the first three orders of the retinal arterial tree found mainly at arterial bifurcations [1]. Saccular arterial macroaneurysms are more likely to burst and develop closer to the optic nerve where perfusion pressure is higher. Retinal arterial macroaneurysms are more frequent in women (60 – 80% probably due to hormonal and hereditary factors) with an average age of 69 years and have a strong association with systemic diseases such as arterial hypertension, aterosclerotic disease, hyperlipidemia, polycythemia and cerebrovascular disease. Retinal arterial macroaneurysms have been described in Leber´s miliary aneurysms, Coats´ disease, branch retinal artery occlusion and Eales´ disease among others [1, 2].

Systemic arterial hypertension causes an increase in hydrostatic pressure and may lead to hyaline degeneration of the vascular wall, loss of autoregulation tone and arterial dilatation [2].

Another theory to support that systemic arterial hypertension is a risk factor to the formation of arterial macroaneurysms is Laplace equation, which states that an increase in the transmural pressure is directly proportional to the increased tension of the wall.

Focal embolic damage to the arterial wall is considered to be a part of the

<sup>\*</sup> **Corresponding author Virgilio Morales Cantón:** Retina Department, Asociación para Evitar la Ceguera en Mexico, Vicente García Torres 46, San Lucas Coyoacan, Mexico City, 04030; Mexico; Tel +52 (55) 10841400, Email: vmoralesc@mac.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

**100** *Ophthalmology: Current and Future Developments, Vol. 1 Lechuga Perezanta and Morales Cantón* mechanism for lesion formation, which may result in localized ischemia.

## **ESSENTIALS OF DIAGNOSIS**

Most of these lesions appear on the superotemporal arterial branch (51%), followed by the inferotemporal branch (28%). Macroaneurysms affecting the nasal arterial branches may be less frequently diagnosed because patients may not notice the loss of visual acuity until the macula is affected, which could not happen, or a vitreous hemorrhage develops. Usually one macroaneurysm is present, but more lesions have been described affecting the same eye and 10% may be bilateral.

The main symptom is decreased visual acuity as a consequence of exudation, edema or hemorrhage. A characteristic finding is the presence of hemorrhage in different layers including subretinal, intraretinal, sub internal limiting membrane (Figs. **1A**, **2A** and **3A**) or in the vitreous cavity [1, 3]. Hourglass hemorrhages are also a typical finding.

These lesions may develop symptoms when acute or chronic decompensation occurs. Acute decompensation is typically associated with rupture and hemorrhage of the macroaneurysm while chronic decompensation is due to abnormal leakage of plasma constituents across the aneurysmal wall leading to the accumulation of yellow perianeurysmal intraretinal exudates [4].

When the arterial macroaneurysm is visible during fundus examination, the correct diagnosis can be achieved without much trouble, but when massive hemorrhage, exudation or retinal edema are present they suppose a diagnostic challenge. Fluorescein angiography (Figs. **1B**, **2B** and **3B**) is useful to locate the lesion when dense hemorrhage is absent so hyperfluorescence is visible. Macroaneurysm typically shows hyperfluorescence during the early arterial phase of the angiogram but late phase varies from little staining of the vessel wall to marked leakage. The absorption and emission spectrum of indocyanine green are close to infrared range and this allows the dye to be seen through hemorrhage. This makes indocyanine green a good alternative when diagnostic dilemma is present due to dense hemorrhage or exudates [5, 6].

**Fig. (1).** A 74-year-old female patient complains of floaters and photopsia in her left eye from 8 days ago. Diagnosis of systemic arterial hypertension was made 20 years before. Visual acuity was 20/100, intraocular pressure 16 mmHg, fundus examination revealed subretinal and intraretinal hemorrhage (**A**) and fluorescein angiography showed a hyperfluorescent lesion in the superior temporal arterial vessel in the second branch (**B**). No treatment was performed and visual acuity was recovered to 20/60 three months later.

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**Fig. (2).** 70-year-old female with floaters, visual acuity 20/100, intraocular pressure 12 mmHg. Fundus examination revealed a intraretinal hemorrhage on the superior temporal artery (**A**) with increased hyperfluorescence on the same spot (**B**). No treatment was performed and final visual acuity was 20/40.

**Fig. (3).** A 77-year-old female with decreased visual acuity from one week before. Visual acuity was counting fingers, intraocular pressure 18 mmHg, in fundus examination a subretinal and subhyaloid hemorrhage was found (**A**). Fluorescein angiography revealed a hyperfluorescent spot that increased in intensity with time (**B**). Laser hyaloidotomy was performed and the final visual acuity was 20/800.

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Optical Coherence Tomography (OCT) can contribute to achieve a correct diagnosis. Typical findings include an abnormal saccular dilatation in the internal layers that characteristically elevates the internal limiting membrane and ganglion cell layer, modifying the normal architecture of the adjacent retina. The layers beneath the macroaneurysm are hyporreflective due to a masking effect (Fig. **4**).

**Fig. (4).** OCT image showing a saccular dilatation (arrow) that elevates the retina, with a posterior shadow. Intraretinal fluid and hyper-reflective foci due to hard exudates may also be observed.

## **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis includes any cause of hemorrhage and exudates, such as diabetic retinopathy, venous occlusions, radiation retinopathy, Coats´ disease, retinal telangiectasis, age-related macular degeneration, retinal capillary angioma, cavernous hemangioma, malignant melanoma.

## **MANAGEMENT**

There is no established consensus regarding the timing to treat the patient or the ideal treatment for this lesion but it is generally accepted to treat when there is exudation involving the fovea with decreased visual acuity [7, 8]. Laser photocoagulation is the most common treatment, and it can be applied directly or

surrounding the macroaneurysm and using threshold or subthreshold laser [9, 10]. Parodi *et al.* found the same obliteration of the lesion and visual recovery using threshold *vs* subthreshold laser but complications including scar growth, choroidal neovascularization, subretinal fibrosis, arterial branch occlusion, epiretinal membranes, increased exudation and retinal traction were avoided using subthreshold laser. They used a diode infrared laser (810 nm) for the subthreshold patients and a krypton laser (647 nm) for the threshold group. The selective damage to the retinal pigment epithelial cells may lead to a better balance of angiogenic factors and cytokine release [7, 9].

Another alternative is the use of antiangiogenic therapy. In 37 eyes, Pichi *et al.* proved that 3 intravitreal injections with bevacizumab (0.05ml/1.25mg) in patients with complicated macroaneurysms affecting the fovea, are safe and effective to improve visual acuity from 20/80 to 20/25 and central macular thickness from 520.38 +/- 191.05 to 214.84 +/- 26.86 microns [10].

Pars plana vitrectomy is recommended when persistent vitreous hemorrhage or preretinal hemorrhage is present. It is also justified when the etiology of the hemorrhage is undefined.

There is poor visual prognosis when subretinal hemorrhage exists because of photoreceptor deterioration and controversy exists whether to treat with pneumatic displacement *versus* observation.

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


### **106** *Ophthalmology: Current and Future Developments, Vol. 1 Lechuga Perezanta and Morales Cantón*


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# **CHAPTER 10**

# **Macular Telangiectasia**

**Yogin Patel<sup>1</sup>** and **Michael D. Ober1,2,\***

*1 Department of Ophthalmology, Henry Ford Health System, Detroit, MI, USA*

*2 Retina Consultants of Michigan, Southfield, MI, USA*

Macular telangiectasia (MacTel) was best classified and described by Gass and Blodi as a form of idiopathic juxtafoveolar retinal telangiectasis [1] and is also commonly referred to as idiopathic perifoveal telangiectasia. This is a group of disorders which affects the vasculature of the posterior pole. Numerous classification schemes have been designed to categorize it, most notably, that of Gass and Blodi [1] and an update by Yannuzzi *et al.* [2]. Two major subclassifications are of greatest importance; MacTel type 1 refers to a unilateral presentation with prominent microaneurysms that is often grouped within the spectrum of Coats disease. MacTel type 2 is more often referred to simply as MacTel, and represents an acquired bilateral retinal vascular disorder. For the purposes of this review, we will focus on MacTel type 2.

Different studies quote very different numbers for the prevalence of this condition ranging from as high as 0.1% in the Beaver Dam Eye Study to 0.0045 to 0.022% in the Melbourne collaborative cohort study [3, 4]. The age at onset is usually in the late 40s to early 60s. There may be a slight female predominance depending on the study population quoted.

### **ESSENTIALS OF DIAGNOSIS**

Patients will often present with a pericentral scotoma or metamorphopsia. Visual acuity rarely progresses to legal blindness but visual dysfunction is common. The clinical presentation begins with subtle changes noted in the posterior pole.

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Michael D. Ober:** Retina Consultants of Michigan, 29201 Telegraph Road, Suite 606, Southfield, MI 48034, USA; Tel: (248) 356-8610; Fax: (248) 356-6473; E-mail: obermike@gmail.com

### **108** *Ophthalmology: Current and Future Developments, Vol. 1 Patel and Ober*

Lesions most often begin just temporal to the fovea (Figs. **1A, B**). They may then further evolve to include the larger perifoveal region. The initial presenting change is often a loss of transparency in the retina temporal to the fovea. With time the lesion may evolve to include dilation of capillaries and will likewise spread from their temporal perifoveal origin. Histological studies have demonstrated that the dilated capillaries are mostly located in the deeper retinal layers [1]. Although, Yannuzzi and others have observed the involvement of both the superficial and deep plexus [2]. Later changes include dilated venules, which are often associated with the abnormal capillaries. These vessels tend to increase in diameter as they approach the fovea, in contrast to normal vessels. In addition, these vessels often take characteristic right angle turns, which represent diving of the vessel toward the deeper retinal layers. Associated changes in the RPE include crystalline deposits (Figs. **3A, B**), pigment migration, and hyperplasia following these venules [2]. Over the time, secondary atrophy of the pigment epithelium and neurosensory retina may develop. Some eyes may accumulate vitelliform material under the central macula. Lamellar thinning of the inner retina within the fovea is common and manifests with the development of inner lamellar cystic changes (Fig. **4**). On occasion the atrophic changes may progress to a full thickness macular hole.

Neovascularization is another common later stage development usually preceded by the appearance of the right angle venules and pigmentary changes. As with any neovascularization, it may be associated with hard exudate, edema, and hemorrhage. The neovascularization stems from retinal vessels, but may be indistinguishable from choroidal neovascularization with chorioretinal anastomosis from other etiologies. Late changes may include the formation of a disciform scar.

Multimodal imaging is critical in the diagnosis of MacTel. One of the earliest signs of the disease, even before clinical changes appear, is the loss of the hypofluorescent center in fundus autofluorescence photos which later progress to more pronounced hypoautofluorescence corresponding to RPE atrophy with adjacent granular hyperautofluorescence (Figs. **5A, B**). This has been postulated as a direct result of the depletion in macular pigment [5]. Fluorescein angiography (FA) findings are often diagnostic and include the characteristic telangiectatic

**Fig. (1).** (**A** and **B**) Color fundus photographs demonstrating the subtle loss of retinal transparency and right angle vessels most notable temporal to both foveae. Retinal pigment epithelial hyperplasia can be seen surrounding the right angle vessels (not shown here). Vessels temporal to the fovea are noted to be of irregular caliber and telangiectatic (Photo Credit: Colin Griffin).

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**Fig. (2).** (**A** and **B**) Venous phase fluorescein angiogram showing characteristic dilatation and leakage of telangiectatic vessels most notably temporal to the foveae (Photo Credit: Colin Griffin).

### *Macular Telangiectasia Ophthalmology: Current and Future Developments, Vol. 1* **111**

**Fig. (3).** (**A** and **B**) Color fundus photographs demonstrating loss of retinal transparency, right angle vessels, and crystalline dots at the vitreoretinal interface (Photo Credit:Matthew Lawrence, CRA)

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capillaries temporal to the fovea that leak in later frames (Figs. **2A, B**). In the absence of neovascularization, corresponding optical coherence tomography (OCT) does not include retinal thickening, subretinal fluid, or pronounced cystic changes in the region of FA leakage, but rather distortion of the foveal pit with the temporal side becoming larger and thinner [5]. As the disease progresses there is often disruption of the normal photoreceptor inner segment and outer segment layer. This is followed by the formation of atrophic lamellar holes, which do not demonstrate corresponding leakage on FA.

**Fig. (4).** Outer retinal cavity formation from photoreceptor disruption. Some abnormality in retinal pigment migration (Photo Credit: Patricia Streasick, CRA).

### *Macular Telangiectasia Ophthalmology: Current and Future Developments, Vol. 1* **113**

**Fig. (5).** (**A** and **B**) Fundus autofluorescence showing moderate increase and decrease in autofluorescence (Photo Credit: Courtney McClenahay).

### **DIFFERENTIAL DIAGNOSIS**

The differential diagnosis includes a variety of vascular anomalies of the retina. Branch retinal vein occlusions may result in abnormal collateral vessels **114** *Ophthalmology: Current and Future Developments, Vol. 1 Patel and Ober*

formation, but emanate from an abnormal arterial-venous crossing point and are most frequently unilateral or at least highly asymmetric. Radiation can cause similar telangiectatic vascular changes, but requires relevant history and often presents with cotton-wool spots and pre-retinal neovascularization. Neovascular AMD may present with similar appearing neovascularization including chorioretinal anastomosis, but occurs in the presence of drusen, pigment, and atrophy without the abnormal retinal capillary vascular telangiectatic changes. Late stage neovascular scar formation from MacTel may be indistinguishable from that of other etiologies, but often age and the fellow eye examination is revealing.

### **MANAGEMENT**

As of yet, there are no accepted methods of treatment for the disorder when it presents without neovascularization. Laser photocoagulation and PDT appear to be of no benefit [6]. Anti-vascular endothelial growth factor (VEGF) treatment has led to debatable anatomic improvement but no visual gain [7, 8]. Intravitreal steroids have likewise demonstrated no positive effect on disease course [9]. Anti-VEGF has shown positive results when treating early stages of neovascularization [10]. Surgical intervention has met with poor outcomes in limited numbers of patients [11]. The macular holes in MacTel have also had limited success with surgical correction, mainly thought to be the result of the atrophic rather than transactional nature of formation [12]. Future efforts are currently focused on a randomized trial utilizing a ciliary neurotrophic factor emitting implant, but no data was yet available at the time of writing [13].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

[1] Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and followup study. Ophthalmology 1993; 100(10): 1536-46.

[http://dx.doi.org/10.1016/S0161-6420(93)31447-8] [PMID: 8414413]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 11**

# **Sickle Cell Retinopathy**

**Luke B. Lindsell** and **Aziz A. Khanifar\***

*Retina Group of Washington, Washington DC, USA*

### **ESSENTIALS OF DIAGNOSIS**

Sickle cell disease is an autosomal recessive condition comprising several different forms of mutated hemoglobin. Patients who are homozygous for the hemoglobin S gene (HbS) have the most severe form of sickle cell anemia. Other genotypes of clinical importance to ophthalmologists include HbSC disease (double heterozygote for HbS and HbC), HbS/b-thal (double heterozygote for HbS and beta-thalassemia), and sickle cell trait (one normal Hb allele and one HbS allele). In general, patients with the more severe genotype of sickle cell disease have less severe ophthalmic manifestations. For example, HbSS has the most critical systemic complications, the ocular manifestations are less severe compared to HbSC disease which has a more moderate systemic course. Although sickle cell trait is relatively asymptomatic, under hypoxic conditions both systemic and ophthalmic consequences can occur [1].

Relative hypoxia causes mutated hemoglobin to polymerize, ultimately altering the morphology of the red blood cell (RBC) to the characteristic sickle shape. These abnormal RBCs occlude terminal arterioles, leading to ischemia and possible tissue infarction [2]. Sickle cell retinopathy is one end-organ manifestation of the disease. Similar to diabetic eye disease, both nonproliferative and proliferative forms occur, and the proliferative disease is associated with more significant visual morbidity [3].

<sup>\*</sup> **Corresponding author Aziz A. Khanifar:** Retina Group of Washington, Washington DC, USA; Tel: (301) 495- 2357, Fax: (301) 495-2359; E-mail: azizkhanifar@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

Non-proliferative sickle cell retinopathy is characterized by several possible findings:


**Fig. (1).** Color photo montage. Resolving intraretinal hemorrhage that will become a sunburst or possibly iridescent spots (black arrow). Faint resolving salmon patch hemorrhage (yellow arrow). Vitreous hemorrhage (white arrow). Vascular tortuosity is also evident.

**Fig. (2).** Color photo. Large peripheral salmon patch.

**Fig. (3).** Color photo. Iridescent spots.

**Fig. (4).** Color photo. Sunburst.

**Fig. (5).** Multiple imaging modalities. **Top**: Color photo. Central vitreous hemorrhage. **Bottom left**: Color photo. Same eye with the peripheral fibrotic sea fan which was the source of the vitreous hemorrhage. Bottom right: Fluorescein angiogram. Irregular peripheral vasculature.

Proliferative sickle cell retinopathy (PSR) causes visual loss primarily with vitreous hemorrhage (Fig. **5**) and retinal detachment (tractional or tractionalrhegmatogenous). Fortunately, however, the incidence of proliferative disease is low [5]. The hallmark of the disease is neovascularization which initially appears as tufts at the interface between vascular and avascular retina. This typically occurs in the temporal quadrant. These tufts can progress to a characteristic "sea

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fan" configuration (Figs. **5**-**7**). Fibroglial tissue can proliferate over the surface of the sea fan and scaffold into the vitreous to potentially initiate a tractional retinal detachment. Wide field fluorescein angiography (FA) is essential in evaluating the extent of peripheral non-perfusion [6, 7] (Fig. **8**).

**Fig. (6).** Multiple imaging modalities. Color photo montage: Peripheral sea fan with hemorrhages at avascular retinal border. Inset fluorescein angiogram: Leakage associated with sea fan.

**Fig. (7).** Color photo montage. Same patient from Fig. (**9**), three years after superotemporal scatter laser photocoagulation. Note regression of the sea fan superotemporally and presence of a newer sea fan nasally.

**Fig. (8).** Fluorescein angiogram. Peripheral non-perfusion in both eyes. An area of arterio-venous anastomosis in the right eye (white arrow).

Other retinal findings of importance in sickle cell disease:


## **DIFFERENTIAL DIAGNOSIS**


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**Fig. (9).** Fluorescein angiogram. Enlarged foveal avascular zone.

**Fig. (10).** Optical coherence tomogram. Neurosensory retinal thinning in the temporal macula of the left eye. The temporal macula is a watershed region, and relative ischemia in this region can produce this finding which usually has no visual consequence.

## **MANAGEMENT**

The non-proliferative form of the disease requires serial observation. Vitreous hemorrhage is the most common proliferative manifestation requiring intervention although a majority of these will clear spontaneously. Sea fans will frequently spontaneously regress, and small peripheral lesions without vitreous hemorrhage can be observed [5, 8]. Scatter photocoagulation is the preferred method for managing large areas of neovascularization or any neovascularization with concurrent vitreous hemorrhage [8]. Case reports have shown success with

intravitreal anti-vascular endothelial growth factor for sea fan regression [11]. Small gauge pars plana vitrectomy surgery is indicated for patients with nonclearing vitreous hemorrhages and tractional retinal detachments. Intraoperatively, segmentation and localized photocoagulation are recommended [12]. Care should be taken to minimize intraocular pressure elevation.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

## **REFERENCES**


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[9] Chow CC, Genead MA, Anastasakis A, Chau FY, Fishman GA, Lim JI. Structural and functional correlation in sickle cell retinopathy using spectral-domain optical coherence tomography and scanning laser ophthalmoscope microperimetry. American Journal of Ophthalmology 2011; 152(4): 704-11 e2. [http://dx.doi.org/10.1016/j.ajo.2011.03.035]

[10] Witkin AJ, Rogers AH, Ko TH, Fujimoto JG, Schuman JS, Duker JS. Optical coherence tomography demonstration of macular infarction in sickle cell retinopathy. Arch Ophthalmol 2006; 124(5): 746-7. [http://dx.doi.org/10.1001/archopht.124.5.746] [PMID: 16682603]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Radiation Retinopathy**

**Veronica Kon Graversen\***

*University of North Carolina at Chapel Hill, NC, USA*

Radiation retinopathy (RR) is the result of ultra-structural impairment of the vascular endothelial cells and pericytes of the retina and choroid after exposure to ionizing radiation [1]. Several factors influence the development of retinopathy, including the type of radiation received (external-beam irradiation *versus* local radioactive plaque therapy), total dosage and fraction size schemes used, concomitant systemic vascular diseases, simultaneous chemotherapy, and pregnancy [2, 3]. These factors determine the interval to onset and severity of the disease. The dose required to produce retinopathy is variable, but it is generally accepted that exposure to 30-35 Gray leads to visual changes [3]. The median time interval to onset of retinopathy is 27 months but may range from few months to several years [4].

### **ESSENTIALS OF DIAGNOSIS**

Photoreceptors are relatively preserved and resistant to the radiation effects. Therefore, the degree of visual loss depends on the severity of the occlusive vasculopathy and its sequelae.

**Clinical Features:** The earliest signs include capillary dilation and microaneurysm formation. Later in the course of the disease, a nonproliferative phase may develop. This phase is exudative. Hard exudates, intraretinal (superficial or deeper) and preretinal hemorrhages, telangiectasia, cotton wool spots and macular edema are frequently seen (Figs. **1** and **2**).

<sup>\*</sup> **Corresponding author Veronica Kon Graversen:** Ophthalmology Department, University of North Carolina at Chapel Hill, NC, USA; Tel: (919)518-6361; Email: veronicakonjara@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

**126** *Ophthalmology: Current and Future Developments, Vol. 1 Veronica Kon Graversen*

**Fig. (1).** Fundus photograph of a patient treated with ophthalmic plaque radiation for choroidal melanoma. The patient developed non-proliferative radiation retinopathy, showing retinal hemorrhages, hard exudates and telangiectasia.

Extensive retinal ischemia may lead to vascular occlusions, retinal neovascularization (Fig. **2**), vitreous hemorrhage, retinal detachment, and, in some cases, neovascular glaucoma. These late changes are recognized as the proliferative phase of the disease [1, 3].

Rarely, choroidal neovascular membranes (CNV), chorioretinal anastomosis and intravitreal polypoidal neovascularization have been reported [5 - 7].

**Imaging**. The diagnosis is mainly clinical; however, retinal diagnostic imaging provides valuable tools monitoring the progression of the disease and treatment response.

Optical coherence tomography: Ensures early recognition of macular changes. More severe and chronic cases may reveal outer retinal disruption [8].

Fluorescein angiography: Initial findings include varying degrees of capillary closure and dilation of microvasculature (Fig. **2**). The most affected areas are the peripapillary region and the macula [9].

Indocyanine green angiography: Detects areas of choriocapillaris perfusion defects [10].

*Radiation Retinopathy Ophthalmology: Current and Future Developments, Vol. 1* **127**

**Fig. (2).** Fundus photograph shows microaneurysms, hard exudates and and retinal hemorrhages. Fluorescein angiography reveals microaneurysms, capillary closure and retinal neovascularization.

## **DIFFERENTIAL DIAGNOSIS**


## **MANAGEMENT**

There are no specific treatment guidelines for radiation retinopathy. Macular ischemia is usually irreversible and is the most feared complication that results in blindness. Focal laser treatment can be applied to areas of macular edema [11]. In recent years, intravitreal or periocular steroids and anti-vascular endothelial growth factor (VEGF) therapies have been successfully used to treat centerinvolving macular edema [11 - 13]. Bevacizumab has been the most studied anti-VEGF in cases of radiation retinopathy. Nevertheless, similar outcomes have been reported with other anti-VEGF agents. Refractory cases may benefit from

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combination therapy with intravitreal triamcinolone and anti-VEGF agents [14]. Anti-VEGF agents have also been combined with micropulse laser with promising results [15].

Argon laser panretinal photocoagulation is the standard therapy for areas of capillary nonperfusion with associated neovascularization. An approach similar to the one published in the ETDRS is applied [11]. Photodynamic therapy has been proposed for the treatment of severe cases of macular edema or CNV. Hyperbaric oxygen therapy remains controversial [11, 12]. One case report proposed oral pentoxifylline as a potential therapy to improve visual acuity [16].

Non-clearing vitreous hemorrhage or retinal detachment is treated with standard vitrectomy techniques [1].

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[http://dx.doi.org/10.1111/j.1755-3768.2008.01280.x] [PMID: 18652579]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 13**

# **Ocular Ischemic Syndrome**

### **Eleonora Lavaque\***

*Retina Department, Hospital Oftalmológico Santa Lucia, Buenos Aires, Argentina Retina Department, Instituto Médico de Ojos, Buenos Aires, Argentina*

Ocular ischemic syndrome (OIS) is caused by ocular hypoperfusion. Carotid stenosis superior to 70% or complete occlusion due to atherosclerosis is the common cause of this rare condition. In 80% of the cases, OIS is found unilaterally, on the same side of the carotid stenosis [1, 2]. Occasional causes of OIS secondary to ophthalmic artery obstruction include Takayasu disease or giant cell arteritis [3].

Described risk factors are: age between 50-80 years, male gender 2:1, and vascular diseases such as arterial hypertension (75%), diabetes (56%), coronary diseases, vascular stroke and hemodialysis [3 - 5].

### **ESSENTIALS OF DIAGNOSIS**

Ninety percent of the patients present with a history of slowly progressive visual loss in the affected eye. Dull ischemic pain develops gradually and is relieved when the patient lies down [4, 5].

Anterior segment ischemic signs include iris or angle neovascularization, iridocyclitis with flare and cells in 20% of cases, cataract, iris atrophy, sluggish pupillary reaction to light [1]. Other less common signs of OIS are dilatation of conjunctival and episcleral vessels, corneal edema, and bullous keratopathy [4, 6].

Posterior segment signs are more frequent than anterior segment signs [4]. Posterior segment ischemic signs include narrow retinal arteries, perifoveal telangi-

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Eleonora Lavaque:** Retina Department, Hospital Oftalmológico Santa Lucia, Buenos Aires, Argentina; Tel: 00-9-54-56458302; Fax: 00-54-11-48124494; E-mail: eblavaque@hotmail.com

ectasia, dilated retinal veins, mid-peripheral retinal hemorrhages and microaneurysms. Neovascularization in the optic disc or retina and its complications (fibrovascular proliferation, cotton-wool spots, vitreous hemorrhage) may be present but are not frequent (Figs. **1**-**3**) [3, 4].

**Fig. (1).** Fundus photograph shows round circumscribed hemorrhages at the classical midperipherical location.

**Fig. (2).** 70-year-old Caucasian male patient. Medical background: diabetes, hypertension, coronary bypass, acute ischemic cerebral stroke, recent left carotid surgery, endarterectomy 2 months before, and indication for future right carotid endarterectomy because of 79% stenosis. Best-corrected visual acuity was 20/40 in the right eye, and hand motion in the left eye. Positive biomicroscopy: rubeosis iridis, hyphema in left eye. Intraocular pressure 15/60 mm hg. Fundus photograph of the right eye: preretinal hyaloid fibrosis, preretinal hemorrhage at an arteriovenous crossing. Ocular fundus findings in left eye: vitreous hemorrhage.

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**Fig. (3).** Left eye of the same patient as Fig. (**2**), after vitrectomy and endophotocoagulation. Round hemorrhages and photocoagulation scars are present. After vitrectomy, visual acuity improved to 20/100, intraocular pressure improved to 26 mmHg with topical treatment.

A cherry-red spot, characteristic of macular ischemia, is seen in 12% of eyes, due to IOP exceeding the perfusion pressure or to a result of embolic occlusion of the central retinal artery [1, 4].

Eighty percent (80%) of OIS present with very characteristic retinal hemorrhages: they are round, located in the external retinal layers, and at the mid-periphery (Fig. **1**) [2, 3].

Intraocular pressure is usually normal or low. Although anterior segment neovascularization is frequent, elevated intraocular pressure is less common than expected due to flow restriction to the ciliary body. Normal-tension glaucoma can be present in eyes with normal ocular tension due to hypoperfusion to the optic disc [1, 2, 4].

In fluorescein angiography, 60% presents prolonged arm-to-choroid and arm-toretina circulation time (Fig. **4**). The normal retinal filling time is approximately 5 seconds, but in the affected eye it may be 1 minute or longer [4].

**Fig. (4).** Fluorescein angiogram of an ocular ischemic syndrome. Top: Image 47 seconds after dye injection, showing only arterial filling. Bottom: Image 1:05 minutes after dye injection, showing delayed vein filling, and significant capillary nonperfusion (Images courtesy of Gerardo Garcia-Aguirre).

The majority of eyes affected with OIS show staining of the retinal vessels at a late phase. Endothelial cell damage and increased permeability due to chronic ischemia are responsible for this sign [2]. Macular edema and hyperfluorescence

of the optic disc are less common signs [4]. The unilateral nature of all these signs should alert the physician of the presence of an OIS.

Due to the frequent association with carotid artery stenosis, patients with OIS must undergo Doppler ultrasound of the carotid arteries to measure the degree of obstruction, which is usually significant. If carotid Doppler ultrasound yields no relevant result, Doppler ultrasound of retrobulbar vessels should be performed. Ocular plethysmography and invasive techniques such as carotid arteriography are usually performed only previous to carotid surgery [4, 7, 8].

## **DIFFERENTIAL DIAGNOSIS**

The main differential diagnosis is made with retinal vascular diseases such as diabetic retinopathy or retinal vein occlusion. In OIS, intraretinal hemorrhages are less numerous than in diabetic retinopathy, they are round and mostly located in the mid-periphery (Fig. **1**). The presence of hard exudates and fibrovascular proliferation also suggests diabetic retinopathy. Absence of delayed choroidal and arterial filling time in a fluorescein angiogram also points to diabetic retinopathy or vein occlusion [4, 8]. Diabetic retinopathy may coexist with OIS, so marked asymmetry of retinopathy in a diabetic patient should raise the suspicion of OIS [3].

## **MANAGEMENT**

Treatment is directed towards reducing retinal and anterior segment ischemia. Panretinal photocoagulation is indicated in patients with iris and posterior segment neovascularization to prevent neovascular glaucoma or intraocular hemorrhages (Fig. **3**). However, it is effective in only 35% of eyes since choroidal ischemia, which is unaffected by laser photocoagulation, plays an important role in developing neovascularization [3, 4, 6].

Since the most frequent etiology is significant carotid artery obstruction, carotid artery endarterectomy (CEA) is the surgical method of choice, and has proven to be effective for the treatment of OIS [9].

Mortality rate for OIS is as high as 40% within 5 years of onset. Patients with ocular ischemic syndrome should be referred for consultation to the neurologist,

vascular surgeon and cardiologist [5].

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[4] Zemba M, Avram CI, Ochinciuc U, Stamate AC, Camburu RL. Ocular ischemic syndrome--a case


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Dry Age-Related Macular Degeneration**

### **Ana Domínguez Yates** and **Virgil Alfaro\***

*Retina Consultants of Charleston, Charleston, South Carolina, USA*

Age related macular degeneration (AMD) is a progressive and chronic disorder, characterized by the onset of degenerative changes in the macular area in people of 50 years of age or older [1]. Besides age, other risk factors are white race [2], smoking [3, 4] and female gender [5, 6]. Advanced AMD, is the leading cause of severe central vision loss in this age group, and geographic atrophy (GA) is responsible for 25% of cases. The Pathophysiologic mechanism still remains unclear but it is well known that the Retinal Pigment Epithelium (RPE) plays a key role [7]. Environmental and genetics factors can alter any given patient's susceptibility to the disease [8].

### **ESSENTIALS OF DIAGNOSIS**

The changes in AMD involve the outer retina, RPE, Bruch's membrane and choriocapillaris [9]. Drusen are the hallmark features of AMD. They become visible on biomicroscopic fundus examination when their diameter exceeds 25 μm. They can be classified [10] by size as small (< 0-63 µm diameter), medium (64-124 µm diameter) or large (> 0-125 µm diameter) (Fig. **1**).

According to their appearance they can be classified as hard or soft. Hard or crystalline drusen (Fig. **2**) appear as small, round yellow-white spots with sharp borders. They correspond to accumulation or entrapment of hyaline material, lipids and mucopolysaccharides underneath RPE [11, 12]. Large areas of small hard drusen increase the risk of soft drusen and RPE atrophy at a relatively young age [13, 14]. Soft drusen are pale yellow-white spots, more than 63 µm in diame-

<sup>\*</sup> **Corresponding author Virgil Alfaro:** Retina Consultants of Charleston, 3531 Mary Ader Ave # D, Charleston, SC 29414, Estados Unidos, USA; Tel: +1 843-763-4466; E-mail: virgil.alfaro@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

*Dry Age-Related Macular Degeneration Ophthalmology: Current and Future Developments, Vol. 1* **137**

**Fig. (1).** 60-year-old patient with Dry AMD and visual acuity of 20/20 in both eyes. Small drusen (filled arrow); medium drusen, with a diameter equal or greater than one half of a large drusen (arrowhead); and large drusen, diameter greater than or equal to a large vein at the disc margin (unfilled arrow).

**Fig. (2).** Some small drusen in the superior macula in a 61-year-old patient. Hard drusen appear bright with sharp and very well defined borders (unfilled arrow).

**Fig. (3).** Soft drusen in a 77-year-old patient. Big and pale yellow–white lesions ill-defined margins (arrow).

ter, with ill-defined boundaries, are preferentially located within the fovea (Fig. **3**). They are a result of RPE dysfunction and derive from basal linear deposits, between the RPE and the Bruch's membrane [11, 12]. Most of the molecular constituents of drusen reflex their complex pathogenesis: protein (immune response modulator; immunoglobulin and complement components; inflammation molecules), cellular components (RPE blebs, lipofuscin, and melanin, as well as choroidal dendritic cell), glycoconjugates, neutral lipids and zinc [15].

On Fluorescein angiography (FA), hard drusen appear as a bright early hyperfluorescence secondary to a window defects (Fig. **4 a-c**). On the other hand, soft drusen appear as progressively hyperfluorescent spots that persist in late phases due to staining (Figs. **5 a-d** and **6 a-c**).

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**Fig. (4). a**) Small hard (unfilled arrow) and medium drusen around and between the temporal arcades, right eye. **b**) Early hyperfluorescence due to transmission defect, secondary to attenuation or hypopigmentation of the RPE cells overlying the drusen. **c**) Fluorescence fades in late frames.

**Fig. (5). a**) Soft drusen (unfilled arrow) and RPE defects in a left eye. **b**) and **c**) Fluorescein angiogram showing progressive increase in intensity through arteriovenous phase; **d**) hyperfluorescence persists in late stages due to staining.

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**Fig. (6).** Soft drusen (unfilled arrow): Funds photographs: **a**) funds photographs; (**b**) early and (**c**) late FA frames.

Optical Coherence Tomography (OCT) shows soft drusen as well-defined convex accumulations of homogenous moderately reflective material, underneath the highly reflective RPE layer (Fig. **7 a, b**) (Figs. **8** and **9**) or like multiple excrescences in succession giving a "sawtooth" configuration (Figs. **7c**, **10** and **11**). The RPE appears to be clearly defined. Hard drusen are discrete nodules with moderately and highly reflective material, producing RPE disruptions. In either case, the hyperreflective junction between the inner and outer photo-receptors segments is elevated, with overlying compression of the outer retinal layers [16].

Drusen may evolve rapidly and are prone to coalesce and become confluent, separating the RPE basement membrane from the rest of Bruch´s membrane over long distances, forming a so-called drusenoid pigment epithelial detachment (DPED). These lesions are often located in the central macula, appearing as a pale yellow or white shallow elevation of the RPE (Figs. **12 a** and **13 a**) [17]. On FA, they appear as a progressive hyperfluorescence secondary to dye pooling and faint stain in the late frames (Figs. **12 b-d** and **13 b-d**). OCT shows areas of elevation of the RPE, with medium to high homogeneous internal reflectivity. Bruch´s membrane is seen as a thin moderately reflective line underneath it (Figs. **12 e**, **13 e** and **14**) [18].

**Fig. (7). a**) Fundus color photograph of soft drusen at the perifoveal area; **b**) OCT showing elevation of the highly reflective RPE layer with homogeneous moderately reflective material below it; **c**) "sawtooth" pattern.

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**Fig. (8).** Soft drusen with moderately reflective material and elevation of the ellipsoid layer.

**Fig. (9).** Soft drusen underneath a clearly defined RPE layer.

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**Fig. (10).** Multiple excrescences in succession given a "sawtooth" of the RPE.

**Fig. (11).** Multiple excrescences in succession given a saw toothed of the RPE.

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**Fig. (12). a**) Fundus Photograph of confluent large drusen conforming a drusenoid PED **b**) and **c**) progressive hyperfluorescence throughout angiogram and **d**) faint stain in late phases; **e**) OCT RPE elevation. The Bruch´membrane is clearly seen as a thin hyperreflective line behind it.

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**Fig. (13). a**) Color photo of drusenoid pigment epithelium detachment **b**), **c**) and **d**) early and late phases of FA with fluorescein pooling into the space. The margins appear to be well-defined during the frames; **e**) OCT shows homogenous reflectivity underneath the RPE layer elevation.

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**Fig. (14).** OCT showing confluent soft drusen (DPED) in the inferior macula.

Depigmentation is an area of RPE atrophy, less weel defined, less regular in shape, and less severe than Atrofia geográfica. Clumps of gray or black pigment may be observed in or beneath the retina. FA shows mottled early hyperfluorescence that fades later in the study and hypofluorescence by blockage respectively (Fig. **15 a-d**) [19]. OCT shows clumping of hyperreflective material at the level of the RPE. Hyperreflective particles in the inner retinal layers indicate RPE migration [16].

Drusen evolve dynamically overtime, and can fade and disappear. This spontaneous regression is coupled with hyper and hypopigmentation changes and calcified drusen (chalky-white or shiny drusen) (Fig. **16**) [20]. More frequently, drusen are able to evolve and progress, and over time increase in volume, height and area. The presence of large, confluent and extensive soft drusen and RPE abnormalities are associated with increased risk of progression to advanced AMD and central visual loss [8, 21, 22]. Furthermore, the presence of DPEDs possesses *Dry Age-Related Macular Degeneration Ophthalmology: Current and Future Developments, Vol. 1* **147** an additional high risk of developing geographic atrophy [17].

**Fig. (15). a**) Drusen and hyper (fill arrow) and hypopigmentation (unfilled arrow) of the RPE in the center of the macula area; **b**) and **c**) FA: low signal intensity due to fluorescein blocking at areas of pigment clumping (fill arrow) and mottled hyperfluorescence secondary to loss of RPE cells (unfilled arrow) during arteriovenous frames; **d**) the window defect fades in the late phase (unfilled arrow) but keeps the same shape and size.

Most authors use the Age-Related Eye Disease Study severity scale to grade AMD [23]. It is subdivided in mild, when only a few drusen are present (Fig. **17**), moderate, when several drusen are present (Fig. **18**), and advanced, when neovascular disease and/or geographic atrophy (GA) involving the center of the macula are present.

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**Fig. (16).** Soft drusen, calcified shiny drusen (unfilled arrow) and hyper and hypopigmentation changes (fill arrow).

**Fig. (17).** Mild AMD with extensive small drusen or at least one intermediate size drusen and / or abnormalities in one or eyes.

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**Fig. (18).** Moderate AMD with extensive intermediate drusen, at least 1 large drusen and /or GA not involving the center of the macula, either in one or both eyes.

GA is usually a round or oval sharply demarcated patch of partial or complete RPE loss, with associated atrophy of the overlying retina and underlying choriocapillaris, typically with exposure of large choroidal blood vessels and relative color change to the surrounding RPE (Figs. **19**-**21**) [24]. It may involve the central macula (Fig. **22**) or spare it (Fig. **23**). GA tends to spare the foveal center until the later stages of the disease (Fig. **24**). In FA, GA appears as a welldefined hyperfluorescent area at late phases, due to staining of the deep choroid and sclera (Fig. **25 a-e**). OCT shows retinal thinning with attenuation of the outer retina, hyporeflectivity of the RPE, and loss of the layered structure of the retina, with prominent choroidal deep vessels (Figs. **26**-**28**) [18].

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**Fig. (19).** Large GA with atrophy of the choriocapillaris and exposure of the underlying choroidal vessels. RPE alteration in the center of the lesion and surrounding the border.

**Fig. (20).** Intermediate GA.

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**Fig. (21).** Small GA.

**Fig. (22).** Round patch of central GA involving the center point of the macula, sharply demarcated, with large choroidal blood vessels in the back in a patient with advanced AMD.

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**Fig. (23).** Drusen, RPE changes and non-central GA in a 95-year-old patient.

**Fig. (24).** Large GA sparing the central fovea until late stages.

**Fig. (25). a**) 71-year-old patient with non-central GA; **b**) **c**) **d**) progressive well-defined hyperfluorescence of the atrophic area. Hyperfluorescence increases in late phases; **e**) late phase shows intense hyperfluorescence because of staining of the underlying choroid and sclera.

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**Fig. (26).** Central GA, with outer retinal thinning (loss of the external limiting membrane -ELM- and inner /outer segment junction) and atrophy of RPE cells, Bruch´s membrane, and choriocapillaris. Highly reflective signal from the choroid vessels in the atrophic area.

Accumulation of lipofuscin (LF) granules in RPE cells increases in AMD [25]. Normally, Funds autofluorescence (FAF) is able to visualize lipofuscin yielding a distinctive pattern (Fig. **29**). Variations in the FAF signal reflect modifications in the density of LF. In early AMD, FAF is able to show more widespread abnormalities than funds examination and FA. Some hard and soft drusen may present a ring pattern. Confluent drusen have a mildly increased signal (Fig. **30**). FAF is useful to identify a drusenoid PED (mild, diffuse increased signal corresponding exactly with the detached area) or an RPE tear. Pigment clumping are focal changes with an increased FAF signal and RPE atrophy appears as decreased autofluorescence patch. The borders of an area of GA (junctional zone) can have five different patterns in FAF, that can predict the rate of progression: no change, indicating slow progression; focal (Fig. **31**), indicating slow progression; banded (Fig. **32**), indicating rapid progression; patchy, indicating slow progression, or diffuse (Fig. **33**), indicating rapid progression [26].

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**Fig. (27).** Central GA with loss of the layered structure of the retina.

**Fig. (28).** Important retinal thinning due to GA in a patient with advanced AMD.

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**Fig. (29).** Topographic distribution of FAF in a normal right eye. There is a homogeneous background with very low intensity on the optic disc (no autofluorescent material) and retina vessels (absorption by blood compounds). A gradual decrease in signal in the inner macula toward the fovea (absorption by luteal pigment).

**Fig. (30).** FAF of a patient with moderate AMD. Drusen in a ring pattern (unfilled arrow) with decreased FAF intensities in the center, within or below the range of the normal background signal, surrounded by an annulus of increased FAF (may correspond to pigment clumping in fundus photos). Large and confluent soft drusen (arrow) have an increased signal.

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**Fig. (31).** GA is seen as an area of strong reduction in FAF signal secondary to RPE cell death. Focal pattern in a left eye: individual hyperautoflorescence spots around the GA margin, not in continuous pattern.

**Fig. (32).** Banded pattern: continuous hyperautofluorescence around the junction area between the normal retina and the atrophy. It is related to rapid progression.

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**Fig. (33).** Diffuse pattern: increased FAF intensity at the junctional zone and some spots elsewhere. It is associated with rapid progression of the atrophy; **a**) right eye and **b**) left eye of two different patients.

### **DIFFERENTIAL DIAGNOSIS**

Sequelae of central serous chorioretinopathy may mimick dry AMD (Fig. **34**) [27]. Pattern dystrophy is a group of macular dystrophies with deposition of yellow or gray pigment at the RPE. They typically appear in younger patients and have a characteristic pattern in FA (Fig. **35**) [28, 29]. Adult-onset foveomacular vitelliform dystrophy may also resemble dry AMD (Fig. **36**), and can be confused with DPED (Fig. **37 a, b**) or with a solely large subfoveal drusen. In FA, the vitelliform material blocks the background fluorescence early and stains in late

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frames. OCT shows a highly reflective material (Fig. **36 b,c**) [30, 31]. Other differential diagnoses include chloroquine toxicity (Fig. **38 a-d**) [32 - 34], cuticular basal laminar drusen (Fig. **39 a-h**) [35], central areolar choroidal [36], and dominant drusen [37].

**Fig. (34).** 49-year-old man, visual acuity 20/20 in both eyes and history of previous CSC; **a**) **b**) fundus photos of RPE defects in both eyes. Early and late FA frames showing blockage and transmission defect in the right eye (**c**) (**d**) and the left eye (**e**) (**f**).

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**Fig. (35).** 43-year-old woman with asymmetric Butterfly Dystrophy. Visual acuity remains 20/20 in both eyes. Fundus photos of right (**a**) and left eye (**b**). FA in early and late phases in the right eye (**c**), (**d**) and left eye; (**e**) and (**f**), showing the typical feature with a hypofluorescence center surrounded by a hyperfluorescent rim.

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**Fig. (36). a**) Fundus photo of a left eye with Adult- onset foveomacular vitelliform dystrophy. Early FA **b**) with central hypofluorescence due to blockage. Late frame shows **c**) hyperfluorescence due to deposit stains.

**Fig. (37). a**) Confluent large soft drusen in the left eye of a 71-year-old patient, imitating a round central yellow vitelliform spot; **b**) OCT showing a DPED.

**Fig. (38).** 65-year-old female patient, with a history of hydroxychloroquine treatment and eye toxicity; **a**) funds photograph of the right eye, showing no abnormalities; **b**) fundus photograph of the left eye, showing pigment changes; **c**) and **d**) visual fields with central scotoma in both eyes.

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**Fig. (39). a**) and **b**) Right and left eyes of a patient with Basal Laminar Drusen. In the color photos there are some drusen and defects in the RPE in the posterior pole in both eyes. Right eye FA (**c**) and (**d**). In FA the small, round and widely spread drusen are more evident, forming a "stars in the sky" pattern presenting early hyperfluorescence.

**Fig. (39).** Left eye FA (**e**) and (**f**). At late phases in the right (**g**) and left eye (**h**), the hyperfluorescence fades.

### **MANAGEMENT**

There is no adequate therapy for GA in advanced AMD. The AREDS Study was designed to assess whether active treatment with antioxidants and/or zinc could reduce the risk of developing advanced AMD or visual acuity loss. The largest risk reduction was observed in patients with confluent soft drusen or patients with contralateral advanced AMD. Treatment options for prevention and progress of GA are limited [38].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


### *Dry Age-Related Macular Degeneration Ophthalmology: Current and Future Developments, Vol. 1* **165**


**166** *Ophthalmology: Current and Future Developments, Vol. 1 Domínguez Yates and Alfaro*

[http://dx.doi.org/10.1016/S0002-9394(01)01218-1] [PMID: 11704028]

[20] Toy BC, Krishnadev N, Indaram M, *et al.* Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration. Am J Ophthalmol 2013; 156(3): 532-42.e1.

[http://dx.doi.org/10.1016/j.ajo.2013.04.031] [PMID: 23830564]


[http://dx.doi.org/10.1016/j.ajo.2009.04.022] [PMID: 19541290]


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therapy. Arch Ophthalmol 2011; 129(1): 30-9. [http://dx.doi.org/10.1001/archophthalmol.2010.321] [PMID: 21220626]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 15**

# **Wet Age-Related Macular Degeneration**

**Gerardo García-Aguirre\*, 1,2**

*1 Retina Department, Asociaciós para Evitar la Ceguera en Mexico, Mexico City, Mexico*

*2 Ophthalmology, Escuela de Medicina - Tec de Monterrey, Mexico City, Mexico*

Age-related macular degeneration (AMD) is one of the leading causes of legal blindness in patients over 60 years, especially in developed countries [1]. The prevalence of the disease varies according to ethnicity [2], and is more common in smokers [3, 4] and in women [5, 6]. The disease is classified in two stages, known as dry AMD (which is discussed in another chapter) which is characterized by the presence of drusen in the posterior pole, and wet AMD, in which the patient develops neovascularization that stems from the choroid, penetrates Bruch's membrane, and by leakage of fluid, hemorrhage and scarring, affecting the center of the macula.

### **ESSENTIALS OF DIAGNOSIS**

When a choroidal neovascularization (CNV) develops, patients may complain of metamorphopsia and a central or paracentral relative scotoma.

*Clinical examination* usually reveals drusen, and the presence of intraretinal or subretinal fluid that causes thickening of the retina. Hemorrhage and hard exudates may also be observed (Figs. **1**-**6**).

<sup>\*</sup> **Corresponding author Gerardo García Aguirre:** Retina Department, Asociaciós para Evitar la Ceguera en Mexico, Vicente García Torres 46, San Lucas Coyoacan, Mexico City 04030, Mexico; Tel: +52 (55) 10841400; E-mail: jerry\_gar\_md@yahoo.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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**Fig. (1).** Fundus photograph of the right eye with subfoveal CNV showing multiple soft and hard drusen in the macular area. A small subretinal hemorrhage may be observed nasal to the fovea.

**Fig. (2).** Fundus photograph of the right eye with a subfoveal CNV and large submacular hemorrhage.

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**Fig. (3).** Red-free fundus photograph of the left eye, showing a subfoveal CNV surrounded by hard exudates and submacular hemorrhage.

**Fig. (4).** Fundus photograph of the left eye displaying an extrafoveal CNV, just adjacent to the inferotemporal border of the optic nerve, with associated subretinal hemorrhage.

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**Fig. (5).** Fundus photograph of the left eye, showing a subfoveal CNV with abundant hard exudates and some subretinal fibrosis.

**Fig. (6).** Fundus photograph of the left eye showing a massive submacular hemorrhage secondary to CNV.

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*Fluorescein angiography* (FA) is very useful, showing an area of early hyperfluorescence that increases in intensity and size as the study progresses due to leakage of fluorescein. Accumulation of dye secondary to a pigment epithelium detachment (PED) may also be observed (Figs. **7**-**15**).

*Optic coherence tomography* (OCT) of the macula is an invaluable adjuvant in the diagnosis and follow-up of patients with CNV secondary to AMD. Different abnormalities may be observed in any given case, including intraretinal fluid, subretinal fluid, PED, and/or a hyper-reflective subretinal lesion. Hard exudates and hemorrhages are also observed as hyper-reflective foci (Figs. **16**-**19**)

*Indocyanine green angiography (ICGa)* is also useful in some cases, especially when suspecting a CNV with an arteriolar component (Figs. **20**, **21**).

If the CNV has not been treated and has been present for several months, subretinal fibrosis begins to appear, which usually grows into a large disciform scar that may occupy the entire macular area. The presence of fibrotic tissue has a very bad visual prognosis (Figs. **22**-**25**).

**Fig. (7).** Early fluorescein angiogram of the same eye as Fig. (**1**), showing hyperfluorescence in the subfoveal area.

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**Fig. (8).** Late fluorescein angiogram of the same eye as in Fig. (**7**), showing increase of hyperfluorescence in the foveal area. Hyperfluorescence secondary to drusen is also observed throughout the macula.

**Fig. (9).** Early fluorescein angiogram of the same eye as in Fig. (**2**), showing mild hyperfluorescence in the center of the macula and blockage secondary to hemorrhage.

**Fig. (10).** Late fluorescein angiogram of the same eye as in Fig. (**9**), showing leakage of fluorescein secondary to CNV, surrounded by blockage secondary to hemorrhage.

**Fig. (11).** Fluorescein angiogram of the same eye as in Fig. (**3**), showing a large area of hyperfluorescence that involves the center of the macula, surrounded by blockage secondary to subretinal hemorrhage.

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**Fig. (12).** Late fluorescein angiogram of the same eye as in Fig. (**11**), showing leakage of fluorescein secondary to a large subfoveal CNV.

**Fig. (13).** Early fluorescein angiogram of the same eye as in Fig. (**4**), showing hyperfluorescence surrounding the optic disc.

**Fig. (14).** Late fluorescein angiogram of the same eye as in Fig. (**13**), showing leakage of fluorescein surrounding the optic nerve.

**Fig. (15).** Fluorescein angiogram of the same eye as in Fig. (**6**), showing a large area of blockage secondary to massive subretinal hemorrhage.

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**Fig. (16).** OCT of the macula showing increased retinal thickness, accumulation of intraretinal fluid and the presence of a subfoveal hyper-reflective lesion corresponding to a CNV.

**Fig. (17).** OCT of the macula showing increased retinal thickness, accumulation of intraretinal fluid and the presence of an extrafoveal hyper-reflective lesion corresponding to a CNV.

**Fig. (18).** OCT of the macula showing accumulation of subretinal fluid and the presence of a pigment epithelial detachment.

**Fig. (19).** OCT of the macula showing accumulation of subretinal fluid and the presence of several pigment epithelial detachments.

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**Fig. (20).** Combined fluorescein-indocyanine green angiography. The image on the left corresponds to fluorescein angiography, showing diffuse hyperfluorescence in the macular area. The image on the right corresponds to indocyanine green angiography, showing thick vessels where the neovascularization originates. These are called arteriolized CNVs.

**Fig. (21).** Combined fluorescein-indocyanine green angiography. The image on the left corresponds to fluorescein angiography, showing diffuse hyperfluorescence in the macular area. The image on the right corresponds to indocyanine green angiography, showing thick vessels where the neovascularization originates. These are called arteriolized CNVs.

**Fig. (22).** Fundus photograph of the right eye showing a large area of subretinal fibrosis. Hard exudates, intraretinal and subretinal hemorrhage can also be observed.

**Fig. (23).** Early fluorescein angiogram of the same eye as in Fig. (**22**) showing mild diffuse hyperfluorescence in the macular area.

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**Fig. (24).** Late fluorescein angiogram of the same eye as in Fig. (**23**), showing an area of intense fluorescein leakage, and some blockage secondary to hemorrhage.

**Fig. (25).** OCT of a case of disciform scar, showing large quantities of intraretinal fluid, distortion of the retinal layers, and presence of a large subretinal hyper-reflective lesion corresponding to subretinal fibrosis.

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### **DIFFERENTIAL DIAGNOSIS**

When putting together the age of the patient, the clinical appearance, the presence of AMD in the contralateral eye, and the findings in FA and OCT, the diagnosis is usually straightforward. An entity that shares some of the features observed in wet AMD is central serous chorioretinopathy (CSC). It presents as subretinal fluid associated to a PED. It usually affects younger patients but may be present at any age. The presence of drusen in the same or the other eye might facilitate the differential diagnosis. Also, CSC lacks hemorrhage or hard exudates, which are relatively common in CNV.

Differential diagnosis should also be made with other causes of CNV, such as high myopia, presumed ocular histoplasmosis syndrome or idiopathic.

**Fig. (26).** OCT of the same eye as in Fig. (**16**) after intravitreal anti-VEGF therapy, showing decreased retinal thickness, recovery of foveal contour and improvement of intraretinal fluid. Some hyper-reflective tissue is still observed in the subfoveal area.

### **MANAGEMENT**

The gold standard for the management of CNV secondary to AMD is the injection of intravitreal anti-VEGF agents. Available agents are aflibercept [7],

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bevacizumab [8, 9] and ranibizumab [8 - 10], which are injected on a monthly basis until intraretinal and/or subretinal fluid disappears. Injection of these agents usually results in the arrest of disease progression and improved visual acuity (Figs. **26**-**28**).

**Fig. (27).** OCT showing loss of foveal depression, increased retinal thickness, presence of intraretinal fluid, and the presence of a hyper-reflective lesion under the fovea.

**Fig. (28).** OCT of the same eye as in Fig. (**27**) after intravitreal anti-VEGF therapy, showing decreased retinal thickness, recovery of foveal contour and improvement of intraretinal fluid. Some hyper-reflective tissue is still observed in the subfoveal area. The retina in the foveal area is thinner than normal.

Other treatments include laser photocoagulation, which is reserved for cases in which the CNV is located outside the macula [11], and photodynamic therapy with verteporfin, which is sometimes used as an adjuvant to anti-VEGF therapy in non-responder cases [12].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[http://dx.doi.org/10.1016/j.ophtha.2014.01.003] [PMID: 24594095]


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2012; 119(7): 1399-411. [http://dx.doi.org/10.1016/j.ophtha.2012.04.015] [PMID: 22578446]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Polypoidal Choroidal Vasculopathy**

### **Jans Fromow Guerra\***

*Retina Department, Asociación para Evitar la Ceguera en México, IAP, México City, México*

### **ESSENTIALS OF DIAGNOSIS**

Polypoidal choroidal vasculopathy (PCV) is a retinal disorder involving the choroidal vasculature characterized by the presence of aneurysmal polypoidal dilations that commonly arise from a network of branching choroidal vessels, that was described in 1982 by Lawrence Yanuzzi. PCV usually shows a broad spectrum of manifestations both clinically and epidemiologically. For this reason, it has been widely debated whether to consider it a subtype of neovascular agerelated macular degeneration (AMD) or a separate clinical entity. Some of the characteristics of PCV are shared by AMD but some others are radically different.

### **Epidemiology Essentials of PCV**


<sup>\*</sup> **Corresponding author Jans Fromow Guerra:** Retina Department, Asociación para Evitar la Ceguera en México, IAP, Vicente García Torres, 46. San Lucas Coyoacán, México DF. México 04030; Tel: +52.55.10841400; Fax: +52.55.10841404; E-mail: fromow@me.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

## **Clinical Essentials of PCV**


**Fig. (1).** Clinical appearance of peripapillary PCV.

● Angiographic & OCT Analysis (Figs. **2**-**6**): Indocyanine green angiography (ICGA) should be considered as the gold standard in PCV diagnosis since findings in FA can be easily mistaken for wet AMD especially in elderly patients with drusen and bilateral disease [8, 9]. ICGA will often reveal single or multiple polyps appearing as vascular aneurysmal dilatations arising from inner choroidal vessels often seen as a neovascular plaque or a so-called "branching vascular networks" (BVN). These findings are usually seen within the first 6 minutes after the injection of ICG [10]. However, PCV lesions may not be easily seen due to minor or extensive hemorrhage. A classification of PCV has been developed regarding the presence or absence of BVN determined by ICGA:

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Type I PCV or "Polypoidal CNV" with an apparent BVN and type 2 PCV or "Typical PCV" with no or faint BVN. These 2 different PCV subtypes have distinct clinical course, treatment response and genetic background [11 - 13]. OCT shows important diagnostic characteristics (Figs. **2**, **3** and **6**). In most cases a sharp elevated PED is observed, that may be associated to a flat, shallower PED. Polypoidal lesions are usually attached to the back surface of the elevated PED. In type I PCV the flat shallower PED is associated with the BVN giving a "double layer sign" [14].

**Fig. (2).** ICGA and OCT appearance of peripapillary PCV of the same patient as Fig. (**1**).

**Fig. (3).** Left: ICG-Macular Type 2 PCV with no or faint branching vascular network. Right. OCT image where an associated PED can be clearly observed.

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**Fig. (4).** Left: Fluorescein Angiogram, Right: ICG-Angiogram. This comparison clearly shows the advantage of ICGA in the diagnosis of PCV, that clearly delineates the lesions, which cannot be distinguished in FA. Macular Type 1 PCV with apparent branching vascular network from which the polyps arise.

**Fig. (5).** ICGA of peripapillary Type 2 PCV with no apparent BVN.

**Fig. (6).** Left: ICGA. Macular Type 1 PCV with apparent branching vascular network from which the polyps arise. Right: OCT showing a polyp PED.

## **DIFFERENTIAL DIAGNOSIS**

There are two main clinical entities that should be considered first in the differential diagnosis of PCV: "Regular" wet AMD, especially if there is a chronic neovascular process with insufficient anti-VEGF treatment response, and central serous chorioretinopathy (CSC), which in fact shares similar characteristics including increased choroidal thickness. Furthermore, CSC has been regarded as a risk factor for PCV [14, 15].

## **MANAGEMENT**

There are several trials that show the efficacy of Anti-VEGF treatment for PCV. Also, since 2002 the efficacy of Photodynamic Therapy with verteporfin for this entity has been proven, and some others promote a combination approach [8, 16, 17]. To give scientific solution to this question, a multicenter, double-masked trial known as EVEREST compared these three treatment regimens. The six-month results revealed that PDT plus ranibizumab therapy and PDT monotherapy were both superior to ranibizumab monotherapy in achieving complete polyp

regression (77.8 percent and 71.4 percent *vs.* 28.6 percent, respectively; p < 0.01) [18]. Ongoing studies are evaluating other Anti-VEGF options such as aflibercept.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


**192** *Ophthalmology: Current and Future Developments, Vol. 1 Jans Fromow Guerra*

[http://dx.doi.org/10.1016/j.ajo.2010.05.035] [PMID: 20719300]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 17**

# **Retinal Angiomatous Proliferation (RAP)**

### **Maximiliano Gordon1,2,\*** and **Guillermo Gordon†**

*1 Centro de la Visión Gordon-Manavella, Rosario, Santa Fe, Argentina*

*2 Retina Department, Ophthalmology Service, Hospital Provincial del Centenario, Rosario, Santa Fe, Argentina*

Retinal Angiomatous Proliferation (RAP), or type 3 neovascularization, is a different form of exudative age-related macular degeneration (AMD) [1]. Its main characteristic is an abnormal anastomosis between the choroidal and the retinal vessels. The pathogenesis of this entity remains controversial [2 - 4]. Yannuzzi *et al.* believe that the neovascular process originates within the neurosensory retina. In contrast, Gass proposed that the process begins with choroidal neovascularization (CNV) [1].

Gass' classification scheme is based on neovascularization relationship to the retinal pigment epithelium (RPE). Type 1 neovascularization describes new blood vessels growing under the RPE, while in Type 2 neovascularization these proliferate over the RPE. Freund has proposed modifying Gass' original classification by adding Type 3 neovascularization, which refers to a type of neovascularization with preference for the retina [1].

### **ESSENTIALS OF DIAGNOSIS**

Symptoms are similar to those of AMD. However, patients with RAP tend to be older. The classical findings include retinal and preretinal hemorrhages, and pigment epithelial detachments, as well as small and multiple intraretinal blood [5].

<sup>\*</sup> **Corresponding author Maximiliano Gordon:** Centro de la Visión Gordon - Manavella, Montevideo 763, CP 2000, Rosario - Santa Fe, Argentina; Tel/Fax: +54(341)4400239/4244850; E-mail: maximilianogordon19@gmail.com † Died

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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RAP classification distinguishes three vasogenic stages based on the nature and progression of the neovascularization process. Stage I involves capillary proliferation within the retina originating from the deep retinal plexus (intraretinal neovascularization [IRN]). Stage II is determined by IRN extending into the subretinal space (subretinal neovascularization [SRN]). Stage III describes progression to CNV, that can be clearly determined clinically or angiographically. This stage is sometimes characterized by a vascularized pigment epithelial detachment and retinal choroidal anastomosis (RCA) [6]. Stage-I RAP lesions manifest with intraretinal neovascularization with telangiectatic retinal capillaries and small angiomatous structures perfused by the retinal circulation. Stage-II RAP lesions extend beyond the photoreceptor layer into the subretinal space resulting in subretinal neovascularization. A serous PED is often seen. In stage-III RAP, it is presumed that an RCA is formed. Patients that are not treated for stage-III RAP lesions can develop large fibrotic scars [7]. In these cases, fluorescein angiography revealed poorly defined staining that simulates occult CNV (Figs. **1** and **3**).

Indocyanine green angiography (Fig. **3**) often helps make an accurate diagnosis. It revealed a focal area of hyperfluorescence corresponding to the neovascularization ("hot spot"). OCT may reveal intraretinal hyperreflectivity, corresponding to angiomatous proliferation associated with intraretinal or subretinal fluid (Figs. **2** and **4**) and/or RPE detachment [6]. Dilated fundus exam showed hemorrhages and lipid exudates in an area of occult CNV on the basis of fluorescein angiography and indocyanine green angiography (ICG) revealed the presence of a hot spot. These findings led to the diagnosis of RAP [6, 7].

## **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis should include other forms of CNV with ICG hot spots (occult CNV) and polypoidal choroidal vasculopathy (PCV). This latter disease presents with normally larger retinal hemorrhages and round reddish-orange macular lesions in the eye fundus. OCT is also a helpful tool in differentiating RAP, PCV, and occult membranes. In PCV, polyps appear in OCT as abrupt neurosensory detachment. Other differential diagnosis is macular telangiectasia.

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**Fig. (1).** A 73-year-old woman with retinal angiomatous proliferation. Fundus photograph and autofluorescence revealing perifoveal lesion (**a** and **b**). Fluorescein angiogram showing hyperfluorescence with diffuse leakage of dye (**c**-**f**) (Courtesy of Alejandro Lavaque, Argentina).

**Fig. (2).** OCT of the same patient shown in Fig. (**1**). OCT scans showing subretinal fluid and hyperreflective subretinal lesion (Courtesy of Alejandro Lavaque, Argentina).

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**Fig. (3).** Fundus photograph (**a-b**), fluorescein angiography (**c-d**) and ICG (**e-f**) of patient with retinal angiomatous proliferation (Courtesy of Gerardo Garcia Aguirre, Mexico).

The main differences are telangiectasias not associated with serous PED, a healthier RPE and less frequent choroidal neovascularization associated with parafoveal telangiectasias [8, 9].

### **MANAGEMENT**

Some treatment options for RAP lesions have been thermal laser photocoagulation, surgical ablation, PDT, intravitreal triamcinolone, intravitreal antiangiogenic drugs and combined treatments.

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**Fig. (4).** OCT of the same patient shown in Fig. (**3**). OCT scans showing intraretinal fluid and hyperreflective subretinal lesion. (Courtesy of Gerardo Garcia Aguirre).

Apparently, traditional thermal laser photocoagulation is an effective treatment for some stage-I and early stage-II RAP lesions outside the fovea. However, when RAP exists in association with a PED, the effectiveness of most treatments is deeply affected.

According to short-term results reported on non-randomized studies, RAP lesions treated with photodynamic therapy (PDT) and intravitreal triamcinolone acetate (IVTA) [10 - 12] revealed apparently better VA outcomes and/or a reduced number of treatment sessions in comparison with PDT alone. However, there was also a high frequency of recurrence [13, 14]. Krebs I. *et al.* [15] found minimal differences between the PDT monotherapy group and the combined PDT and IVTA group regarding progress of distance VA, retinal thickness and lesion size, and he concluded that new therapeutic strategies might be necessary to address RAP lesions, probably including therapy with antiangiogenic drugs. As is the case

with classic and occult lesions, intravitreal injection of antiangiogenic agents seems to be more effective in the treatment of RAP lesions than PDT alone.

Short-term experience with intravitreal injection of anti-vascular endothelial growth factor (VEGF) in RAP has only been reported in some uncontrolled studies [16, 17], which showed favorable outcomes; however, frequent intravitreal injections are expected [18 - 21].

Another treatment option consists of surgical excision of the feeder artery and vein by means of diathermy technique, if appropriate, for stage-II RAP lesions with or without serous PED [22]. Future treatments include a combined therapeutic approach to the management of RAP lesions.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


### *Retinal Angiomatous Proliferation (RAP) Ophthalmology: Current and Future Developments, Vol. 1* **199**


[http://dx.doi.org/10.1001/archopht.1982.01030030773010] [PMID: 7082207]


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[http://dx.doi.org/10.1097/IAE.0b013e3181a0be1d] [PMID: 19516116]

[22] Borrillo JL, Sivalingam A, Martidis A, Federman JL. Surgical ablation of retinal angiomatous proliferation. Arch Ophthalmol 2003; 121(4): 558-61. [http://dx.doi.org/10.1001/archopht.121.4.558] [PMID: 12695253]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

**CHAPTER 18**

# **Choroidal Neovascular Membrane in Degenerative Myopia**

**Federico Furno Sola1,2,\***

*1 Ophthalmology Service, Sanatorio Mapaci, Rosario, Santa Fe, Argentina 2 Grupo Laser Visión, Rosario, Santa Fe, Argentina*

### **ESSENTIALS OF DIAGNOSIS**

Myopia is a common condition in many countries, particularly in East Asia, affecting approximately 40% of Chinese adults older than 40 years. The prevalence of myopia in developed countries is reported to be between 11% and 36%. The overall prevalence of pathologic myopia is approximately 1% to 4% in the general adult population although there is a wide geographical variation. The associated prevalence of visual impairment due to pathologic myopia is estimated to be 0.1% to 1.4%. The definition of pathologic myopia is not standardized, but is historically classified in clinical trial literature as a myopic refractive error greater than -6 diopters, or an axial length >26 mm, associated to degenerative changes involving the sclera, choroid and retina. Choroidal neovascularization secondary to pathological myopia is a common vision-threatening complication and often affects adults of working age, and develops in approximately 5% to 10% of patients with pathological myopia. The overall prevalence of choroidal neovascularization secondary to pathological myopia is therefore estimated to be approximately 0.04% to 0.05% in the general population [1, 2].

The chorioretinal lesions are viewed as a consequence of excessive axial elongation. It is believed that progressive distension of the posterior pole stretches the retina, choroid and sclera, as evidenced by the straightening of the temporal

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Federico Furno Sola:** Grupo Laser Visión, Mariano Moreno 1397, Rosario – Santa Fe, Argentina; Tel: +54 (0341) 4472122; Email: furnosola@gmail.com

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retinal vessels, the appearance of peripapillary atrophy, and the thinning of the retina and choroid. Various changes may occur in the fundus of a patient with myopia, related to the presence of myopic conus, staphylomas, retinal pigment epithelium and choroid disturbances and atrophic areas (Figs. **1**-**3**). Lacquer cracks are linear or stellate; the lines are fine, irregular in caliber, yellowish-white, horizontally oriented, single and/or multiple. Lacquer cracks are ruptures of Bruch´s elastic lamina and carry a guarded visual prognosis because of their association with focal degenerative lesions and subretinal neovascularization along their course [1, 2].

It is generally accepted that the pigmented lesion described by Fuchs and the hemorrhagic lesion reported by Foerster represent different stages of the process of the development of CNV in myopia (Fig. **2**). Neovascularization has been identified to precede the development of Fuchs spots. The growth of choroidal new vessels induces a sudden painless reduction in vision usually associated with metamorphopsia. Biomicroscopically, it is observed as a light-gray, round or elliptic macular lesion (Fig. **3**). The lesion is usually discrete in size and located next to the fovea [1, 2].

**Fig. (1).** Numerous areas of pigment epithelium atrophy and choriocapillaris extend to the macular region. A circular myopic crescent is visible.

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**Fig. (2).** Numerous areas of pigment epithelium and choriocapillaris atrophy extend into the macular region. A circular myopic crescent is visible. Hemorrhage occupies the center of the fovea.

**Fig. (3).** Numerous areas of atrophy of the pigment epithelium and choriocapillaris extend to the macular region. A circular myopic crescent is visible. Choroidal new vessels with neovascular lesion and macular edema.

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Fluorescein angiography usually shows a lesion that is hyperfluorescent early in the study (Fig. **4**). Later in the study, the hyperfluorescent area grows, although leakage does not increase significantly (Fig. **5**). ICG angiography may detect a focal hyperfluorescent area that fades with dye washout. On OCT, the CNV extends above the RPE (Figs. **6** and **7**), and generally lacks a significant amount of subretinal or intraretinal fluid [1, 2].

**Fig. (4).** Mid phase of fluorescein angiography shows a hyperfluorescent zone located at the foveal avascular zone.

**Fig. (5).** Late frame of fluorescein angiography, showing dye leakage.

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**Fig. (6).** Optical coherence tomography, showing hyperreflective subretinal material with macular edema.

**Fig. (7).** Optical coherence tomography showing hyperreflective subretinal material.

## **DIFFERENTIAL DIAGNOSIS**

The differential diagnosis of myopic CNV should include other causes of CNV such as age-related macular degeneration, idiopathic, angioid streaks, trauma, tumors, multifocal choroiditis and presumed ocular histoplasmosis syndrome. The refractive error and the presence of findings compatible with high myopia such as

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a posterior staphyloma or the rectification of the temporal arcades should make the diagnosis relatively straightforward.

### **MANAGEMENT**

The visual prognosis in cases of choroidal new vessels in degenerative myopia remains controversial. Laser photocoagulation and photodynamic therapy has fallen by the wayside with the advent of anti-VEGF therapies. The RADIANCE study is the first controlled trial in patients with myopic CNV to demonstrate that intravitreal ranibizumab treatment was superior compared with photodynamic therapy. During the RADIANCE study different dose regimens were assessed, which showed rapid and similar improvements in mean BCVA from baseline up to month 3 that were sustained with continued individualized ranibizumab treatment up to month 12 [1, 2].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Angioid Streaks**

**Michael Larsen1,\* , Mette K.G. Andersen<sup>1</sup> , Naresh Mandava<sup>2</sup>** and **Richard Hwang<sup>3</sup>**

*1 Department of Ophthalmology, Glostrup Hospital and Faculty of Health Sciences, University of Copenhagen, Kobenhave Denmark*

*2 Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA*

*3 Vitreoreitnal Disease and Surgery, Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA*

Angioid streaks is the term used for a characteristic type of posterior segment lesion consisting of irregular and sometimes branching lines with a red or brownish appearance that extend from the rim of the optic disc to the periphery of the fundus (Figs. **1**-**4**, **8A, B**, **9A, B**) [1]. They were originally described by Doyne in 1889 [2]. The streaks are caused by breaks in the Bruch's membrane – retinal pigment epithelium (RPE) complex [1].

Angioid streaks can be seen in the presence of various extraocular conditions, most commonly pseudoxanthoma elasticum, a connective tissue disorder caused by defects in the *ABCC6* gene [3]. It gives rise to lax and dimpled skin, mainly on the flexor side of the neck, elbows and knees (Fig. **6**). The inheritance is mostly autosomal recessive, but autosomal dominant patterns can also be seen. The precise physiological function of ABCC6 is unknown, but it can be seen to be involved in transporting intracellular elements to the extracellular space. Defects in the ABCC6 protein lead to the accumulation of mineralized and fragmented

<sup>\*</sup> **Corresponding author Michael Larsen:** Department of Ophthalmology, Glostrup Hospital and Faculty of Health Sciences, University of Copenhagen, Kobenhave, Denmark; Email: MICLAR01@regionh.dk

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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**Fig. (1).** Angioid streaks (black arrows) of the classic red type that resemble large choroidal blood vessels. The streaks are found behind the retinal blood vessels at the level of the retinal pigment epithelium. Red streaks stain early and prominently on fluorescein angiograms. Subfoveal choroidal neovascularization is also seen in this case (white arrow).

**Fig. (2).** Brownish and greyish pigmented angioid streaks temporal and superior of the optic disc in a patient with pseudoxanthoma elasticum. Note also subfoveal hemorrhage and choroidal neovascularization.

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**Fig. (3).** Parafoveal classic subretinal neovascularization of choroidal origin (black arrows) in a patient with angioid steaks, one of which can be seen superior to the optic nerve head. Fluorescein angiography (lower right) shows prominent leakage, which explains the serous detachment of the neurosensory retina (black arrowheads). The upper right part of the color fundus photograph shows the spotted orange peel (peau d'orange) appearance of the diffuse outer retinal degeneration.

**Fig. (4).** Angioid streaks, a mixture of brownish streaks, pale atrophic areas, mainly around the margin of the optic disc, curved streaks concentric with the disc that are reminiscent of traumatic choroidal rupture lines and a small active choroidal neovascularization of approximately 250 µm diameter at the inferonasal margin of the fovea, emanating from the inferior tip of the large pale defect of the retinal pigment epithelium.

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**Fig. (5).** Angioid streaks and diffuse degeneration of the outer retina in a man aged 42 with pseudoxanthoma elasticum. A peau d'orange pattern is seen most prominently in the temporal fundus. It is highlighted in a color-stretched section shown in the upper right of the montage. Fundus autofluorescence is absent corresponding to the streaks and elevated in the scattered dots that are spread over the rest of the macula. Optical coherence tomography shows varying degrees of photoreceptor outer segment atrophy and pigment epithelium attenuation in the central macula.

**Fig. (6).** Hyperkeratotic papules and rugged skin surface in an 18-year-old woman with pseudoxanthoma elasticum (left) and loose skin that remains elevated after having been pinched on the neck of a 45-year-old man (right) with the same condition.

elastic fibers in the connective tissue of the skin, vessel walls, and Bruch's membrane with consequent weakening of these tissues. Angioid streaks have also been reported in Paget's disease, hemolytic conditions such as hereditary spherocytosis, sickle cell disease and thalassemia and in Ehlers-Danlos syndrome (type 6), Marfans syndrome, senile elastosis, acromegaly, retinitis pigmentosa, lead poisoning, and Bassen-Kornzweig syndrome.

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Sporadic observations suggest that minor blunt trauma to the eye can lead to the formation or expansion of angioid streaks and induction of choroidal neovascularization (CNV). The same mechanism is suspected to be the cause of subretinal hemorrhage in the absence of CNV. Patients with angioid streaks are therefore advised to avoid contact sports and to wear protective goggles when engaging in activities where eye trauma may occur.

**Fig. (7).** Fibrotic end-stage submacular choroidal neovascularization in an eye with angioid streaks, two of which are crossing the rim of the image at 12 o'clock and 1 o'clock, respectively.

## **ESSENTIALS OF DIAGNOSIS**

Clinical diagnosis can usually be made with fundoscopy. Angioid streaks typically appear as bilateral narrow jagged lines beneath the retina with an interconnecting pattern radiating out from the peripapillary region (Figs. **1**-**4**, **8A, B**, **9A, B**). They are evident a few millimeters from the optic disc and have a thickness of 50-500 µm [4 - 6]. The streaks develop and spread very slowly over decades, presumably as a result of mechanical stress in a thickened, calcified and fragile Bruch's membrane. The streaks are often bright red and can be mistaken for large fundus vessels, hence the term angioid (Greek, having the appearance of a blood vessel). Pale atrophic streaks can also be seen as hyperpigmentation along

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the borders of the streaks. Angioid streaks are associated with a high risk of invasion of the subretinal space by CNV arising from the streaks. Smaller localized defects in Bruch's membrane can also give rise to pink patches in the peripheral fundus called salmon spots. Multiple small semiconfluent yellow dots are seen in many cases, mostly temporal of the fovea, a characteristic that has been likened to the skin of an orange and therefore is called *peau d'orange* (Figs. **3**, **5**, **8A, B**, **9B**). Autofluorescence fundus photography shows absence of autofluorescence corresponding to the streaks and hyperfluorescence in areas with *peau d'orange* elements (Figs. **5**, **9H-J**).

**Fig. (8).** A 24-year-old female with biopsy-proven pseudoxanthoma elasticum, with angioid streaks emanating from the peripapillary region with a peau d' orange pigmentary pattern of the peripheral retina in the right (**A**) and left (**B**) eyes.

**Fig. (9).** A 36-year-old female with skin biopsy proven pseudoxanthoma elasticum, with angioid streaks in the right (**A**) and left (**B**) eyes. Note the retinal pigment epithelial changes in the left macula and the peau d' orange changes in the left temporal macula. Fluorescein angiogram of the right (**C**) and left (**D**) eyes defines the angioid streaks well and shows no evidence of leakage. One year after diagnosis, the patient developed subfoveal hemorrhage and subretinal fluid in the left eye (**E**). Fluorescein angiogram demonstrated leakage from an active choroidal neovascularization (CNV) (**F**). Her left eye was treated with two bevacizumab injections without improvement.

During fluorescein angiography, angioid streaks can have a "window defect" due to RPE atrophy adjacent to them (Figs. **9C, D**). Angioid streaks may show up as irregular hyperfluoresence during early phases and varied degrees of staining in late phases (Figs. **10B, C, E**). Leakage is evident when CNV is present (Figs. **9F**, **10C**). Angiography can help aid in diagnosis when the clinical appearance on ophthalmoscopy is unclear [6, 7].

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**Fig. (9).** Four years later, she developed CNV in the right eye, and has been treated with scheduled bevacizumab in the right eye. Vision remained stable one year after initiating scheduled bevacizumab treatment. Her right eye shows RPE atrophy and mild cystoid macular edema without hemorrhage (**G**) and her left eye shows a disciform scar (**I**). Fundus autofluorescence clearly defines the areas of RPE atrophy in both eyes (**H,J**).

When neither fundoscopy nor fluorescein angiography can confirm the diagnosis, indocyanine green angiography (ICG) can be a useful tool. Angioid streaks show up as well defined late phase hyperfluoresence and in some cases are only detectable by ICG angiography [8].

CNV with foveal involvement is the primary cause of symptomatic visual dysfunction in eyes with angioid streaks (Figs. **2**-**4**, **9E, F**). Neovascularization arises from streaks that approach or reach the fovea and must be considered a constant threat that increases with the proximity of the streak to the fovea. Neovascularization is believed to be promoted by the underlying defect in Bruch's membrane. The lesion is commonly a classic (type 2) choroidal neovascularization. Fibrotic involution of streaks after intravitreal VEGF-inhibition therapy

indicates that angioid streaks are composed of vascular tissue that bridges the gap left by the rupture in Bruch's membrane [9]. Fibrotic involution is also the natural end-stage of the spontaneous course of CNV development (Figs. **7**, **9I**, **10A, D, F, G**).

**Fig. (10).** A 54 year-old male with angioid streaks, with a disciform scar and crystalline bodies in the right eye (**A**). Fluorescein angiography of left eye shows early hyperfluoresence (**B**) with late leakage (**C**) consistent with a choroidal neovascular membrane along the superior arcade. The CNV was treated with laser and was inactive the following month. Six months after laser, there is a subretinal scar underneath the superior arcade (**D**) in the left eye and fluorescein angiography shows late staining but no active leakage (**E**). Eight years later, he developed additional scarring in the right (**F**) and left (**G**) eyes.

### **DIFFERENTIAL DIAGNOSIS**

The occasional observation of curvilinear RPE defects that are concentric with the optic disc in eyes with angioid streaks suggests that these eyes are prone to traumatic choroidal rupture (Fig. **4**). Consequently, patients with lesions typical of traumatic choroidal rupture should be examined for angioid streaks and systemic conditions related to angioid streaks. Angioid streaks should be suspected in cases that may at first glance appear to be age-related macular degeneration with CNV, idiopathic peripapillary degeneration, peripapillary choroidal neovascularization, or lacquer-cracks in myopic degeneration.

### **MANAGEMENT**

Patients with angioid streaks are usually asymptomatic and can be monitored. Because of the brittleness of Bruch's membrane, patients should be warned of the potential risk of choroidal rupture from mild trauma. Symptoms arise if the lesions extend to the foveola, resulting in metamorphopsia, scotomas, and decreased vision. Complications such as traumatic Bruch's membrane rupture or macular CNV can also dramatically impact vision. Untreated CNV has poor prognosis because of the possible development of a disciform scar (Fig. **9G-J**, **10A**). Historically, several treatments have been evaluated including laser photocoagulation, transpupillary thermotherapy, photodynamic therapy, subretinal CNV extraction, and macular translocation therapy. Most treatments, when effective, were only able to achieve short term stabilization or a delay of disease progression, with recurrence being the rule [5]. While certain treatments may be considered in select cases, treatment with anti-VEGF agents has proven to be the most effective. Most studies, which have a limited number of patients and use either bevacizumab [10 - 12] or ranibizumab, have found stabilization or improvement of best corrected visual acuity (BCVA) in a majority of patients after treatment [13 - 18]. Treatment in earlier disease stages appears to result in increased BCVA more frequently than treatment in advanced stages, where only stabilization is achieved [12]. Frequent follow up is still required given the high rate of recurrence and currently there is no data to support any one particular treatment regimen *e.g.* fixed interval *vs* pro re nata (PRN). Several studies have investigated combined treatments such as PDT and anti-VEGF [5, 16 - 18] with

encouraging results but further studies will be required to determine whether combination therapy offers significant advantages over single therapy treatment.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


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[http://dx.doi.org/10.1159/000161879] [PMID: 18849633]

[18] Prabhu VV, Morris RJ, Shah PK, Narendran V. Combination treatment of low fluence photodynamic therapy and intravitreal ranibizumab for choroidal neovascular membrane secondary to angioid streaks in Paget's disease - 12 month results. Indian J Ophthalmol 2011; 59(4): 306-8. [http://dx.doi.org/10.4103/0301-4738.82000] [PMID: 21666317]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

**CHAPTER 20**

# **Presumed Ocular Histoplasmosis Syndrome**

**Manuel Garza-León1,\* , Luz Elena Concha del Río<sup>2</sup>** and **Miguel Pedroza Seres<sup>3</sup>**

*1 Department of Medical Sciences, Division of Health Sciences, Universidad de Monterrey, Monterrey, Nuevo León, México*

*2 Uveitis Department, Asociación para Evitar la Ceguera en México. I.A.P, Mexico*

*3 Uveitis and Ocular Inmunology Department, Instituto de Oftalmología Conde de Valenciana, México, DF. Clínica de Retina, Guadalajara, J., Mexico*

Presumed ocular histoplasmosis syndrome (POHS) is an inflammatory eye disease that has been reported to be associated with systemic fungal infection by *Histoplasma capsulatum* [1]. It is restricted mainly to endemic countries and is mainly seen in the midwest of the United States and where *Histoplasma capsulatum* is endemic [2], although there have been reports of a similar disease from countries that are nonendemic zones for the microorganism [3].

### **ESSENTIALS OF DIAGNOSIS**

POHS is a posterior uveitis, predominantly diagnosed clinically by the observation of characteristic fundus lesions in one or both eyes. The ocular triad of POHS consists in the presence of multiple atrophic choroidal spots (known as *histo spots*) (Fig. **1**), peripapillary atrophy (PPA) and maculopathy (Figs. **2**-**5**). Macular lesions are secondary to choroidal neovascularization (CNV) or atrophy and most of the time display a disciform pattern (Figs. **4**, **6**). Also, one of the key manifestations of POHS is the absence of inflammation in the vitreous. The disease occurs predominately in young adults and linear streaks are described in 5-16% of cases [3, 4]. Initially the disease occurs in one eye, being able to affect the second eye in 9-22% of cases [5, 6].

<sup>\*</sup> **Corresponding author Manuel Garza-León:** Department of Medical Sciences, Division of Health Sciences, Universidad de Monterrey, Monterrey, Nuevo León, México; Tel: +52 8188824208; Fax: +52 81888242'8; E-mail: manuel@drgarza.mx

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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**Fig. (1).** Fundus photographs of a 62-year-old female. Visual acuity was 20/30 in the right eye and 20/25 in the left eye. The anterior segment had no inflammation, there were no vitreous cells. Several chorioretinal scars were observed in the posterior pole and periphery.

**Fig. (2).** Fundus photograph of the same patient as Fig. (**1**).

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**Fig. (3).** Fluorescein angiogram of the same patient as Figs. (**1** and **2**). Dye accumulation due to a fibrous scar is observed adjacent to the optic nerve. Several histo spots may be observed in the periphery.

**Fig. (4).** OCT of the macula of the same eye as Figs. (**1**-**3**). A large area of subretinal fibrosis is observed.

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**Fig. (5).** Color fundus photograph of the posterior pole of a right eye displaying all the components of the triad: circumferential, pigmented peripapillary atrophy with a subretinal choroidal neovascularization superotemporal to the fovea, and chorioretinal scars.

**Fig. (6).** Fluorescein angiogram of the same eye as Fig. (**5**), showing zones of atrophy of the RPE and choriocapillaris, and leakage secondary to CNV.

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Patients may describe metamorphopsia, reduced vision, or paracentral scotomas from possible active CNV. Those with PPA and extrafoveal chorioretinal scars do not manifest visual symptoms. The characteristic ocular presentation was associated with infection with *H. capsulatum* through epidemiological studies. However, only rarely has the *H. capsulatum* antigen and organism been identified in an eye with POHS. Diagnosis by histoplasmin skin testing (Fig. **7**) has been abandoned since it was suggested that there was a possibility of flare-up of maculopathy when performing the test [7].

**Fig. (7).** Histoplasmin skin testing.

## **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis includes multifocal choroiditis and panuveitis (MFC), which belong to the group of conditions called "white dot syndromes" and may mimic lesions of POHS. A disease similar to MFC but without the vitritis seen in the active phase is called punctate inner choroidopathy (PIC) [8]. POHS should **224** *Ophthalmology: Current and Future Developments, Vol. 1 Garza-León et al.*

also be differentiated from multiple evanescent white-dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy and birdshot retinochoroidopathy.

Other causes of CNV, like idiopathic CNV, choroidal rupture with CNV, myopic CNV, and exudative age-related macular degeneration (AMD) are also included in the differential diagnosis of POHS. Other infectious conditions such as ocular inflammation secondary to tuberculosis, syphilis, toxoplasmosis, and sarcoidosis produce granulomatous fundus lesions that may resemble those of POHS. But these conditions are usually related to other signs of inflammation in any part of the eye, such as keratic precipitates, anterior uveitis, vitreous cells, and cotton balls in the vitreous. As mentioned earlier, the absence of these inflammatory signs and very importantly the presence of a clear vitreous help diagnoses POHS.

## **MANAGEMENT**

Due to the absence of inflammation, treatment of patients with POHS is indicated only when there is evidence of CNV. In up to 60% of patients who don't receive treatment for CNV, visual acuity result is 20/200 or worse, and almost three quarters of these patients experience reduced visual acuity after initial diagnosis [9].

Visual prognosis for patients with subfoveal CNV secondary to POHS is poor. Photodynamic therapy [10], submacular surgery [11], systemic, periocular and intravitreal steroids [12, 13], and radiation [14] were proposed as therapy options, but intravitreal anti-vascular endothelial growth factor therapy [15, 16] is the treatment of choice nowadays.

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


[http://dx.doi.org/10.1089/jop.1999.15.425]

### **226** *Ophthalmology: Current and Future Developments, Vol. 1 Garza-León et al.*

[13] Rechtman E, Allen VD, Danis RP, Pratt LM, Harris A, Speicher MA. Intravitreal triamcinolone for choroidal neovascularization in ocular histoplasmosis syndrome. Am J Ophthalmol 2003; 136(4): 739- 41.

[http://dx.doi.org/10.1016/S0002-9394(03)00389-1] [PMID: 14516819]


[http://dx.doi.org/10.3928/23258160-20121221-07] [PMID: 23410808]

[16] Cionni DA, Lewis SA, Petersen MR, *et al.* Analysis of outcomes for intravitreal bevacizumab in the treatment of choroidal neovascularization secondary to ocular histoplasmosis. Ophthalmology 2012; 119(2): 327-32.

[http://dx.doi.org/10.1016/j.ophtha.2011.08.032] [PMID: 22133795]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 21**

# **Epiretinal Membrane**

**Aristides J. Mendoza1,2,\***

*1 Retina Department, Centro Oftalmológico de Valencia (CEOVAL), Valencia, Venezuela*

*2 Retina Department, OftalmoSalud, Arequipa, Peru*

The epiretinal membrane (ERM) represents the growth of avascular fibrotic tissue on the surface of the retina in the macular area, which causes loss of vision and distortion of images when it contracts [1].

ERMs can be caused by a variety of eye problems. They are classified as idiopathic when not linked to any other eye disease and usually appear after a posterior vitreous detachment as a result of the formation of retinal tears that release inflammatory cells and pigment epithelial cells deposited at the posterior pole. Secondary ERMs are associated with retinal detachment, intraocular inflammation, trauma and vascular diseases of the retina [2]. There are two types of ERMs that have different clinical presentations: simple and contractile. Simple ERMs are membranes with cellophane-like films on the internal limiting membrane (ILM) with little or no visual symptoms. In general, they are composed mainly of glial cells. On the contrary, tractional ERMs are thicker with contractile properties that cause wrinkling of the retina and are usually accompanied by decreased vision and metamorphopsia. They are composed of glial cells and contractile cells [3], and are also known as "macular puckers" (Fig. **1**).

Epiretinal membranes cause macular structural changes such as retinal folds, vascular leakage, macular thickening, cystoid macular edema, pseudohole formation, foveal ectopia, and foveal detachment by tractional forces on the retinal surface [4].

<sup>\*</sup> **Corresponding author Aristides J. Mendoza:** Retina Department, OftalmoSalud, Arequipa, Av Mariscal Benavides No 307, Urb Selva Alegre, Arequipa, Peru; Tel: +51(054)287373; E-mail ampcff@hotmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

**228** *Ophthalmology: Current and Future Developments, Vol. 1 Aristides J. Mendoza*

**Fig. (1).** Macular pucker secondary to BRVO (Courtesy of Mitzy E. Torres Soriano).

## **ESSENTIALS OF DIAGNOSIS**

Epiretinal membranes typically affect otherwise healthy elderly individuals and are unilateral in approximately 90% of cases. Visual symptoms and decreased visual acuity will depend on the degree of distortion caused in the traction retinal membrane, which can generate a micro detachment of the posterior pole, as well as the presence or absence of macular or perimacular edema. Usually, thin epiretinal membranes don't cause many symptoms. However, in advanced cases, there is a reduction in vision, micropsia, metamorphopsia, Amsler grid distortion and, occasionally, monocular diplopia. Spontaneous separation of an epiretinal macular membrane, although uncommon, can occur [5, 6].

Slit lamp ophthalmoscopy: brightness or abnormal reflectivity in the macular region suggests the presence of an ERM (Fig. **2a**). More advanced ERMs can become opaque and thick, and may obscure underlying retinal features (Fig. **1**). ERMs cause changes in the retinal architecture with loss of foveal contour as a result of contraction.

**Fig. (2).** (**a**) Fundus photograph that shows the typical clinical appearance of an ERM. The membrane adherent to the surface of the retina contracts and the retinal surface appears wrinkled. (**b**) OCT scan confirms ERM (Courtesy of Mitzy E. Torres Soriano).

In addition to visual acuity testing, the most common clinical tests involve fluorescein angiography and optic coherence tomography (OCT). Fluorescein angiography is moderately helpful, since it can show retinal vascular tortuosity, straightening, and leakage, as well as cystoid macular edema. OCT is the diagnostic method of choice, typically demonstrating a hyperreflective line in the surface of the retina that may be associated to retinal folding, increased macular thickness, cystoid macular edema, traction macular retinal detachment, and both lamellar or macular hole formation (Figs. **2b**, **3**-**6**). Amsler grid testing may help quantifying metamorphopsia in eyes with macular distortion [7]. Abnormal macular function has been shown using the electroretinogram [8, 9].

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**Fig. (3).** (**a**) and (**b**) OCT of epiretinal membrane showing marked corrugation of the retinal surface, loss of foveal depression and diffuse retinal thickening with intraretinal fluid in multiple layers (Courtesy of Centro de la Visión Gordon-Manavella, Rosario-Argentina).

**Fig. (4).** Spectral domain optical coherence tomography image showing epiretinal membrane with retinal folds, and macular thickening (Courtesy of Centro de la Visión Gordon-Manavella, Rosario-Argentina).

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**Fig. (5).** OCT demonstrates ERM and intraretinal fluid (Courtesy of Mitzy E. Torres Soriano).

**Fig. (6).** OCT scan of the same lesion shown in Fig. (**5**), demonstrating a thickened ERM with severe distortion of the retina (Courtesy of Mitzy E. Torres Soriano).

### **DIFFERENTIAL DIAGNOSIS**

The clinical appearance of an ERM is fairly distinctive. However, macular hole,

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parafoveal telangiectasia, vitreomacular traction syndrome, subfoveal neovascular membrane and macular edema must also be considered. It is a very common pathology, and therefore may coexist with any of the diagnoses mentioned above.

### **MANAGEMENT**

Most of patients with ERM have symptoms that are mild and either nonprogressive or slowly progressive, and treatment is rarely indicated. In a few cases, the membrane may spontaneously release, with a marked decrease in symptomatology and improvement in visual acuity (VA). For patients with significant symptoms and substantially reduced VA (usually 20/60 or less), pars plana vitrectomy (20, 23 or 25 gauge) with epiretinal membrane peeling can diminish the severity of symptoms and improve VA in 75% of cases or more. There is no difference in visual outcome between eyes operated with 23 gauge and 25 gauge [10]. ERM recurrence is observed in approximately 10% of cases after surgery [11]. The reasons for recurrence are the incomplete removal of the ERM and the presence of residual ILM after ERM peeling. To enhance the visualization of these transparent or semi-transparent structures and to overcome ERM recurrence, various staining methods have been used, including indocyanine green (ICG), trypan blue (TB), triamcinolone acetonide (TA), and brilliant blue G (BBG) [12].

The best candidates for surgery are those who have had membranes for a relatively short time, because the potential for visual recovery decreases as the duration of preoperative symptoms increases. Integrity of the retinal layers seen by OCT may be used to predict a good visual outcome [13].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

[1] Bu SC, Kuijer R, Li XR, Hooymans JM, Los LI. Idiopathic epiretinal membrane. Retina 2014; 34(12):

2317-35. [http://dx.doi.org/10.1097/IAE.0000000000000349] [PMID: 25360790]


[http://dx.doi.org/10.1016/S0002-9394(98)00447-4] [PMID: 10334349]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Idiophatic Macular Hole**

**Luis M. Suarez-Tata1,\* , Moravia B. Suarez-Tata<sup>1</sup>** and **Reinaldo García<sup>1</sup>**

*1 Retina & Vitreous Service, Clínica Oftalmológica El Viñedo, Valencia, Venezuela*

Idiopathic macular hole (MH) is an acquired full thickness defect of the retina in the central macula. Macular holes were first described by Knapp in 1869 [1]. They typically occur in the sixth to eighth decade of life with a 3:1 predominance in women. The incidence of bilaterally is 5% to 10%. Tangential vitreoretinal traction (TVT) is the presumed cause of the MH.

### **ESSENTIALS OF DIAGNOSIS**

Visual acuity, depending on the stage and severity of the MH, may be near normal or severely reduced to less than 20/400. Amsler grid will often reveal a central scotoma or metamorphopsia.

Slit-lamp biomicroscopic examination usually shows a round retinal defect that involves the fovea. Several diagnostic maneuvers may be used to find out if the lesion observed in examination is indeed a full-thickness defect (*vs.* a macular *pseudo* hole). If a tall, narrow beam is focused on the lesion, the patient may perceive a break or dent in the beam (the so-called "Watzke-Allen test). This also may be tested using the aiming beam of a retinal laser photocoagulator.

The gold-standard diagnostic tool is optic coherence tomography (OCT), due to the fact that it is non-invasive, has a very high resolution, allows careful evaluation of retinal structures and the vitreomacular interface.

<sup>\*</sup> **Corresponding author Luis M. Suarez Tata:** Clínica Oftalmológica El Viñedo, Valencia, Venezuela; Tel/Fax: +58 (412) 3474188; E-mail: luismiguelsuarez@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

It also enables quantitative information such as minimum hole diameter, base diameter and retinal edge thickness [2].

Fluorescein angiography may also be used but has fallen into disuse, since findings are vague (a window defect corresponding to loss of xanthophyll pigment), and compared to OCT has very little sensitivity and specificity.

## **Classification**

Gass described different stages of development of MH (Table **1**) [3, 4]. Nowadays, with OCT and the identification of vitreomacular traction and its relationship with MH, the International Vitreomacular Traction Study Group has proposed a new classification based on OCT findings and the status of the vitreomacular interface (Tables **2**-**4**) [5].



Based on Gass JD [3, 4].

## **DIFFERENTIAL DIAGNOSIS**

There are several diseases that may resemble MH clinically but have distinct appearances on OCT. Macular pseudohole is an epiretinal membrane that spares the center of the fovea, causing its borders to elevate, clinically resembling a MH. The Watzke-Allen test is negative, and on OCT, the outer retinal layers are spared (Figs. **12**-**14**). Lamellar macular hole is also usually associated to an epiretinal membrane, and on OCT shows an irregular foveal contour with schisis of the

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retinal layers in the parafovea, and a preserved photoreceptor layer (Figs. **14**-**19**). Vitreomacular traction syndrome has also to be considered, and actually is believed to play an important role in the pathophysiology of MH. Other differential diagnoses include macular telangiectasia and solar retinopathy [6, 7].

**Fig. (1).** Fundus photograph showing a normal macula.

**Fig. (2).** Optical coherence tomography (OCT) image of a normal macula.

**Fig. (3).** OCT image of a macular hole stage 1-A, showing hyporeflective spaces in the inner and outer retina.

**Fig. (4).** OCT image of a macular hole stage 1-B, showing hyporeflective space in the inner retina.

**Fig. (5).** OCT image of a macular hole stage 1-A, showing extensive hyporeflective spaces in the inner retina.

**Fig. (6).** A 74-year-old patient with a reduction of visual acuity to 20/70. Idiopathic macular hole stage 2. Appears as a small round defect in the fovea. Fluorescein angiogram shows an area of window defect.

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**Fig. (7).** OCT image of a macular hole stage 2, showing extensive defect in the outer retina.

**Fig. (8).** OCT image of a stage 3 macular hole with extensive separation of the outer layers.

**Fig. (9).** OCT image of a stage 3 macular hole, showing separation of the inner and outer retinal layers.

**Fig. (10).** OCT image of a full thickness macular hole with elevated borders, cystoid macular degeneration and irregular retinal pigment epithelium.

**Fig. (11).** OCT image of a full thickness macular hole with a pseudo-operculum.

**Fig. (12).** Fundus photograph (top) and OCT (bottom) of a chronic macular hole. The photograph shows a large hole with pigment changes at its bottom. OCT shows a large hole with somewhat flat borders and irregular retinal pigment epithelium.

**Fig. (13).** Full thickness macular hole with small dots at the level of the retinal pigment epithelium.

**Table 2. Correlation between commonly used clinical macular hole stages and the international vitreomacular traction study (IVTS) classification system [5].**


Abbreviations: FTMH full thickness macular hole; PVD posterior vitreous detachment. Based on International Vitreomacular Traction Study Classification.

### **Table 3. IVTS classification system for vitreomacular adhesion, traction, and macular hole [5].**


Based on International Vitreomacular Traction Study Classification.

### **Table 4. IVTS classification system for macular hole [5].**

Full-thickness macular hole (FTMH) Full-thickness foveal lesion that interrupts all macular layers from the ILM to the RPE **Classification** By Size (horizontally measured linear width across hole at narrowest point, not ILM) Small (≤250 µm) Medium (>250 µm and ≤400 µm) Large (>400 µm) By presence or absence of VMT By Cause Primary (initiated by VMT) Secondary (directly due to associated disease or trauma known to cause macular hole in the absence of prior VMT) Based on International Vitreomacular Traction Study Classification.

Based on International Vitreomacular Traction Study Classification.

**Fig. (14).** Macular pseudohole with epiretinal membrane, but no full thickness interruption of all retinal layers.

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**Fig. (15).** OCT image of a macular pseudohole with epiretinal membrane with cystoid macular edema.

**Fig. (16).** OCT image of a macular pseudohole with epiretinal membrane that causes an irregular foveal contour.

**Fig. (17).** OCT image of an epiretinal membrane causing a lamellar macular hole.

**Fig. (18).** OCT image showing another case of epiretinal membrane causing a lamellar macular hole. The foveal contour is irregular and there is some separation of the inner retinal layers.

*Idiophatic Macular Hole Ophthalmology: Current and Future Developments, Vol. 1* **243**

**Fig. (19).** OCT image showing another case of epiretinal membrane causing a lamellar macular hole. There is some fibrous epiretinal proliferation seen as a very thick epiretinal membrane that covers the entire macular surface.

Pre- and postoperative

*Fig. 20 contd.....*

B

### **244** *Ophthalmology: Current and Future Developments, Vol. 1 Suarez-Tata et al.*

**Fig. (20). A**. Fundus photograph of the right eye of a 65 year old female patient showing the pre-operative appearance of a stage 4 macular hole (yellow dots in the center of the hole at the level of the retinal pigment epithelium).Visual acuity was 20/200.

**B**. Fluorescein angiogram showing a window defect in the fovea.

**C**. OCT image showing a full thickness macular hole.

**D.E.F.** Fundus photograph, angiogram and OCT of the same eye three months after vitrectomy and ILM removal. Three months post-operative appearance of full thickness macular hole, now closed and vision improved to20/50.

*Idiophatic Macular Hole Ophthalmology: Current and Future Developments, Vol. 1* **245**

**Fig. (21). A**. Preoperative OCT image of a full-thickness macular hole. **B**. Postoperative appearance of the same eye.

**Fig. (22). A**. OCT image showing a full thickness macular hole with pseudo-operculum. **B**. Postoperative OCT image showing some defects in the outer retinal layers.

### **MANAGEMENT**

The standard surgery for the repair of MH was described by Kelly and Wendel [8] in 1991 and involves a standard three-port pars plana vitrectomy, posterior hyaloid separation, stripping of epiretinal/internal limiting membranes (ILM) and gas tamponade. A total air-fluid gas exchange is performed, followed by an airgas exchange using a non-expansile concentration of gas (C2F<sup>6</sup> , C3F<sup>8</sup> or SF<sup>6</sup> ). Although closure of the hole is the rule, the fovea rarely recovers its normal contour (Figs. **20-22**)

Controversial issues in macular hole surgery today involve peeling and staining the ILM. The most common dyes are Indocyanine green (ICG) [9, 10], Trypan blue [11], triamcinolone acetonide [12, 13], and Brilliant blue G (BBG) [14]. Staining improves the visibility and the ease of stripping the ILM, but studies suggest that it may also cause retinal damage.

Different instruments have been used to grasp the ILM creating a surgical plane. These instruments include the micro-barbed micro-vitreoretinal blade or the diamond-dusted silicone cannula. After lifting an edge of the membrane, it is stripped with fine end-gripping tissue forceps.

The success rate for macular hole surgery approaches 80% to 90% with closure of the macular hole and improvement in visual acuity. However, the most important predictors of visual outcomes are its size and the time of duration [15].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**



[http://dx.doi.org/10.1016/S0161-6420(01)00593-0] [PMID: 11425673]


# **CHAPTER 23**

# **Macular Pseudo-hole**

**Jose A. Roca1,\* , Hugo Luglio<sup>2</sup>** and **Daniela Roca<sup>1</sup>**

*1 Ophthalmology Department, Clínica Ricardo Palma, Lima-Peru, Peru*

*2 Macula D&T, Lima-Peru, Peru*

### **ESSENTIALS OF DIAGNOSIS**

The term "macular pseudo-hole" (MPH) was coined by Allen and Gass in 1976 [1] to describe any foveal lesion that has a biomicroscopic appearance of a fullthickness macular hole (FTMH), but is not. It is usually formed by a centrifugal contraction of an epiretinal tissue (epiretinal membrane) that surrounds but does not cover the foveolar area, making the borders have a more vertical appearance [2].

The patient usually has no complaints, and the visual acuity is normal or nearly normal, ranging from 20/15 to 20/100 (median 20/25) [3]. Because of the good surgical results of true macular holes, it is important to differentiate between a true macular hole and a macular pseudo-hole. The appearance of a true macular hole is different, usually very round, with a halo of marginal detachment surrounding the hole, tiny yellow deposits in its base (within the hole), a translucent operculum in front of some holes, and a zone of hyperfluorescence corresponding to the size of the hole during the early stages of angiography. These characteristics are not seen in a macular pseudo-hole.

Biomicroscopy of a patient with a macular pseudo-hole usually reveals crinkling of the inner retinal surface surrounding the hole in the epiretinal membrane and a punched-out appearance in the area of the hole (Fig. **1**) [4]. As the slit beam is

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

Correspondence: **Corresponding author Jose A. Roca:** Ophthalmology Department, Clínica Ricardo Palma, Torre B, piso 10, San Isidro, Lima-Peru; Tel: +51 (1) 2242224; E-mail: jaroca62@gmail.com

*Macular Pseudo-hole Ophthalmology: Current and Future Developments, Vol. 1* **249**

**Fig. (1).** Fundus photograph of the left eye, showing a macular pseudohole with an epiretinal membrane.

**Fig. (2).** OCT of the same patient of Fig. (**1**), showing a macular pseudo-hole with an epiretinal membrane with a U form fovea and preserved outer retinal layers.

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**Fig. (3).** Autofluorescence of a macular pseudo-hole.

**Fig. (4).** OCT image of a macular pseudohole showing slight distortion of the foveal contour.

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moved across the pseudo-hole, there is usually a light reflex that is evidence of retinal tissue in the base; the Watzke-Allen sign is negative (positive in FTMH). The Amsler grid test usually is not decisive in the diagnosis because some patients who have macular pseudo-holes present scotomas. Fluorescein angiography is generally normal but may show a very faint zone of hyperfluorescence corresponding with the pseudo-hole. This zone of hyperfluorescence is typically much less prominent than the finely granular area of hyperfluorescence seen with a full-thickness hole [3]. The presence of the semitransparent perifoveolar epiretinal membrane probably causes the foveolar area to appear faintly hyperfluorescent in contrast to the perifoveolar area. Autofluorescence imaging demonstrates bright fluorescence of macular holes with appearance similar to that obtained by fluorescein angiography. In contrast, macular pseuodoholes show no such autofluorescence (Fig. **3**) [5]. Scanning laser ophthalmoscope (SLO) microperimetry examination shows no deep scotomas (patients with FTMH have deep scotomas); this exam has 100% sensitivity and specificity for the differential diagnosis with FTMH [6]. Optical coherent tomography (OCT) examination makes the diagnosis of macular pseudo-holes much easier; the OCT characteristics of a macular pseudo-holes are: thickening of the macula contracted by an ERM, the U or V shape of the fovea, and no loss of retinal tissue at the umbo of the fovea (retention of photoreceptors) (Figs. **2** and **4**) [7 - 9]. Using high-resolution OCT, Witkin *et al.* also described cases combining foveal thickening due to ERM contraction, with stretching of the foveal edge resulting in the thinning of the foveal floor. These cases may in fact represent a type of macular pseudohole induced by both centripetal and centrifugal contraction of the ERM between several eccentric epicenters [10].

Fish *et al.* reported that the diagnosis by the initial examining physician was correct in only 43% of eyes with macular pseudo-holes [11].

### **DIFFERENTIAL DIAGNOSIS**

Differential diagnosis should be made with a stage 1-A impending hole (foveolar yellow lesion), solitary drusen, small RPE detachment, small atrophy of the RPE, choroidal neovascularization, a small focal area of central serous chorioretinopathy, foveolar detachment with epiretinal membrane, focal retinal atrophy associated with bilateral idiopathic juxtafoveolar retinal telangiectasis, pattern dystrophy, cystoid macular edema, and solar maculopathy [12].

### **MANAGEMENT**

Visual prognosis in these patients is usually good. In a few patients, the additional contraction of an eccentrically located perifoveal epiretinal membrane may distort the foveal area. Pars plana vitrectomy to peel the epiretinal membrane may be indicated in patients with worsening vision. In few of them, the epiretinal membrane may peel free from the inner retinal surface. Most patients with MPH will not experience much visual changes.

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


lamellar macular holes by optical coherence tomography. Am J Ophthalmol 2004; 138(5): 732-9. [http://dx.doi.org/10.1016/j.ajo.2004.06.088] [PMID: 15531306]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 24**

# **Vitreomacular Traction**

**Mitzy E. Torres Soriano1,2,3,\*** and **Maximiliano Gordon2,3**

*<sup>1</sup> Unidad Oftalmológica "Dr. Torres López", Centro Médico Cagua, Cagua, Venezuela*

*2 Retina Department, Ophthalmology Service, Hospital Provincial del Centenario, Rosario, Santa Fe, Argentina*

*3 Centro de la Visión Gordon-Manavella, Rosario, Argentina*

Vitreomacular Traction Syndrome (VMT) occurs as a result of incomplete posterior vitreous detachment, resulting in persistent vitreous traction on the posterior retina [1].

The prevalence of VMT syndrome is 22.5 per 100,000 population. The annual incidence is 0.6 per 100,000 population. The prevalence and incidence of VMT associated with diabetic retinopathy, diabetic macular edema, age-related macular degeneration, and other macular diseases (concurrent VMT) are much higher [2].

### **ESSENTIALS OF DIAGNOSIS**

Patients may be asymptomatic or present the following symptoms: decreased visual acuity, metamorphopsia, photopsia, and micropsia [1]. Symptoms usually progress gradually [3].

Optical coherence tomography (OCT) allows visualization of the vitreomacular interface and confirms vitreomacular adhesion or traction. Intraretinal cystic changes and foveal detachment can be seen.

Recently, OCT-based anatomic definitions and classifications have been proposed by the International Vitreomacular Traction Study (IVTS) Group to define these entities (Table **1**) [4].

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Corresponding author Mitzy E. Torres Soriano:** Centro de la Visión Gordon - Manavella, Montevideo 763, CP 2000, Rosario - Santa Fe, Argentina; Tel: +54 (0341) 4400239; E-mail: mitzytorres@yahoo.com

### **Table 1. IVTS classification system for vitreomacular adhesion and vitreomacular traction.**


Based on International Vitreomacular Traction Study Classification.

**Fig. (1).** Focal vitreomacular adhesion: partial vitreous detachment.

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**Fig. (2).** Focal vitreomacular traction causing distortion of the foveal contour and separation of retinal layers.

**Fig. (3).** Focal vitreomacular traction in V pattern, epiretinal membrane and significant distortion of the retinal architecture.

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**Fig. (4).** Spectral domain OCT scan reveals a broad vitreomacular traction and severe distortion of retinal layers.

**Fig. (5).** OCT image showing severe vitreomacular traction causing foveal detachment (Courtesy of Francys Torres MD, Maracay, Venezuela).

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Fluorescein angiography can reveal retinal capillary leakage in the macula due to cystoid macular edema (CME). An associated foveal retinal detachment may be noted as fluorescein pooling [3, 5].

B-scan ultrasound reveals partial posterior vitreous detachment which is seen as a thin, smooth, continuous membrane with focal attachment to the retinal surface [3, 6].

## **DIFFERENTIAL DIAGNOSIS**

The differential diagnosis can include [3]: early full thickness macular hole, pseudophakic CME, other causes of CME (uveitis, diabetic macular edema, exudative age related macular degeneration, macular telangiectasia) and ERM, which could be present as concurrent macular disease (Fig. **3**).

## **MANAGEMENT**

Asymptomatic VMA patients are not candidates for surgical therapy [8]. VMA usually resolves spontaneously as part of the normal process of PVD, although it may progress to VMT. Periodic monitoring with OCT every 3 months is necessary. Even in cases that progress to a VMT syndrome, observation still remains an option, given the possibility of spontaneous resolution (11%) of VMT (Fig. **6**) [7, 9].

*Fig. 6 contd.....*

**Fig. (6).** (**a**) Vitreomacular traction causing distortion of the foveal contour. (**b**) Spontaneous resolution of vitreomacular traction after 4 months.

Posterior vitrectomy combined with stripping of the posterior hyaloid and ILM peeling would be the surgical treatment of choice [10, 11].

The medical therapy of VMT consists of pharmacologic vitreolysis. Jetrea® (ocriplasmin) was approved for the treatment of patients with symptomatic VMA [12 - 14]. Vitrectomy may still be required in patients failing ocriplasmin therapy and also in about 20% of the patients successfully treated with ocriplasmin [15, 16].

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

## **REFERENCES**


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[http://dx.doi.org/10.1016/j.ophtha.2013.07.042] [PMID: 24053995]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

**CHAPTER 25**

# **Pseudophakic Cystoid Macular Edema**

**Andrés Bastien\***

*Universidad de Buenos Aires-Universidad del Salvador, Retina and Vitreous, Argentina*

### **ESSENTIALS OF DIAGNOSIS**

Pseudophakic cystoid macular edema (CME) was first described in 1953 by A. Ray Irvine, Jr., in patients with unexplained visual loss following intracapsular cataract surgery [1]. The cause of the visual loss was identified by Gass and Norton as marked macular edema with a classic perifoveal petalloid pattern of staining and late leakage from the optic nerve on intravenous fluorescein angiography (Figs. **1 - 3**) (FA) [2]. The incidence of angiographic CME has decreased with the transition from intracapsular cataract extraction (60%) to extracapsular cataract surgery (20%) and with small-incision phacoemulsification [3, 4]; 20-30% of patients undergoing phacoemulsification have CME on FA [5, 6] and optical coherence tomography (OCT) (Figs. **4** and **5**) suggests that it may be found in up to 40% of patients [7]. The majority of patients do not experience visual changes [6, 8]. The incidence is lower with current surgical techniques (0.1% to 2.35%) [9, 10].

Most patients with CME have spontaneous resolution of the edema within 3-4 months [11] One year after surgery, a small minority of patients (<1%) in the absence of treatment may still have decreased visual acuity from CME [12].

### **Pathogenesis**

Various factors and many presumed mechanisms may be involved in the pathogenesis of CME, including the release of mediators of inflammation such as

<sup>\*</sup> **Corresponding author Andr**é**s Bastien:** Universidad de Buenos Aires-Universidad del Salvador, Retina and Vitreous, Argentina; Tel/Fax: 00541148114482; E-mail: andresbastien@aol.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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prostaglandins, light toxicity, and mechanical irritation [13 - 15]. Inflammatory mediators disrupt the blood-aqueous barrier (BAB) and blood-retinal barrier (BRB), leading to increased vascular permeability resulting in macular edema. Breakdown of the BAB and BRB may be associated with diabetes, glaucoma, and uveitis [16]. Surgical complication of the anterior segment may lead to the release of arachidonic acid from cell membranes, with production of either leukotrienes *via* the lipooxygenase pathway or prostaglandins *via* the cyclooxygenase pathway [13, 14]. These inflammatory biomarkers result in increased retinal vessel permeability and the development of edema. Contraction of the posterior hyaloid as a result of inflammation may lead to mechanical traction onto the perifoveal retinal capillaries and result in CME [15].

**Fig. (1).** Fluorescein angiography. Perifoveal petalloid staining.

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**Fig. (2).** Fluorescein angiography. Perifoveal petalloid staining.

**Fig. (3).** Fluorescein angiography with macular late leakage.

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**Fig. (4).** OCT. Macular thickening. Cystic spaces in outer plexiform layer.

**Fig. (5).** OCT. Macular thickening. Cystic spaces in outer plexiform layer and subfoveal fluid.

### **Incidence and Risk Factors**

The most frequent appearance of CME occurs at 6 weeks after surgery. Incidence increases in patients with high-risk characteristics including diabetes mellitus,

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hypertension, history of central retinal vein occlusion, history of uveitis, epiretinal membrane, or following complicated cataract surgery (Fig. **6**) [3, 9]. A recent large retrospective study showed no increased incidence of clinical CME in glaucoma patients undergoing uncomplicated cataract extraction [17]. Although that study found no relationship between the use of prostaglandin analogs for the treatment of glaucoma and the development of CME, other studies have found that prostaglandins, synthesized by the uvea and lens epithelial cells, may be one of the inflammatory mediators associated with CME [18].

**Fig. (6).** Complicated anterior segment surgeries. Subluxated IOLS, anterior vitreous.

## **DIFFERENTIAL DIAGNOSIS**

Metabolic disorders: Diabetes, Retinitis pigmentosa, Inherited CME (autosomaldominant).

Ischemia: Vein occlusion, Diabetic retinopathy, Hypertensive retinopathy, Vasculitis, Collagenosis (Fig. **7**).

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**Fig. (7).** Cystoid macular edema in telangiectasias.

Hydrostatic forces: Retinal vascular occlusions, Venous occlusion, Arterial hypertension, Low Intraocular Pression (Fig. **8**).

Mechanical forces: Vitreo macular traction (Fig. **9**) [21].

Inflammation: Intermediate uveitis, Diabetic Macular Edema, Choroidal inflammatory diseases (Vogt-Koyanagi Harada, Birdshot).

Pharmacotoxic effects: Latanoprost, Betaxolol [19].

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**Fig. (8).** Differential diagnosis: cystoid macular edema in retinal vein occlusion.

**Fig. (9).** Macular edema associated with vitreo macular traction, epiretinal membrane and central serous retinopathy.

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**Graphic 1.** Mechanism of action for Steroids and NSAID in CME.

## **MANAGEMENT**

CME is diagnosed by decreased visual acuity, by FA with the classic appearance of perifoveal petalloid staining with or without late leakage from the optic disk, or by OCT. Characteristics of CME on OCT include macular thickening and cystic spaces in the outer plexiform layer, occasionally with subfoveal fluid [16, 20]. (Figs. **10 - 13**).

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**Fig. (10).** Degenerative myopic patients. History of bilateral retinal detachment surgery. Cataract surgery and pseudophakic macular edema. Treatment with topical non-steroidal anti-inflammatory drugs plus topical steroids for 3 months. Edema resolution.

**Fig. (11-A).** Pseudophakic patients with chronic edema.

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**Fig. (11-B).** OCT with cystoid edema and the evolution during 6 months treated with topical steroids plus topical non-steroidal anti-inflammatory drugs. Edema resolution.

**Fig. (12).** Pseudophakic macular edema in complicated cataract surgery, with vitreous loss. Resolution after 8 months of topical combination of steroids and non-steroids.

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**Fig. (13).** Pseudophakic macular edema. Resolution after 7 months of treatment with topical combination of steroids and non-steroids.

Corticosteroids (Graphic 1) [13, 22 - 31].


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Nonsteroidal anti-inflammatory drugs (Graphic 1) [32 - 39].

• Topical.

Anti-vascular endothelial growth factor [40 - 48].

Surgical: pars plana vitrectomy [49 - 53].

### **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

[1] Irvine SR. A newly defined vitreous syndrome following cataract surgery. Am J Ophthalmol 1953; 36(5): 599-619.

[http://dx.doi.org/10.1016/0002-9394(53)90302-X] [PMID: 13040458]


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optical coherence tomography in a healthy population before and after uncomplicated cataract phacoemulsification surgery. Curr Eye Res 2009; 34(12): 1036-41. [http://dx.doi.org/10.3109/02713680903288937] [PMID: 19958122]


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[http://dx.doi.org/10.2147/OPTH.S46399] [PMID: 23818753]

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2009; 116(8): 1481-1487, 1487.e1. [http://dx.doi.org/10.1016/j.ophtha.2009.04.006] [PMID: 19545901]


[PMID: 23264866]


© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 26**

# **Central Serous Chorioretinopathy**

**Daniel D. Kim<sup>1</sup> , Paul Baciu<sup>1</sup>** and **Michael D. Ober1,2,\***

*1 Department of Ophthalmology, Henry Ford Health Systems, Detroit, MI, USA*

*2 Retina Consultants of Michigan, Southfield, MI, USA*

### **ESSENTIALS OF DIAGNOSIS**

Central serous chorioretinopathy (CSC) is an idiopathic disorder characterized by serous detachment of the neurosensory retina. It has an incidence of roughly 6/100,000 individuals [1 - 3]. Affected patients are usually young to middle age adults (ages 25-45), male (5-10:1 male:female ratio), and of "Type A" personality [4 - 6]. The symptoms present unilaterally (60-90% of the time) and patients often complain of blurred central vision and metamorphopsia with a hyperopic shift [1 - 3, 5, 7]. A history of recent psychosocial stressors, or steroid use is often present. Disorders causing elevated levels of catecholamines are known to predispose. Furthermore, pregnancy, phosphodiesterase inhibitors, and illicit drug use have also less commonly been associated with onset of symptoms [2, 3, 6, 8].

Despite decades of study, the precise etiology and pathophysiology remain elusive. Much has been learned, however, through multimodal imaging studies that often yield pathognomonic findings (Fig. **1**). Fluorescein angiography (FA) in acute cases reveals a focal leak at the level of the retinal pigment epithelium (RPE) appearing as an expanding hyperfluorescent dot (30% have more than one) sometimes elevating into a smokestack appearance in 10-20% (Figs. **2** and **3**). Ultimately, the subretinal fluid pocket can extend inferiorly due to gravity creating descending atrophic tracts, which are best seen with fundus autofluorescence (FAF) [2, 3, 6, 8]. Chronic cases reveal multiple leaks in close

<sup>\*</sup> **Corresponding author Michael D. Ober:** Retina Consultants of Michigan, 29201 Telegraph Road, Suite 606, Southfield, MI 48034, USA; Tel: (248) 356-6473; Fax: (248) 356-6473; E-mail: obermike@gmail.com

**Mitzy E. Torres Soriano, Gerardo García Aguirre, Maximiliano Gordon & Veronica Kon Graversen (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

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proximity with mottled hyper and hypofluorescence of the RPE corresponding to "sick RPE syndrome" [9, 10]. Indocyanine green angiography (ICGA) demonstrates hyperfluorescence in mid-frames (not present early or late) often described as choroidal hyperpermeability (Fig. **4**) [2, 3, 6, 8, 11, 12].

As OCT technology has improved, it has become critical for diagnosis. Findings include subretinal fluid, RPE detachments, and retinal atrophy. Less common features include cystoid macular edema or cystoid macular degeneration, which is differentiated by lack of corresponding FA leakage and poor visual potential [2, 5, 8]. While relatively new, visualization of the choroid using enhanced-depth imaging shows marked thickening of the choroid in CSC (Fig. **5**), most prominent in zones of choroidal permeability with active angiographic leakage [8, 13].

**Fig. (1).** CSC Fundus photo showing subretinal fluid causing serous retinal detachment (Photo Credit: Henry Ford Ophthalmic Photography).

Fundus autofluorescence is being used more frequently to image patients with CSC. Over time, a neurosensory detachment leads to an accumulation of lipofuscin from shed photoreceptor outer segments yielding patches of speckled hyperautofluorescence that can become more prominent when subretinal fluid first resolves. Over time, these areas become hypoautofluorescent as noted around

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old leaks and chronic descending atrophic tracts [2, 8, 14]. Other diagnostic modalities include multifocal ERG, which shows broad retinal functional disturbances, and abnormal visual field testing, especially on microperimetry, indicating that central visual acuity underestimates the amount of visual impairment [8, 15].

**Fig. (2).** RPE blowout as imaged by fundus photography (**A**), early (**B**) and late (**C**) fluorescein angiography, autofluorescence (**D**) and OCT (**E**) (Photo Credit: Lorrene Santiego).

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**Fig. (3).** Classic fluorescein angiography findings. Expansile dot, early (**A**) and late phase (**C**). Smokestack, mid (**B**) and late phase (**D**) (Photo Credit: A & C – Courtney McClenahan, B & D – Henry Ford Ophthalmic Photography).

**Fig. (4).** Mid-phase hyperpermeability on ICGA (Photo Credit: Courtney McClenahay).

**Fig. (5).** Enhanced Depth OCT imaging showing choroidal thickening and subretinal fluid (Photo Credit: Logan Jabouri).

## **DIFFERENTIAL DIAGNOSIS**

Polypoidal choroidal vasculopathy is well known to masquerade as CSC in the active phase while pattern dystrophy may mimic the late pigmentary changes [16]. Severe variants of CSC are known to occur with multiple large RPE detachments, dependent exudative retinal detachment and RPE tears all of which can simulate severe inflammatory disorders such as Vogt-Koyanagi-Harada syndrome or posterior uveitis. The most common item on the differential, however is age related macular degeneration with occult choroidal neovascularization, especially in patients older than 50 years old [2, 3]

## **MANAGEMENT**

Patients who fit a "typical" patient profile for CSC, generally require no further work-up, but testing for elevated systemic catecholamine levels or sleep apnea should be considered in the appropriate patient context [2, 3]. CSC is generally treated conservatively as it most often consists of self-limited episodes that resolve over weeks to months. However, chronic CSC can lead to permanent visual impairment [4, 17, 18].

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Improving underlying conditions such as eliminating or reducing corticosteroid use and stress reduction are first line treatments. Most patients are observed without any further intervention for the first few months, but timing of potential treatment is individual. Many factors can trigger the need for additional treatment including failure of spontaneous resolution, monocular status, specific vocational needs (*i.e.* pilot or commercial drivers license), recurrent disease, need for ongoing or increased corticosteroid use, *etc*.

Verteporfin based photodynamic therapy (PDT) (QLT, Vancouver, CA) has orphan drug designation for the treatment of CSC and is the current mainstay of therapy. PDT leads to coagulation of the choroid. The subsequent reperfusion typically yields a reduction in choroidal thickness, elimination of choroidal hyperpeability on ICGA and focal leak on FA as well as resolution of subretinal fluid (Fig. **6**). The vast majority of patients treated with PDT have resolution of fluid and improvement in vision [2 - 4, 8, 10 - 12, 17].

**Fig. (6).** OCT imaging of PED before (**A**) and after (**B**) PDT. (Photo Credit: Courney McClenahay).

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Thermal laser photocoagulation will also successfully treat CSC, but is only indicated for extrafoveal leaks due to the laser induced scotoma and propensity for secondary choroidal neovascularization [2, 8]. Furthermore, it does not address the underlying choroidal hyperpermeability and thus may, in theory, carry a greater risk of recurrence in the first year. Micropulse diode laser is currently being investigated as a safer alternative to thermal laser photocoagulation [2, 8].

Anti-VEGF agents continue to be investigated with several studies showing promise; however the self-limiting nature of CSC is a confounding factor in measuring outcomes. In the authors' opinion, anti-VEGF does not significantly alter natural history based upon detailed examination patients showing no change in choroidal thickness or choroidal hyperpermeability following treatment (unpublished data) [2, 3, 8, 11, 17]. Numerous systemic medications have also been investigated with studies looking at anti-glucocorticoid (mifepristone), antimineralocorticoid (eplerenone, finesteride), ketoconazole, rifampin, *H pylori* eradication, and high dose anti-oxidants but thus far, evidence has been inconclusive [1, 6, 7, 19 - 21].

## **CONFLICT OF INTEREST**

The author(s) confirm that this chapter contents have no conflict of interest.

## **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**


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central serous chorioretinopathy: one-year results of a randomized controlled trial. Ophthalmology 2008; 115(10): 1756-65. [http://dx.doi.org/10.1016/j.ophtha.2008.04.014] [PMID: 18538401]

[5] Plateroti AM, Witmer MT, Kiss S, D'Amico DJ. Characteristics of intraretinal deposits in acute central serous chorioretinopathy. Clin Ophthalmol 2014; 8: 673-6.

[http://dx.doi.org/10.2147/OPTH.S48894] [PMID: 24729682]


[http://dx.doi.org/10.1097/00006982-200306000-00002] [PMID: 12824827]



© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

## **SUBJECT INDEX**

### **A**

Accelerated-malignant hypertension 68, 73, 74, 76, 77, 78 Acceleration-malignancy 74, 75 Anemia 23, 29, 74 Anterior segment neovascularization 53, 55, 132 Anti-inflammatory drugs 269, 270, 272 Anti-VEGF agents 40, 64, 128, 216, 283 Anti-VEGF treatment 54, 65 Areas, subfoveal 172, 182, 183 Arterial attenuation 84 Arterial hypertension, systemic 67, 99 Arterial macroaneurysms 99, 100 Arterioles, copper wiring of 69, 70, 71, 75 Arteriolized CNVs 179 Arteriolovenous crossings, abnormal 69, 70, 71, 73, 79 Asymptomatic VMA patients 258 Autofluorescence 93, 113, 195, 212, 250, 251, 279

### **B**

Best corrected visual acuity (BCVA) 53, 55, 206, 216 Blood-aqueous barrier (BAB) 262 Blood-retinal barrier (BRB) 31, 262 Blood vessels, large choroidal 149, 151, 208 Brilliant blue G (BBG) 232, 246 Bruch's membrane 138, 168, 207, 210, 212, 214, 215, 216 B-wave amplitude 87

### **C**

Capillaries, perifoveal retinal 262 Capillary non-perfusion 49, 61, 62, 64 Cataract surgery, complicated 265, 270 Cells, glial 227 Centrifugal contraction 248, 251 Chorioretinal anastomosis 108, 114, 126 Chorioretinal scars 220, 222

Choroidal infarctions 78 Choroidal neovascularization 39, 105, 108, 168, 193, 201, 208, 211, 213, 214, 219, 251 active 39, 213 subfoveal 121, 208 Choroidal rupture, traumatic 216 Choroidal thickness 282, 283 Chronic arterial hypertension 67, 70, 71, 79 Chronic decompensation 100 Chronic hypertensive arteriolosclerosis 69, 72, 74 Chronic secondary accelerated hypertension 74, 75 Cilioretinal arteries 84, 85, 92, 93 Circular myopic crescent 202, 203 Clinically significant macular edema (CSME) 29, 30, 33, 38 CNV 205, 206, 224 myopic 205, 206, 224 occult 194 Color photo montage 117, 120 Combined fluorescein-indocyanine 179 Cotton-wool spots (CWS) 3, 4, 5, 9, 12, 13, 58, 59, 91, 114, 131 Cystic spaces 31, 264, 268 Cystoid macular edema (CME) 32, 35, 227, 229, 242, 252, 258, 261, 262, 264, 265,

### **D**

Decreased visual acuity 91, 100, 103, 104, 228, 254, 261, 268 Dexamethasone intravitreal implants 53 Diabetes mellitus 3, 20, 22, 24, 27, 90, 264 Diabetic retinopathy 3, 5, 13, 15, 18, 26, 29, 31, 36, 41, 64, 74, 86, 94, 127, 134 severe non-proliferative 18 Diabetic retinopathy vitrectomy study (DRVS) 26 Diastolic blood pressure readings 68 Differential diagnosis of CRVO 53 Disciform scar 108, 181, 214, 215, 216 Disease, proliferative 116, 119

266, 267, 268, 278

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### *Subject Index Ophthalmology: Current and Future Developments, 2016, Vol. 1* **287**

Disease progression 183, 216 Domain-optical coherence tomography 36, 37, 39, 41 Drusen 137, 138, 139, 140, 159, 163, 169 basal laminar 159, 163 hard 137, 138, 140, 169 large 137, 149 medium 137, 139 Drusenoid pigment epithelial detachment (DPED) 140, 146, 158, 161

### **E**

Eales disease and CMV retinitis 14 Early fluorescein angiogram 172, 173, 175, 180 Early hyperfluorescence 139, 163, 172 Early treatment diabetic retinopathy study (ETDRS) 29, 40, 128 Edema resolution 269, 270 Electroretinogram 52, 87, 229 Epiretinal membrane 243, 228, 251, 252, located perifoveal 252 semitransparent perifoveolar 251 thick 243 thin 228 Epiretinal membrane peeling 232 Epithelial detachments 8, 178, 187, 193, 194 Extrafoveal chorioretinal scars 223 Exudates, hemorrhages and hard 34, 168 Eyes 130, 132, 182 affected 130, 132 contralateral 182

### **F**

Factors, anti-vascular endothelial growth 114, 123, 128, 198, 272 FAF signal 154, 157 Faint stain 141, 144 Features, fundoscopic 44, 47 Female patient 34, 76, 90, 162, 244 diabetic 34 Female patient complains 101 Fibrinoid necrosis 72, 73 Fibrotic end-stage submacular choroidal neovascularization 211

Flamed-shaped hemorrhages and retinal edema in superior macular area 59 Fluorescein 147, 172, 174, 175, 176 Fluorescein angiogram 3, 5, 6, 119, 121, 122, 133, 134, 139, 174, 176, 189, 213, 221, 222 Fluorescein angiogram (FA) 3, 4, 5, 20, 31, 34, 61, 62, 93, 94, 120, 121, 172, 173, 174 Fluorescein angiography 47, 48, 49, 77, 78, 79, 126, 127, 179, 194, 204, 213, 229, 251, 263 Focal vitreomacular traction 256 Foveal avascular zone, enlarged 20, 121, 122 Foveal contour 182, 183, 235, 242 irregular 235, 242 recovery of 182, 183 Foveal depression 183, 230 Foveal detachment 227, 235, 254, 257 FTMH, large 240 Full-thickness macular hole (FTMH) 240, 241, 245, 248, 251 Fundus autofluorescence 86, 93, 113, 210, 277, 278

## **G**

Geographic atrophy (GA) 136, 147, 149, 151, 152, 153, 154, 155, 157, 164 Giant cell arteritis 93, 96, 130 Glaucoma 40, 44, 262, 265

## **H**

Hard exudates and hemorrhages 172 Hemoglobin, mutated 116 Hemorrhages 23, 45, 47, 74, 100, 105, 125, 193, 208, 213 dense 100 diffuse retinal 74 flame-shaped 45, 47 preretinal 105, 125, 193 pre-retinal 23 subfoveal 208, 213 Henry ford ophthalmic photography 278, 280 Heterozygote, double 116 *Histoplasma capsulatum* 219

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Hyperfluorescence 74, 77, 100, 133, 139, 141, 144, 153, 161, 173, 174, 194, 212, 248, 251, 278 progressive 141, 144 showing 172, 175, 195 Hyperfluorescent points, multiple 31, 33 Hyperreflective 4, 8 Hyperreflective subretinal material, showing 205 Hyper-reflective tissue 182, 183 Hypertension 67, 68, 73, 80 chronic 68, 73, 80 primary 67, 68 Hypertensive patients 67, 68, 80 Hypertensive subject 67 Hypofluorescence 34, 49, 61, 146, 161, 278 Hyporeflective spaces, showing 236, 237

## **I**

Idiopathic macular hole 234, 235 Indocyanine 100, 127, 172, 179, 187, 194, 214, 232, 246, 278 Inferotemporal BRVO 59, 63, 65 Inner retinal layers 4, 5, 6, 83, 85, 87, 146, 242 Interface, vitreomacular 234, 235, 254 Internal limiting membrane (ILM) 55, 100, 104, 117, 227, 235, 241, 246 International clinical diabetic retinopathy disease severity scale 12, 13 International vitreomacular traction stud, (IVTS) 240, 254 International vitreomacular traction study classification 240, 241, 255 Intraocular pressure 55, 96, 101, 102, 103, 131, 132 Intraretinal fluid 54, 65, 177, 182, 183 accumulation of 177 recovery of foveal contour and improvement of 182, 183 showing accumulation of 54, 65 Intraretinal hemorrhages 3, 4, 13, 18, 45, 60, 95, 101, 102, 117, 134 diffuse 18 largest 4 showing massive 45

Intraretinal hemorrhages and microaneurysms 4 Intra retinal microvascular abnormalities (IRMAs) 3, 10, 18, 31 Intraretinal neovascularization 194 Intravitreal anti-VEGF therapy 182, 183 Intravitreal injections 40, 53, 105, 198, 271 IVTS classification system for vitreomacular adhesion 241, 255

### **L**

Laser, subthreshold 105 Laser photocoagulation 40, 104, 134, 184, 196, 206, 216, 283 thermal 196, 283 Late fluorescein angiogram 173, 174, 175, 176, 181 Leakage 31, 33, 34, 195, 215, 261, 263, 268 diffuse 31, 195 late 215, 261, 263, 268 mild 31, 33, 34 Left ventricular hypertrophy 68, 71, 77 Lesions 177, 181, 183, 195, 197 Hyper reflective 177, 181, 183 hyperreflective subretinal 195, 197

### **M**

Macroaneurysm 100, 104, 105 Macula, normal 236 Macular area 72, 136, 169, 172, 179, 180, 227 Macular attachment 255 Macular edema 39, 45, 53, 54, 55, 58, 60, 61, 64, 65, 78, 125, 128, 133, 203, 205, 269, 270, 271 pseudophakic 39, 269, 270, 271 Macular hole 235, 241, 242, 243, 245, 248 full-thickness 241, 245, 248 lamellar 235, 242, 243 Macular hole (MH) 114, 232, 234, 235, 236, 238, 240, 241, 244, 246, 248, 251 Macular hole stage 236, 237, 238 Macular pseudohole 235, 241, 242, 249, 250, 251 Macular retinal pigment 84 Macular thickening 227, 230, 264, 268

### *Subject Index Ophthalmology: Current and Future Developments, 2016, Vol. 1* **289**

Maculopathy 121, 219, 223 Membrane 100, 104, 117, 227, 228, 235 epiretinal macular 228 internal limiting 100, 104, 117, 227, 235 Metamorphopsia 107, 168, 202, 216, 223, 227, 228, 234, 254, 277 Microaneurysms 3, 4, 6, 11, 13, 21, 24, 30, 33, 107, 127 Microemboli 91 Multiple evanescent white-dot syndrome (MEWDS) 224 Multiple imaging modalities 119, 120 Myopia 201 pathologic 201 pathological 201

### **N**

Neovascularization 53, 114, 130 angle 53, 130 pre-retinal 114 Nerve fiber layer 3, 4, 5, 6, 9, 83, 91 Network, vascular 188, 189 Non-clearing vitreous hemorrhage 123, 128 Non-ischemic CRVO 46, 47, 54 Normal autofluorescence 93

### **O**

OCT image 52, 104, 188, 236, 237, 238, 239, 242, 243, 244, 245, 250, 257 OCT of epiretinal membrane 230 OCT scans 195, 197, 229, 231 Ophthalmic arteries 82, 88 Optical coherence tomography 51, 61, 85, 93, 104, 126, 140, 205, 210, 236, 254, 261 Optic coherence tomography (OCT) 4, 51, 54, 61, 63, 141, 146, 177, 178, 182, 183, 194, 229, 234, 235

### **P**

Panretinal photocoagulation 24, 26, 46, 53, 94, 134 Papillomacular bundle 92, 93 Perifoveal vitreous cortex detachment 255 Peripapillary PCV 187, 188

Permanent BRAO 90, 91 Photodynamic therapy 128, 184, 190, 197, 206, 216, 224 Pigment epithelium 108, 203, 238, 239 irregular retinal 238, 239 Pigment epithelium detachment (PED) 172, 182, 187, 197, 282 Plexiform layer, outer 4, 8, 264, 268 Posterior hyaloid 18, 259, 262 PPA and extrafoveal chorioretinal scars 223 Progressive glomerulonephritis 74, 77 Pro re nata (PRN) 216 Prostaglandins 262, 265 Pseudoxanthoma elasticum 207, 208, 210, 213 Punctate inner choroidopathy (PIC) 223

## **R**

Radiance study 206 Ranibizumab 40, 53, 64, 183, 216 Rapid progression 154, 157, 158 indicating 154 RAP lesions 196, 197, 198 Red blood cell (RBC) 116 Reflective material 140, 141, 142, 159 Reflective RPE layer 140, 141 Regions, peripapillary 126, 211, 212 Resolving intraretinal hemorrhage 117 Retina , adjacent 29, 104 Retina 52, 108, 136, 149, 193, 209, 210, 236, 238, 277 neurosensory 52, 108, 193, 209, 277 outer 136, 149, 210, 236, 238 Retinal angiomatous proliferation 193, 195, 196, 197 Retinal architecture 228, 256 Retinal artery 72, 82, 83, 90, 93, 132 Retinal artery occlusion 82, 86, 93 Retinal choroidal anastomosis (RCA) 194 Retinal damage 68, 246 Retinal detachment 23, 25, 26, 35, 52, 54, 61, 63, 64, 65, 119, 120, 123, 126, 128, 227, 229, 258, 278 associated foveal 258 serous 35, 52, 54, 61, 63, 65, 278 tractional 23, 25, 26, 64, 120, 123 traction macular 229

Retinal edema 58, 59, 72, 76, 85, 100 Retinal emboli 90, 91 Retinal folds 227, 230 Retinal hemorrhages 30, 44, 47, 48, 52, 59, 132, 127, 131, 194 characteristic 132 intra 52 mid-peripheral 131 Retinal layers 4, 6, 72, 108, 140, 181, 232, 235, 236, 238, 241, 245, 255, 256, 257 deeper 72, 108 middle 4, 6 outer 140, 235, 238, 245 Retinal neovascularization 61, 64, 126, 127 Retinal pallor 91, 92 Retinal pigment 105, 109, 213 Retinal pigment epithelium (RPE) 117, 136, 140, 141, 143, 146, 147, 193, 207, 208, 209, 240, 241, 255, 277 Retinal signs 72, 75 Retinal stroma 3, 4 Retinal surface 117, 227, 229, 230, 255, 258 inner 248, 252 Retinal telangiectasia 62, 127 Retinal thickening 29, 30, 112 Retinal thickness 41, 51, 52, 93, 177, 182, 183, 197 increased 51, 52, 183 showing decreased 182, 183 showing increased 177 Retinal tissue 88, 251 Retinal traction 35, 105 Retinal transparency 109, 111 Retinal vein 45, 47, 58, 80 Retinal vein occlusion 44, 58, 74, 121, 134, 267 Retinal vessels 108, 133, 193, 202 Retinitis pigmentosa 210, 265 Retinopathy 121, 125, 134 Retinovascular diseases 18 Right eye 19, 20, 24, 34, 36, 131, 158, 159, 160, 162, 169, 214, 215, 220, 222 RPE atrophy 108, 136, 146, 154, 213, 214 RPE cells 139, 147, 154

## **S**

Scanning laser ophthalmoscope (SLO) 251 Scotomas 91, 162, 216, 234, 251 Serous chorioretinopathy 182, 251, 277 Serous PED 194, 196, 198 Showing epiretinal membrane 230 Showing retinal hemorrhages 126 Showing subretinal fluid 195, 278 Sickle cell disease 14, 95, 116, 121, 210 Sickle cell trait 116 Skin, histoplasmin 223 Small drusen 137 Soft drusen 136, 138, 139, 140, 141, 142, 148, 154, 156, 164 confluent 156, 164 Spectral domain optical coherence tomography (SDOCT) 121, 230 Spots 3, 58, 59, 91, 114, 117, 118, 131 cotton-wool 3, 58, 59, 91, 114, 131 iridescent 117, 118 Stage-II RAP lesions 194, 198 Staining 47, 48, 50, 262, 263, 268 perifoveal petalloid 262, 263, 268 vessel wall 47, 48, 50 Stenosis, carotid 130 Subfoveal CNV 169, 170, 171, 224 Subfoveal fluid 264, 268 Subhyaloid hemorrhage 18, 78, 103 Submacular hemorrhage 169, 170, 171 large 169 massive 171 Subretinal fibrosis 105, 171, 172, 180, 181, 221 Subretinal fluid 52, 54, 65, 112, 168, 172, 178, 182, 183, 194, 213, 278, 281, 282 Subretinal hemorrhage 105, 169, 170, 174, 176, 180, 187, 211 associated 170 massive 176 small 169 Subretinal neovascularization 194, 202, 209 classic 209

Subretinal space 117, 194, 212 Superotemporal, subretinal choroidal neovascularization 222 Superotemporal arcade 20, 24, 94

## **T**

Tangential vitreoretinal traction (TVT) 234 Telangiectasias 125, 126, 196, 232, 266 parafoveal 196, 232 Temporal macula 122 Thickness macular hole 108, 238, 239, 240, 244, 245, 258 Topical combination 270, 271 Topical non-steroidal 269, 270 Tortuosity, vascular 117, 229 Traction, vitreo macular 266, 267 Transit time, arteriovenous 47, 48 Treatment of CRVO 53 Triamcinolone 53, 55, 64 Trypan blue (TB) 232, 246

## **V**

Vascular diseases 58, 121, 130, 134, 227 Vascular endothelial growth factor (VEGF) 31, 40, 114, 123, 128, 198, 224, 272 Vascular occlusions 73, 126, 127, 266 Vascular retinal diseases 44

Vein occlusions 13, 14, 18, 39, 73, 93, 134, 265 Venous beading 3, 10, 11, 12, 18, 24 severe 11 Vessels 6, 59, 60, 91, 93, 94, 108, 109, 111, 179 affected 91, 93, 94 normal 6, 108 right angle 109, 111 sclerotic 59, 60 showing thick 179 VH eyes 26 Visual acuity 54, 64, 65, 100, 101, 102, 103, 105, 107, 159, 160, 232, 234, 244, 246 Visual field defects 58, 93, 95, 96 Visual fields 83, 87, 162 Visual loss 29, 91, 96, 119, 125, 146, 261 Vitrectomy 25, 55, 132, 244, 259 Vitreomacular Adhesion (VMA) 240, 241, 254, 255, 258 Vitreomacular traction syndrome 232, 236, 254 Vitreous cells 220, 224 Vitreous cortex 235, 255 Vitreous hemorrhage (VH) 23, 61, 64, 117, 119, 122, 126, 131

## **W**

Watzke-Allen test 234, 235 Wool spots, multiple cotton 74, 75

*Ophthalmology: Current and Future Developments, Vol. 1 Kim et al.*