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Essentials in Ophthalmology	Medical Retina
	F. G. Holz R. F. Spaide
	Editors


Essentials in Ophthalmology	Glaucoma
G. K. Krieglstein R. N. Weinreb	Cataract and Refractive Surgery
Series Editors	Uveitis and Immunological Disorders
	Uveitis and Immunological Disorders
	Vitreo-retinal Surgery
	Medical Retina
	Oculoplastics and Orbit
	Pediatric Ophthalmology,
	Neuro-Ophthalmology, Genetics
	Cornea and External Eye Disease

Editors Frank G. Holz

Richard F. Spaide

Medical Retina

With 91 Figures, Mostly in Colour

and 13 Tables

123


Series Editors	Volume Editors
Günter K. Krieglstein, MD	Frank G. Holz, MD
Professor and Chairman	Professor and Chairman
Department of Ophthalmology	Department of Ophthalmology
University of Cologne	University of Bonn
Kerpener Straße 62	Ernst-Abbe-Straße 2
50924 Cologne	53127 Bonn
Germany	Germany
Robert N. Weinreb, MD	Richard F. Spaide, MD
Professor and Director	Assistant Clinical Professor
Hamilton Glaucoma Center	Vitreous, Retina, and Macula Consultants
Department of Ophthalmology	of New York, and
University of California at San Diego	LuEsther T. Mertz Retinal Research Center
9500 Gilman Drive	Manhattan Eye, Ear, and Throat Hospital
La Jolla, CA 92093-0946	460 Park Avenue
USA	New York, NY 10022
	USA

ISBN 978-3-540-33671-6	ISSN 1612-3212
Springer Berlin Heidelberg NewYork

Library of Congress Control Number: 2007927503

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from SpringerVerlag. Violations are liable for prosecution under the German Copyright Law.

Springer is a part of Springer Science + Business Media springer.com

The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature.

Editor: Marion Philipp, Heidelberg, Germany

Desk Editor: Martina Himberger, Heidelberg, Germany Production: LE-TeX Jelonek, Schmidt & Vöckler GbR, Leipzig, Germany

Cover Design: WMXDesign GmbH, Heidelberg, Germany

Printed on acid-free paper 24/3180Wa 5 4 3 2 1 0

Foreword

The series Essentials in Ophthalmology was initiated two years ago to expedite the timely transfer of new information in vision science and evidence-based medicine into clinical practice. We thought that this prospicient idea would be moved and guided by a resolute commitment to excellence. It is reasonable to now update our readers with what has been achieved.

The immediate goal was to transfer information through a high quality quarterly publication in which ophthalmology would be represented by eight subspecialties. In this regard, each issue has had a subspecialty theme and has been overseen by two internationally recognized volume editors, who in turn have invited a bevy of experts

to discuss clinically relevant and appropriate topics. Summaries of clinically relevant information have been provided throughout each chapter.

Each subspecialty area now has been covered once, and the response to the first eight volumes in the series has been enthusiastically positive. With the start of the second cycle of subspecialty coverage, the dissemination of practical information will be continued as we learn more about the emerging advances in various ophthalmic subspecialties that can be applied to obtain the best possible care of our patients. Moreover, we will continue to highlight clinically relevant information and maintain our commitment to excellence.

G. K. Krieglstein

R. N.Weinreb

Series Editors

Preface

Clinicians and basic scientists from the fields of ophthalmology and vision research have made tremendous progress in understanding the pathogenesis of retinal diseases, developing novel diagnostic techniques, and instituting new treatments for retinal conditions.

This multi-authored volume provides concise updates on the relevant and most challenging topics in medical retina. It is a practical and useful publication that will help all ophthalmologists, whether in training or in practice, to manage patients with retinal diseases.

The first two chapters on microperimetry and scanning laser fundus imaging highlight the advances in diagnostic technology that have contributed significantly to our understanding of the pathophysiology and treatment of various diseases. The following chapters address the latest developments in the area of age-related

macular degeneration including an update on genetic factors, current management strategies using anti-VEGF therapy, the role of combination treatments, and nutritional supplementation. The atrophic form of late AMD, i.e., geographic atrophy, is also addressed. Furthermore, current treatment approaches to diabetic macular edema and retinal vein occlusions are described. Finally, there is a discussion of the novel insights into Stargardt’s disease and idiopathic macular teleangiectasia, as well as perspectives on the expanding field of artificial vision.

Time and effort have been generously given by the contributing authors, to whom we, as editors, are extremely grateful. We are indebted to the editorial and production staff at Springer for their commitment to a timely publication in this rapidly moving field.

Frank G. Holz

Richard F. Spaide

Contents

Chapter 1

Microperimetry in Macular Disease

Klaus Rohrschneider

1.1	Introduction . . . . . . . . . . . . . . . .	1
1.2	Instruments . . . . . . . . . . . . . . . . .	2
1.2.1	Scanning Laser
	Ophthalmoscope . . . . . . . . . . . .	2

1.2.1.1Fundus Perimetry

	(Microperimetry) . . . . . . . . . . . .	3
1.2.2	Micro Perimeter 1 . . . . . . . . . . .	4

1.2.2.1Static Threshold Fundus

Perimetry . . . . . . . . . . . . . . .	. . . . 4
1.2.2.2 Kinetic Fundus Perimetry	. . . . 6

1.2.3Comparison Between SLO

Perimetry and MP 1 . . . . . . . . .

1.2.4Accuracy of Fundus

	Perimetry . . . . . . . . . . . . . . .	. . . 6
1.2.4.1	Static Threshold Perimetry	. . . 6
1.2.4.2	Kinetic Perimetry . . . . . . . .	. . . 7

1.2.5Fundus-related Perimetry

	Versus Cupola Perimetry	. . . . .	7
1.3	Clinical Implementation	. . . . .	8
1.3.1	Macular Holes . . . . . . . . . .	. . . . .	8

1.3.2Age-related Macular

Degeneration . . . . . . . . . . . . . . 10

1.3.2.1Geographic Atrophy of the

RPE . . . . . . . . . . . . . . . . . . . . . . . 10

1.3.2.2Choroidal

	Neovascularization in AMD . .	10
1.3.3	Diabetic Retinopathy . . . . . . .	10

1.3.4Central Serous

	Chorioretinopathy . . . . . . . . . .	14
1.3.5	Stargardt’s Disease . . . . . . . . .	15
1.3.6	Vitelliform Macular
	Dystrophy (Best’s Disease) . . .	16
1.4	Conclusion . . . . . . . . . . . . . . . . .	16

Chapter 2

New Developments

in cSLO Fundus Imaging

Giovanni Staurenghi, Grazia Levi,

Silvia Pedenovi, Chiara Veronese

2.1	Introduction . . . . . . . . . . . . . . .	21
2.2	Near Infrared Imaging . . . . . .	22
2.2.1	Introduction . . . . . . . . . . . . . . .	22

2.2.2The Effect of Wavelength

on Imaging in the Human Fundus . . . . . . . . . . . . . . . . . . . . 22

2.2.3Comparison of Light Tissue Interactions for Visible and Near Infrared Wavelengths

	Using SLO . . . . . . . . . . . . . . . . .	22
2.2.4	Mode of Imaging . . . . . . . . . . .	22
2.2.5	Contrast of the Fundus . . . . . .	23
2.2.6	Fundus Features . . . . . . . . . . . .	23

2.2.7Imaging of Pathological

Features in Direct

and Indirect Mode . . . . . . . . . . 23

2.3Blue Autofluorescence

Imaging . . . . . . . . . . . . . . . . . . . 23

2.3.1Autofluorescence and the

Eye . . . . . . . . . . . . . . . . . . . . . . . . 24

2.3.1.1Fluorescence of the Retinal

Pigment Epithelium . . . . . . . .

2.3.1.2How to Evaluate RPE

Autofluorescence . . . . . . . . . . 24

2.3.2Fundus Autofluorescence

Changes in Early AMD . . . . . .

2.3.3Fundus Autofluorescence

Changes in Choroidal Neovascularization in AMD . . 26

2.3.4Fundus Autofluorescence Changes in Geographic

Atrophy in AMD . . . . . . . . . . . .

2.3.5Fundus Autofluorescence in Acute and Chronic

Recurrent Central Serous

Chorioretinopathy . . . . . . . . . . 27

XContents

2.3.6	Fundus Autofluorescence		4.1.1	Historical Perspective . . . . . .	53
	in Stargardt’s Macular		4.1.2	VEGF Isoforms . . . . . . . . . . . . .	54
	Dystrophy-Fundus		4.1.3	VEGF Expression . . . . . . . . . . .	54
	Flavimaculatus . . . . . . . . . . . . .	27	4.1.4	VEGF Receptors . . . . . . . . . . . .	54
2.3.7	Fundus Autofluorescence		4.1.5	VEGF Activity . . . . . . . . . . . . . .	55
	in Patients with Macular	28	4.2	Current Anti-VEGF Therapies	55
	Holes . . . . . . . . . . . . . . . . . . . . . .	28	4.2.1	Aptamers: Pegaptanib	55
2.4	Wide-Field Contact Lens	28		Sodium (Macugen) . . . . . . . . .	55
	System . . . . . . . . . . . . . . . . . . . .	28	4.2.2	Monoclonal Antibodies:
2.4.1	Introduction . . . . . . . . . . . . . . .	28		Ranibizumab (Lucentis) . . . . .	56
2.4.2	Materials and Methods . . . . .	29	4.2.3	Monoclonal Antibodies:	58
2.4.2.1	Structure of a Wide-Field	29		Bevacizumab (Avastin) . . . . . .	58
	Contact Lens System . . . . . . . .	29	4.3	Anti-VEGF Therapy: Practical	60
2.4.2.2	Limit and Advantage of a			Considerations . . . . . . . . . . . . .	60
	Wide-Field Contact Lens	29	4.3.1	Intravitreal Injection	60
	System . . . . . . . . . . . . . . . . . . . .	29		Technique . . . . . . . . . . . . . . . . .	60
2.4.2.3	Technique for Performing	29	4.3.2	Safety Considerations . . . . . .	60
	the Examination . . . . . . . . . . . .	29	4.3.3	Bevacizumab (Avastin)
2.4.3	Other Techniques			Preparation: Compounding	61
	of Execution of Wide-field			Pharmacies . . . . . . . . . . . . . . . .	61
	Fluorescein Angiograms . . . .	30	4.4	Future Anti-VEGF Therapies	61
2.4.4	Clinical Application . . . . . . . . .	31	4.4.1	VEGF Trap . . . . . . . . . . . . . . . . . .	61
Chapter 3			4.4.2	Small Interfering RNAs . . . . . .	62
Chapter 3			4.4.3	Receptor Tyrosine Kinase
Genetics of Age-Related Macular				Inhibitors . . . . . . . . . . . . . . . . . .	63
Degeneration: Update			4.5	Conclusion . . . . . . . . . . . . . . . . .	64
Hendrik P.N. Scholl, Monika Fleckenstein,			Chapter 5
Peter Charbel Issa, Claudia Keilhauer, Frank			Chapter 5
G. Holz, Bernhard H.F. Weber			Intravitreal Injections:
			Techniques and Sequelae
3.1	Introduction:	35	Heinrich Heimann
	Genetic Influence on AMD . .	35	5.1	Introduction	67
3.2	Analysis of Candidate Genes	36	5.1	Introduction	67
	for AMD . . . . . . . . . . . . . . . . . . .	36	5.2	Complications of Intravitreal	68
3.3	Linkage and Association			Injections . . . . . . . . . . . . . . . . . .	68
	Studies in AMD . . . . . . . . . . . .	38	5.2.1	Methodology . . . . . . . . . . . . . .	69
3.4	Complement Factor H Gene	38	5.2.2	Perioperative Complications	69
3.5	LOC387715 . . . . . . . . . . . . . . . .	43	5.2.2.1	Conjunctival Hemorrhage . . .	69
3.6	Factor B . . . . . . . . . . . . . . . . . . .	44	5.2.2.2	Conjunctival Scarring . . . . . .	72
3.7	Gene–Gene		5.2.2.3	Pain . . . . . . . . . . . . . . . . . . . . . . .	72
	and Gene–Environment	45	5.2.2.4	Punctate Keratitis	72
	Interaction in AMD . . . . . . . . .	45		and Corneal Edema . . . . . . . . .	72
3.8	Conclusions . . . . . . . . . . . . . . . .	46	5.2.2.5	Vitreous Reflux . . . . . . . . . . . . .	72
Chapter 4			5.2.2.6	Traumatic Cataract . . . . . . . . .	72
Chapter 4			5.2.2.7	Cataract Progression . . . . . . . .	73
Anti-VEGF Treatment for Age-			5.2.2.8	Retinal Perforation . . . . . . . . .	73
Related Macular Degeneration			5.2.2.9	Vitreous Floaters . . . . . . . . . . .	74
Todd R. Klesert, Jennifer I. Lim			5.2.2.10	Vitreous Hemorrhage . . . . . . .	74
			5.2.2.11	Retinal Toxicity . . . . . . . . . . . . .	74
4.1	Basic Science . . . . . . . . . . . . . . .	53	5.2.2.12	Intraocular Inflammation . . . .	74

Contents XI

5.2.2.13 Uveitis and Pseudo-

endophthalmitis . . . . . . . . . . . 75

5.2.2.14 Endophthalmitis . . . . . . . . . . . 76

5.2.2.15 Retinal Artery and Vein

Occlusion . . . . . . . . . . . . . . . . . . 78

5.2.2.16 Retinal Detachment . . . . . . . . 78

5.2.2.17 Acute Rise in Intraocular

Pressure . . . . . . . . . . . . . . . . . . . 79

5.2.2.18 Ocular Hypertension and

Glaucoma . . . . . . . . . . . . . . . . . 79

5.3Surgical Technique

for Intravitreal Injection . . . . . 80

5.3.1Guidelines and Preferred

Practice Survey . . . . . . . . . . . . . 81

5.3.2Preoperative Assessment

	and Preparation . . . . . . . . .	. .. ..	81
5.3.2.1	Concomitant Eye Diseases	. .. ..	81
5.3.2.2	Preoperative Assessment	. . .	81

5.3.2.3Preoperative Medication . . . . 81

5.3.2.4 Location . . . . . . . . . . . . . . . . . . . 81

5.3.2.5Preparation of the Eye and

Ocular Adnexa . . . . . . . . . . . . . 81

5.3.2.6Preparation of the Surgeon . . 84

5.3.2.7Preparation of the Drug . . . . . 84

5.3.3	Injection . . . . . . . . . . . . . . . . . . .	84
5.3.3.1	Syringe and Needle . . . . . . . . .	84

5.3.3.2Position of the Injection . . . . . 84

5.3.3.3 Entry Path . . . . . . . . . . . . . . . . .

5.3.3.4Advancement of Needle and

	Injection . . . . . . . . . . . . . . . . .	. . 84
5.3.4	Postoperative Assessment	. . 84

5.3.4.1Assessment Immediately

	Following the Injection	. . . . .	84
5.3.4.2	Topical Therapy . . . . . . .	. .. .. .. ..	85
5.3.4.3	Follow-up Examinations	. .. .. .. ..	85

Chapter 6

Combination Therapies for Choroidal Neovascularization

Richard F. Spaide

6.1	Introduction . . . . . . . . . . . .	. . . 90
6.2	Angiogenesis . . . . . . . . . . .	. . . 90
6.2.1	Development of CNV . . . .	. . . 91
6.2.2	Cancer and Angiogenesis	. . . 91

6.3Normalization of Tumor

Vasculature . . . . . . . . . . . . . . . . 92

6.4Two-Component Model of

CNV . . . . . . . . . . . . . . . . . . . . . . .

6.5Two-Component Model and

Therapy . . . . . . . . . . . . . . . . . . . 94

6.5.1Are There Cytokines to Block

	Other Than VEGF? . . . . . . . . . .	95
6.6	Combination Therapies . . . . .	96
6.6.1	Anti-VEGF Biologics
	and Photodynamic Therapy .	96
6.6.2	Anecortave Acetate
	and Photodynamic Therapy .	97

6.6.3Intravitreal Triamcinolone

and Photodynamic Therapy . 97

6.6.4Triamcinolone and Anti-

VEGF Therapy . . . . . . . . . . . . . . 97

6.6.5Triamcinolone

	and Anecortave Acetate	. . . . 98
6.7	Conclusion . . . . . . . . . . . . .	. . . . 99

Chapter 7

Nutritional Supplementation in Agerelated Macular Degeneration

Hanna R. Coleman, Emily Y. Chew

7.1	Introduction . . . . . . . . . . . . . .	105
7.2	Risk Factors . . . . . . . . . . . . . . .	105

7.3Age-Related Eye Disease

	Study . . . . . . . . . . . . . . . . . . . . .	106
7.4	Lutein/Zeaxanthin . . . . . . . . .	106
7.5	Zinc . . . . . . . . . . . . . . . . . . . . . .	106
7.6	Vitamin E . . . . . . . . . . . . . . . . .	107
7.7	Dietary Fat Intake . . . . . . . . . .	107

7.8Age-Related Eye Disease

	Study 2 . . . . . . . . . . . . . . . . . . .	107
7.9	Conclusion . . . . . . . . . . . . . . . .	108

Chapter 8

New Perspectives in Geographic Atrophy Associated with AMD

Steffen Schmitz-Valckenberg, Monika

Fleckenstein, Hendrik P.N. Scholl, Frank G.

Holz

8.1	Introduction . . . . . . . . . . . . . .	114
8.1.1	Basics . . . . . . . . . . . . . . . . . . . .	114

8.1.2Development and Spread of

Atrophy . . . . . . . . . . . . . . . . . . 115

8.2Fundus Autofluorescence

Imaging in Geographic
Atrophy . . . . . . . . . . . . . . . . . .	116

8.3Quantification of Atrophy

Progression . . . . . . . . . . . . . . .

117

XII Contents

8.4	Risk Factors . . . . . . . . . . . . . . .	118	9.8.2.2	Aldose Reductase and AGE
8.4.1	Genetic Factors . . . . . . . . . . .	118		Inhibitors . . . . . . . . . . . . . . . . .	136
8.4.2	Systemic Risk Factors . . . . . .	118	9.8.2.3	Antioxidants . . . . . . . . . . . . . .	136
8.4.3	Ocular Risk Factors . . . . . . . .	119	9.8.3	A Team Approach
8.5	Development of CNV in Eyes	122		to the Prevention of Loss
	with GA . . . . . . . . . . . . . . . . . .	122		of Vision in People with	137
8.6	Visual Function in GA	123		Diabetes . . . . . . . . . . . . . . . . . .	137
	Patients . . . . . . . . . . . . . . . . . .	123	9.8.4	Local Ophthalmic	138
8.6.1	Measurement of Visual			Treatment . . . . . . . . . . . . . . . .	138
	Acuity . . . . . . . . . . . . . . . . . . . .	123	9.8.4.1	Focal Macular Laser . . . . . . . .	138
8.6.2	Contrast Sensitivity . . . . . . . .	124	9.8.4.2	Grid Macular Laser . . . . . . . . .	138
8.6.3	Reading Speed . . . . . . . . . . . .	124	9.8.4.3	Recent Trends in Macular
8.6.4	Fundus Perimetry . . . . . . . . .	124		Laser Therapy . . . . . . . . . . . . .	138
			9.8.4.4	Micropulsed, Sub-threshold
Chapter 9				“Selective” Laser Therapy . . .	139
Diabetic Macular Edema:			9.8.4.5	Vitrectomy . . . . . . . . . . . . . . . .	139
Current Treatments			9.8.4.6	Intravitreal Steroids . . . . . . . .	139
Florian K.P. Sutter, Mark C. Gillies, Horst			9.8.4.7	Periocular Steroids . . . . . . . .	140
Helbig			9.8.4.8	Intravitreal Anti-VEGF	140
				Antibodies . . . . . . . . . . . . . . . .	140
9.1	Introduction . . . . . . . . . . . . . .	131	9.8.4.9	Cataract Surgery . . . . . . . . . .	141
9.2	Epidemiology . . . . . . . . . . . . .	131	9.9	Current Clinical Practice/
9.3	Pathophysiology . . . . . . . . . .	132		Recommendations . . . . . . . .	141

9.4Diabetic Macular Edema and

	Laboratory Science . . . . . . . .	132	Chapter 10
9.5	Quality of Life . . . . . . . . . . . . .	133	Treatment of Retinal Vein Occlusions
9.6	Diagnosis and Screening . . .	133	Rajeev S. Ramchandran, R. Keith Shuler,
9.7	Types of Diabetic Macular	134	Sharon Fekrat
	Edema . . . . . . . . . . . . . . . . . . . .	134			147
9.7.1	Clinically Significant Macular		10.1	Introduction . . . . . . . . . . . . . .	147
	Edema . . . . . . . . . . . . . . . . . . . .	134	10.2	Pathophysiology . . . . . . . . . .	148
9.7.2	Focal Diabetic Macular	134	10.3	Branch and Central Vein	148
	Edema . . . . . . . . . . . . . . . . . . . .	134		Occlusion Studies . . . . . . . . .	148
9.7.3	Diffuse Diabetic Macular	134	10.3.1	Background . . . . . . . . . . . . . . .	148
	Edema . . . . . . . . . . . . . . . . . . . .	134	10.3.2	Branch Vein Occlusion
9.7.4	Cystoid Macular Edema . . . .	134		Study . . . . . . . . . . . . . . . . . . . . .	149
9.7.5	Ischemic Macular Edema . .	134	10.3.3	Central Vein Occlusion	149
9.7.6	OCT Patterns of Diabetic	134		Study . . . . . . . . . . . . . . . . . . . . .	149
	Macular Edema . . . . . . . . . . .	134	10.4	Systemic Pharmacologic
9.8	Treatment . . . . . . . . . . . . . . . .	135		Treatments . . . . . . . . . . . . . . .	150
9.8.1	Systemic Treatment . . . . . . . .	135	10.5	Targeting Macular Edema . .	151
9.8.1.1	Glycemic Control . . . . . . . . . .	135	10.6	Intravitreal
9.8.1.2	Blood Pressure Control . . . . .	135		Pharmacotherapy . . . . . . . . .	151
9.8.1.3	Reducing Levels of Blood	135	10.6.1	Background . . . . . . . . . . . . . . .	151
	Lipids . . . . . . . . . . . . . . . . . . . .	135	10.6.2	Intravitreal Triamcinolone:	153
9.8.1.4	Treatment of Renal			BRVO . . . . . . . . . . . . . . . . . . . . .	153
	Dysfunction and Anemia . . .	136	10.6.3	Intravitreal Triamcinolone:
9.8.1.5	Smoking . . . . . . . . . . . . . . . . . .	136		CRVO . . . . . . . . . . . . . . . . . . . . .	153
9.8.2	Systemic Pharmacotherapy	136	10.6.4	Fluocinolone Acetonide
9.8.2.1	PKC-ß Inhibitors . . . . . . . . . . .	136		Intravitreal Implant . . . . . . . .	153

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