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Ophthalmology
Ophthalmology
LEAD EDITORS FIFTH EDITION
Myron Yanoff, MD Jay S. Duker, MD
Chair Emeritus, Ophthalmology Director
Professor of Ophthalmology & Pathology New England Eye Center
Departments of Ophthalmology & Pathology Professor and Chairman
College of Medicine Department of Ophthalmology
Drexel University Tufts Medical Center
Philadelphia, PA, USA Tufts University School of Medicine
Boston, MA, USA

SECTION EDITORS
James J. Augsburger, MD Michael H. Goldstein, MD, MBA Alfredo A. Sadun, MD, PhD
Professor and Chairman Co-Director, Cornea and External Diseases Flora Thornton Chair, Doheny
Department of Ophthalmology Service Professor of Ophthalmology
University of Cincinnati College of Medicine New England Eye Center Vice-Chair of Ophthalmology, UCLA
Cincinnati, OH, USA Tufts Medical Center Los Angeles, CA, USA
Boston, MA, USA
Dimitri T. Azar, MD, MBA Joel S. Schuman, MD
Senior Director, Google Verily Life Sciences Narsing A. Rao, MD Professor and Chairman of Ophthalmology
Distinguished University Professor and B.A. Professor of Ophthalmology and Pathology Director, NYU Eye Center
Field Chair of Ophthalmic Research USC Roski Eye Institute Professor of Neuroscience and Physiology
Professor of Ophthalmology, Pharmacology, and Department of Ophthalmology Neuroscience Institute
Bioengineering University of Southern California NYU School of Medicine
University of Illinois at Chicago Los Angeles, CA, USA Professor of Electrical and Computer
Chicago, IL, USA Engineering
Shira L. Robbins, MD NYU Tandon School of Engineering
Sophie J. Bakri, MD Clinical Professor of Ophthalmology
Professor of Neural Science
Professor of Ophthalmology Ratner Children’s Eye Center at the Shiley Eye
Center for Neural Science, NYU
Vitreoretinal Diseases & Surgery Institute
New York, NY, USA
Mayo Clinic University of California San Diego
Rochester, MN, USA La Jolla, CA, USA Janey L. Wiggs, MD, PhD
Paul Austin Chandler Professor of
Scott E. Brodie, MD, PhD Emanuel S. Rosen, MD, FRCS, Ophthalmology
Professor of Ophthalmology FRCOphth Harvard Medical School
NYU School of Medicine Private Practice Boston, MA, USA
New York, NY, USA Case Reports Editor for Journal of Cataract &
Jonathan J. Dutton, MD, PhD Refractive Surgery
Professor Emeritus Manchester, UK
Department of Ophthalmology
University of North Carolina
Chapel Hill, NC, USA
For additional online content visit ExpertConsult.com

Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019


© 2019, Elsevier Inc. All rights reserved.

First edition 1999


Second edition 2004
Third edition 2009
Fourth edition 2014

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about
the Publisher’s permissions policies and our arrangements with organizations such as the Copyright
Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/
permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Chapter 4.29: “Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction” by
Marianne O. Price, Francis W. Price, Jr.
Marianne O. Price and Francis W. Price, Jr. retain copyright of the video accompanying this chapter.

Chapter 6.5: “Contact B-Scan Ultrasonography” by Yale L. Fisher, Dov B. Sebrow


Yale L. Fisher retains copyright of the video accompanying this chapter. The remainder of this lecture as
well as additional lectures on ophthalmology can be found at www.OphthalmicEdge.org.

Chapter 7.2: “Mechanisms of Uveitis” by Igal Gery, Chi-Chao Chan


This chapter is in the Public Domain.

Chapter 7.23: “Masquerade Syndromes: Neoplasms” by Nirali Bhatt, Chi-Chao Chan, H. Nida Sen
This chapter is in the Public Domain.

Chapter 11.8: “Torsional Strabismus” by Scott K. McClatchey, Linda R. Dagi


This chapter is in the Public Domain.

Chapter 12.16: “Aesthetic Fillers and Botulinum Toxin for Wrinkle Reduction” by Jean Carruthers,
Alastair Carruthers
Jean Carruthers retains copyright of Figures 12.16.1 & 12.16.6.

Notices

Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds or experiments described herein. Because of
rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug
dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier,
authors, editors or contributors for any injury and/or damage to persons or property as a matter of
products liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.

ISBN: 978-0-323-52819-1
E-ISBN: 978-0-323-52821-4
ISBN: 978-0-323-52820-7

Content Strategist: Russell Gabbedy


Content Development Specialist: Sharon Nash
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Marketing Manager: Claire McKenzie

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1


User Guide

User Guide
COLOR CODING
Ophthalmology is organized into 12 parts, which are color-coded as follows
for quick and easy reference:

Part 1: Genetics

Part 2: Optics and Refraction

Part 3: Refractive Surgery

Part 4: Cornea and Ocular Surface Diseases

Part 5: The Lens

Part 6: Retina and Vitreous

Part 7: Uveitis and Other Intraocular Inflammations

Part 8: Intraocular Tumors

Part 9: Neuro-Ophthalmology

Part 10: Glaucoma

Part 11: Pediatric and Adult Strabismus

Part 12: Orbit and Oculoplastics

EXPERTCONSULT WEBSITE
n Full searchable text and downloadable image gallery
n Full reference lists for each chapter
n Additional online content including text, figures, & video clips

v
Video Contents Video available at
Video Contents
ExpertConsult.com

Part 3: Refractive Surgery Chapter 6.25 Coats’ Disease and Retinal Telangiectasia
Chapter 3.4 LASIK 6.25.1 Pars Plana Vitrectomy and Subretinal Fluid and Exudate Drainage Performed
for a Severe Exudative Retinal Detachment
3.4.1 iLASIK
Chapter 6.32 Macular Hole
Chapter 3.5 Small Incision Lenticule Extraction (SMILE)
6.32.1 Macular Hole Surgery
3.5.1 SMILE Instructional Video
Chapter 6.33 Epiretinal Membrane
Chapter 3.7 Phakic Intraocular Lenses
6.33.1 Epiretinal Membrane Removal
3.7.1 Cachet Lens
3.7.2 Artisan/Verisyse Lens Implantation for Hyperopia After Radial Keratotomy Chapter 6.34 Vitreomacular Traction
3.7.3 Toric Artiflex Phakic Intraocular Lens in a Patient With High Myopia and
6.34.1 Vitreomacular Traction Syndrome
Astigmatism After Deep Anterior Lamellar Keratoplasty
3.7.4 Toric Artiflex Lens Implantation in a Patient With a Previous Intracorneal Chapter 6.39 Rhegmatogenous Retinal Detachment
Ring for Keratoconus 6.39.1 Internal Limiting Membrane (ILM) Peeling for Primary Rhegmatogenous
3.7.5 ICL Implantation Repair to Reduce Postoperative Macular Pucker
3.7.6 ICL Exchange
Chapter 6.41 Choroidal Hemorrhage
Part 4: Cornea and Ocular Surface Diseases 6.41.1 Transconjunctival Trocar/Cannula Drainage of Suprachoroidal Fluid
Chapter 4.17 Noninfectious Keratitis
Chapter 6.43 Posterior Segment Ocular Trauma
4.17.1 Patient With Lax Eyelids Recommended for Sleep Study
6.43.1 Intraocular Foreign Body Removal
Chapter 4.29 Endothelial Keratoplasty: Targeted Treatment for Corneal 6.43.2 Intraocular Foreign Body Removal With Rare Earth Magnet
Endothelial Dysfunction
Part 9: Neuro-Ophthalmology
4.29.1 DSEK Pull-Through
4.29.2 DMEK Donor Preparation Chapter 9.19 Nystagmus, Saccadic Intrusions, and Oscillations
4.29.3 Descemet’s Membrane Endothelial Keratoplasty (DMEK) 9.19.1 Congenital Nystagmus
9.19.2 Oculocutaneous Albinism With Associated Nystagmus
Part 5: The Lens 9.19.3 Latent Nystagmus
Chapter 5.8 Anesthesia for Cataract Surgery 9.19.4 Spasmus Nutans
5.8.1 Standard Technique for Sub-Tenon’s Anesthesia 9.19.5 Right Internuclear Ophthalmoplegia
5.8.2 “Incisionless” Technique for Sub-Tenon’s Anesthesia 9.19.6 Convergence Retraction Nystagmus in Parinaud’s Syndrome

Chapter 5.9 Phacoemulsification Part 10: Glaucoma


5.9.1 Two Examples of “Sculpting” Using Low Flow and Vacuum but Higher Chapter 10.7 Optic Nerve Analysis
Power/Amplitude 10.7.1 Three-Dimensional Imaging of the Optic Nerve Head
5.9.2 Two Examples of Using Higher Flow and Vacuum for Nucleus Fragment
Removal Chapter 10.28 Minimally Invasive and Microincisional Glaucoma Surgeries
Chapter 5.11 Small Incision and Femtosecond Laser-Assisted 10.28.1 iStent G1 Implantation
Cataract Surgery 10.28.2 Key Steps in Trabectome Surgery
5.11.1 Unexpected Subluxation Chapter 10.29 Trabeculectomy
5.11.2 Microincision Phaco 10.29.1 Bleb Leak Detection Using Concentrated Fluorescein Dye
5.11.3 Microincision Refractive Lens Exchange 10.29.2 Trabeculectomy With Mitomycin C
5.11.4 700µ Phaco 10.29.3 5-Fluorouracil Subconjunctival Injection
Chapter 5.13 Combined Procedures Chapter 10.32 Complications of Glaucoma Surgery and Their Management
5.13.1 Combined Phacoemulsification Cataract Surgery and Descemet’s Stripping 10.32.1 Small Pupil Cataract Surgery With Use of Pupil Expansion Ring (I-Ring;
Automated Endothelial Keratoplasty (DSAEK) Beaver Visitec, Waltham, MA) and Trypan Blue Capsular Staining
5.13.2 Combined Phacovitrectomy 10.32.2 Repair of Bleb Leak
Chapter 5.16 Complications of Cataract Surgery
Part 11: Pediatric and Adult Strabismus
5.16.1 Artisan Implantation
Chapter 11.3 Examination of Ocular Alignment and Eye Movements
Part 6: Retina and Vitreous 11.3.1 Strabismus Exam Elements
Chapter 6.3 Retinal and Choroidal Circulation 11.3.2 Cover/Uncover Test
11.3.3 Exotropia
6.3.1 Fluorescein and Indocyanine Green (ICG) Video Angiogram 11.3.4 Esotropia
Chapter 6.5 Contact B-Scan Ultrasonography 11.3.5 Hypertropia
11.3.6 Prism Alternate Cover Test
6.5.1 Examination Techniques for Contact B-Scan Ultrasonography
11.3.7 Simultaneous Prism Cover Test
Chapter 6.11 Scleral Buckling Surgery 11.3.8 Exophoria
11.3.9 Alternate or Cross Cover Test
6.11.1 Scleral Buckle
6.11.2 Suture Total running time approximately 2 hours and 34 minutes
6.11.3 Drain
Chapter 6.12 Vitrectomy
6.12.1 Vitrectomy for Nonclearing Vitreous Hemorrhage

vi
Preface
Preface

It’s been 20 years since the first edition of Ophthalmology was published. Ophthalmology was never intended to be encyclopedic, but with each
We are delighted that our textbook now has gone to a fifth edition. The lon- edition we strived to make it quite comprehensive, readable, and easy to
gevity of this title reflects the uniqueness and utility of its format; the hard access. Like the fourth edition, this edition is thoroughly revised, with new
work of our authors, editors, and publishers; and the pressing need in our section editors and many new authors. Chapters have been rewritten and
field for updated, clinically relevant information. We continue to recognize restricted to reflect the new way diseases are diagnosed, categorized, and
the advantage of a complete textbook of ophthalmology in a single volume treated. We have discarded out-of-date material and have added numerous
rather than multiple volumes. The basic visual science is admixed with new items. Extra references and other material have been moved online to
clinical information throughout, and we have maintained an entire sepa- keep the book itself as one volume.
rate section dedicated to genetics and the eye.

xii
Preface to First Edition

Preface to First Edition


Over the past 30 years, enormous technologic advances have occurred in To achieve the same continuity of presentation in the figures as well
many different areas of medicine—lasers, molecular genetics, and immu- as in the text, all of the artworks have been redesigned from the authors’
nology to name a few. This progress has fueled similar advances in almost originals, maximizing their accessibility for the reader. Each section is
every aspect of ophthalmic practice. The assimilation and integration of color coded for easy cross-referencing and navigation through the book.
so much new information makes narrower and more focused ophthalmic Despite the extensive use of color in artworks and photographs through-
practices a necessity. As a direct consequence, many subspecialty textbooks out, the cost of this comprehensive book has been kept to a fraction of the
with extremely narrow focus are now available, covering every aspect of multivolume sets. We hope to make this volume more accessible to more
ophthalmic practice. Concurrently, several excellent multivolume textbooks practitioners throughout the world.
detailing all aspects of ophthalmic practice have been developed. Yet there Although comprehensive, Ophthalmology is not intended to be encyclo-
remains a need for a complete single-volume textbook of ophthalmology pedic. In particular, in dealing with surgery, we do not stress specific tech-
for trainees, nonophthalmologists, and those general ophthalmologists niques or describe rarer ones in meticulous detail. The rapidly changing
(and perhaps specialists) who need an update in specific areas in which nature of surgical aspects of ophthalmic practice is such that the reader
they do not have expertise. Ophthalmology was created to fill this void will need to refer to one or more of the plethora of excellent books that
between the multivolume and narrow subspecialty book. cover specific current techniques in depth. We concentrate instead on
This book is an entirely new, comprehensive, clinically relevant, sin- the areas that are less volatile but, nevertheless, vital surgical indications,
gle-volume textbook of ophthalmology, with a new approach to content and general principles of surgical technique, and complications. The approach
presentation that allows the reader to access key information quickly. Our to referencing is parallel to this: For every topic, all the key references are
approach, from the outset, has been to use templates to maintain a uniform listed, but with the aim of avoiding pages of redundant references where a
chapter structure throughout the book so that the material is presented in smaller number of recent classic reviews will suffice. The overall emphasis
a logical, consistent manner, without repetition. The majority of chapters of Ophthalmology is current information that is relevant to clinical practice
in the book follow one of three templates: the disease-oriented template, superimposed on the broad framework that comprises ophthalmology as
the surgical procedure template, or the diagnostic testing template. Metic- a subspecialty.
ulous planning went into the content, sectioning, and chapter organization Essential to the realization of this ambitious project is the ream of
of the book, with the aim of presenting ophthalmology as it is practiced, Section Editors, each bringing unique insight and expertise to the book.
rather than as a collection of artificially divided aspects. Thus, pediatric They have coordinated their efforts in shaping the contents list, finding
ophthalmology is not in a separate section but is integrated into relevant contributors, and editing chapters to produce a book that we hope will
sections across the book. The basic visual science and clinical information, make a great contribution to ophthalmology.
including systemic manifestations, is integrated throughout, with only two We are grateful to the editors and authors who have contributed to
exceptions. We dedicated an entire section to genetics and the eye, in rec- Ophthalmology and to the superb, dedicated team at Mosby.
ognition of the increasing importance of genetics in ophthalmology. Optics Myron Yanoff
and refraction are included in a single section as well because an under- Jay S. Duker
standing of these subjects is fundamental to all of ophthalmology. July 1998

xiii
List of Contributors
List of Contributors

The editor(s) would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition
would not have been possible.

Erika C. Acera, OC(C) Ferhina S. Ali, MD, MPH Steve A. Arshinoff, MD, FRCSC Nicole Balducci, MD
Clinical Orthoptist Vitreoretinal Surgery Fellow Associate Professor Consultant
Department of Ophthalmology Wills Eye Hospital University of Toronto Ophthalmology Division
Anne F. and Abraham Ratner Retina Service Department of Ophthalmology and Studio Oculistico d’Azeglio
Children’s Eye Center Mid Atlantic Retina Visual Sciences Bologna, Italy
Shiley Eye Institute Philadelphia, PA, USA Toronto, ON, Canada
University of California San Diego Piero Barboni, MD
La Jolla, CA, USA Jorge L. Alió, MD, PhD Penny A. Asbell, MD, FACS, FARVO Consultant
Professor of Ophthalmology Professor of Ophthalmology Neuro-Ophthalmology
Natalie A. Afshari, MD Miguel Hernandez University, Vissum Icahn School of Medicine at Mount Scientific Institute San Raffaele
Stuart I. Brown MD Chair in Alicante, Spain Sinai Milan, Italy
Ophthalmology in Memory of New York, NY, USA Studio Oculistico d’Azeglio
Donald P. Shiley Norma Allemann, MD Bologna, Italy
Professor of Ophthalmology Adjunct Professor Kerry K. Assil, MD
Chief of Cornea and Refractive Surgery Department of Ophthalmology and Corneal, Cataract and Refractive Cullen J. Barnett, COT, CRA, OCT-C,
Vice Chair of Education Visual Sciences Surgeon CDOS
Shiley Eye Institute University of Illinois at Chicago Medical Director Clinical Supervisor of Ophthalmology
University of California San Diego Chicago, IL, USA The Assil Eye Institute Roski Eye Institute
La Jolla, CA, USA Adjunct Professor Beverly Hills, CA, USA Keck Medicine USC
Department of Ophthalmology and Los Angeles, CA, USA
Anita Agarwal, MD Visual Sciences Neal H. Atebara, MD, FACS
Adjoint Professor of Ophthalmology Escola Paulista de Medicina (EPM) Associate Professor Soumyava Basu, MS
Vanderbilt Eye Institute Universidade Federal de São Paulo Department of Surgery Head of Uveitis Services
West Coast Retina (UNIFESP) University of Hawaii LVPEI Network
Vanderbilt University Medical Center São Paulo, SP, Brazil John A. Burns School of Medicine L V Prasad Eye Institute
San Francisco, CA, USA Honolulu, HI, USA Bhubaneswar, Odisha, India
David Allen, BSc, MB, BS, FRCS,
Joshua S. Agranat, MD FRCOphth James J. Augsburger, MD Priti Batta, MD
Resident Physician Consultant Ophthalmologist (Cataract) Professor of Ophthalmology Assistant Professor of Ophthalmology
Department of Ophthalmology Cataract Treatment Centre Dr. E. Vernon & Eloise C. Smith Chair Director of Medical Student Education
Massachusetts Eye and Ear Sunderland Eye Infirmary of Ophthalmology New York Eye and Ear Infirmary of
Harvard Medical School Sunderland, Tyne & Wear, UK College of Medicine, University of Mount Sinai
Boston, MA, USA Cincinnati New York, NY, USA
Keith G. Allman, MBChB, MD, FRCA Founding Director, Ocular Oncology &
Radwan S. Ajlan, MBBCh, FRCS(C), Consultant Anaesthetist Diagnostic Ultrasonography Service, Caroline R. Baumal, MD, FRCSC
FICO, DABO West of England Eye Unit University of Cincinnati Medical Associate Professor of Ophthalmology
Assistant Professor Royal Devon and Exeter NHS Trust Center Director ROP Service
Retina and Vitreous Exeter, Devon, UK Attending Surgeon, University of Vitreoretinal Surgery
Department of Ophthalmology Cincinnati Medical Center New England Eye Center
University of Kansas School of Nishat P. Alvi, MD Consulting Surgeon, Cincinnati Tufts University
Medicine Medical Director of Ophthalmology Children’s Hospital Medical Center School of Medicine
Kansas City, KS, USA The Vision Institute of Illinois Cincinnati, OH, USA Boston, MA, USA
Elgin, IL, USA
Anam Akhlaq, MBBS G. William Aylward, FRCS, FRCOphth, Srilaxmi Bearelly, MD, MHS
Postdoctoral Fellow Leonard P.K. Ang, MBBS, MD, FRCS, MD Assistant Professor of Ophthalmology
Center for Translational Ocular MRCOphth, MMed, FAMS Consultant Ophthalmologist Ophthalmology
Immunology Associate Professor of Ophthalmology London, UK Columbia University Medical Center
Department of Ophthalmology Medical Director, Lang Eye Centre New York, NY, USA
Tufts Medical Center Singapore Dimitri T. Azar, MD, MBA
Senior Director, Google Verily Life Jesse L. Berry, MD
Boston, MA, USA David J. Apple, MD †
Associate Director, Ocular Oncology
Sciences
Thomas A. Albini, MD Formerly Professor of Ophthalmology Distinguished University Professor Service
Associate Professor of Ophthalmology and Pathology and B.A. Field Chair of Ophthalmic Associate Residency Program Director
Department of Ophthalmology Director, Laboratories for Ophthalmic Research for Ophthalmology
Bascom Palmer Eye Institute Devices Research Professor of Ophthalmology, USC Roski Eye Institute
University of Miami John A. Moran Eye Center Pharmacology, and Bioengineering Keck School of Medicine, University of
Miami, FL, USA University of Utah University of Illinois at Chicago Illinois Southern California
Salt Lake City, UT, USA College of Medicine Attending Surgeon, Children’s Hospital
Ahmed Al-Ghoul, MD, MBA, FRCSC, Chicago, IL, USA of Los Angeles
DipABO Maria Cecilia D. Aquino, MD, MMED, Los Angeles, CA, USA
Clinical Lecturer (Ophthalmology) Sophie J. Bakri, MD
Division of Ophthalmology Resident Physician II Professor of Ophthalmology Angela P. Bessette, MD
Department of Surgery Ophthalmology/Glaucoma Vitreoretinal Diseases & Surgery Assistant Professor
University of Calgary National University Hospital Mayo Clinic Department of Ophthalmology
Calgary, AB, Canada National University Health System Rochester, MN, USA Flaum Eye Institute
Singapore University of Rochester
Laura J. Balcer, MD, MSCE Rochester, NY, USA
Anthony C. Arnold, MD Professor of Neurology
Professor and Chief Vice-Chair, Neurology
Neuro-Ophthalmology Division New York University
xiv UCLA Stein Eye Institute
Los Angeles, CA, USA
School of Medicine

Deceased New York, NY, USA
Nirali Bhatt, MD Igor I. Bussel, MS, MHA Chi-Chao Chan, MD Abbot (Abe) Clark, PhD, FARVO
Assistant Professor Doris Duke Clinical Research Fellow Scientist Emeritus Regents Professor of Pharmacology

List of Contributors
Department of Ophthalmology Department of Ophthalmology Laboratory of Immunology and Neuroscience
University of Pennsylvania University of Pittsburgh School of National Eye Institute Executive Director, North Texas Eye
Perelman School of Medicine Medicine National Institutes of Health Research Institute
Philadelphia, PA, USA Pittsburgh, PA, USA Bethesda, MD, USA University of North Texas Health
Visiting Professor Science Center
Orry C. Birdsong, MD Louis B. Cantor, MD Zhongshan Ophthalmic Center Fort Worth, TX, USA
Clinical Fellow Jay C. and Lucile L. Kahn Professor Sun Yat-Sen University
Ophthalmology and Chair China Jonathan C.K. Clarke, MD, FRCOphth
Hoopes Vision Department of Ophthalmology Consultant Ophthalmologist
Draper, UT, USA Indiana University Melinda Y. Chang, MD NIHR Moorfields Biomedical Research
School of Medicine Assistant Professor of Ophthalmology Centre
Jyotirmay Biswas, MS, FMRF, FNAMS, Indianapolis, IN, USA USC Roski Eye Institute and Children’s Moorfields Eye Hospital
FIC, Path, FAICO Hospital Los Angeles UCL Institute of Ophthalmology
Director Hilda Capó, MD Keck School of Medicine of the London, UK
Uveitis and Ocular Pathology Professor of Clinical Ophthalmology University of Southern California
Department Bascom Palmer Eye Institute Los Angeles, CA, USA François Codère, MD
Sankara Nethralaya Division Chief Pediatric Associate Professor
Chennai, Tamil Nadu, India Ophthalmology and Adult Stanley Chang, MD Ophthalmology/Oculoplastic and
Strabismus KK Tse and KT Ying Professor of Orbital Surgery Section
Bahram Bodaghi, MD, PhD, FEBOphth Miller School of Medicine Ophthalmology Université de Montréal
Professor of Ophthalmology John T. Flynn Professor of Department of Ophthalmology Montréal, QC, Canada
DHU ViewRestore Ophthalmology Chair Columbia University
APHP, UPMC, Sorbonne University University of Miami New York, NY, USA Ian P. Conner, MD, PhD
Paris, France Miami, FL, USA Assistant Professor
Victoria S. Chang, MD Ophthalmology
Swaraj Bose, MD Antonio Capone, Jr., MD Assistant Professor of Clinical UPMC Eye Center
Associate Professor of Ophthalmology Professor Ophthalmology Pittsburgh, PA, USA
UCI and Attending Physician Department of Ophthalmology Ophthalmology, Cornea and External
Cedars Sinai Medical Center Oakland University Disease Peter Coombs, MD
Los Angeles, CA, USA William Beaumont Hospital Bascom Palmer Eye Institute Vitreoretinal Physician and Surgeon
School of Medicine University of Miami Utah Eye Centers
Charles S. Bouchard, MD, MA Salt Lake City, UT, USA
Professor and Chairman of Auburn HIlls, MI, USA Naples, FL, USA
Ophthalmology Alastair Carruthers, MA, BM, BCh, David G. Charteris, MD, FRCS(Ed), Zélia M. Corrêa, MD, PhD
Loyola University Health System FRCP(Lon), FRCPC FRCOphth Tom Clancy Endowed Professor of
Maywood, IL, USA Clinical Professor Professor Ophthalmology
Department of Dermatology and Skin Vitreoretinal Unit Head of Ocular Oncology and
Michael E. Boulton, PhD Echography
Susan and Dowd Ritter/RPB Endowed Science Moorfields Eye Hospital
University of British Columbia London, UK Retina Service, Wilmer Eye Institute
Chair of Ophthalmology Johns Hopkins University School of
University of Alabama Birmingham Vancouver, BC, Canada
Soon-Phaik Chee, MD Medicine
Birmingham, AL, USA Jean Carruthers, MD, FRCSC, Professor Baltimore, MD, USA
James D. Brandt, MD FRC(OPHTH) Cataract Service, Ocular Inflammation
Clinical Professor & Immunology Service Steven M. Couch, MD, FACS
Professor Assistant Professor
Department of Ophthalmology & Department of Ophthalmology Singapore National Eye Centre
University of British Columbia Singapore Department of Ophthalmology &
Vision Science Visual Sciences
Vice-Chair for International Programs Fellow
American Society for Ophthalmic John J. Chen, MD, PhD Washington University in St Louis
and New Techology Assistant Professor St Louis, MO, USA
Director - Glaucoma Service Plastic and Reconstructive Surgery
Vancouver, BC, Canada Department of Ophthalmology and
University of California Davis Neurology Stuart G. Coupland, PhD
Sacramento, CA, USA Keith D. Carter, MD, FACS Mayo Clinic Associate Professor
Lillian C. O’Brien and Dr. C.S. O’Brien Rochester, MN, USA Department of Ophthalmology
Scott E. Brodie, MD, PhD University of Ottawa
Professor of Ophthalmology Chair in Ophthalmology
Professor and Chair Xuejing Chen, MD, MS Ottawa, ON, Canada
NYU School of Medicine Clinical Fellow
New York, NY, USA Department of Ophthalmology & Claude L. Cowan, Jr., MD, MPH
Visual Sciences Retina
Ophthalmic Consultants of Boston Clinical Professor of Ophthalmology
Michael C. Brodsky, MD Carver College of Medicine Georgetown University Medical Center
Professor of Ophthalmology and University of Iowa New England Eye Center at Tufts
Medical Center Washington, DC, USA
Neurology Iowa City, IA, USA Staff Physician
Knights Templar Research Professor of Boston, MA, USA
Rafael C. Caruso, MD Surgical Service
Ophthalmology Paul T.K. Chew, MMed, FRCOphth Veterans Affairs Medical Center
Mayo Clinic Staff Clinician
National Eye Institute Director Glaucoma Division Washington, DC, USA
Rochester, MN, USA Ophthalmology/Glaucoma
National Institutes of Health E. Randy Craven, MD
Cassandra C. Brooks, MD Bethesda, MD, USA National University Hospital Singapore
Singapore Associate Professor, Glaucoma
Resident in Ophthalmology Johns Hopkins University
Duke Eye Center Harinderpal S. Chahal, MD
Oculofacial Plastic and Reconstructive Bing Chiu, MD Baltimore, MD, USA
Duke University School of Medicine Ophthalmology Resident
Durham, NC, USA Surgery Catherine A. Cukras, MD, PhD
Eye Medical Center New York University
New York, NY, USA Director, Medical Retina Fellowship
Matthew V. Brumm, MD Fresno, CA, USA Program
Ophthalmologist Clement C. Chow, MD National Eye Institute
Cataract and Refractive Surgery Wallace Chamon, MD
Adjunct Professor Partner Physician National Institutes of Health
Brumm Eye Center Retinal Diagnostic Center Bethesda, MD, USA
Omaha, NE, USA Department of Ophthalmology and
Visual Sciences Campbell, CA, USA
Linda R. Dagi, MD
Donald L. Budenz, MD, MPH University of Illinois at Chicago Mortimer M. Civan, MD Director of Adult Strabismus
Kittner Family Distinguished Professor Chicago, IL, USA Professor of Physiology and Professor Boston Children’s Hospital
and Chairman Adjunct Professor of Medicine Associate Professor of Ophthalmology
Department of Ophthalmology Department of Ophthalmology and Department of Physiology Director of Quality Assurance
University of North Carolina at Chapel Visual Sciences University of Pennsylvania Department of Ophthalmology
Hill Escola Paulista de Medicina (EPM) Perelman School of Medicine Children’s Hospital Ophthalmology
Chapel Hill, NC, USA Universidade Federal de São Paulo Philadelphia, PA, USA Foundation Chair
(UNIFESP) Harvard Medical School
São Paulo, SP, Brazil Boston, MA, USA
xv
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Elie Dahan, MD, MMed, (Ophth)† Gary R. Diamond, MD† Bryan Edgington, MD Ayad A. Farjo, MD
Formerly Senior Consultant Pediatric Formerly Professor of Ophthalmology Associate Professor, Cornea Division President & Director
List of Contributors
Ophthalmology and Glaucoma and Pediatrics Casey Eye Institute Brighton Vision Center
Department of Ophthalmology Drexel University School of Medicine Oregon Health Sciences University Brighton, MI, USA
Ein Tal Eye Hospital Philadelphia, PA, USA Staff Ophthalmologist
Tel Aviv, Israel Veterans Health Administration Eric Feinstein, MD
Daniel Diniz, MD Portland Health Care System Surgical Retina Fellow
Iben Bach Damgaard, MD Surgical Optics Fellow Portland, OR, USA Department of Ophthalmology
PhD Fellow Department of Ophthalmology & Rocky Mountain Lions Eye Institute
Department of Ophthalmology Visual Sciences Howard M. Eggers, MD University of Colorado
Aarhus University Hospital Federal University of São Paulo Professor of Clinical Ophthalmology School of Medicine
Aarhus, Denmark (UNIFESP) Harkness Eye Institute Denver, CO, USA
São Paulo, SP, Brazil New York, NY, USA
Karim F. Damji, MD, FRCSC, MBA Karen B. Fernandez, MD
Professor Diana V. Do, MD Dean Eliott, MD Consultant
Department of Ophthalmology & Professor of Ophthalmology Stelios Evangelos Gragoudas Associate Department of Ophthalmology
Visual Sciences Byers Eye Institute Professor of Ophthalmology The Medical City
University of Alberta Stanford University Harvard Medical School Pasig City, Metro Manila, Philippines
Edmonton, AL, Canada School of Medicine Associate Director, Retina Service
Palo Alto, CA, USA Massachusetts Eye & Ear Yale L. Fisher, MD
Dipankar Das, MD Boston, MA, USA Voluntary Clinical Professor
Senior Consultant & Ocular Pathologist Peter J. Dolman, MD, FRCSC Department of Ophthalmology
Uveitis, Ocular Pathology and Neuro- Clinical Professor George S. Ellis, Jr., MD, FAAP, FAAO, Bascom Palmer Eye Institute
ophthalmology Services Division Head of Oculoplastics and FACS Miami, FL, USA
Sri Sankaradeva Nethralaya Orbital Surgery Director Ophthalmology Voluntary Clinical Professor
Guwahati, Assam, India Fellowship Director Children’s Hospital New Orleans Department of Ophthalmology
Department of Ophthalmology & Associate Clinical Professor of Weill Cornell Medical Center
Adam DeBusk, DO, MS Visual Sciences Ophthalmology and Pediatrics New York, NY, USA
Instructor Division of Oculoplastics and Orbit Tulane University
Department of Ophthalmology University of British Columbia Associate Clinical Professor of Gerald A. Fishman, MD
Wills Eye Hospital Vancouver General Hospital Ophthalmology and Pediatrics Director
Sidney Kimmel Medical College Vancouver, BC, Canada Louisiana State Universities Schools of The Pangere Center for Inherited
Thomas Jefferson University Medicine Retinal Diseases
Philadelphia, PA, USA Sean P. Donahue, MD, PhD New Orleans, LA, USA The Chicago Lighthouse
Professor Professor Emeritus of Ophthalmology
Jose de la Cruz, MD, MSc Department of Ophthalmology & Michael Engelbert, MD, PhD Department of Ophthalmology &
Assistant Professor Visual Sciences Research Assistant Professor Visual Sciences
Ophthalmology, Cornea Refractive Vanderbilt University Department of Ophthalmology University of Illinois at Chicago
Surgery Service Nashville, TN, USA NYU/VRMNY College of Medicine
University of Illinois Eye and Ear New York, NY, USA Chicago, IL, USA
Infirmary Richard K. Dortzbach, MD
Chicago, IL, USA Professor Emeritus Miriam Englander, MD Jorge A. Fortun, MD
Department of Ophthalmology and Attending Surgeon Associate Professor of Ophthalmology
Joseph L. Demer, MD, PhD Visual Sciences Vitreo-Retinal Surgery Vitreoretinal Diseases and Surgery
Arthur L. Rosenbaum Chair in University of Wisconsin Ophthalmic Consultants of Boston Medical Director of Bascom Palmer
Pediatric Ophthalmology School of Medicine and Public Health Boston, MA, USA Eye Institute
Professor of Neurology Madison, WI, USA Palm Beach Gardens Bascom Palmer
Chief, Pediatric Ophthalmology and Bita Esmaeli, MD, FACS Eye Institute
Strabismus Division Kimberly A. Drenser, MD, PhD Professor of Ophthalmology University of Miami Miller School of
Director, Ocular Motility Laboratories Associated Retinal Consultants, PC Director, Ophthalmic Plastic & Medicine
Chair, EyeSTAR Residency/PhD and Department of Ophthalmology Reconstructive Surgery Fellowship Miami, FL, USA
Post-doctoral Fellowship Program in Oakland University Program, Department of Plastic
Ophthalmology and Visual Science William Beaumont Hospital School of Surgery Veronica Vargas Fragoso, MD
Member, Neuroscience Medicine Chair, Graduate Medical Education Refractive Surgery Fellow
Interdepartmental Program Royal Oak, MI, USA Committee Vissum Corporation
Member, Bioengineering University of Texas MD Anderson Alicante, Spain
Interdepartmental Program Jacob S. Duker, MD Cancer Center
University of California Los Angeles Resident Physician Houston, TX, USA Nicola Freeman, MBChB, FCOphth,
Los Angeles, CA, USA Department of Ophthalmology MMed
Bascom Palmer Eye Institute Joshua W. Evans, MD Senior Specialist
Shilpa J. Desai, MD University of Miami Assistant Professor of Ophthalmology Department of Pediatric
Assistant Professor Miami, FL, USA Division of Glaucoma Ophthalmology
Department of Ophthalmology University of Kentucky Red Cross Children’s Hospital
Tufts University Jay S. Duker, MD Lexington, KY, USA Cape Town, Western Province, South
School of Medicine Director Africa
Boston, MA, USA New England Eye Center Monica Evans, MD
Professor and Chairman Ophthalmology David S. Friedman, MD, MPH, PhD
Deepinder K. Dhaliwal, MD, L.Ac Department of Ophthalmology San Jose, Costa Rica Director, Dana Center for Preventive
Professor of Ophthalmology, University Tufts Medical Center Ophthalmology
of Pittsburgh School of Medicine Tufts University School of Medicine Daoud S. Fahd, MD Professor of Ophthalmology, Wilmer/
Director, Cornea and Refractive Boston, MA, USA Clinical Assistant Professor Glaucoma
Surgery Services Department of Ophthalmology Johns Hopkins University
Director and Founder, Center for Vikram D. Durairaj, MD, FACS Ophthalmic Consultants of Beirut Baltimore, MD, USA
Integrative Eye Care ASOPRS Fellowship Director and Jal el Dib, Metn, Lebanon
Co-Director, Cornea and Refractive Managing Partner Deborah I. Friedman, MD, MPH
Oculoplastic and Orbital Surgery Lisa J. Faia, MD Professor
Surgery Fellowship Partner, Associated Retinal Consultants
Associate Medical Director, Charles TOC Eye and Face Department of Neurology
Austin, TX, USA Associate Professor & Neurotherapeutics and
T. Campbell Ocular Microbiology Oakland University
Laboratory Ophthalmology
Jonathan J. Dutton, MD, PhD William Beaumont School of Medicine University of Texas
Medical Director, UPMC Laser Vision Professor Emeritus Ophthalmology - Retina
Center Southwestern Medical Center
Department of Ophthalmology Royal Oak, MI, USA Dallas, TX, USA
University of Pittsburgh Medical University of North Carolina
Center Chapel Hill, NC, USA Katherine A. Fallano, MD Neil J. Friedman, MD
Pittsburgh, PA, USA Department of Ophthalmology Adjunct Clinical Associate Professor
University of Pittsburgh School of Department of Ophthalmology
Medicine Stanford University School of Medicine
Pittsburgh, PA, USA
xvi †
Stanford, CA, USA
Deceased
Nicoletta Fynn-Thompson, MD Jeffrey L. Goldberg, MD, PhD Jason R. Guercio, MD, MBA Joshua H. Hou, MD
Partner Professor and Chairman Senior Resident in Anesthesiology Assistant Professor

List of Contributors
Cornea, Cataract and Refractive Surgery Department of Ophthalmology Department of Anesthesiology Department of Ophthalmology &
Ophthalmic Consultants of Boston Byers Eye Institute at Stanford Duke University Medical Center Visual Neurosciences
Boston, MA, USA University Durham, NC, USA University of Minnesota
Palo Alto, CA, USA Minneapolis, MN, USA
Neha Gadaria-Rathod, MD Julie Gueudry, MD
Assistant Clinical Instructor Debra A. Goldstein, MD, FRCSC Senior Consultant Odette M. Houghton, MD
Department of Ophthalmology Magerstadt Professor of Ophthalmology Senior Associate Consultant
SUNY Downstate Medical Center Ophthalmology Charles Nicolle University Hospital Ophthalmology
New York, NY, USA Director Uveitis Service Rouen, France Mayo Clinic
Northwestern University Scottsdale, AZ, USA
Debora E. Garcia-Zalisnak, MD Feinberg School of Medicine Ahmet Kaan Gündüz, MD
Cornea Fellow Chicago, IL, USA Professor of Ophthalmology Kourtney Houser, MD
Department of Ophthalmology Ankara University Assistant Professor
University of Illinois at Chicago Michael H. Goldstein, MD, MBA Faculty of Medicine Ophthalmology
Chicago, IL, USA Co-Director, Cornea and External Ankara, Turkey University of Tennessee
Diseases Service Health Science Center
Gregg S. Gayre, MD New England Eye Center Joelle A. Hallak, PhD Memphis, TN, USA
Chief of Eye Care Services Tufts Medical Center Assistant Professor, Executive Director
Department of Ophthalmology Boston, MA, USA Ophthalmic Clinical Trials & Frank W. Howes, MBChB, MMed, FCS,
Kaiser Permanente Translational Center FRCS, FRCOphth, FRANZCO
San Rafael, CA, USA John A. Gonzales, MD Department of Ophthalmology & Associate Professor
Assistant Professor Visual Sciences Bond University
Steven J. Gedde, MD Francis I. Proctor Foundation and University of Illinois at Chicago Company and Clinical Director
Professor of Ophthalmology, John Department of Ophthalmology Chicago, IL, USA Cataract Refractive & Glaucoma
G. Clarkson Chair, Vice Chair of University of California San Francisco Surgery
Education San Francisco, CA, USA Julia A. Haller, MD Eye & Laser Centre
Bascom Palmer Eye Institute Ophthalmologist-in-Chief, Wills Eye Gold Coast, QLD, Australia
University of Miami Miller David B. Granet, MD, FACS, FAAp Hospital
School of Medicine Anne F. Ratner Chair of Pediatric William Tasman, MD Endowed Chair Jason Hsu, MD
Miami, FL, USA Ophthalmology Professor and Chair of Ophthalmology Co-Director of Retina Research
Professor of Ophthalmology & Sidney Kimmel Medical College at Retina Service of Wills Eye Hospital
Igal Gery, PhD Pediatrics Thomas Jefferson University Associate Professor of Ophthalmology
Scientist Emerita Director of the Ratner Children’s Eye Philadelphia, PA, USA Thomas Jefferson University
Laboratory of Immunology Center at the Shiley Eye Institute Mid Atlantic Retina
National Eye Institute University of California San Diego Pedram Hamrah, MD, FACS Philadelphia, PA, USA
National Institutes of Health La Jolla, CA, USA Director of Clinical Research
Bethesda, MD, USA Director, Center for Translational Jeffrey J. Hurwitz, MD, FRCS(C)
Matthew J. Gray, MD Ocular Immunology Professsor, Ophthalmology
Ramon C. Ghanem, MD, PhD Assistant Professor Cornea and Associate Professor, Ophthalmology University of Toronto
Director External Disease Tufts Medical Center Oculoplastic Specialist
Cornea and Refractive Surgery Department of Ophthalmology Tufts University Mount Sinai Hospital
Department University of Florida School of Medicine Toronto, ON, Canada
Sadalla Amin Ghanem Eye Hospital Gainesville, FL, USA Boston, MA, USA
Joinville, SC, Brazil Francisco Irochima, PhD
Kyle M. Green, BA David R. Hardten, MD Professor, Biotechnology
Vinícius C. Ghanem, MD, PhD Medical Student Researcher Director of Refractive Surgery Universidade Potiguar
Ophthalmologist, Medical Director Ophthalmology Department of Ophthalmology Natal, Rio Grande do Norte, Brazil
Department of Ophthalmology University of Southern California Minnesota Eye Consultants
Sadalla Amin Ghanem Eye Hospital Roski Eye Institute Minnetonka, MN, USA Jihad Isteitiya, MD
Joinville, SC, Brazil Los Angeles, CA, USA Cornea Fellow, Ophthalmology
Alon Harris, MS, PhD, FARVO Icahn School of Medicine at Mount
Saurabh Ghosh, MBBS, DipOphth, Craig M. Greven, MD Professor of Ophthalmology Sinai
MRCOphth, FRCOphth Richard G. Weaver Professor and Letzter Endowed Chair in New York, NY, USA
Consultant Ophthalmologist Chairman Ophthalmology
Cornea, Cataract, External Eye Disease Department of Ophthalmology Director of Clinical Research Andrea M. Izak, MD
Sunderland Eye Infirmary Wake Forest University Eugene and Marilyn Glick Eye Institute Post-Doctoral Fellow
Sunderland, Tyne & Wear, UK School of Medicine Indiana University Storm Eye Institute
Winston-Salem, NC, USA School of Medicine Medical University of South Carolina
Allister Gibbons, MD Charleston, SC, USA
Assistant Professor Indianapolis, IN, USA
Margaret A. Greven, MD
Bascom Palmer Eye Institute Assistant Professor Jeffrey S. Heier, MD Deborah S. Jacobs, MD
University of Miami Ophthalmology Co-President and Medical Director Associate Professor of Ophthalmology
Miami, FL, USA Wake Forest University Director, Vitreoretinal Service Harvard Medical School
School of Medicine Ophthalmic Consultants of Boston Medical Director
James W. Gigantelli, MD, FACS BostonSight
Professor Winston-Salem, NC, USA Boston, MA, USA
Needham, MA, USA
Department Ophthalmology & Visual Josh C. Gross, MD Leon W. Herndon, Jr., MD
Sciences Clinical Research Fellow Professor, Ophthalmology Sandeep Jain, MD
University of Nebraska Medical Center Ophthalmology Duke University Eye Center Associate Professor, Ophthalmology
Omaha, NE, USA Eugene and Marilyn Glick Eye Institute Durham, NC, USA University of Illinois at Chicago
Indiana School of Medicine Chicago, IL, USA
Pushpanjali Giri, BA Allen C. Ho, MD
Research Specialist Indianapolis, IN, USA Henry D. Jampel, MD, MHS
Wills Eye Hospital Director of Retina
Department of Ophthalmology Ronald L. Gross, MD Research Odd Fellows Professor of
University of Illinois at Chicago Professor and Jane McDermott Schott Retina Service Ophthalmology
College of Medicine Chair Wills Eye Hospital Wilmer Eye Institute
Chicago, IL, USA Chairman, Department of Philadelphia, PA, USA Johns Hopkins University
Ophthalmology School of Medicine
Ivan Goldberg, AM, MB, BS, FRANZCO, Christopher T. Hood, MD Baltimore, MD, USA
FRACS West Virginia University
Morgantown, WV, USA Clinical Assistant Professor
Clinical Professor Michigan Medicine Ophthalmology Lee M. Jampol, MD
University of Sydney Sandeep Grover, MD Cornea and Refractive Surgery Clinic Louis Feinberg Professor of
Head of Discipline of Ophthalmology Associate Professor & Associate Chair W.K. Kellogg Eye Center Ophthalmology
and Glaucoma Unit of Ophthalmology Ann Arbor, MI, USA Feinberg School of Medicine
Sydney Eye Hospital University of Florida Northwestern University
Director Jacksonville, FL, USA Chicago, IL, USA
Eye Associates xvii
Sydney, NSW, Australia
Aliza Jap, FRCS(G), FRCOphth, FRCS Kevin Kaplowitz, MD Jeremy D. Keenan, MD, MPH Victor T.C. Koh, MBBS, MMed(Oph),
(Ed) Assistant Professor Associate Professor of Ophthalmology FAMS
List of Contributors
Senior Consultant Ophthalmologist Ophthalmology, VA Loma Linda Francis I. Proctor Foundation and Associate Consultant, Ophthalmology
Division of Ophthalmology Loma Linda University Department of Ophthalmology National University Hospital
Changi General Hospital, Singapore Loma Linda, CA, USA University of California San Francisco Singapore
Singapore National Eye Centre San Francisco, CA, USA
Singapore Michael A. Kapusta, MD, FRCSC Thomas Kohnen, MD, PhD, FEBO
Associate Professor Kenneth R. Kenyon, MD Professor and Director
Chris A. Johnson, PhD, DSc Director of Retina and Vitreous Surgery Clinical Professor, Ophthalmology Department of Ophthalmology
Professor Department of Ophthalmology Tufts University University Clinic Frankfurt
Department of Ophthalmology & Jewish General Hospital School of Medicine Goethe University
Visual Sciences McGill University Harvard Medical School Frankfurt am Main
University of Iowa Hospitals and Montreal, QC, Canada Schepens Eye Research Institute Germany
Clinics Boston, MA, USA
Iowa City, IA, USA Rustum Karanjia, MD, PhD, FRCSC Andrew Koustenis, BS
Assistant Professor, Ophthalmology Sir Peng Tee Khaw, PhD, FRCS, FRCP, Medical Student
Mark W. Johnson, MD University of Ottawa FRCOphth, FRCPath, FRSB, FCOptom Clinical Ophthalmology Research
Professor, Chief of Retina Section Ottawa Hospital Research Institute (Hon), DSc, FARVO, FMedSci Internship
Department of Ophthalmology & The Ottawa Hospital Professor of Glaucoma and Ocular Department of Ophthalmology
Visual Sciences Ottawa, ON, Canada Healing Eugene and Marilyn Glick Eye Institute
University of Michigan Doheny Eye Institute Consultant Ophthalmic Surgeon Indiana University
Ann Arbor, MI, USA Doheny Eye Centers Director, National Institute for Health School of Medicine
UCLA, David Geffen School of Research, Biomedical Research Indianapolis, IN, USA
T. Mark Johnson, MD, FRCS(C) Medicine Centre for Ophthalmology
Attending Surgeon, Vitreo-Retinal Los Angeles, CA, USA Moorfields Eye Hospital Stephen S. Lane, MD
Surgery UCL Institute of Ophthalmology Medical Director
Retina Group of Washington Randy H. Kardon, MD, PhD London, UK Adjunct Clinical Professor
Rockville, MD, USA Professor and Director of Neuro- Chief Medical Officer and Head Global
ophthalmology and Pomerantz Gene Kim, MD Franchise Clinical Strategy
Mark M. Kaehr, MD Family Chair in Ophthalmology Assistant Professor and Residency Associated Eye Care
Partner Ophthalmology/Neuro-ophthalmology Program Director University of Minnesota, Alcon
Associated Vitreoretinal and Uveitis Director of the Iowa City VA Center Department of Ophthalmology & Minneapolis, MN, USA
Consultants for the Prevention and Treatment of Visual Science at McGovern Medical
Assistant Clinical Professor of Visual Loss School at UTHealth Patrick J.M. Lavin, MB, MRCPI
Ophthalmology University of Iowa and Iowa City VA Houston, TX, USA Prof. Neurology and Ophthalmology
Indiana University Medical Center Neurology, Ophthalmology and Visual
Associated Vitreoretinal and Uveitis Iowa City, IA, USA Ivana K. Kim, MD Science
Consultants Associate Professor of Ophthalmology Vanderbilt University Medical Center
Indiana University Carol L. Karp, MD Retina Service, Massachusetts Eye and Nashville, TN, USA
School Of Medicine Professor of Ophthalmology Ear
Indianapolis, IN, USA Richard K. Forster Chair in Harvard Medical School Fabio Lavinsky, MD, PhD, MBA
Ophthalmology Boston, MA, USA Research Fellow
Malik Y. Kahook, MD Bascom Palmer Eye Institute NYU Langone Eye Center
The Slater Family Endowed Chair in University of Miami Alan E. Kimura, MD, MPH NYU School of Medicine
Ophthalmology Miller School of Medicine Clinical Associate Professor New York, NY, USA
Vice Chair of Clinical & Translational Miami, FL, USA Department of Ophthalmology Director, Ophthalmic Imaging
Research University of Colorado Department
Professor of Ophthalmology & Chief of Amir H. Kashani, MD, PhD Health Sciences Center Lavinsky Eye Institute
Glaucoma Service Assistant Professor of Clinical Aurora, CO, USA Porto Alegre, Brazil
Director of Glaucoma Fellowship Ophthalmology
University of Colorado University of Southern California Michael Kinori, MD Andrew W. Lawton, MD
School of Medicine Roski Eye Institute Senior Physician Director, Neuro-Ophthalmology
Aurora, CO, USA Los Angeles, CA, USA The Goldschleger Eye Institute Division
Sheba Medical Center, Tel Hashomer Ochsner Health Services
Peter K. Kaiser, MD Michael A. Kass, MD Ramat Gan, Israel New Orleans, LA, USA
Chaney Family Endowed Chair in Bernard Becker Professor,
Ophthalmology Research Ophthalmology and Visual Science Caitriona Kirwan, FRCSI(Ophth) Bryan S. Lee, MD, JD
Professor of Ophthalmology Washington University Consultant Ophthalmic Surgeon Private Practitioner
Cleveland Clinic School of Medicine Mater Private Hospital Altos Eye Physicians
Cole Eye Institute St Louis, MO, USA Dublin, Ireland Los Altos, CA, USA
Cleveland, OH, USA Adjunct Clinical Assistant Professor of
Paula Kataguiri, MD Szilárd Kiss, MD Ophthalmology
Sachin P. Kalarn, MD Research Fellow Chief, Retina Service Director Stanford University
Resident Physician Department of Ophthalmology and Clinical Research Director Stanford, CA, USA
Department of Ophthalmology & Center for Translational Ocular Tele-Ophthalmology Director
Visual Sciences Immunology Compliance Associate Professor of Daniel Lee, MD
University of Maryland Tufts Medical Center Ophthalmology Clinical Instructor, Glaucoma Service
Baltimore, MD, USA New England Eye Center Weill Cornell Medical College Wills Eye Hospital
Boston, MA, USA New York, NY, USA Philadelphia, PA, USA
Ananda Kalevar, MD, FRCSC, DABO PhD Candidate
Associate Professor, Department of John W. Kitchens, MD Gregory D. Lee, MD
Department of Ophthalmology Retina Surgeon, Partner Assistant Professor, Ophthalmology/
Ophthalmology Universidade Federal de São Paulo
University of Sherbrooke Co-Fellowship Director Retina
(UNIFESP) Retina Associates of Kentucky New York University
Sherbrooke, QC, Canada São Paulo, SP, Brazil Lexington, KY, USA New York, NY, USA
Steven Kane, MD L. Jay Katz, MD
Cornea, Cataract, and Refractive Kendra Klein, MD Olivia L. Lee, MD
Director, Glaucoma Service Faculty Physician Assistant Professor of Ophthalmology
Surgery Specialist Wills Eye Hospital
Eye Institute of West Florida Department of Ophthalmology David Geffen School of Medicine
Philadelphia, PA, USA University of Arizona University of California Los Angeles
Largo, FL, USA
Paul L. Kaufman, MD Associated Retina Consultants Los Angeles, CA, USA
Elliott M. Kanner, MD, PhD Ernst H. Bárány Professor of Ocular Phoenix, AZ, USA Associate Medical Director
Chief, Glaucoma Service Pharmacology Doheny Image Reading Center
Hamilton Eye Institute Douglas D. Koch, MD Doheny Eye Institute
Department Chair Emeritus Professor and Allen, Mosbacher, and
University of Tennessee Department of Ophthalmology & Los Angeles, CA, USA
Health Science Center Law Chair in Ophthalmology
Visual Sciences Cullen Eye Institute
Memphis, TN, USA University of Wisconsin-Madison Baylor College of Medicine
xviii School of Medicine & Public Health Houston, TX, USA
Madison, WI, USA
Paul P. Lee, MD, JD Pedro F. Lopez, MD Jodhbir S. Mehta, BSc, MD, MBBS, Majid Moshirfar, MD, FACS
F. Bruce Fralick Professor and Chair Professor and Founding Chair FRCS(Ed), FRCOphth, FAMS Professor of Ophthalmology

List of Contributors
Director W.K. Kellogg Eye Center Department of Ophthalmology Associate Professor, Cornea and Hoopes Vision and John A. Moran Eye
Department of Ophthalmology & Herbert Wertheim College of Medicine External Disease Center
Visual Sciences Florida International University Singapore National Eye Centre Draper, UT, USA
University of Michigan Director of Vitreoretina and Macular Singapore
Heather E. Moss, MD, PhD
Ann Arbor, MI, USA Division
Luis J. Mejico, MD Assistant Professor
Center for Excellence in Eye Care
Richard M.H. Lee, MSc, FRCOphth Professor and Chair of Neurology Departments of Ophthalmology and
Miami, FL, USA
Clinical Fellow Professor of Ophthalmology Neurology & Neurological Sciences
Department of Glaucoma Mats Lundström, MD, PhD SUNY Upstate Medical University Stanford University
Moorfields Eye Hospital Adjunct Professor Emeritus Syracuse, NY, USA Palo Alto, CA, USA
London, UK Department of Clinical Sciences,
Carolina L. Mercado, MD Mark L. Moster, MD
Ophthalmology
Dawn K.A. Lim, MBBS, MRCP, Clinical Research Fellow, Director, Neuro-Ophthalmology
Faculty of Medicine
MMed(Int, Med), MMed(Ophth), FAMS Ophthalmology Fellowship
Lund University
Consultant, Ophthalmology/Glaucoma Bascom Palmer Eye Institute Professor, Neurology and
Lund, Region Skåne, Sweden
National University Hospital Miami, FL, USA Ophthalmology
Singapore Robi N. Maamari, MD Wills Eye Hospital
Ophthalmology Resident Shahzad I. Mian, MD Sidney Kimmel Medical College of
Jennifer I. Lim, MD, FARVO Department of Ophthalmology & Associate Chair, Terry J. Bergstrom Thomas Jefferson University
Marion H. Schenk Esq. Chair in Visual Sciences Professor Philadelphia, PA, USA
Ophthalmology for Research of the Washington University School of Associate Professor, Ophthalmology &
Aging Eye Visual Sciences Kelly W. Muir, MD, MHSc
Medicine in St Louis
Professor of Ophthalmology University of Michigan Associate Professor of Ophthalmology,
St Louis, MO, USA
Director of the Retina Service Ann Arbor, MI, USA Glaucoma Division
University of Illinois at Chicago Assumpta Madu, MD, MBA, PharmD Duke University
Illinois Eye and Ear Infirmary Vice Chair, Operations William F. Mieler, MD, FACS School of Medicine
Chicago, IL, USA Associate Clinical Professor of Cless Family Professor of Durham, NC, USA
Ophthalmology Ophthalmology
Ridia Lim, MBBS, MPH, FRANZCO Vice-Chairman of Education Ann G. Neff, MD
NYU School of Medicine
Ophthalmic Surgeon Illinois Eye and Ear Infirmary Dermatology Associates
NYU Langone Medical Center
Glaucoma Service University of Illinois at Chicago Sarasota, FL, USA
New York, NY, USA
Sydney Eye Hospital College of Medicine Jeffrey A. Nerad, MD
Sydney, NSW, Australia Maya H. Maloney, MD Chicago, IL, USA Oculoplastic & Reconstructive Surgery
Consultant, Medical Retina
Tony K.Y. Lin, MD, FRCSC David Miller, MD Cincinnati Eye Institute
Mayo Clinic
Assistant Professor Associate Clinical Professor of Volunteer Professor, Ophthalmology
Rochester, MN, USA
Department of Ophthalmology Ophthalmology University of Cincinnati
Schulich School of Medicine and Naresh Mandava, MD Harvard Medical School Cincinnati, OH, USA
Dentistry Professor and Chair Boston, MA, USA Neda Nikpoor, MD
Western University Department of Ophthalmology
Clinical Instructor, Ophthalmology
London, ON, Canada University of Colorado Kyle E. Miller, MD
Byers Eye Institute
School of Medicine Assistant Professor, Ophthalmology
Stanford University
John T. Lind, MD, MS Denver, CO, USA Naval Medical Center Portsmouth
Palo Alto, CA, USA
Associate Professor Portsmouth, VA, USA
Michael F. Marmor, MD
Department of Ophthalmology & Robert J. Noecker, MD, MBA
Professor Tatsuya Mimura, MD, PhD
Visual Sciences Director of Glaucoma
Department of Ophthamology Tokyo Womens Medical University
Washington University in St Louis Ophthalmic Consultants of
Byers Eye Institute Medical Center East
St Louis, MO, USA Connecticut
Stanford University Tokyo, Japan
Fairfield, CT, USA
Yao Liu, MD School of Medicine
Assistant Professor Palo Alto, CA, USA Rukhsana G. Mirza, MD Ricardo Nosé, MD
Department of Ophthalmology & Associate Professor Clinical Research Fellow
Jeevan R. Mathura, Jr., MD Department of Ophthalmology
Visual Sciences New England Eye Center
Private Practitioner and Owner Northwestern University
University of Wisconsin-Madison Tufts Medical Center
Diabetic Eye and Macular Disease Feinberg School of Medicine
Madison, WI, USA Boston, MA, USA
Specialists, LLC Chicago, IL, USA
Sidath E. Liyanage, MBBS, FRCOphth, Washington, DC, USA Annabelle A. Okada, MD, DMSc
PhD Mihai Mititelu, MD, MPH Professor of Ophthalmology
Cynthia Mattox, MD Assistant Professor
Consultant Ophthalmologist Kyorin University
Associate Professor, Ophthalmology Department of Ophthalmology &
Bristol Eye Hospital School of Medicine
Tufts University Visual Sciences
Bristol, UK Tokyo, Japan
School of Medicine University of Wisconsin-Madison
Alastair J. Lockwood, BM, BCh, Boston, MA, USA School of Medicine and Public Health Michael O’Keefe, FRCS
FRCOphth, PhD Madison, WI, USA Professor, Ophthalmology
Scott K. McClatchey, MD
Consultant, Ophthalmology Mater Private Hospital
Associate Professor, Ophthalmology Ramana S. Moorthy, MD
Queen Alexandra Hospital Dublin, Ireland
Naval Medical Center Clinical Associate Professor,
Portsmouth, Hampshire, UK San Diego, CA, USA Jeffrey L. Olson, MD
Ophthalmology
Nils A. Loewen, MD, PhD Indiana University Associate Professor
Stephen D. McLeod, MD
Associate Professor of Ophthalmology School of Medicine Department of Ophthalmology
Theresa M. and Wayne M. Caygill
Vice Chair of Electronic Health Founding Partner and CEO University of Colorado
Distinguished Professor and Chair,
Records in Ophthalmology Associated Vitreoretinal and Uveitis School of Medicine
Ophthalmology
University of Pittsburgh Consultants Denver, CO, USA
University of California San Francisco
Pittsburgh, PA, USA San Francisco, CA, USA Indianapolis, IN, USA Jane M. Olver, MB, BS, BSc, FRCS,
Reid A. Longmuir, MD Andrew A. Moshfeghi, MD, MBA FRCOphth
Brian D. McMillan, MD
Assistant Professor Director, Vitreoretinal Fellowship Consultant Ophthalmologist
Assistant Professor of Ophthalmology
Department of Ophthalmology & Associate Professor of Clinical Eye Department
WVU Eye Institute
Visual Sciences Ophthalmology Clinica London
West Virginia University
Vanderbilt University University of Southern California London, UK
School of Medicine
Nashville, TN, USA Morgantown, WV, USA Roski Eye Institute Yvonne A.V. Opalinski, BSc, MD, BFA,
Keck School of Medicine MFA
Alan A. McNab, DMedSc, FRANZCO, Los Angeles, CA, USA Clinical Associate Cardiovascular
FRCOphth
Surgery
Associate Professor and Director
Department of Cardiovascular Surgery
Orbital Plastic and Lacrimal Clinic
Royal Victorian Eye and Ear Hospital Trillium Health Partners xix
Toronto, ON, Canada
Melbourne, VIC, Australia
Faruk H. Örge, MD Alfio P. Piva, MD P. Kumar Rao, MD Damien C. Rodger, MD, PhD
William R. and Margaret E. Althans Professor of Neurosurgery and Professor of Ophthalmology and Visual Assistant Professor of Clinical
List of Contributors
Chair and Professor Ophthalmology Science Ophthalmology
Director, Center for Pediatric University of Costa Rica Washington University Research Assistant Professor of
Ophthalmology and Adult San Jose, Costa Rica St Louis, MO, USA Biomedical Engineering
Strabismus USC Roski Eye Institute and Viterbi
Rainbow Babies, Children’s Hospital, Dominik W. Podbielski, HonBSc, MSc, Rajesh C. Rao, MD School of Engineering
UH Eye Institute MD, FRCSC Leslie H. and Abigail S. Wexner University of Southern California
Cleveland Medical Center Staff Physician, Ophthalmology Emerging Scholar Los Angeles, CA, USA
Cleveland, OH, USA Prism Eye Institute Assistant Professor, Retina Service
North Toronto Eye Care Department of Ophthalmology & Miin Roh, MD, PhD
Mark Packer, MD, FACS, CPI Toronto, ON, Canada Visual Sciences Vitreoretina Surgery Clinical Fellow
President W.K. Kellogg Eye Center Department of Ophthalmology/Retina
Mark Packer MD Consulting, Inc. Nicolas J. Pondelis, BA University of Michigan Service
Boulder, CO, USA Ophthalmic Photographer and VA Ann Arbor Health System Massachusetts Eye and Ear
Research Assistant Ann Arbor, MI, USA Boston, MA, USA
Suresh K. Pandey, MD Tufts Medical Center
Director, Ophthalmology Boston, MA, USA Sivakumar Rathinam, FAMS, PhD Shiyoung Roh, MD
SuVi Eye Institute and Lasik Laser Professor of Ophthalmology Associate Clinical Professor
Center Francis W. Price, Jr., MD Head of Uveitis Service Tufts University
Kota, Rajasthan, India President Aravind Eye Hospital School of Medicine
Visiting Assistant Professor Price Vision Group Post Graduate Institute of Vice-Chair Division of Ophthalmology
John A. Moran Eye Center Indianapolis, IN, USA Ophthalmology Vice-Chair Department of Surgery
University of Utah Marianne O. Price, PhD, MBA Madurai, Tamil Nadu, India Lahey Hospital and Medical Center
Salt Lake City, UT, USA Executive Director Peabody, MA, USA
Russell W. Read, MD, PhD
Vishal S. Parikh, MD Cornea Research Foundation of Max and Lorayne Cooper Endowed Noel Rosado-Adames, MD
Vitreoretinal Surgery Fellow, Retina America Professor in Ophthalmology Cornea and External Disease Specialist
Service Indianapolis, IN, USA Residency Training Private Practitioner
The Retina Institute Cindy Pritchard, CO University of Alabama at Birmingham OMNI Eye Specialists
St Louis, MO, USA Orthoptist Birmingham, AL, USA Baltimore, MD, USA
Louis R. Pasquale, MD, FARVO Clinical Instructor of Ophthalmology Caio Vinicius Saito Regatieri, MD, PhD Emanuel S. Rosen, MD, FRCS,
Professor of Ophthalmology Children’s Hospital of New Orleans Professor, Ohalmology FRCOphth
Harvard Medical School Tulane University Tufts Medical School Professor
Boston, MA, USA Department of Ophthalmology Boston, MA, USA Department of Vision Sciences
New Orleans, LA, USA Federal University of São Paulo University of Manchester
Sarju S. Patel, MD, MPH, MSc São Paulo, Brazil Manchester, UK
Director of Uveitis Peter A. Quiros, MD
Department of Ophthalmology Associate Professor, Ophthalmology Carl D. Regillo, MD Jonathan B. Rubenstein, MD
Weill Cornell College of Medicine University of California Los Angeles Director Retina Service Deutsch Family Endowed Chair in
New York City, NY, USA Los Angeles, CA, USA Professor of Ophthalmology Ophthalmology
Aleksandra V. Rachitskaya, MD Wills Eye Hospital Retina Service Vice-Chairman of the Department of
Vivek R. Patel, MD Thomas Jefferson University Ophthalmology
Associate Professor, Ophthalmology Assistant Professor of Ophthalmology,
Cleveland Clinic Lerner College of Philadelphia, PA, USA Rush University Medical Center
USC Roski Eye Institute Chicago, IL, USA
Keck School of Medicine Medicine of Case Western Reserve Elias Reichel, MD
Los Angeles, CA, USA University Professor and Vice Chair Richard M. Rubin, MD, LT, COL, USAF,
Vitreoretinal Staff Physician New England Eye Center MC, SFS
Carlos E. Pavesio, MD Cole Eye Institute Tufts University Neuro-Ophthalmologist and Senior
Consultant Ophthalmic Surgeon Cleveland Clinic School of Medicine Flight Surgeon
Medical Retina Cleveland, OH, USA Boston, MA, USA Departments of Ophthalmology and
Moorfields Eye Hospital Aerospace Medicine
London, UK Pradeep Y. Ramulu, MD, MHS, PhD Douglas J. Rhee, MD
Associate Professor of Ophthalmology David Grant USAF Medical Center
Chairman Travis AFB, CA, USA
Victor L. Perez, MD Chief, Glaucoma Division Department of Ophthalmology and
Professor of Ophthalmology Wilmer Eye Institute Visual Sciences Steven E. Rubin, MD
Stephen and Frances Foster Professor Johns Hopkins School of Medicine University Hospitals Case Medical Vice Chair, Residency Program
of Ophthalmology Baltimore, MD, USA Center Director and Co-Chief, Pediatric
Duke University School of Medicine Case Western Reserve University Ophthalmology
Director, Duke Center for Ocular J. Bradley Randleman, MD
Editor-in-Chief School of Medicine Hofstra North Shore–Long Island
Immunology Cleveland, OH, USA Jewish School of Medicine
Durham, NC, USA Journal of Refractive Surgery
Professor of Ophthalmology Great Neck, NY, USA
Alexander L. Ringeisen, MD
Claudia E. Perez-Straziota, MD Director, Cornea & Refractive Surgery Vitreoretinal Surgery Fellow Patrick E. Rubsamen, MD
Clinical Assistant Professor of USC Roski Eye Institute VitreoRetinal Surgery, PA Physician, Vitreoretinal Surgery
Ophthalmology Keck School of Medicine of USC Minneapolis, MN, USA Retina Group of Florida
Roski Eye Institute Los Angeles, CA, USA Boca Raton, FL, USA
University of Southern California Robert Ritch, MD, FACS
Private Practitioner Narsing A. Rao, MD Shelley and Steven Einhorn Jason D. Rupp, MD
Los Angeles, CA, USA Professor of Ophthalmology and Distinguished Chair Ophthalmology Specialist
Pathology Professor of Ophthalmology Department of Ophthalmology and
Lauren T. Phillips, MD Chief of Uveitis Service and New York Eye and Ear Infirmary of Visual Sciences
Assistant Professor, Neurology & Ophthalmic Pathology Laboratory Mount Sinai Washington University
Neurotherapeutics USC Roski Eye Institute New York, NY, USA School of Medicine
University of Texas Keck School of Medicine St Louis, MO, USA
Southwestern Medical Center University of Southern California Shira L. Robbins, MD
Dallas, TX, USA Los Angeles, CA, USA Clinical Professor of Ophthalmology Hossein G. Saadati, MD
Director of Neonatal Ophthalmology Oculofacial/Reconstructive Surgeon,
Jody R. Piltz-Seymour, MD Naveen K. Rao, MD Division of Pediatric Ophthalmology Ophthalmology
Adjunct Professor, Ophthalmology Cornea, Cataract, and Anterior and Strabismus Kaiser Permanente Medical Offices
Perelman School of Medicine Segment Surgery Ratner Children’s Eye Center at the Stockton, CA, USA
University of Pennsylvania Lahey Hospital and Medical Center Shiley Eye Institute
Glaucoma Care Center at Valley Eye Burlington, MA, USA La Jolla, CA, USA Alfredo A. Sadun, MD, PhD
Professionals, LLC Assistant Professor of Ophthalmology Flora Thornton Chair, Doheny
Glaucoma Service, Wills Eye Hospital Tufts University Professor of Ophthalmology
Philadelphia, PA, USA School of Medicine Vice-Chair of Ophthalmology, UCLA
Boston, MA, USA Los Angeles, CA, USA
xx
Osamah J. Saeedi, MD Hermann D. Schubert, MD Roni M. Shtein, MD, MS Sunil K. Srivastava, MD
Associate Professor Professor of Clinical Ophthalmology Associate Professor Staff Physician

List of Contributors
Director of Clinical Research and Pathology Department of Ophthalmology & Cleveland Clinic
Associate Residency Program Director E.S. Harkness Eye Institute Visual Sciences Cole Eye Institute
Department of Ophthalmology & Columbia University University of Michigan Cleveland, OH, USA
Visual Sciences New York, NY, USA Ann Arbor, MI, USA
University of Maryland Brian C. Stagg, MD
Joel S. Schuman, MD Ryan W. Shultz, MD Clinical Lecturer
School of Medicine
Professor and Chairman of Ophthalmologist, Vitreoretinal Department of Ophthalmology &
Baltimore, MD, USA
Ophthalmology Diseases Visual Sciences
Daniel J. Salchow, MD Director, NYU Eye Center Colorado Permanente Medical Group University of Michigan
Professor of Ophthalmology Professor of Neuroscience and Denver, CO, USA Ann Arbor, MI, USA
Section of Pediatric Ophthalmology, Physiology
Patricia B. Sierra, MD David H.W. Steel, MBBS, FRCOphth
Strabismus and Neuro- Neuroscience Institute
Sacramento Eye Consultants Consultant Ophthalmologist and
ophthalmology NYU School of Medicine
Sacramento, CA, USA Vitreoretinal Surgeon
Department of Ophthalmology Professor of Electrical and Computer
Charité – University Medicine Berlin Engineering Brent Siesky, PhD Sunderland Eye Infirmary
Berlin, Germany NYU Tandon School of Engineering Assistant Director, Research Associate City Hospitals Sunderland NHS
Professor of Neural Engineering Ophthalmology, Glaucoma Research Foundation Trust
Sarwat Salim, MD, FACS Center for Neural Science, NYU and Diagnostic Center Sunderland, Tyne & Wear, UK
Professor of Ophthalmology New York, NY, USA Eugene and Marilyn Glick Eye Institute
Eye Institute Joshua D. Stein, MD, MS
Indiana University Associate Professor, Ophthalmology &
Medical College of Wisconsin Gary S. Schwartz, MD, MHA School of Medicine
Milwaukee, WI, USA Adjunct Associate Professor Visual Sciences
Indianapolis, IN, USA Associate Professor, Health
Department of Ophthalmology
Thomas W. Samuelson, MD University of Minnesota Paul A. Sieving, MD, PhD Management & Policy
Attending Surgeon School of Medicine Associated Eye Director University of Michigan
Glaucoma and Anterior Segment Care National Eye Institute Ann Arbor, MI, USA
Surgery Stillwater, MN, USA National Institutes of Health
Minnesota Eye Consultants, PA Mitchell B. Strominger, MD
Bethesda, MD, USA Professor of Ophthalmology and
Adjunct Associate Professor J. Sebag, MD, FACS, FRCOphth, FARVO
Department of Ophthalmology Founding Director Dimitra Skondra, MD, PhD Pediatrics
University of Minnesota VMR Institute for Vitreous Macula Assistant Professor of Ophthalmology Tufts Medical Center
Minneapolis, MN, USA Retina and Visual Science Boston, MA, USA
Huntington Beach, CA, USA Director, J. Terry Ernest Ocular Alan Sugar, MD
Simrenjeet Sandhu, MD Imaging Center
Ophthalmology Resident Dov B. Sebrow, MD Professor and Vice-Chair,
The University of Chicago Ophthalmology & Visual Sciences
University of Alberta Senior Vitreoretinal Surgical Fellow, Chicago, IL, USA
Edmonton, AL, Canada Ophthalmology/Vitreoretinal Kellogg Eye Center
Diseases Kent W. Small, MD University of Michigan
Marcony R. Santhiago, MD, PhD Edward S. Harkness Eye Institute President/Founder, Vitreo-Retinal Ann Arbor, MI, USA
Adjunct Professor of Ophthalmology Columbia University Medical Center Surgery
Refractive Surgery Department Joel Sugar, MD
Vitreous Retina Macula Consultants of Molecular Insight Research Foundation
University of Southern California Professor and Vice Head,
New York Glendale, CA, USA
Los Angeles, CA, USA Ophthalmology & Visual Sciences
Manhattan Eye, Ear and Throat William E. Smiddy, MD University of Illinois Eye and Ear
Professor of Ophthalmology Hospital
Refractive Surgery Department Professor, Ophthalmology Infirmary
New York, NY, USA Bascom Palmer Eye Institute Chicago, IL, USA
University of São Paulo
São Paulo, SP, Brazil H. Nida Sen, MD, MHS University of Miami
Yevgeniy V. Sychev, MD
Director, Uveitis Felowship Program Miller School of Medicine
Giacomo Savini, MD Senior Clinical Fellow
National Eye Institute Miami, FL, USA
Researcher Ophthalmology/Vitreoretinal Disease
National Institutes of Health Marie Somogyi, MD and Surgery
G.B. Bietti Foundation Bethesda, MD, USA
Rome, Italy Oculoplastic and Orbital Surgery Washington University
Gaurav K. Shah, MD TOC Eye and Face School of Medicine in St Louis
Ibrahim O. Sayed-Ahmed, MD Professor of Clinical Ophthalmology & Austin, TX, USA St Louis, MO, USA
Research Fellow Visual Sciences
Graduate Student in Vision Science H. Kaz Soong, MD Tak Yee Tania Tai, MD
The Retina Institute Chief of Cornea and Refractive Service Assistant Professor, Ophthalmology
and Investigative Ophthalmology Washington University
Bascom Palmer Eye Institute Co-Director of International New York Eye and Ear Infirmary of
School of Medicine Ophthalmology Mount Sinai
Miami, FL, USA St Louis, MO, USA Department of Ophthalmology & New York, NY, USA
Amy C. Scheffler, MD Carol L. Shields, MD Visual Sciences
Assistant Professor of Clinical University of Michigan James C. Tan, MD, PhD
Director, Ocular Oncology Service Associate Professor, Department of
Ophthalmology Wills Eye Hospital Ann Arbor, MI, USA
Assistant Clinical Member, Research Ophthalmology
Professor of Ophthalmology Sarkis H. Soukiasian, MD Doheny Eye Institute
Institute Thomas Jefferson University Director, Cornea and External Diseases University of California Los Angeles
Weill Cornell Medical College Philadelphia, PA, USA Director, Ocular Inflammation and Los Angeles, CA, USA
Houston Methodist Hospital Medical
Uveitis
Center Yevgeniy (Eugene) Shildkrot, MD Myron Tanenbaum, MD
Lahey Health Systems
Retina Consultants of Houston Associate Professor of Ophthalmology Voluntary Professor
Burlington, MA, USA
Houston, TX, USA Ocular Oncology and Vitreoretinal Department of Ophthalmology
Diseases and Surgery Richard F. Spaide, MD Bascom Palmer Eye Institute
Paulo Schor, MD, MSci, DSci University of Virginia Vitreous, Retina, Macula Consultants
Director of Research and Technological University of Miami
Charlottesville, VA, USA of New York Miller School of Medicine
Development New York, NY, USA
Professor of Ophthalmology Bradford J. Shingleton, MD Miami, FL, USA
Department of Ophthalmology & Clinical Associate Professor, Tatyana Spektor, MD Suphi Taneri, MD
Visual Sciences Ophthalmology Cornea and Refractive Surgery Fellow Director, Center for Refractive Surgery,
Escola Paulista de Medicina (EPM) – Harvard Medical School Department of Ophthalmology Eye Department
Universidade Federal de São Paulo Partner, Ophthalmic Consultants Baylor College of Medicine St. Francis Hospital
(UNIFESP) of Boston Houston, TX, USA Associate Professor, Eye Clinic
São Paulo, Brazil Boston, MA, USA Ruhr University Bochum
Thomas C. Spoor, MD, FACS
Private Practitioner Munster, NRW, Germany
Neuro-Ophthalmology and Oculo-
Plastic Surgery
Sarasota Retina Institute xxi
Sarasota, FL, USA
William Tasman, MD† Julie H. Tsai, MD Brian D. Walker, BS Matthew T. Witmer, MD
Formerly Professor and Emeritus Assistant Professor of Clinical Medical Student Partner Physician, Vitreoretinal Surgery
List of Contributors
Chairman Ophthalmology McGovern Medical School Retina Associates of Western New York
Department of Ophthalmology Albany, NY, USA Houston, TX, USA Rochester, NY, USA
Wills Eye Hospital and Jefferson Clinical Instructor
Medical College Nancy Tucker, MD, FRCSC David S. Walton, MD University of Rochester Medical Center
Philadelphia, PA, USA Chief of Oculoplastics, Ophthalmology President, Children’s Glaucoma Rochester, NY, USA
University of Toronto Foundation
David G. Telander, MD, PhD Toronto, ON, Canada Clinical Professor of Ophthalmology Gadi Wollstein, MD
Clinical Professor Harvard Medical School Professor of Ophthalmology
Department of Ophthalmology Sonal S. Tuli, MD, MEd Surgeon in Ophthalmology Vice Chairman for Clinical Research
University of California Davis Professor and Chair, Ophthalmology Massachusetts Eye and Ear Infirmary Director of Ophthalmic Imaging
Davis, CA, USA University of Florida Boston, MA, USA Research Laboratory
Associate Professor Gainesville, FL, USA Director of Research Education
California Northstate Li Wang, MD, PhD NYU School of Medicine
Caroline W. Vargason, MD, PhD Associate Professor, Ophthalmology
School of Medicine Oculoplastic & Reconstructive Surgery New York, NY, USA
Sacramento, CA, USA Baylor College of Medicine
Fellow Houston, TX, USA Maria A. Woodward, MD, MS
Edmond H. Thall, MD, MS Cincinnati Eye Institute Assistant Professor of Ophthalmology
Consultant in Aerospace Cincinnati, OH, USA Michelle Y. Wang, MD & Visual Sciences
Ophthalmology Associate Physician University of Michigan
Roshni A. Vasaiwala, MD Department of Ophthalmology/
Aeromedical Consultation Service Assistant Professor of Ophthalmology Ann Arbor, MI, USA
Ophthalmology Branch Neuro-Ophthalmology
Director of Cornea Service Southern California Permanente Nicholas K. Wride, MB, ChB, FRCOphth
United States Air Force School of Loyola University Medical Center
Aerospace Medicine Medical Group Consultant Ophthalmologist
Maywood, IL, USA Los Angeles, CA, USA Sunderland Eye Infirmary
Wright–Patterson Air Force Base
Dayton, OH, USA Daniel Vitor Vasconcelos-Santos, MD, City Hospitals Sunderland
Robert C. Wang, MD Sunderland, Tyne & Wear, UK
PhD Partner
Aristomenis Thanos, MD Adjunct Professor of Ophthalmology
Retina Department Texas Retina Assoc Albert Wu, MD, PhD
Director of Uveitis Clinical Associate Professor of Associate Professor of Ophthalmology
Devers Eye Institute Universidade Federal de Minas Gerais
Portland, OR, USA Ophthalmology Icahn School of Medicine at Mount
Belo Horizonte, Minas Gerais, Brazil UT Southwestern Sinai
Christos N. Theophanous, MD Gregory J. Vaughn, MD Dallas, TX, USA New York, NY, USA
Resident Physician Consultant, Global Healthcare Practice
Department of Ophthalmology and Martin Wax, MD David Xu, MD
Spencer Stuart Chief Medical Officer and Executive Resident Physician
Visual Science Atlanta, GA, USA
University of Chicago Medicine Vice-President R&D Stein Eye Institute
Chicago, IL, USA Arthi Venkat, MD, MS, BA PanOptica, Inc. University of California Los Angeles
Staff Physician in Medical Retina and Bernardsville, NJ, USA Los Angeles, CA, USA
Benjamin J. Thomas, MD Uveitis
Physician, Vitreoretinal Surgery Joel M. Weinstein, MD Joshua A. Young, MD
Cleveland Clinic Professor of Ophthalmology and Clinical Professor
Florida Retina Institute Cole Eye Institute
Jacksonville, FL, USA Pediatrics Department of Ophthalmology
Cleveland, OH, USA Penn State University M.S. Hershey New York University
Praneetha Thulasi, MD Guadalupe Villarreal, Jr., MD Medical Center School of Medicine
Assistant Professor of Ophthalmology Attending Hershey, PA, USA Chief Ophthalmologist Correspondent
Cornea, External Diseases, and Department of Ophthalmology EyeWorld Magazine
Refractive Surgery John J. Weiter, MD, PhD Producer and Manager of Podcasting
Mid-Atlantic Permanente Medical Associate Professor of Ophthalmology
Emory University Group American Society of Cataract and
Atlanta, GA, USA Harvard Medical School Refractive Surgery
Falls Church, VA, USA Boston, MA, USA New York, NY, USA
Michael D. Tibbetts, MD Kateki Vinod, MD
Director of Retina Services Liliana Werner, MD, PhD Edward S. Yung, MD
Assistant Professor of Ophthalmology Professor of Ophthalmology & Visual
Tyson Eye Center New York Eye and Ear Infirmary of Clinical Instructor, Glaucoma
Cape Coral, FL, USA Sciences Wills Eye Hospital
Mount Sinai Co-Director Intermountain Ocular
Icahn School of Medicine at Mount Philadelphia, PA, USA
David P. Tingey, BA, MD, FRCSC Research Center
Associate Professor, Ophthalmology Sinai University of Utah Cynthia Yu-Wai-Man, PhD, FRCOphth
Western University New York, NY, USA John A. Moran Eye Center Postdoctoral Research Fellow
London, ON, Canada Jesse M. Vislisel, MD Salt Lake City, UT, USA Rescue, Repair and Regeneration
Staff Physician, Cornea & External UCL Institute of Ophthalmology
Faisal M. Tobaigy, MD Mark Wevill, MBChB, FRCSE, FCS(SA) London, UK
Associate Professor of Ophthalmology Disease Consultant Ophthalmologist
Jazan University Associated Eye Care Optegra Birmingham Eye Hospital Wadih M. Zein, MD
Jazan, Saudi Arabia Stillwater, MN, USA Birmingham, West Midlands, UK Staff Clinician
Ivan Vrcek, MD Ophthalmic Genetics and Visual
Bozho Todorich, MD, PhD Janey L. Wiggs, MD, PhD Function Branch
Staff Physician Partner, Texas Ophthalmic Plastic, Paul Austin Chandler Professor of
Reconstructive, and Orbit Surgery National Eye Institute, NIH
Pennsylvania Retina Specialists, PC Ophthalmology Bethesda, MD, USA
Camp Hill, PA, USA President, Ivan Vrcek, M.D. PA Harvard Medical School
Associate Adjunct Professor of Boston, MA, USA Ivy Zhu, MD
Stuart W. Tompson, PhD Ophthalmology and Oculoplastic Resident Physician
Associate Scientist Surgery, Texas A&M Medical School, Andrew M. Williams, MD Department of Ophthalmology &
Department of Ophthalmology & Dallas Campus Resident Visual Sciences
Visual Sciences Clinical Assistant Professor of Department of Ophthalmology Illinois Eye and Ear Infirmary
University of Wisconsin-Madison Ophthalmology and Oculoplastic University of Pittsburgh University of Illinois at Chicago
Madison, WI, USA Surgery, UT Southwestern Medical School of Medicine College of Medicine
Center Pittsburgh, PA, USA Chicago, IL, USA
James C. Tsai, MD, MBA Dallas, TX, USA
President, New York Eye & Ear George A. Williams, MD
Infirmary of Mount Sinai, Delafield- Hormuz P. Wadia, MD Chair, Department of Ophthalmology
Rodgers Professor and System Chair Assistant Clinical Professor Oakland University
Department of Ophthalmology Department of Ophthalmology William Beaumont School of Medicine
Icahn School of Medicine at Mount James A. Haley VAMC Royal Oak, MI, USA
Sinai Morsani School of Medicine
New York, NY, USA University of South Florida Eye
Institute
xxii †
Tampa, FL, USA
Deceased
Acknowledgments

Acknowledgments
We are grateful to the editors and authors who have contributed to
Ophthalmology and to the superb, dedicated Ophthalmology team at Else-
vier. We especially would like to thank Sharon Nash and Russell Gabbedy
for their tireless efforts in keeping us on track and making our job
much easier. We would also like to thank Josh Mearns, Content Coordi-
nator; Joanna Souch, Project Manager; Brian Salisbury, Designer; Karen
Giacomucci, Illustration Manager; Richard Tibbitts, Illustrator; Vinod
Kothaparamtath, Multimedia Producer; and Claire McKenzie, Marketing
Manager.
Dedication

Dedication
We would like to dedicate this book to our wives, Karin Yanoff and Julie
Starr-Duker, and to our children—Steven, David, and Alexis Leyva-Yanoff;
Joanne Grune-Yanoff; and Jake, Claire, Bear, Becca, Sam, Colette, and Elly
Duker—all of whom play such an important part in our lives and without
whose help and understanding we would have never come this far.

xxiii
Part 1 Genetics


Fundamentals of Human Genetics


Janey L. Wiggs 1.1
Definition: The central principles of human genetics with relevance to HUMAN GENOME
eye disease. Human DNA is packaged as chromosomes located in the nuclei of cells.
Chromosomes are composed of individual strands of DNA wound about
proteins called histones. The complex winding and coiling process culmi-
nates in the formation of a chromosome. The entire collection of human
chromosomes includes 22 paired autosomes and two sex chromosomes.
Women have two copies of the X chromosome, and men have one X and
Key Features one Y chromosome (Fig. 1.1.3).
• Gene structure and expression. The set consisting of one of each autosome as well as both sex chro-
• Organization and inheritance of the human genome. mosomes is called the human genome. The chromosomal molecules of
• Mutations and clinical phenotypes. DNA from one human genome, if arranged in tandem end to end, contain
• Gene-based therapies. approximately 3.2 billion base pairs (bp). The Human Genome Project was
formally begun in 1990 with the defined goals to: identify all the approxi-
mately 20,000–25,000 genes in human DNA; determine the sequences of
the 3 billion chemical base pairs that make up human DNA; store this
information in publicly available databases; improve tools for data anal-
DNA AND THE CENTRAL DOGMA OF ysis; transfer related technologies to the private sector; and address the
HUMAN GENETICS
The regulation of cellular growth and function in all human tissue is depen-
dent on the activities of specific protein molecules. In turn, protein activity
STRUCTURE OF THE DNA DOUBLE HELIX
is dependent on the expression of the genes that contain the correct DNA
sequence for protein synthesis. The DNA molecule is a double-stranded
helix. Each strand is composed of a sequence of four nucleotide bases— Sugar–phosphate backbone Separation of individual
adenine (A), guanine (G), cytosine (C), and thymine (T)—joined to a sugar and nitrogenous bases strands allows DNA replication
and a phosphate. The order of the bases in the DNA sequence forms the
genetic code that directs the expression of genes. The double-stranded helix
sugar–
is formed as a result of hydrogen bonding between the nucleotide bases of
phosphate
opposite strands.1 The bonding is specific, such that A always pairs with backbone
T, and G always pairs with C. The specificity of the hydrogen bonding is
one helical turn = 3.4 nm

the molecular basis of the accurate copying of the DNA sequence that is
required during the processes of DNA replication (necessary for cell divi-
sion) and transcription of DNA into RNA (necessary for gene expression
and protein synthesis; Fig. 1.1.1).
Gene expression begins with the recognition of a particular DNA
sequence called the promoter sequence as the start site for RNA synthe-
sis by the enzyme RNA polymerase. The RNA polymerase “reads” the
DNA sequence and assembles a strand of RNA that is complementary
to the DNA sequence. RNA is a single-stranded nucleic acid composed
of the same nucleotide bases as DNA, except that uracil takes the place
of thymine. Human genes (and genes found in other eukaryotic organ-
bases
isms) contain many DNA sequences that are not translated into polypep-
tides and proteins. These sequences are called intervening sequences or
introns. Introns do not have any known specific function, and although
they are transcribed into RNA by RNA polymerase, they are spliced out of
the initial RNA product (termed heteronuclear RNA, or hnRNA) to form
the completed messenger RNA (mRNA). Untranslated RNA may have spe-
cific functions. For example, antisense RNA and micro RNAs (miRNA) 5l 3l 5l 3l
appear to regulate expression of genes.2 The mRNA is the template for original
new chains
original
protein synthesis. Proteins consist of one or more polypeptide chains, chain chain
forming
which are sequences of specific amino acids. The sequence of bases in
the mRNA directs the order of amino acids that make up the polypeptide adenine thymine guanine cytosine
chain. Individual amino acids are encoded by units of three mRNA bases,
termed codons. Transfer RNA (tRNA) molecules bind specific amino acids
Fig. 1.1.1 Structure of the DNA Double Helix. The sugar–phosphate backbone
and recognize the corresponding three-base codon in the mRNA. Cellular and nitrogenous bases of each individual strand are arranged as shown. The two
organelles called ribosomes bind the mRNA in such a configuration that strands of DNA pair by hydrogen bonding between the appropriate bases to form
the RNA sequence is accessible to tRNA molecules and the amino acids the double-helical structure. Separation of individual strands of the DNA molecule
are aligned to form the polypeptide. The polypeptide chain may be pro- allows DNA replication, catalyzed by DNA polymerase. As the new complementary
cessed by a number of other chemical reactions to form the mature protein strands of DNA are synthesized, hydrogen bonds are formed between the 1
(Fig. 1.1.2). appropriate nitrogenous bases.
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1 CENTRAL DOGMA OF MOLECULAR GENETICS

nucleus
PACKAGING OF DNA INTO CHROMOSOMES

DNA double helix


Genetics

cytoplasm chromosome

DNA
transcription

primary
mRNA
processing
mature Nucleosome
mRNA
histone
nucleosome

translation DNA
nuclear nuclear
pore envelope
200 bp of DNA
plasma
membrane protein

Solenoid
exon intron intron spliced out

Fig. 1.1.2 The Central Dogma of Molecular Genetics. Transcription of DNA into
RNA occurs in the nucleus of the cell, catalyzed by the enzyme RNA polymerase.
Mature mRNA is transported to the cytoplasm, where translation of the code
produces amino acids linked to form a polypeptide chain, and ultimately a mature
protein is produced.

Chromosome

ethical, legal, and social issues that may arise from the project. One of chromatin loop
the most important goals, the complete sequence of the human genome, contains approximately
100, 000 bp of DNA
was completed in draft form in 2001.3 Catalogs of variation in the human
genome sequence have also been completed, with the microsatellite repeat
map in 1994,4 the release of the HapMap from the International HapMap
Consortium in 2004,5 and more recently a catalog of variants from the 1000
genomes project.6 dbSNP (https://www.ncbi.nlm.nih.gov/projects/SNP/)
is a database listing single nucleotide polymorphisms (SNPs) that are
single-letter variations in a DNA base sequence. SNPs are bound together chromatin
strand chromatid
to form haplotypes, which are blocks of SNPs that are commonly inherited
together. This binding occurs through the phenomenon of linkage disequi-
librium. Within a haplotype block, which may extend for 10,000–100,000
bases of DNA, the analysis of only a subset of all SNPs may “tag” the entire Fig. 1.1.3 The Packaging of DNA Into Chromosomes. Strands of DNA are wound
haplotype. The International HapMap project has performed an initial tightly around proteins called histones. The DNA–histone complex becomes further
characterization of the linkage disequilibrium patterns between SNPs in coiled to form a nucleosome, which in turn coils to form a solenoid. Solenoids then
multiple different populations. The SNP haplotype blocks identified can form complexes with additional proteins to become the chromatin that ultimately
be examined for association with human disease, especially common dis- forms the chromosome.
orders with complex inheritance. Knowledge about the effects of DNA
variations among individuals can lead to new ways to diagnose, treat,
and prevent human disease. This approach has been used successfully to between chromosomes by recombination (Fig. 1.1.5). The homologous
identify the risk loci for age-related macular degeneration,7–9 myopia,10,11 chromosome pairs line up on the microtubule spindle and divide such
primary open-angle glaucoma,12–14 and Fuchs’ endothelial dystrophy.15 that the maternal and paternal copies of the doubled chromosomes are
distributed to separate daughter cells. A second cell division occurs, and
Mitosis and Meiosis the doubled chromosomes divide, which results in daughter cells that have
half the genetic material of somatic (tissue) cells.
In order for cells to divide, the entire DNA sequence must be copied so
that each daughter cell can receive a complete complement of DNA. The
growth phase of the cell cycle terminates with the separation of the two
BASIC MENDELIAN PRINCIPLES
sister chromatids of each chromosome, and the cell divides during mitosis. Two important rules central to human genetics emerged from the work of
Before cell division, the complete DNA sequence is copied by the enzyme Gregor Mendel, a nineteenth century Austrian monk. The first is the prin-
DNA polymerase in a process called DNA replication. DNA polymerase is ciple of segregation, which states that genes exist in pairs and that only one
an enzyme capable of the synthesis of new strands of DNA using the exact member of each pair is transmitted to the offspring of a mating couple.
sequence of the original DNA as a template. Once the DNA is copied, the The principle of segregation describes the behavior of chromosomes in
old and new copies of the chromosomes form their respective pairs, and meiosis. Mendel’s second rule is the law of independent assortment, which
the cell divides such that one copy of each chromosome pair belongs to states that genes at different loci are transmitted independently. This work
each cell (Fig. 1.1.4). Mitotic cell division produces a daughter cell that is also demonstrated the concepts of dominant and recessive traits. Mendel
an exact replica of the dividing cell. found that certain traits were dominant and could mask the presence of a
Meiotic cell division is a special type of cell division that results in a recessive gene.
reduction of the genetic material in the daughter cells, which become At the same time that Mendel observed that most traits segregate
the reproductive cells—eggs (women) and sperm (men). Meiosis begins independently, according to the law of independent assortment, he unex-
2 with DNA replication, followed by a pairing of the maternal and paternal pectedly found that some traits frequently segregate together. The phys-
chromosomes (homologous pairing) and an exchange of genetic material ical arrangement of genes in a linear array along a chromosome is the
MITOTIC CELL CYCLE MEIOTIC CELL CYCLE
1.1
Interphase

Fundamentals of Human Genetics


centrioles plasma membrane Metaphase I
nucleus cytoplasm
nucleolus
nuclear envelope

chiasmata

Daughter Anaphase I
cells Prophase
primary oocyte
bipolar primary spermatocyte
spindle
fiber

Prophase I
Telophase I
secondary oocyte
Telophase Prometaphase secondary spermatocyte
microtubule
spindle pole
Metaphase II
centromere
chromatid

Anaphase Metaphase Anaphase II

large egg and


polar bodies
spermatids of
equatorial equal size Haploid gametes
plane (meta-
phase plate)

Fig. 1.1.5 The Meiotic Cell Cycle. During meiosis, the DNA of a diploid cell is
Fig. 1.1.4 The Mitotic Cell Cycle. During mitosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides twice
replicated, which results in the formation of a tetraploid cell that divides to form to form four haploid cells (gametes). As a consequence of the crossing over and
two identical diploid daughter cells. recombination events that occur during the pairing of homologous chromosomes
before the first division, the four haploid cells may contain different segments of
the original parental chromosomes. For brevity, prophase II and telophase II are not
explanation for this surprising observation. On average, a recombination shown.
event occurs once or twice between two paired homologous chromosomes
during meiosis (Fig. 1.1.6). Most observable traits, by chance, are located
far away from one another on a chromosome, such that recombination is GENETIC RECOMBINATION BY CROSSING OVER
likely to occur between them, or they are located on entirely different chro-
mosomes. If two traits are on separate chromosomes, or a recombination
A a A A a a A a A a A a A a
event is likely to occur between them on the same chromosome, the resul-
tant gamete formed during meiosis has a 50% chance of inheriting differ- B b B B b b B b B b B b B b
ent alleles from each loci, and the two traits respect the law of independent
C c C C c c C C c c C C c c
assortment. If, however, the loci for these two traits are close together on
a chromosome, with the result that a recombination event occurs between D d D D d d D D d d D D d d
them only rarely, the alleles at each loci are passed to descendent gametes
E e E E e e E E e e E E e e
“in phase.” This means that the particular alleles present at each loci in the
offspring reflect the orientation in the parent, and the traits appear to be recombination
“linked.” For example, in Mendel’s study of pea plants, curly leaves were
always found with pink flowers, even though the genes for curly leaves and Fig. 1.1.6 Genetic Recombination by Crossing Over. Two copies of a chromosome
pink flowers are located at distinct loci. These traits are linked, because the are copied by DNA replication. During meiosis, pairing of homologous
curly leaf gene and the pink-flower gene are located close to each other chromosomes occurs, which enables a crossover between chromosomes to take
on a chromosome, and a recombination event only rarely occurs between place. During cell division, the recombined chromosomes separate into individual
them. Recombination and linkage are the fundamental concepts behind daughter cells.
genetic linkage analysis.
particular gene is mutated, the protein product might not be produced,
MUTATIONS or it might be produced but function poorly or even pathologically (dom-
inant negative effect). Point mutations (the substitution of a single base
Mutations are changes in the gene DNA sequence that result in a bio- pair) are the most common mutations encountered in human genetics. 3
logically significant change in the function of the encoded protein. If a Missense mutations are point mutations that cause a change in the amino
Fig. 1.1.7 Reciprocal GENES AND PHENOTYPES
1 RECIPROCAL TRANSLOCATION Translocation Between
Two Chromosomes. The
Philadelphia chromosome
The relationship between genes and phenotypes is complex. More than
one genetic defect can lead to the same clinical phenotype (genetic het-
(responsible for chronic erogeneity), and different phenotypes can result from the same genetic
Genetics

normal 9 der (9) myelogenous leukemia) is


defect (variable expressivity). Retinitis pigmentosa is an excellent example
shown as an example of
a reciprocal chromosomal
of genetic heterogeneity, as it may be inherited as an X-linked, autosomal
translocation that results dominant, autosomal recessive, or digenic trait, and more than 200 caus-
in an abnormal gene ative genes have been identified.23 Other ocular disorders that are geneti-
product responsible for cally heterogeneous include congenital cataract, glaucoma, and age-related
a clinical disorder. In this macular degeneration. Different genes may contribute to a common phe-
case an exchange occurs notype because they affect different steps in a common pathway. Under-
between the long arm of standing the role of each gene in the disease process can help define the
chromosome 9 and the cellular mechanisms that are responsible for the disease.
normal 22 der (22) long arm of chromosome For many genes, a single mutation that alters a critical site in the
22. protein results in an abnormal phenotype. For some diseases, the resulting
phenotypes are remarkably similar regardless of the nature of the muta-
tion. For example, a wide variety of mutations in RB1 cause retinoblas-
toma. Other diseases, however, exhibit variable expressivity, in which an
individual’s mutation may be responsible for severe disease, mild disease,
or disease that is not clinically detectable (incomplete penetrance). There
are many examples of ocular disease demonstrating variable expressivity,
including Kjer’s autosomal dominant optic atrophy,24 Axenfeld–Rieger syn-
drome,25 and aniridia.26
Different mutations in the same gene can also result in different pheno-
acid sequence of the polypeptide chain. The severity of the missense muta- types (allelic heterogeneity). Allelic heterogeneity accounts for the different
tion is dependent on the chemical properties of the switched amino acids phenotypes of dominant corneal stromal dystrophies caused by mutations
and on the importance of a particular amino acid in the function of the in the TGFB1/BIGH3.27 The phenotypic expression of a mutation may
mature protein. Point mutations also may decrease the level of polypep- depend on its location within a gene. Such variable expressivity based on
tide production because they interrupt the promoter sequence, splice site the location of the mutation is exemplified by mutations in the rds gene,
sequences, or create a premature stop codon. which may cause typical autosomal dominant retinitis pigmentosa or
Gene expression can be affected by the insertion or deletion of large macular dystrophy depending on the position of the genetic defect.28
blocks of DNA sequence. These types of mutations are less common than
point mutations but may result in a more severe change in the activity
of the protein product. A specific category of insertion mutations is the
PATTERNS OF HUMAN INHERITANCE
expansion of trinucleotide repeats found in patients affected by certain The most common patterns of human inheritance are autosomal domi-
neurodegenerative disorders. An interesting clinical phenomenon, “antic- nant, autosomal recessive, X-linked recessive, and mitochondrial. Fig. 1.1.8
ipation,” was understood on a molecular level with the discovery of trinu- shows examples of these four inheritance patterns. Other inheritance pat-
cleotide repeats as the cause of myotonic dystrophy.16 Frequently, offspring terns less commonly encountered in human disease include X-linked dom-
with myotonic dystrophy were affected more severely and at an earlier inant, digenic inheritance (polygenic), pseudodominance, and imprinting.
age than their affected parents and grandparents. Examination of the Fig. 1.1.9 defines the notation and symbols used in pedigree construction.
disease-causing trinucleotide repeat in affected pedigrees demonstrated
that the severity of the disease correlated with the number of repeats found Autosomal Dominant
in the myotonic dystrophy gene in affected individuals. This phenomenon
has been observed in a number of other diseases, including Huntington’s A disease-causing mutation that is present in only one of the two gene
disease.17 copies at an autosomal locus (heterozygous) is a dominant mutation. For
Chromosomal rearrangements may result in breaks in specific genes that example, a patient with dominant retinitis pigmentosa will have a defect in
cause an interruption in the DNA sequence. Usually, the break in DNA one copy of one retinitis pigmentosa gene inherited from one parent who,
sequence results in a truncated, unstable, dysfunctional protein product. in most cases, is also affected by retinitis pigmentosa. The other copy of
Occasionally, the broken gene fuses with another gene to cause a “fusion that gene, the one inherited from the unaffected parent, is normal (wild
polypeptide product,” which may have a novel activity in the cell. Often, type). Affected individuals have a 50% chance of having affected siblings
such a novel activity results in an abnormality in the function of the and a 50% chance of passing the abnormal gene to their offspring; 50% of
cell. An example of such a fusion protein is the product of the chromo- children of an affected individual will be affected. For a dominant disease,
some 9;22 translocation that is associated with many cases of leukemia males and females transmit the disease equally and are affected equally.
(Fig. 1.1.7).18,19 True dominant alleles produce the same phenotype in the heterozy-
A set consisting of one of each autosome as well as an X or a Y chro- gous and homozygous states. In humans, most individuals affected by
mosome is called a haploid set of chromosomes. The normal complement a disease caused by a dominant allele are heterozygous, but occasionally
of two copies of each gene (or two copies of each chromosome) is called homozygous mutations have been described. In cases where the homozy-
diploidy. Rarely, as a result of abnormal chromosome separation during gous individual is more severely affected than the heterozygous individual,
cell division, a cell or organism may have three copies of each chromo- the disease is more appropriately noted to be inherited as a semidomi-
some, which is called triploidy. A triploid human is not viable, but some nant trait. For example, alleles in the PAX3 gene, causing Waardenburg’s
patients have an extra chromosome or an extra segment of a chromosome. syndrome, are semidominant, because a homozygote with more severe
In such a situation, the abnormality is called trisomy for the chromosome disease compared with their heterozygote relatives has been described.29
involved. For example, patients with Down syndrome have three copies of In some pedigrees with an autosomal dominant disease, some indi-
chromosome 21, also referred to as trisomy 21.20 viduals who carry the defective gene do not have the affected phenotype.
If one copy of a pair of chromosomes is absent, the defect is called However, these individuals can still transmit the disease gene to offspring
haploidy. Deletions of the X chromosome are frequently the cause of and have affected children. This phenomenon is called reduced pene-
Duchenne’s muscular dystrophy.21 trance. The gene responsible for retinoblastoma (RB1) is only 90% pene-
Polymorphisms are changes in DNA sequence that don’t have a signif- trant, which means that 10% of the individuals who inherit a mutant copy
icant biological effect. These DNA sequence variants may modify disease of the gene do not develop the tumor.30
processes, but alone are not sufficient to cause disease. Human DNA
sequence is highly variable and includes single nucleotide polymorphisms Autosomal Recessive
(SNPs), microsatellite repeat polymorphisms (20–50 bp repeats of CA or
4 GT sequence), variable number of tandem repeat polymorphisms (VNTR, Diseases that require both copies of a gene to be abnormal for development
repeats of 50–100 bp of DNA), or larger insertion deletions.22 are inherited as recessive traits. Heterozygous carriers of mutant genes are
Fig. 1.1.8 Patterns of Inheritance. For pedigrees with
PATTERNS OF INHERITANCE an autosomal dominant trait, panel 1 shows inheritance
that originates from a previous generation, panel 1.1
Pedigrees with an autosomal dominant trait 2 shows segregation that originates in the second
generation of this pedigree, and panel 3 shows an

Fundamentals of Human Genetics


Generation apparent “sporadic” case, which is actually a new
I 1 2 3 mutation that arises in the most recent generation.
This mutation has a 50% chance of being passed to
II offspring of the affected individual. For pedigrees with
an autosomal recessive trait, panel 1 shows an isolated
III affected individual in the most recent generation
(whose parents are obligatory carriers of the mutant
Pedigrees with an autosomal recessive trait gene responsible for the condition), panel 2 shows a
pair of affected siblings whose father is also affected
(for the siblings to be affected, the mother must be
I 1 2 3
an obligate carrier of the mutant gene), and panel 3
II shows an isolated affected individual in the most recent
generation who is a product of a consanguineous
III marriage between two obligate carriers of the mutant
gene. For pedigrees with an X-chromosomal trait,
IV panel 1 shows an isolated affected individual whose
disease is caused by a new mutation in the gene
Pedigrees with an X-chromosomal inheritance responsible for this condition, panel 2 shows an isolated
individual who inherited a mutant copy of the gene
from the mother (who is an obligate carrier), and panel
I 1 2 3 3 shows segregation of an X-linked trait through a
multigeneration pedigree (50% of the male offspring are
II affected, and their mothers are obligate carriers of the
disease). For pedigrees with a mitochondrial trait, the
III
panel shows a large, multigeneration pedigree—men
IV and women are affected, but only women have affected
offspring.
V

Pedigrees with a mitochondrial trait

II

III

IV

affected affected unaffected unaffected male, gene unaffected unaffected female, gene
male female male carrier (heterozygous) female carrier (heterozygous)

usually clinically normal. The same recessive defect might affect both gene gene, he will be affected. If a daughter inherits the defective gene, she
copies, in which case the patient is said to be a homozygote. Different reces- will be a carrier. An important characteristic of X-linked recessive disor-
sive defects might affect the two gene copies, in which case the patient is a ders is that males never transmit the disease to sons directly (male-to-male
compound heterozygote. In a family with recessive disease, both parents are transmission).
unaffected carriers, each having one wild-type gene (allele) and one mutant Usually female carriers of an X-linked disease gene do not have any
gene (allele). Each parent has a 50% chance of transmitting the defective clinical evidence of the disease. However, for some X-linked diseases, mild
allele to a child. Because a child must receive a defective allele from both clinical features can be found in female carriers. For example, in X-linked
parents to be affected, each child has a 25% chance of being affected (50% retinoschisis, affected males are severely affected, whereas carrier females
× 50% = 25%), and 50% of the offspring will be carriers of the disease. If have a visually insignificant but clinically detectable retinal abnormality.31
the parents are related, they may be carriers of the same rare mutations, Mild phenotypic expression of the disease gene can be caused by the
and there is a greater chance that a recessive disease can be transmitted process of lyonization. In order for males (with one X chromosome) and
to offspring. Males and females have an equal chance of transmitting and females (with two X chromosomes) to have equal levels of expression of
inheriting the disease alleles. X-linked genes, female cells express genes from only one of their two X
chromosomes. The decision as to which X chromosome is expressed is
X-Linked Recessive made early in embryogenesis, and the line of descending cells faithfully
adheres to the early choice. As a result, females are mosaics, with some
Mutations of the X chromosome produce distinctive inheritance patterns, cells in each tissue expressing the maternally derived X chromosome and
because males have only one copy of the X chromosome and females the remainder expressing the paternally derived X chromosome. When
have two. Most X-linked gene defects are inherited as X-linked recessive one of the X chromosomes carries an abnormal gene, the proportion
traits. Carrier females are typically unaffected because they have both a of cells that express the mutant versus the normal gene in each tissue
normal copy and a defective copy of the disease-associated gene. Carrier can vary.
males are affected because they only have one defective X chromosome Females can also be affected by an X-linked recessive disease if the
and they do not have a normal gene copy to compensate for the defec- father is affected and the mother coincidentally is a carrier of a mutation
tive copy. All of the daughters of an affected male will be carriers of the in the disease gene. In this case, 50% of daughters would be affected,
disease gene because they will inherit the defective X chromosome. None because 50% would inherit the X chromosome from the mother carrying
of the sons of an affected male will be affected or be carriers because the disease gene, and all the daughters would inherit the X chromosome
they will inherit the Y chromosome. Each child of a carrier female has a from the father carrying the disease gene. Because most X-linked disorders 5
50% chance of inheriting the disease gene. If a son inherits the defective are rare, the carrier frequency of disease genes in the general population is
X-Linked Dominant Inheritance
1 or
BASIC PEDIGREE NOTATION

normal female fraternal twins


This inheritance pattern is similar to X-linked recessive inheritance, except
that all females who are carriers of an abnormal gene on the X chromo-
(not identical) some are affected rather than unaffected. All of the male offspring are also
Genetics

affected. Incontinentia pigmenti is probably inherited as an X-linked dom-


or normal male
identical twins inant trait. Affected females have irregularly pigmented atrophic scars on
the trunk and the extremities and congenital avascularity in the peripheral
single bar retina with secondary retinal neovascularization.34 This and other X-linked
number of children
indicates mating 2 6 for each sex dominant disorders occur almost always in females, and it is likely that the
X chromosome gene defects causing these diseases are embryonic lethals
normal parents and darkened square or
normal offspring, two when present in males.
I circle means affected
girls and a boy, in individual; arrow (when
II birth order indicated or present) indicates the Digenic Inheritance and Polygenic Inheritance
by the numbers; I and affected individual is
1 2 3 Digenic inheritance occurs when a patient has heterozygous defects in
II indicate generations propositus, the begin-
ning of the analysis two different genes, and the combination of the two gene defects causes
single parent as disease. Individuals who have a mutation in only one of the genes are
presented means normal. Digenic inheritance is different from recessive inheritance,
partner is normal autosomal heterozygous
and because the two mutations involve different disease genes. In some retini-
or of no significance recessive
tis pigmentosa families, mutation analysis of the peripherin gene and the
to the analysis
X-linked carrier ROM1 gene showed that the affected individuals harbor specific mutations
in both genes. Individuals with a mutation in only one copy of either gene
double bar indicates dead
and were unaffected by the disease.35 Triallelic inheritance has been described
a consanguineous union
(mating between in some families affected by Bardet–Biedl syndrome (BBS). In these pedi-
close relatives) aborted or stillborn grees, affected individuals carry three mutations in one or two BBS genes
(12 BBS genes have been identified),36 and unaffected individuals have only
two abnormal alleles. In some families, it has been proposed that BBS may
not be a single-gene recessive disease but a complex trait requiring at least
Fig. 1.1.9 Basic Pedigree Notation. Typical symbols used in pedigree construction three mutant alleles to manifest the phenotype. This would be an example
are defined. of triallelic inheritance.37
If the expression of a heritable trait or predisposition is influenced by
the combination of alleles at three or more loci, it is polygenic. Because
low, and the chance that a carrier female would mate with a male affected of the complex inheritance, conditions caused by multiple alleles do not
by the same disease is quite low. demonstrate a simple inheritance pattern. These complex traits may also
be influenced by environmental conditions. Examples of phenotypes in
Mitochondrial Inheritance ophthalmology that exhibit complex inheritance because of contributions
of multiple genes and environmental factors are myopia,38 age-related
Mitochondria are small organelles located in the cytoplasm of cells. They macular degeneration,39 and adult-onset open-angle glaucoma.40
function to generate ATP for the cell and are most abundant in cells that
have high energy requirements, such as muscle and nerve cells. Mito- Imprinting
chondria have their own small chromosome—16,569 bp of DNA encoding
for 13 mitochondrial proteins, 2 ribosomal RNAs, and 22 tRNAs. Muta- Some mutations give rise to autosomal dominant traits that are transmitted
tions occurring in genes located on the mitochondrial chromosome cause by parents of either sex, but they are expressed only when inherited from a
a number of diseases, including Leber’s hereditary optic atrophy32 and parent of one particular sex. In families affected with these disorders, they
Kearns–Sayre syndrome.33 Mutations occurring on the mitochondrial chro- would appear to be transmitted in an autosomal dominant pattern from
mosome are inherited only from the mother because virtually all human one parent (either the mother or the father) and would not be transmitted
mitochondria are derived from the maternal egg. Fathers do not transmit from the other parent. Occasionally, the same mutation gives rise to a dif-
mitochondria to their offspring. ferent disorder depending on the sex of the parent transmitting the trait.
Cells vary in the number of mitochondria they contain, and when These parental sex effects are evidence of a phenomenon called imprinting.
cells divide, the mitochondria are divided randomly. As a result, different Although the molecular mechanisms responsible for imprinting are not
cells can have varying numbers of mitochondria, and if a fraction of the completely understood, it appears to be associated with DNA methylation
mitochondria contain a mutated gene, different cells will have a varying patterns that can mark certain genes with their parental origin.41
proportion of healthy versus mutant mitochondria. The distribution of
mutant mitochondria is called heteroplasmy, and the proportion of mutant
mitochondria can vary from cell to cell and can also change with age. Dif-
MOLECULAR MECHANISMS OF DISEASE
ferences in the relative proportions of mutant mitochondria can partly Autosomal Dominant
explain the observed variable severity of mitochondrial diseases and also
the variable age of onset of mitochondrial diseases. Disorders inherited as autosomal dominant traits result from mutations
that occur in only one copy of a gene (i.e., in heterozygous individuals).
Pseudodominance Usually, the parental origin of the mutation does not matter. However, if
the gene is subject to imprinting, then mutations in the maternal or pater-
This term describes an apparent dominant inheritance pattern due to reces- nal copy of the gene may give rise to different phenotypes.
sive defects in a disease gene. This situation arises when a parent affected
by a recessive disease (two abnormal copies of the disease gene) has a Haploinsufficiency
spouse who is a carrier of one abnormal copy of the disease gene. Children Under normal circumstances, each copy of a gene produces a protein
from this couple will always inherit a defective gene copy from the affected product. If a mutation occurs such that one copy of a gene no longer pro-
parent and will have a 50% chance of inheriting the defective gene copy duces a protein product, then the amount of that protein in the cell has
from the unaffected carrier parent. On average, half of the children will been reduced by half. Mutations that cause a reduction in the amount of
inherit two defective gene copies and will be affected. The pedigree would protein or lead to inactivation of the protein are called loss-of-function muta-
mimic a dominant pedigree because of apparent direct transmission of the tions. For many cellular processes, this reduction in protein quantity does
disease from the affected parent to affected children and because approxi- not have consequences, i.e., the heterozygous state is normal, and these
mately 50% of the children will be affected. Pseudodominant transmission mutations may be inherited as recessive traits (see later section). However,
6 is uncommon, because few people are asymptomatic carriers for any par- for some cellular processes there is an absolute requirement for the full
ticular recessive gene. dosage of protein product, which can only be furnished if both copies of
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Faubourg St. Germain, the aristocracy of the empire, and the
bureaucracy of the present French republic.
The imperial princes of the blood, all nearly related to the Emperor,
rank above the ten created princes, who head the list of the nobility.
Five of these ten princely houses are the old Gosekke, the first five
of the one hundred and fifty-five kugé families comprising the old
Kioto court. With the Gosekke, which includes the Ichijo, Kujo,
Takatsukasa, Nijo, and Konoye families, rank, since 1883, the
houses of Sanjo, Iwakura, Shimadzu, Mori, and Tokugawa, sharing
with them the privilege of offering the bride to the heir-apparent.
The Emperor visits personally at the houses of these ten princes,
and recently the Tokugawas entertained him with a fencing-match
and a No dance in old style, the costumes and masks for which had
been used at Tokugawa fêtes for centuries. In accordance with other
old customs, a sword by a famous maker was presented to the guest
of honor, and a commemorative poem offered in a gold lacquer box.
Yet the head of the Tokugawa house is a grandson of the Shogun
who first refused to treat with Commodore Perry, and son of Keiki,
the arch rebel and last of the Shoguns, who for so long lived
forgotten as a private citizen on a small estate near Shidzuoka,
keeping alive no faction, awaking no interest—attaining, in fact, a
political Nirvana.
Under new titles the old fiefs are lost sight of and old associations
broken up. The marquises, counts, and barons of to-day are slender,
dapper little men, wearing the smartest and most irreproachable
London clothes, able to converse in one or two foreign languages on
the subjects that interest cosmopolitans of their rank in other
empires, and are with difficulty identified with their feudal titles. The
Daimio of Kaga has become the Marquis Maeda, his sister married
the Emperor’s cousin, and the great yashiki of their ancestors has
given way to the buildings of the Imperial University. The Daimio of
Satsuma is now Prince Shimadzu. It is not easy to associate these
modern men-about-town, who dance at state balls, who play billiards
and read the files of foreign newspapers at the Rokumeikwan, who
pay afternoon calls, attend teas, garden-parties, dinners, concerts,
and races; who have taken up poker and tennis with equal ardor,
and are victimized at charity fairs and bazaars, with their pompous,
stately, two-sworded, brocade and buckram bound ancestors.
There are great beauties, favorites, and social leaders among the
ladies of the court circle, and the change in their social position and
personal importance is incredible. Japanese matrons, who, a few
years ago, led the most quiet and secluded existence, now preside
with ease and grace over large establishments, built and maintained
like the official residences of London or Berlin. Their struggles with
the difficulties of a new language, dress, and etiquette were heroic.
Mothers and daughters studied together with the same English
governess, and princesses and diplomats’ wives, returning from
abroad, gave new ideas to their friends at home. Two Japanese
ladies, now foremost at court, are graduates of Vassar College, and
many high officials are happily married to foreign wives; American,
English, and German women having assumed Japanese names with
their wedding vows. The court has its reigning beauty in the wife of
the grand master of ceremonies, the richest peer of his day, and
representative of that family which gave its name to the finest
porcelain known to the ceramic art of the empire.
Tokio society delights in dancing, and every one at court dances
well. Leaders of fashion go through the quadrille d’honneur, with
which state balls open, and follow the changes of the lancers with
the exactness of soldiers on drill, every step and movement as
precise and finished as the bending of the fingers in cha no yu. The
careless foreigner who attempts to dance an unfamiliar figure
repents him of his folly. Japanese politeness is incomparable, but the
sedateness, the precision, and exactness of the other dancers in the
set will reproach the blunderer until he feels himself a criminal. The
ball is the more usual form of state entertainments. The prime-
minister gives a ball on the night of the Emperor’s birthday, and the
governor of Tokio gives a ball each winter. From time to time the
imperial princes and the ministers of state offer similar
entertainments, and every legation has its ball-room. The members
of the diplomatic corps are as much in social unison with the higher
Japanese circles as it is possible to be with such subjects at any
capital, and the round of tiffins, dinners, garden-parties, and small
dances makes Tokio very gay during the greater part of the year.
The first formal visiting of the season begins in October, and by
May social life is at an end until hot weather is over. Lent makes little
break in the social chain. Great seriousness and exactness in social
usage is inherent in this high-bred people. Visits of ceremony are
scrupulously paid within the allotted time, and a newly-arrived official
in Tokio finds no diminution of the card-leaving and visiting which
awaits him in any other capital. At the houses of the imperial princes
cards are not left, the visitor inscribing his name in a book in the hall.
After each state ball, a guest must call at once upon the princess, or
minister’s wife, who presided, and any remissness strikes his name
from her list.
Garden-parties are the favorite expression of Tokio hospitality. All
official residences in the city have fine grounds, and many ministers
of state own suburban villas. A few of the legations are able to
entertain in the same way, and many military officers make the
garden of the old Mito yashiki, now the Arsenal grounds, the scene
of their courtesies.
There is a stately court journal, which is the official bulletin, but
Tokio has not yet set up a paper of society gossip and scandal for
the rigorous censorship of the Japanese press to expunge; nor are
there books of court memoirs. Yet what memoirs could be more
interesting than those that might be written by the men and women
who were born in feudal times, who have lived through the exciting
days of the Restoration, and have watched the birth and growth of
New Japan.
CHAPTER XIII
THE SUBURBS OF TOKIO

The suburbs of Tokio are full of holiday resorts for the people and
the beautiful villas of nobles. To the north-east, in Oji, are the
Government chemical works and paper mills, where rough bits of
mulberry-wood are turned into papers of a dozen kinds, the silkiest
tissue-paper, smooth, creamy writing-paper, thick parchment, bristol-
board, and the thin paper for artists and etchers. On a sheet of the
heaviest parchment paper I once stood and was lifted from the floor,
the fabric showing no mark of rent or strain, and it is wellnigh
impossible to tear even a transparent Oji letter sheet. The Oji tea-
house has a famous garden, and in autumn Oji’s hill-sides blaze with
colored maples, and then the holiday makers mark the place for their
own.
Waseda, the northern suburb, contains an old temple, a vast,
gloomy bamboo-grove, and the villa of Countess Okuma, to whose
genius for landscape-gardening is also due the French Legation’s
paradise of a garden, in the heart of the city, that place having been
Count Okuma’s town residence before he sold it to the French
Government. From Waseda’s rice fields a greater marvel grew.
Meguro, south of Tokio, is a place of sentimental pilgrimage to the
lovers of Gompachi and Komurasaki, the Abelard and Heloise of the
East, around whose tomb the trees flutter with paper poems, and
prayers. In the temple grounds are falling streams of water, beneath
which, summer and winter, praying pilgrims stand, to be thus
pumped on for their sins. Similar penitents may be seen at a little
temple niched in the bluff of Mississippi Bay. Meguro has an annual
azalea fête and a celebration of the maple-leaf, and its resident
nobles, among whom is General Saigo, give feasts in honor of the
season’s blooms.
The Sengakuji temple, near Shinagawa, is a sacred spot and
shrine of chivalry, the burial-place of the Forty-seven Ronins; and
here come pious pilgrims to say a prayer and leave a stick of burning
incense, and view the images and relics in the little temple.
Near Omori, half-way between Yokohama and Tokio, Professor
Morse discovered the shell-heaps of prehistoric man. The
neighborhood is made beautiful by old groves, old temples and
shrines, tiny villages, picturesque farm-houses, and hedge-lined
roads, while Ikegami’s temples shine upon the hill that stands an
evergreen island in the lake of greener rice fields or golden stubble.
Here died Nichiren, founder of the Buddhist sect bearing his name.
For six centuries these splendid temples have resounded with the
chantings of his priesthood, who still expound his teachings to the
letter. The Nichiren sect is the largest, richest, most influential, and
aggressive in Japan. They are the Protestants and Presbyterians of
the Buddhist religion; firm, hard, and unrelenting in their faith,
rejecting all other creeds as false, and zealously proselyting.
Nichiren was a great scholar, who, poring over Chinese and Sanscrit
sutras, believed himself to have discovered the true and hidden
meaning of the sacred books. His labors were colossal, and though
exiled, imprisoned, tortured, and condemned to death, he lived to
see his followers increasing to a great body of true believers, and
himself established as high-priest over the temples of Ikegami. In the
popular play “Nichiren,” one has thrilling evidence of what the pious
founder and his disciples endured.
On the twelfth and thirteenth of each October special services are
held in memory of Nichiren, which thousands of people attend. On
the first day of this matsuri the railway is crowded with passengers.
Bonfires and strings of lanterns mark the Omori station by night, and
by day the neighboring matsuri is announced by tall bamboo poles,
from which spring whorls of reeds covered with huge paper flowers.
These giant flower-stalks are the conventional sign for festivities, and
when a row of them is planted by the road-side, or paraded up and
down with an accompaniment of gongs, the holiday spirit responds
at once. The quiet country road is blockaded with hundreds of
jinrikishas going to and returning from Ikegami’s terraced gate-ways.
Men, women, and children, priests, beggars, and peddlers pack the
highway. The crowd is amazing—as though these thousands of
people had been suddenly conjured from the ground, or grown from
some magician’s powder—for nothing could be quieter than Omori
lanes on all the other days of the year.
Along the foot-paths of the fields women in tightly-wrapped
kimonos with big umbrellas over their beautifully-dressed heads;
young girls with the scarlet petticoats and gay hair-pins indicative of
maidenhood; little girls and boys with smaller brothers and sisters
strapped on their backs, trudge along in single files, high above the
stubble patches, to the great matsuri. In farm-house yards
persimmon-trees hang full of mellow, golden fruit, and the road is
literally lined with these apples of the Hesperides. Peddlers sit on
their heels behind their heaped persimmons and busily tie straw to
the short stems of the fruit, that the buyer may carry his purchase
like a bunch of giant golden grapes. Fries, stews, bakes, and grills
scent the air with savors, and all sorts of little balls and cubes, pats
and cakes, lumps and rolls of eatables are set out along the country
road. A queer sort of sea-weed scales, stained bright red, is the
chewing-gum of the East, and finds a ready market.
On the days of the matsuri the village street is impassable, and the
whole broad walk of the temple grounds leading from the pagoda is
lined with booths, jugglers, acrobats, side-shows, and catch-penny
tricksters. The “sand-man,” with bags of different colored sands,
makes beautiful pictures on a cleared space of ground, rattling and
gabbling without cessation while he works. First he dredges the
surface with a sieve full of clean white sand, and then sifts a little thin
stream of black or red sand through his closed hand, painting
warriors, maidens, dragons, flowers, and landscapes in the swiftest,
easiest way. It is a fine example of the trained hand and eye, and of
excellent free-hand drawing. A juggler tosses rings, balls, and knives
in the air, and spins plates on top of a twenty-foot pole. His colleague
balances a big bamboo on one shoulder, and a small boy climbs it
and goes through wonderful feats on the cross-piece at the top. A
ring of gaping admirers surrounds a master of the black art, who
swallows a lighted pipe, drinks, whistles, produces the pipe for a puff
or two, swallows it again, and complacently emits fanciful rings and
wreaths of smoke. Hair-pins, rosaries, toys, and sweets are
everywhere for sale.
A huge, towering, heavy-roofed red gate-way admits streams of
people to the great court-yard, surrounded on three sides by temples
large and small, where the priests chant and pound and the faithful
pray, rubbing their rosaries and tossing in their coins. At one shrine
greasy locks of hair tied to the lattices are votive offerings from those
who have appealed to the deity within. There is a little temple to the
North Star, where seamen and fisher-folk pray, and one to Daikoku,
the god of riches and abundance, the latter a fat little man sitting on
bags of rice, and always beset by applicants.
In the great temple pyramids of candles burn, incense rises, bells
sound, and money rains into the big cash-box at the head of the
steps. The splendid interior is a mass of lacquer, gilding, and color,
the panelled ceiling has an immense filigree brass baldaquin
hanging like a frosted canopy over the heads of the priests, and a
superb altar, all images, lotus-leaves, lights, and gilded doors,
dazzles the eye. Under the baldaquin sits the high-priest of the
temple, who is a bishop of the largest diocese in Japan, while at
either side of him more than two hundred celebrants face each other
in rows. The priestly heads are shaven, the smooth faces wear the
ecstatic, exalted expression of devotees purified by vigil and fasting,
and over their white or yellow gauze kimonos are tied kesas, or
cloaks of rich brocade. The lesser hierarchy appear in subdued
colors—gray, purple, russet—but the head priest is arrayed in
gorgeous scarlet and gold, and sits before a reading-desk, whose
books are covered with squares of similar brocade. He leads the
chanted service from a parchment roll spread before him, at certain
places touching a silver-toned gong, when all the priests bow low
and chant a response, sitting for hours immovable upon the mats,
intoning and reading from the sacred books in concert. At intervals
each raps the low lacquer table before him and bends low, while the
big temple drum sounds, the high-priest touches his gong, and
slowly, behind the lights and incense clouds of the altar, the gilded
doors of the shrine swing open to disclose the precious image of
sainted Nichiren. On all sides stand the faithful, extending their
rosary-wrapped hands and muttering the Nichirene’s special form of
prayer: “Namu mio ho ren ge kio” (Glory to the salvation-bringing
book, the blossom of doctrine).
After seven hours of worship a last litany is uttered, and the
procession of priests files through the grounds to the monastery,
stopping to select from the two hundred and odd pairs of wooden
clogs, waiting at the edge of the temple mats, each his proper pair.
The high-priest walks near the middle of the line underneath an
immense red umbrella. He carries an elaborate red lacquer staff, not
unlike a crozier, and even his clogs are of red lacquered wood. The
service in the temple suggests the forms of the Roman Church, and
this Buddhist cardinal, in his red robes and umbrella, is much like his
fellow-dignitary of the West.
To citizens of the United States Ikegami has a peculiar interest.
When the American man-of-war Oneida was run down and sunk with
her officers and crew by the P. and O. steamer Bombay, near the
mouth of Yeddo Bay, January 23, 1870, our Government made no
effort to raise the wreck or search it, and finally sold it to a Japanese
wrecking company for fifteen hundred dollars. The wreckers found
many bones of the lost men among the ship’s timbers, and when the
work was entirely completed, with their voluntary contributions they
erected a tablet in the Ikegami grounds to the memory of the dead,
and celebrated there the impressive Buddhist segaki (feast of hungry
souls), in May, 1889. The great temple was in ceremonial array;
seventy-five priests in their richest robes assisted at the mass, and
among the congregation were the American admiral and his officers,
one hundred men from the fleet, and one survivor of the solitary
boat’s crew that escaped from the Oneida.
The Scriptures were read, a service was chanted, the Sutra
repeated, incense burned, the symbolic lotus-leaves cast before the
altar, and after an address in English by Mr. Amenomori explaining
the segaki, the procession of priests walked to the tablet in the
grounds to chant prayers and burn incense again.
No other country, no other religion, offers a parallel to this
experience; and Americans may well take to heart the example of
piety, charity, magnanimity, and liberality that this company of hard-
working Japanese fishermen and wreckers have set them.
CHAPTER XIV
A TRIP TO NIKKO

The Nikko mountains, one hundred miles north of Tokio, are the
favorite summer resort of foreign residents and Tokio officials. The
railway now reaches Nikko, and one no longer travels for the last
twenty-five miles in jinrikisha over the most beautiful highway,
leading through an unbroken avenue of over-arching trees to the
village of Hachi-ishi, or Nikko.
On the very hottest day of the hottest week of August we packed
our koris, the telescope baskets which constitute the Japanese trunk,
and fled to the hills. Smoke and dust poured in at the car windows,
the roof crackled in the sun, the green groves and luxuriant fields
that we whirled through quivered with heat, and a chorus of
grasshoppers and scissors-grinders deafened us at every halt. At
Utsonomiya it was a felicity to sit in the upper room of a tea-house
and dip our faces and hold our hands in basins of cool spring-water,
held for us by the sympathetic nesans. They looked perfectly cool,
fresh, and unruffled in their clean blue-and-white cotton kimonos, for
the Japanese, like the creoles, appear never to feel the heat of
summer, and, indeed, to be wholly indifferent to any weather. The
same placid Utsonomiya babies, whose little shaved heads bobbed
around helplessly in the blaze of that midsummer sun, I have seen
equally serene with their bare skulls reddening, uncovered, on the
frostiest winter mornings.
Once out of the streets of this little provincial capital, the way to
Nikko leads up a straight broad avenue, lined on both sides for
twenty-seven miles with tall and ancient cryptomerias, whose
branches meet in a Gothic arch overhead. The blue outlines of the
Nikko mountains showed in the distance as we entered the grand
avenue. The road is a fine piece of engineering, with its ascent so
slow and even as to seem level; but at times the highway, with its
superb walls of cryptomeria, is above the level of the fields, then
even with them, and then below them, as it follows its appointed
lines. Before the railway reached Utsonomiya, travellers from Tokio
had a boat journey, and then a jinrikisha ride of seventy miles
through the shaded avenue. This road was made two centuries ago,
when the Shoguns chose Nikko as their burial place, and these
venerable trees have shaded the magnificent funeral trains of the old
warriors, and the splendid processions of their successors, who
made pilgrimages to the tombs of Iyeyasu and Iyemitsu. In our day,
alas, instead of mighty daimios and men-at-arms in coats of mail, or
brocaded grandees in gilded palanquins, telegraph-poles, slim, ugly,
and utilitarian, impertinently thrust themselves forward before the
grand old tree-trunks, and the jinrikisha and the rattle-trap basha
take their plebeian way.
The cryptomeria has the reddish bark and long, smooth bole of the
California sequoia, and through the mat of leaves and branches,
high overhead, the light filters down in a soft twilight that casts a
spell over the place. After sunset the silence and stillness of the
shaded avenue were solemn, and its coolness and the fragrance of
moist earth most grateful. Two men ran tandem with each jinrikisha,
and they went racing up the avenue for ten miles, halting only once
for a sip of cold water before they stopped at the hamlet of Osawa.
The villages, a row of low houses on either side of the way, make the
only break in the long avenue. With its dividing screens drawn back,
the Osawa tea-house was one long room, with only side walls and a
roof, the front open to the street, and the back facing a garden where
a stream dashed through a liliputian landscape, fell in a liliputian fall,
and ran under liliputian bridges. At the street end was a square
fireplace, sunk in the floor, with a big teakettle swinging by an iron
chain from a beam of the roof, teapots sitting in the warm ashes, and
bits of fowl and fish skewered on chopsticks and set up in the ashes
to broil before the coals. The coolies, sitting around this kitchen,
fortified their muscle and brawn with thimble cups of green tea,
bowls of rice, and a few shreds of pickled fish. We, as their masters
and superiors, were placed as far as possible from them, and
picnicked at a table in the pretty garden. After the severe exertion of
sitting still and letting the coolies draw us, we restored our wasting
tissues by rich soup, meats, and all the stimulating food that might
be thought more necessary to the laboring jinrikisha men.
When we started again, with all the tea-house staff singing sweet
sayonaras, a glow in the east foretold the rising moon, and a huge
stone torii at the end of the village loomed ghostly against the
blackness of the forest. The glancing moonlight shot strange
shadows across the path, and we went whirling through this lattice of
light and darkness in stillness and solitude. The moon rose higher
and was hidden in the leafy arch overhead, and before we realized
that its faint light was fading, came flashes of lightning, the rumble of
approaching thunder, and a sudden crash, as the flood of rain struck
the tree-tops and poured through. The hoods of the jinrikishas were
drawn up, the oil-papers fastened across us, and through pitch
darkness the coolies raced along. Vivid flashes of lightning showed
the thick, white sheet of rain, which gusts of wind blew into our faces,
while insidious streams slipped down our shoulders and glided into
our laps. Putting their heads down, the coolies beat their way against
the rain for two more soaking miles to Imaichi, the last village on the
road, only five miles from Nikko. The tea-house into which we turned
for shelter was crowded with belated and storm-bound pilgrims
coming down from the sacred places of Nikko and Chiuzenji. All
Japanese are talkative, the lower in station the more loquacious, and
the whole coolie company was chattering at once. As the place was
too comfortless to stay in, we turned out again in the rain, and the
coolies splashed away at a walk, through a darkness so dense as to
be felt. At midnight our seven jinrikishas rattling into the hotel court,
and fourteen coolies shouting to one another as they unharnessed
and unpacked, roused the house and the whole neighborhood of
Nikko. Awakened sleepers up-stairs looked out at us and banged the
screens angrily, but no sounds can be deadened in a tea-house.
To the traveller the tea-house presents many phases of comfort,
interest, and amusement altogether wanting in the conventional
hotel, which is, unfortunately, becoming common on the great routes
of travel. The dimensions of every house in the empire conform to
certain unvarying rules. The verandas, or outer galleries of the
house, are always exactly three feet wide. A foreigner, who insisted
on a nine-feet-wide veranda, entailed upon his Nikko carpenter many
days of painful thought, pipe-smoking, and conference with his
fellows. These mechanics were utterly upset in their calculations.
They sawed the boards and beams too long or too short, and finally
produced a very bad, un-Japanese piece of work. The floors of these
galleries are polished to a wonderful smoothness and surface. They
are not varnished, nor oiled, nor waxed, but every morning rubbed
with a cloth wrung out of hot bath-water which contains oily matter
enough to give, in time, this peculiar lustre. Three years of daily
rubbing with a hot cloth are required to give a satisfactory result, and
every subsequent year adds to the richness of tone and polish, until
old tea-houses and temples disclose floors of common pine looking
like rosewood, or six-century-old oak.
The area of every room is some multiple of three feet, because the
soft tatami, or floor-mats, measure six feet in length by three in
width. These are woven of common straw and rushes, faced with a
closely-wrought mat of rice-straw. It is to save these tatami and the
polished floors that shoes are left outside the house.
The thick screens, ornamented with sketches or poems, that
separate one room from another, are the fusuma; the screens
shutting off the veranda, pretty lattice frames covered with rice-paper
that admit a peculiarly soft light to the rooms, are the shoji, and in
their management is involved an elaborate etiquette. In opening or
closing them, well-bred persons and trained servants kneel and use
each thumb and finger with ordered precision, while it is possible to
convey slight, contempt, and mortal insult in the manner of handling
these sliding doors. The outer veranda is closed at night and in bad
weather by amados, solid wooden screens or shutters, that rumble
and bang their way back and forth in their grooves. These amados
are without windows or air-holes, and the servants will not willingly
leave a gap for ventilation. “But thieves may get in, or the kappa!”
they cry, the kappa being a mythical animal always ready to fly away
with them. In every room is placed an andon, or night-lamp. If one
clap his hands at any hour of the twenty-four, he hears a chorus of
answering Hei! hei! hei’s! and the thump of the nesans’ bare feet, as
they run to attend him. While he talks to them, they keep ducking
and saying Heh! heh! which politely signifies that they are giving their
whole attention.
The Japanese bed is the floor, with a wooden box under the neck
for a pillow and a futon for a covering. To the foreigner the Japanese
landlord allows five or six futons, or cotton-wadded comforters, and
they make a tolerable mattress, although not springy, and rather apt
to be damp and musty. The traveller carries his own sheets, woolen
blankets, feather or air pillows, and flea-powder, the latter the most
necessary provision of all. The straw mats and the futons swarm with
fleas, and without a liberal powdering, or, better, an anointing with oil
of pennyroyal, it is impossible to sleep. These sleeping
arrangements are not really comfortable, and, after the fatigue of
walking and mountain-climbing, stiffen the joints. By day the futons
are placed in closets out of sight, or hung over the balconies to air,
coming back damper than ever, if the servants forget to bring them in
before sunset. The bedroom walls are the sliding paper screens; and
if one’s next neighbor be curious, he may slip the screen a little or
poke a hole through the paper. A whisper or a pin-drop travels from
room to room, and an Anglo-Saxon snorer would rock the whole
structure.
At ordinary Japanese inns the charge for a day’s accommodation
ranges from a half-yen upward. A Japanese can get his lodgings and
all his meals for about thirty cents, but foreigners are so clumsy,
untidy, and destructive, and they demand so many unusual things,
that they are charged the highest price, which includes lodging,
bedding, and all the tea, rice, and hot water they may wish. All other
things are extra. In the beaten tracks bread and fresh beef may
always be found, and each year there is less need of carrying the
supplies formerly so essential. Chairs and tables, cots, knives and
forks, and corkscrews have gradually penetrated to the remotest
mountain hamlets. At the so-called foreign hotels at Nikko and other
resorts, charges are usually made at a fixed price for each day, with
everything included, as at an American hotel.
Foreigners travelling away from the ports take with them a guide,
who acts as courier, cooks and serves the meals, and asks two and
a half yens a day with expenses. Thus accompanied, everything
goes smoothly and easily; rooms are found ready, meals are served
promptly, show-places open their doors, the best conveyances await
the traveller’s wish, and an encyclopædic interpreter is always at his
elbow. Without a guide or an experienced servant, even a resident
who speaks the language fares hardly. Like all Orientals, the
Japanese are impressed by a retinue and the appearances of
wealth. They wear their best clothes when travelling, make a great
show, and give liberal tips. The foreigner who goes to the
Nakasendo or to remote provinces alone, trusting to the phrase-
book, finds but little consideration or comfort. He ranks with the class
of pilgrims, and the guest-room and the choicest dishes are not for
him. The guide may swindle his master a little, but the comforts and
advantages he secures are well worth the cost. All the guides are
well-to-do men with tidy fortunes. They exact commissions wherever
they bring custom, and can make or break landlords or merchants if
they choose to combine. Some travellers, who, thinking it sharp to
deprive the guides of these percentages, have been left by them in
distant provinces and forced to make their way alone, have found the
rest of the journey a succession of impositions, difficulties, and even
of real hardships. After engaging a guide and handing him the
passport, the traveller has only to enjoy Japan and pay his bill at the
end of the journey. The guides know more than the guide-book; and
with Ito, made famous by Miss Bird, Nikko and Kioto yielded to us
many pleasures which we should otherwise have missed. An
acquaintance with Miyashta and his sweet-potato hash made the
Tokaido a straight and pleasant way; and Moto’s judicial
countenance caused Nikko, Chiuzenji, and Yumoto to disclose
unimagined beauties and luxuries; and Utaki always marshalled the
impossible and the unexpected.
CHAPTER XV
NIKKO

Of all Japan’s sacred places, Nikko, or Sun’s Brightness, is


dearest to the Japanese heart. Art, architecture, and landscape-
gardening add to Nature’s opulence, history and legend people it
with ancient splendors, and all the land is full of memories. “He who
has not seen Nikko cannot say Kekko!” (beautiful, splendid, superb),
runs the Japanese saying.
With its forest shades, its vast groves, and lofty avenues, its hush,
its calm religious air, Nikko is an ideal and dream-like place, where
rulers and prelates may well long to be buried, and where priests,
poets, scholars, artists, and pilgrims love to abide. Each day of a
whole summer has new charms, and Nikko’s strange fascination but
deepens with acquaintance.
The one long street of Hachi-ishi, or lower Nikko village, ends at
the banks of the Dayagawa, a roaring stream that courses down a
narrow valley, walled at its upper end by the bold, blue bar of
Nantaisan, the sacred mountain. Legend has peopled this valley of
the Dayagawa with impossible beings—giants, fairies, demons, and
monsters. Most of the national fairy stories begin with, “Once upon a
time in the Nikko mountains,” and one half expects to meet imp or
fay in the green shadows. Mound builder and prehistoric man had
lived their squalid lives here; the crudest and earliest forms of
religion had been observed in these forest sanctuaries long before
Kobo Daishi induced the Shinto priests to believe that their god of
the mountain was but a manifestation of Buddha. Everything
proclaims a hoary past—trees, moss-grown stones, battered images,
crumbling tombs, overgrown and forgotten graveyards.
Each summer half the Tokio legations move bodily to Nikko, and
temples, monastery wings, priests’ houses, and the homes of the
dwellers in the upper village are rented to foreigners in ever-
increasing numbers. Nikko habitations do not yet bring the prices of
Newport cottages, but the extravagant rate of three and even five
hundred yens for a season of three months is a Japanese
equivalent. Besides the foreigners, there are many Japanese
residents; and, while the Crown-Prince occupies his summer palace,
he is daily to be met in the streets, the forest paths, or temple
grounds. The white-clad pilgrims throng hither by thousands during
July and early August, march picturesquely to the jingle of their staffs
and bells round the great temples, and trudge on to the sanctuary on
Chiuzenji’s shores within the shadow of holy Nantaisan.
Two bridges cross the Daiyagawa, and lead to the groves and
temples that make Nikko’s fame. One bridge is an every-day affair of
plain, unpainted timbers, across which jinrikishas rumble noisily, and
figures pass and repass. The other is the sacred bridge, over which
only the Emperor may pass, in lieu of the Shoguns of old, for whom it
was reserved. It is built of wood, covered with red lacquer, with many
brass plates and tips, and rests on foundation piles of Titanic stone
columns, joined by cross-pieces of stone, carefully fitted and
mortised in. Tradition maintains that the gods sent down this rainbow
bridge from the clouds in answer to saintly prayer. Its sanctity is so
carefully preserved, that when the Emperor wished to pay the
highest conceivable honor to General Grant, he ordered the barrier
to the bridge to be opened that his guest might walk across. Greatly
to his credit, that modest soldier refused to accept this honor, lest it
should seem a desecration to the humble believers in the sanctity of
the red bridge.
Shaded avenues, broad staircases, and climbing slopes lead to
the gate-ways of the two great sanctuaries—the mortuary temples
and tombs of the Shogun Iyeyasu and his worthy grandson, the
Shogun Iyemitsu. The hill-side is shaded by magnificent old
cryptomerias; and these sacred groves, with the soft cathedral light
under the high canopy of leaves, are as wonderful as the sacred
buildings. Each splendid gate-way, as well as the soaring pagoda,
can be seen in fine perspective at the end of long avenues of trees,
and bronze or stone torii form lofty portals to the holy places. The
torii is a distinctively national structure, and these grand skeleton
gates of two columns and an upward curving cross-piece are
impressive and characteristic features of every Japanese landscape,
standing before even the tiniest shrines in the Liliputian gardens of
Japanese homes, as well as forming the approach to every temple.
The stone torii and the rows of stone lanterns are mossy and lichen-
covered, and every foot of terrace or embankment is spread with fine
velvety moss of the freshest green. Although two hundred years old,
the temples themselves are in as perfect condition and color as
when built; and nothing is finer, perhaps, than the five-storied
pagoda with its red lacquered walls, the brass trimmings of roofs and
rails, the discolored bells pendent from every angle, and a queer,
corkscrew spiral atop, the whole showing like a great piece of
jeweller’s work in a deep, green grove.
Iyeyasu, founder of Yeddo, successor of the Taiko, and military
ruler in the golden age of the arts in Japan, was the first Shogun
buried on Nikko’s sacred hill-side, and it was intended to make the
mortuary temple before his tomb as splendid as the crafts of the day
permitted. His grandson, Iyemitsu, was the next and only other
Shogun interred at Nikko, and his temple fairly rivals that of his
ancestor.
At each shrine rise broad stone steps leading to the first and outer
court-yards, where stand the magnificent gates, exquisitely carved,
set with superb metal plates, and all ablaze with color and gilding.
The eye is confused in the infinite detail of structure and ornament,
and the intricacy of beams and brackets upholding the heavy roofs of
these gate-ways. Walls of red lacquer and gold, with carved and
colored panels topped with black tiles, surround each enclosure, and
through inner and outer courts and gate-ways, growing ever more
and more splendid, the visitor approaches the temples proper, their
soaring roofs, curved gables, and ridge-poles set with the Tokugawa
crest in gold, sharp cut against the forest background. At the lowest
step his shoes are taken off, and he is permitted to wander slowly
through the magnificent buildings on the soft, silk-bordered mats.
Richly panelled ceilings, lacquered pillars, carved walls, and curtains
of the finest split bamboo belong to both alike, and in the gloom of
inner rooms are marvels of carving and decoration, only half visible.
Both temples were once splendid with all the emblems and
trappings of Buddhism, redolent with incense, musical with bells and
gongs, and resounding all day with chanted services. But after the
Restoration, when the Shinto became the state religion and the
Emperor made a pilgrimage to Nikko, Iyeyasu’s temple was stripped
of its splendid altar ornaments, banners, and symbols, and the
simple mirror and bits of paper of the empty Shinto creed were
substituted. In the dark chapel behind the first room there remains a
large gong, whose dark bowl rests on a silken pad, and when softly
struck fills the place with rising and falling, recurring and wavering,
tones of sweetness for five whole minutes, while Ito stands with open
watch and warning finger, and the priest bends low and drinks in the
music with ecstatic countenance. Iyemitsu’s temple was spared, and
there stand the rows of superb lacquered boxes containing the
sacred writings. There, too, are the gilded images, golden lotus-
leaves, massive candlesticks, drums, gongs, banners and pendent
ornaments, besides the giant koros, breathing forth pale clouds of
incense, that accompanied the rites of the grand old Buddhist faith.
INTERIOR OF THE IYEMITSU TEMPLE

Each temple has a fine water-tank in its outer court; an open


pavilion, with solid corner posts supporting the heavy and ornate roof
above the granite trough. Each basin is a single, huge block of
stone, hollowed out and cut with such exactness that the water,
welling up from the bottom, pours over the smooth edges so evenly
as to give it the look of a cube of polished glass. The fountain at the
Iyemitsu temple was the gift of the princes of Nabeshima, and its
eaves flutter with the myriad flags left there by pilgrims who come to
pray at the great shrine. All about the temple grounds is heard the
noise of rushing water, and the music and gurgle of these tiny
streams, the rustle of the high branches, and the cawing of huge
solitary rooks are the only sounds that break the stillness of the
enchanted groves between the soft boomings of the morning and
evening bells. The noise of voices is lost in the great leafy spaces,
and the sacredness of the place subdues even the unbelieving
foreigner, while native tourists and pilgrims move silently, or speak

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