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ADVANCES IN
Ophthalmology
and Optometry
Editor-in-Chief
Myron Yanoff, MD
Chair Emeritus, Department of Ophthalmology, Drexel University,
Adjunct Professor, Department of Ophthalmology,
University of Pennsylvania, Philadelphia, Pennsylvania
ELSEVIER
PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO

ADVANCES IN
Ophthalmology and Optometry
CONTENTS VOLUME 6 2021
Editorial Board vii
Contributors ix
Preface xxvii
Myron Yanoff
In Memoriam xxix
David A. Crandall
Optometry
Optical Coherence Technology in Glaucoma Diagnosis
Joseph Sowka, Jessica Steen, and Greg Caldwell
Introduction 1
Optical coherence tomography retinal nerve fiber layer analysis in
glaucoma diagnosis 2
Optical coherence tomography macular analysis in glaucoma diagnosis 4
Optical coherence tomography angiography in glaucoma diagnosis 7
Clinics care points 10
Disclosure 10
An Update on Neurodegenerative Disease for Eye Care

Providers
Kelly A. Malloy, Erin M. Draper, Ashley Kay Maglione,
Tina Zeng, and Elizabeth Marunde
Introduction: neurodegenerative disease and the eye 13
Neurodegenerative disease definition 13
Varied pathophysiology of neurodegenerative diseases 14
Prevalent visual and ocular associations of neurodegenerative disease 14
Role of eye care providers in neurodegenerative disease 16
Visual and ocular associations of neurodegenerative disease 16
Eyelid function in neurodegenerative disease 16
Anterior segment findings in neurodegenerative disease 20
Posterior segment findings in neurodegenerative disease 21
Afferent visual function in neurodegenerative disease 22
xv
CONTENTS continued
Efferent visual function in neurodegenerative disease 24

Hallucinations in neurodegenerative disease 25
Visual and ocular side effects of neurodegenerative disease treatments 27
Adverse sequela 28
Associated improvement in neurodegenerative disease manifestations 28
Future avenues: neurodegenerative disease, the eye, and the visual system 28
Expected increase in prevalence of neurodegenerative disease 28
Optimal biomarkers involve eyes and vision 31
Summary: neurodegenerative disease, the eye, and the visual system 31
Eye care providers as screeners of neurodegenerative disease 31
Early identification and neurology referral is key 31
Eye care providers help improve quality of life of patients with
neurodegenerative disease 32
Expected surge of research into neurodegenerative disease 34
Disclosure 34
Neuroanatomical Structures in Extraocular Muscles and

Their Potential Implication in the Management of
Strabismus
Jan Richard Bruenech
Introduction 39
Structure and function of human extraocular muscles 40
Sensory receptors in human extraocular muscles 41
Muscle spindles 41
Tendon receptors 41
The role of proprioception in oculomotor control 43
The neural pathway for proprioception 43
The neural substrate for the control of eye movements 44
Binocular vision anomalies 45
Current concepts in the diagnosis and management of strabismus 46
Nonsurgical management of strabismus 46
Optical corrections 46
Neuromuscular stimulation through exercise 47
Surgical management of strabismus 48
Summary and discussion 49
Summary 51
Disclosure 51
Pediatric
Prenatal Diagnosis of Retinoblastoma
Kelsey Chen, Luis F. Goncalves, and
Aparna Ramasubramanian
Introduction 55
Incidence 56
Risk factors 56
xvi
CONTENTS continued
Genetics 56
Tumor staging 57
Treatment 57
Prenatal diagnosis 57
Rationale 57
Prenatal genetic testing 58
Summary 62
Current Management of Pediatric Glaucoma

Sushmita Kaushik, Deepika Dhingra, and Surinder S. Pandav
Introduction 70
Standardized nomenclature 70
Diagnosis 71
Classification 71
Diagnostic techniques 72
Intraocular pressure measurement and current understanding of
its role in pediatric glaucoma 72
Ocular biometry 74
Refractive error 75
Ultrasound biomicroscopy 76
Handheld optical coherence tomography 77
Genetic testing 77
Anesthesia 79
Treatment 79
Medical treatment 79
Surgery 80
Disclosure 83
Systemic Immunomodulatory Therapy in Pediatric

Uveitis
Ilaria Maccora, Ethan S. Sen, and Athimalaipet V. Ramanan
Introduction 87
Significance 89
Current guidelines 89
Recent advances in treatment 89
Disclosure 97
Update on Intravitreal Chemotherapy for

Retinoblastoma
Irem Koç, Hayyam Kiratli, and Bhavna Chawla
Introduction 101
Challenges of endophytic retinoblastoma 102
Treatment of intraocular seeding 102
Safety of intravitreal injections in eyes with retinoblastoma 103
xvii
CONTENTS continued
Classification of seeding 104

Impact of intravitreal injections on patient management 105
Uses of intravitreal chemotherapy other than for vitreous seeds 107
Dosage 107
Pharmacokinetics of intravitreal melphalan 112
Use of intravitreal topotecan 113
Pharmacokinetics of intravitreal topotecan 113
Stability of melphalan and topotecan 114
Future avenues 115
Summary 115
Ophthalmic Pathology & Ocular Oncology
Applications of Plaque Brachytherapy in Posterior

Segment Tumors: A Clinical Review
Puneet Jain, Paul T. Finger, and Bhavna Chawla
Introduction 119
Historical perspective 120
Choroidal hemangioma 121
Management of choroidal hemangioma 122
Management of diffuse choroidal hemangioma 122
Retinal capillary hemangioma 124
Vasoproliferative retinal tumors 125
Retinoblastoma 126
Choroidal melanoma 127
Limitations of plaque brachytherapy 129
Future avenues 129
Methods for dose de-escalation 129
Intraocular Tumors—Advances in Ophthalmic Pathology

Sneha Giridhar, Dipankar Das, and Jyotirmay Biswas
Retinoblastoma 133
Pathology 134
Molecular Pathology 138
Uveal melanoma 138
Pathology 140
Genetics 141
Primary vitreoretinal lymphoma 142
Cytology and immunohistochemistry 142
Molecular features 144
Summary 145
Acknowledgments 145
Disclosure 146
xviii
CONTENTS continued
Adenoid Cystic Carcinoma of the Lacrimal Gland

Nur Khatib, Ioana Catalina Ionescu, Daniel Briscoe, and
Peerooz Saeed
Introduction 147
Significance (in-depth analysis) 148
Signs and symptoms 148
Staging 148
Histopathology 148
Imaging 150
Treatment approach 150
Future avenues 155
Summary 155
Cataract & Refractive Surgery

Micro-Invasive Glaucoma Surgery
David A. Crandall and Candice Yousif
Introduction 159
Significance and current relevance 160
IStent trabecular micro-bypass stent 162
Hydrus microstent 163
Goniotomy-assisted trabeculotomy 165
Trab360 trabeculotomy 166
Trabectome 167
Kahook dual blade 167
Ab interno canaloplasty 168
Visco360 and OMNI 169
XEN gel stent 169
Preserflo 170
Summary 170
Disclosure 172
Vitreoretinal Disease
Artificial Intelligence in Retina

Minh Trinh, Mark Ghassibi, and Ronni Lieberman
Background and introduction 175
Overview of artificial intelligence 176
Evaluating deep learning algorithms 178
Diabetic retinopathy 179
Age-related macular degeneration 181
Future 182
Summary 183
Disclosure 184
xix
CONTENTS continued
Retina in the Age of COVID-19

Samuel Gelnick, Marib Akanda, and Ronni Lieberman
Background 187
Introduction 188
General cleaning and hygiene 188
Personal protective equipment 188
Pandemic restrictions 189
Care in an active pandemic 189
Scheduling visits 189
Precautions for procedures 192
Intravitreal injections 192
Precautions for laser procedures 193
Scheduling follow-up visits 193
Patients with positive screening or testing for COVID-19 194
Care after immediate pandemic restrictions are lifted 195
Continued screening and scheduling precautions 195
Day of appointment precautions 195
Performing elective surgery 196
Operating room precautions 197
Summary 197
Disclosure 198
Diagnostic and Treatment Update on Sickle Cell

Retinopathy
Cesar Alfaro, Ethan K. Sobol, and Robin Ginsburg
Introduction 201
Pathophysiology 202
Epidemiology 202
Ocular manifestations 203
Classification system 205
Diagnosis 206
Optical coherence tomography 207
Optical coherence tomography angiography 207
Ultra-wide fluorescein angiography 209
Management 210
Screening 210
Laser 210
Anti-vascular endothelial growth factor 211
Surgical treatment 212
Summary 212
Glaucoma
Glaucoma Surgery: Which Surgery to Pick for Your

Patient?
Rabea Kassem and Paul Harasymowycz
xx
CONTENTS continued
Introduction 218
Significance 218
Subconjunctival surgery 219
When not to opt for subconjunctival surgery? 219
Nonpenetrating glaucoma surgery 219
Trabeculectomy 222
XEN Gel Implant (Allergan Inc, Irvine, CA, USA) 222
Preserflo Microshunt (Santen Pharmaceutical Co Ltd, Osaka,
Japan) 223
Tube shunts 223
Cyclodestructive procedures 224
Schlemm canal–based procedures 225
Selective laser trabeculoplasty 225
Schlemm canal-based microinvasive glaucoma surgery 226
Suprachoroidal 231
CyPass (Alcon, Fort Worth, TX, USA) 231
Special considerations 231
Patients with very advanced disease 231
Patients with very high intraocular pressure 232
Patients with angle-closure glaucoma 232
Primary angle closure 233
Primary angle-closure glaucoma 233
Patients with neovascular glaucoma 234
Reoperation after failed glaucoma surgery 234
Current relevance and future avenues 236
Summary 239
Disclosure 241
Ocular Blood Flow as It Relates to Race and Disease on

Glaucoma
Brent Siesky, Alon Harris, Alice C. Verticchio Vercellin,
Giovanna Guidoboni, and James C. Tsai
Introduction 245
Significance 246
Racial disparities in glaucoma 248
Mechanisms behind racial disparities in glaucoma 248
Summary 258
Clinical care points 259
Funding 259
Financial disclosures 259
Neuro-ophthalmology
Glaucoma as a Neurodegenerative Disease: A Clinician

Perspective
Noel C.Y. Chan and Jane W. Chan
Introduction 263
xxi
CONTENTS continued
Is glaucoma a neurodegenerative disease? 264

Sick eye comes with a sick brain 264
Common clinical characteristics between glaucoma and
Overlapping pathophysiology between glaucoma and other
Neuroinflammation 267
Oxidative stress and mitochondrial dysfunction 267
Dysregulation of calcium dependent process 268
Alterations of autophagy machinery 268
Misfolding of proteins 268
Activation of glia 269
Glaucoma and cerebrospinal fluid 269
Looking into the future 269
Summary 270
Disclosure 271
Neuro-Ophthalmologic Manifestations of Novel

Coronavirus
Devin Betsch and Paul R. Freund
Introduction 275
Article body 276
Neuro-ophthalmic presentations 276
Management changes 282
Relevance 284
Summary 285
Disclosure 285
Cornea and External Diseases
Advances in Endothelial Keratoplasty Surgery

Ariel Chen, Daniel Choi, and Michael E. Sulewski Jr.
Introduction 289
Significance 290
Lamellar keratoplasty 290
Descemet stripping endothelial keratoplasty 293
Descemet’s membrane endothelial keratoplasty 295
Descemetorhexis without endothelial keratoplasty 298
Relevance and future avenues 298
Summary 301
Disclosure 302
Update in the Management of Keratoconus

Enny Oyeniran and Zujaja Tauqeer
xxii
CONTENTS continued
Introduction 307
Corneal cross-linking 310
Spectacles and contact lenses 313
Scleral contact lenses 315
Intrastromal corneal ring segments 317
Penetrating keratoplasty 319
Deep anterior lamellar keratoplasty 320
Summary 320
Disclosure 321
Update on Refractive Surgery

Tianyu Liu, Brian M. Shafer, and Vance Thompson
Introduction 325
Significance and in-depth analysis of the topic 326
Corneal refractive surgery 326
Intraocular refractive surgery 328
Treatment of presbyopia 330
Current relevance and future avenues to investigate the topic 332
Management of higher-order aberrations: wavefront-optimized,
wavefront-guided, and topography-guided laser ablation 332
Advances in refractive lenticule surgery 333
Accommodative intraocular lens 334
Summary 336
Disclosure 337
Oculoplastics
Xanthelasma Palpebrarum: An Oculoplastic Viewpoint of
Optimal Treatment
Liron Pe’er and Arie Y. Nemet
Introduction 341
Significance (in-depth analysis) 342
Pathophysiology 342
Treatment 343
Surgical or laser treatment 349
Discussion 350
The location 350
Nasal lower eyelid-primary 351
Lesion extending to temporal lower lid 352
Extensive lower lid lesions 352
Nasal bridge 352
Giant xanthelasmas 353
xxiii
CONTENTS continued
Refractive Error Changes Associated with Eyelid Weight

Placement
Cat N. Burkat and Susan Luo
Introduction 358
Significance 359
Efficacy of upper eyelid weight placement 359
Causes of lagophthalmos 360
Operative technique 360
Complications of upper eyelid loading 360
Refractive error changes 360
Transition to platinum 368
Cost of platinum versus gold 368
Future avenues 369
Summary 369
Acknowledgments 371
Disclosure 371
Refractive Change after Upper Eyelid Surgery

Chintan A. Pathak, Nenita Maganti, and Cat N. Burkat
Introduction 373
Preoperative changes 375
Postoperative changes 376
Clinical relevance 377
Acknowledgments 378
Canalicular Stenosis Secondary to Chemotherapeutic

Agents
Nenita Maganti, Chintan A. Pathak, and Cat N. Burkat
Introduction 379
Chemotherapeutic agents known to cause canalicular stenosis 380
5-Fluorouracil 380
Mitomycin-C 381
Docetaxel 381
Significance of epiphora secondary to canalicular abnormality 382
Management of canalicular stenosis 382
Summary 386
Acknowledgments 387
Uveitis
Optical Coherence Tomography Angiography in White Dot

Syndromes
Karl N. Becker, Angeline C. Rivkin, and Pooja V. Bhat
xxiv
CONTENTS continued
Introduction 391
Overview 392
Cross-sectional and en face visualizations of the posterior circulation 393
Birdshot chorioretinopathy 394
Multiple evanescent white dot syndrome 395
Punctate inner choroiditis 396
Serpiginous choroiditis 397
Acute posterior multifocal placoid pigment epitheliopathy 398
Acute zonal occult outer retinopathy 399
Multifocal choroiditis 400
Summary 401
xxv
ADVANCES IN
Ophthalmology and Optometry
Editor-in-Chief
MYRON YANOFF, MD, Chair Emeritus, Department of Ophthalmology, Drexel Uni-
versity, Adjunct Professor, Department of Ophthalmology, University of Penn-
sylvania, Philadelphia, Pennsylvania
Section Editors
BHAVNA CHAWLA, MD – Ophthalmic Pathology & Ocular Oncology
RP Center for Ophthalmic Sciences, All India Institute of
Medical Sciences, New Delhi, India
DAVID A. CRANDALL, MD – Cataract & Refractive Surgery

Glaucoma Fellowship Director, Henry Ford Health System, Detroit, Michigan
University of Utah, Salt Lake City, Wayne State University, Salt Lake City, Utah
PAUL B. FREEMAN, OD, FAAO, FCOVD – Optometry

Diplomate, Low Vision, Pittsburgh, Pennsylvania, Clinical Professor, Rosenberg
School of Optometry, University of the Incarnate, Word, San Antonio, Texas
MORRIS E. HARTSTEIN, MD, FACS – Oculoplastics

Director, Ophthalmic Plastic and Reconstructive Surgery, Ophthalmology, Shamir
Medical Center, Zerifin, Israel; Tel Aviv University, Sackler School of Medicine,
Tel Aviv, Israel
RUSTUM KARANJIA, MD, PhD, FRCSC, DABO – Neuro-ophthalmology

Department of Ophthalmology, David Geffen School of Medicine at
UCLA, Los Angeles, California; Doheny Eye Institute, Los Angeles,
California, Doheny Eye Institute, Los Angeles, California, Department of Oph-
thalmology, University of Ottawa, Ottawa, Ontario, Canada, Ottawa Hospital
Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
RONNI M. LIEBERMAN, MD – Vitreoretinal Disease

Assistant Professor of Ophthalmology, Icahn School of Medicine at Mt. Sinai,
Queens Hospital Center, Jamaica, New York
ANN-MARIE LOBO, MD – Uveitis

Co-Director, Uveitis Service, Assistant Professor, Department of
Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary,
University of Illinois at Chicago, Chicago, Ilinois
vii
SECTION EDITORS continued
STEPHEN ORLIN, MD – Cornea and External Diseases

Associate Professor, Scheie Eye Institute, University of Pennsylvania, Perelman
School of Medicine, Philadelphia, Pennsylvania
JOSEPH M. ORTIZ, MD, FRCOphth – Glaucoma

Consultant in Ophthalmology, Sacred Heart Hospital, Allentown,
Pennsylvania; Consultant in Ophthalmology, Abington Memorial Hospital,
Abington, Pennsylvania; Formerly Assistant Professor of Ophthalmology,
Hahnemann University Hospital, Drexel University School of Medicine,
Philadelphia, Pennsylvania
LEONARD J. PRESS, OD, FAAO, FCOVD – Optometry

Press Consulting, P.C., Lakewood, New Jersey; Adjunct Professor, Southern
College of Optometry, Memphis, Tennessee
APARNA RAMASUBRAMANIAN, MD – Pediatric Ophthalmology

Director of Retinoblasma and Ocular Oncology, Phoenix Children’s Hospital,
Phoenix, Arizona
viii
Director, Continuity Publishing: Dolores Meloni
Editor: Lauren Boyle
Developmental Editor: Jessica Cañaberal
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Advances in Ophthalmology and Optometry 6 (2021) xxix–xxxi
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
In Memoriam
IN MEMORY OF DR ALAN CRANDALL
W
e were extremely saddened to hear about the passing of Dr Alan
Crandall, renown ophthalmologist and internationally known hu-
manitarian, this past October. Dr Crandall was a founding member
of Advances in Ophthalmology and Optometry and has served as our Cataracts Sec-
tion Editor for the last five consecutive issues of publication. Dr Crandall’s
boundless expertise and commitment to the publication have, without a doubt,
helped us grow the series into a true and trusted resource for our readers, cli-
nicians around the world. We wanted to acknowledge his passing with some
words of tribute from our Editor-in-Chief, Dr Myron Yanoff, as well as from
Dr Crandall’s son, Dr David A. Crandall.
Even as a resident, Alan stood out as being a very special person. So special that
at the end of his residency, I asked him to stay on staff. He accepted. Whatever
he did, he did it well with a sparkle in his eyes. Whether patient care, surgical
prowess, or my tennis partner, he was a joy to be with. After a few years on
staff, we decided that it was time to perform intraocular lens implantation at the
Scheie Eye Institute (only intracapsular cataract extraction was done by the full-
time staff). We operated together and taught ourselves first to do extracapsular
surgery and then entered into the world of lens implants (all under an air bubble,
as Healon had not yet been invented). Alan was a brilliant surgeon, a gifted
clinician, and a personality that made one wish to work with him. One of my
https://doi.org/10.1016/j.yaoo.2021.05.002
2452-1760/21/ª 2021 Published by Elsevier Inc.
xxx IN MEMORIAM
saddest days was when Alan decided that it would be best for his family for him
to leave and go back to where he grew up in Salt Lake City.
We remained fast friends until the end. In fact, a year before he left us, he removed
my cataracts (I would have no other cataract surgeon anywhere do the surgery),
of course, with perfect results. Each year at the American Academy of
Ophthalmology meeting, we would have dinner together the night before the
meeting started. I cherished our friendship. I also marveled at his other en-
deavors. He trained hundreds of surgeons around the world and performed
countless free surgeries to restore sight in Utah, on the Navajo Nation, and in
more than 20 countries, including Ghana, Nepal, and South Sudan. Among
many awards, he received the AAO Humanitarian Award, the American So-
ciety of Cataract and Refractive Surgery (ASCRS) Humanitarian Award, and the
inaugural ASCRS Foundation Chang Humanitarian Award.
Alan has left a legacy that few other ophthalmologists even come close to. He left
this world a better place than he found it. He certainly is missed, but his teaching
and training live on. He still lives on in my mind, and always will.
Myron Yanoff, MD
Chair Emeritus
Department of Ophthalmology
Drexel University
Adjunct Professor
Department of Ophthalmology
University of Pennsylvania
Philadelphia, Pennsylvania
E-mail address: myanoff4@gmail.com
Like most children growing up, I did not have a strong sense of my father’s day-to-
day life. I knew that he worked long hours. I knew that he often went in on
weekends to see patients. I knew that he often brought home charts for dicta-
tions, slides to review, and surgical videos. He would have the videos playing
while we worked out in the evening (my siblings and I all knew the steps of
cataract surgery before we had finished high school). As I got older, I came to
appreciate that he did this because he loved what he was doing.
Dad always wanted everyone around him to be happy. For myself and my sib-
lings, he wanted us to find something we enjoyed doing, something that we
would want to do every day, and then strive to be the best at it that we could. He
never made any effort to push me into ophthalmology, or even medicine, except
by the example he provided. The joy he had in his work helped me decide my
path. I’m so thankful this gave me the opportunity to work with him at meetings
and on outreach surgical trips.
He always encouraged me to push myself surgically, always saying, ‘‘oh yeah,
you have the skills to do that,’’ when I would discuss tough cases or new
techniques with him. In him, I had the ultimate phone support for these hard
cases and hard decisions. I knew he would answer any time I called with
questions. Many know that this was not a special benefit I had by being family.
He would do that for anyone who called him at any time.
IN MEMORIAM xxxi
He cast an enormous shadow in ophthalmology, one that I long ago accepted I

would never get out of, but I can continue to do what he wanted, which is to try
to make the world around me better and to be the best I can be. The world (and
my personal world) is poorer for his loss, but rich in the legacy he has left for us.
David A. Crandall, MD
Glaucoma Fellowship Director
Henry Ford Health System
Detroit, Michigan
University of Utah
Salt Lake City, Utah
Wayne State University

Salt Lake City, Utah
Advances in Ophthalmology and Optometry 6 (2021) xxvii
Preface
Myron Yanoff, MD
Editor
I
n Volume 6 of Advances in Ophthalmology and Optometry, we again have asked
experts in each of the pertinent fields to sift through the current literature to
give us insights on the latest developments, such as: Optical Coherence
Technology in Glaucoma Diagnosis; Prenatal Diagnosis of Retinoblastoma;
Systemic Immunomodulatory Therapy in Pediatric Uveitis; Update on Intra-
vitreal Chemotherapy for Retinoblastoma; Microinvasive Glaucoma Surgery;
Artificial Intelligence in Retina; Artificial Intelligence in Neuroophthalmology
Review; Retina in the Age of COVID-19; Neuroophthalmologic Manifesta-
tions of Novel Coronavirus; Advances in Endothelial Keratoplasty Surgery;
Adenoid Cystic Carcinoma of the Lacrimal Gland; Refractive Error Changes
Associated with Eyelid Weight Placement; Optical Coherence Tomography
Angiography in White Dot Syndromes; and much more.
We continue to explore the new ideas, new treatments, and new ways of do-
ing things to give us a fresh frame of reference to sort through the crush of data
and to make sense in a real way of how to proceed.
Myron Yanoff, MD
1915 Foulkeways
Gwynedd, PA 19436, USA
E-mail address: myanoff4@gmail.com
2452-1760/21/ª 2021 Published by Elsevier Inc.
Advances in Ophthalmology and Optometry 6 (2021) 263–274
Glaucoma as a
Neurodegenerative Disease
A Clinician Perspective
Noel C.Y. Chan, MBChB, FRCSEda,b,*, Jane W. Chan, MDc

a
Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital & Alice Ho Miu Ling
Nethersole Hospital, 1/F, Eye Center, Prince of Wales Hospital, Shatin, HKSAR, China; bDe-
partment of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, HKSAR,
China; cDoheny Eye Institute, Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA
90033, USA
Keywords
Glaucoma Neurodegenerative Neuroprotection Retinal ganglion cells
Neuro-ophthalmology
Key points
Glaucoma is a neurodegenerative disease with changes in other parts of the
central nervous system. Glaucoma should be viewed as a dichotomy, as a sole
disease of the eye, not as a primary neurologic disease.
Intraocular pressure, cerebrospinal fluid pressure, translaminar cribrosa pres-
sure, as well as other ocular or systemic risk factors all play an intricate role in the
disease development and progression.
A neurologic perspective is crucial for clinicians to understand retinal ganglion
cell insult, subsequent brain damage, and concomitant functional morbidity in the
glaucoma patient. It may bring insights into future therapeutic innovations and
open up opportunities for better patient care.
INTRODUCTION
Rather than being considered primarily an eye disease, glaucoma is increas-
ingly being recognized as a neurodegenerative disease in recent years. This
transition is further propagated by the increasing awareness of the existence
of normal tension glaucoma (NTG) and the recognition of the presence of
*Corresponding author. 1/F, Eye Center, Prince of Wales Hospital, Shatin, HKSAR, China.
E-mail address: noelccy@gmail.com
2452-1760/21/ª 2021 Elsevier Inc. All rights reserved.
264 CHAN & CHAN
non-intraocular pressure (IOP) -dependent risk factors. Despite the paradigm

shift in thinking, controversies persist as to whether glaucoma should be
viewed as a neurologic disease.
IS GLAUCOMA A NEURODEGENERATIVE DISEASE?

Neurodegenerative disease classically is characterized by selective loss of a spe-
cific neuron population with subsequent progressive functional decline. Clas-
sical examples include Parkinson disease (PD), Alzheimer disease (AD),
amyotrophic lateral sclerosis (ALS), and Huntington disease (HD). Anatomi-
cally and developmentally, the optic nerve should not be considered a nerve
but rather an extension of the brain with retinal ganglion cells (RGC) represent-
ing a specialized part of the central nervous system. Glaucoma is a progressive
optic neuropathy resulting from a decrease in axonal transportation with sub-
sequent loss of RGC, resulting in irreversible visual loss [1]. In this context, it is
not difficult to understand why glaucoma is a neurodegenerative disease.
Increasing evidence shows that glaucoma shares similar pathophysiological
mechanisms as other neurodegenerative diseases. The question of interest is
whether glaucoma begins as a brain disease and, second, whether glaucoma
is related to other neurodegenerative diseases.
SICK EYE COMES WITH A SICK BRAIN

Like other axons, damage of the RGC will result in both anterograde and retro-
grade axonal degeneration of the injured tract proximally and distally through
transsynaptic degenerative processes. In glaucoma, where RGC is the primary
injured site, retrograde degeneration will lead to a loss in the cell bodies in the
retina, whereas anterograde (or Wallerian) degeneration will result in degener-
ative changes of all the connected visual pathways [2]. Evidence exists that
physiologic or functional abnormalities account for the reduction of retrograde
transportation before structural loss and axonal dystrophy become apparent
[3]. Instead of an ocular disease, it is important to perceive glaucoma as a dis-
order of visual neurons of the eye as well as the brain. This concept will help
understand the progressive nature of the disease and the importance of compre-
hensive treatment strategies in the future to prevent visual loss in glaucoma [4].
Experimental models in primates have demonstrated loss of magnocellular
and parvocellular lateral geniculate nucleus (LGN) neurons in glaucoma
when compared with controls. Studies also were able to indicate that the loss
of LGN neuronal area follows a linear pattern with increasing mean IOP or
optic nerve fiber loss [5], and that a higher mean IOP reduced the period dur-
ing which these changes occur [6]. Evidence shows that these visual pathway
disturbances in glaucoma is a relatively early phenomenon, as decreased den-
tritic complexity of LGN neurons can occur with elevated IOP without detect-
able optic nerve fiber loss in primate glaucoma [7]. Elevated IOP with or
without optic nerve fiber loss also reduced the expression of a major postsyn-
aptic density protein in the koniocellular neurons [8], leading to the theory of
impaired transsynaptic changes in LGN in early glaucoma.
GLAUCOMA AS A NEURODEGENERATIVE DISEASE 265
Beyond the LGN, a postmortem case report has shown pathologic evidence
of neural degeneration in multiple vision stations within the brain, including
the visual cortex in the presence of advanced glaucoma with 50% visual field
loss [9]. Neuroimaging studies are now able to measure LGN volume and
objectively document LGN atrophy in patients with glaucoma with the extent
correlating to clinical stage [10]. Compared with normal controls, diffusion
tensor imaging of the visual pathway using a 3-T MRI has further confirmed
radiological evidence of neurodegeneration of the optic tracts and optic radia-
tions [11] as well as occipital white matter [12] in primary open-angle glaucoma
(POAG) patients. High-resolution structural MRI detected significant bilateral
cortical thinning in the anterior half of the visual cortex around the calcarine
sulci and in some smaller regions located in the left middle temporal gyrus,
and fusiform gyrus of which the reduction of visual cortex thickness correlated
positively with the retinal nerve fiber layer (RNFL) thickness [13]. With the
advent of functional MRI (fMRI), function-specific neuronal activity of the vi-
sual afferent pathways can be assessed in glaucoma patients noninvasively
in vivo. By using fMRI signals to assess cortical function, blood oxygen
level–dependent signal in visual cortex was found to be altered for patients
with POAG in a manner consistent with the loss of visual function [14].
Although one may consider the atrophy of the relaying visual pathway as
part of the anterograde degeneration from RGC, there are intracranial changes
for which transsynaptic degeneration cannot account. Three-dimensional MRI
has revealed widespread abnormalities in the central nervous system beyond
the visual cortex with significant reduction of bilateral gray-matter volume in
lingual gyrus, calcarine gyrus, postcentral gyrus, right cuneus, right inferior oc-
cipital gyrus, left occipital gyrus, left paracentral lobule, and right supramargi-
nal gyrus [15]. More recent imaging study using multimodal MRI has
demonstrated anatomic and functional connectivity changes since early glau-
coma in visual as well as nonvisual systems, such as working memory net-
works and subcortical networks, whereas atrophy is confined to severe stage
[16]. These widespread disruptions of anatomic connectivity and altered func-
tional connectivity beyond the visual system can be detected from the early
stage of disease. A more recent cross-sectional observational study using multi-
modal MRI has demonstrated that, like inner retinal layer or RNFL thinning,
reduced visual cortex activity occurred at a tipping point long before visual
field impairment in glaucoma patients. Primary visual cortex was found to
be more severely affected than higher-order cortical region in glaucoma,
whereas its activity loss has a stronger association with RNFL thinning than
ganglion cell inner plexiform layer thinning. However, further longitudinal
studies are required, as the decreased visual cortex activation could be second-
ary to reduced retinal visual input in established glaucoma patients.
Intracranial vascular changes were also identified in glaucoma patients. Case
control studies using MRI have shown an increased number of white-matter
hyperintense lesions (a reflection of covert vascular brain injury) in POAG pa-
tients [17] and diffuse cerebral small-vessel ischemic changes in NTG [18]. The
266 CHAN & CHAN
potential ischemic pathophysiological basis in low-tension glaucoma is further

supported by the findings of a greater extent of cerebral infarcts and corpus cal-
losum atrophy in this group of patients [19]. NTG patients with ischemic
changes in the brain MRI also were found to have more depressed inferior peri-
central visual fields [20]. The authors’ group has shown that the most common
location of silent cerebral infarction (SCI) in NTG patients was at the basal
ganglia, and SCI may be an independent risk factor for visual field progression
in patients with NTG [21]. Besides brain volume, glaucoma patients were noted
to have lower middle cerebral artery blood flow velocities and an absence of
vasoreactivity to hyperoxia compared with controls [22]. This finding sug-
gested that diminished central visual function may be 1 manifestation of wide-
spread cerebrovascular insufficiency in certain POAG patients.
COMMON CLINICAL CHARACTERISTICS BETWEEN GLAUCOMA

AND NEURODEGENERATIVE DISEASE
Besides intracranial changes in glaucoma patients, one can easily identify com-
mon clinical features shared between glaucoma and other neurodegenerative
diseases, including insidious onset with preclinical stage, progressive nature,
increased incidence with age, predisposing genetic susceptibility, and early
functional deficit preceding loss of neuronal substrates. Despite the heteroge-
neous phenotypes, there is a predilection of specific target population cells in
each of the different neurodegenerative diseases. AD affects hippocampal
and cortical neurons; PD affects nigrostriatal dopaminergic neurons; ALS af-
fects upper and lower motor neurons, while glaucoma affects RGC [23].
Epidemiologic studies have examined the hypothesis of the connection between
glaucoma and other neurodegenerative diseases. The occurrence rate of glaucoma
in AD patients was found to be higher than age-matched controls (23.8%–25.9% vs
5.2%–9.9%) in the absence of altered IOP levels [24–27]. Similarly, incidence of
glaucoma was noted to be higher in PD patients (16%-23.7% vs 6.5%–6.6%) despite
a normal or low IOP [25]. Besides abnormal glaucomatous visual fields, PD pa-
tients were found to have significantly reduced RNFL and macular ganglion cell
volume [28]. Conversely, a retrospective population-based cohort of patients
aged 60 or over reported that patients with POAG have a higher risk of developing
AD but not PD [29]. These observations may suggest similarities between AD and
POAG at a molecular or pathophysiological level. However, other nationwide co-
horts did not find any increased risk of AD in POAG patients [30]. Later, a meta-
analysis concluded that the association of AD and glaucoma is heterogenous, and
further studies are warranted to clarify the association [31]. On the other hand, a
weak association between glaucoma and dementia was being identified [32],
whereas a prospective study confirmed the finding and noted that POAG patients
were 4 times more likely to develop dementia after adjusting for age, gender, edu-
cation, family history, vascular comorbidities, and apolipoprotein E-e4 [33]. The
actual mechanisms contributing to this association are not fully understood, but
the adjustment analysis suggests that vascular risk factors are not the sole mecha-
nism [32,33].
OVERLAPPING PATHOPHYSIOLOGY BETWEEN GLAUCOMA

AND OTHER NEURODEGENERATIVE DISEASE
Different neurodegenerative diseases share common pathogenic mechanisms
leading to impaired axonal transportation, neuronal apoptosis, and eventual
neuronal death. Emerging evidence suggests that glaucoma bears striking sim-
ilarities in the pathophysiology, including neuroinflammation, oxidative stress,
mitochondrial dysfunction, disrupted calcium homeostasis, alteration of auto-
phagy machinery, protein misfolding, and glial activation.
Neuroinflammation
Neuroinflammation is one of the major contributors in the development of
chronic neurodegenerative diseases like AD and PD. Similarly, mounting evi-
dence suggests neuroinflammation is a key process in the pathogenesis of glau-
coma. In the past, neuroinflammatory process was thought to be a result
instead of a causative factor in neuronal death. Epidemiologic studies indicate
that prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) can pre-
vent or delay the development of AD [34] and PD [35]. However, randomized
controlled trials and meta-analysis failed to demonstrate the efficacy of NSAIDs
in the treatment of AD [36]. Ongoing research has led to the identification of
the pivotal molecule in the inflammatory process of AD, such as glycogen syn-
thase kinase-3 or nuclear factor-jB (NF-jB) [37,38]. Phase I and IIa clinical tri-
als suggested that tumor necrosis factor-a inhibitors might slow down cognitive
decline and improve daily activities in AD patients [39].
Unlike in AD and PD, the precise role of neuroinflammation in glaucoma is
yet to be identified. The RGC axons at the optic nerve head were thought to be
the site of initial insult, as evident by the infiltration of leukocytes into the optic
nerve head [40]. Although the initial trigger is unknown, mechanical alterations
at the lamina cribrosa, direct pressure on RGC, and activation of glial cells (as-
trocytes and/or microglia) are potential factors to drive this damage. Blood
samples from patients with glaucoma have indicated abnormal T-cell subsets
and increased cytokines levels [41,42]. Compared with nonglaucoma controls,
higher levels of pro-inflammatory cytokines have been found in the aqueous
humor of glaucoma patients [43,44]. Further advancement in the understand-
ing of the role of neuroinflammation in glaucoma may eventually open up
an opportunity for future treatment in this aspect.
Oxidative stress and mitochondrial dysfunction
Because of the high oxygen consumption of human brain and neurons, the cen-
tral nervous system is especially susceptible to oxidative stress. Mitochondrial
dysfunction and overproduction of reactive oxygen species (ROS) are common
pathogenic mechanisms in AD, PD, ALS, and HD. Oxidative stress is associ-
ated with amyloid b accumulation in AD and played an important role in
PD. RGC also are susceptible to oxidative stress, as they are very thin and
yet metabolically demanding, which is a disadvantage should available ATP
diminish rapidly. Over time, light exposure to RGC promotes photo interac-
tions, resulting in accelerated breakdown of endogenous antioxidant repair
268 CHAN & CHAN
machinery of the mitochondria. There is cumulating evidence to support the

involvement of oxidative stress as a component of glaucomatous neurodegen-
eration [45]. It has been shown that increased generation of ROS within RGCs
from mitochondrial stress and DNA damage occurs early in glaucoma.
Without altering IOP, oral administration of vitamin B3 (NAD þ precursor
nicotinamide) has been shown to be protective both prophylactically and inter-
ventionally against glaucoma development and RGC soma loss [46]. A pro-
spective population-based study in a glaucoma cohort of 3500 individuals
revealed an association between low dietary intake of antioxidant (including
retinol equivalents and vitamin B1) and a higher risk of open-angle glaucoma
[47]. The exact pathogenic mechanism of oxidative stress in RGC loss was not
fully understood. Besides direct cytotoxic effect, it is now thought that ROS can
cause secondary RGC death via modulation of signaling pathway, dysfunction
of glial cells, and activation of immune responses.
Dysregulation of calcium dependent process

Another important component of axonopathy across neurodegenerative dis-
ease is increased influx of extracellular Ca2þ, which triggers cytoskeletal degra-
dation through enzymatic activity and eventually cell death. In glaucoma,
cleavage of calcineurin (a Ca2þ-dependent protein phosphatase) occurs in
response to elevated IOP, and calpains (a class of Ca2þ-dependent protease)
are activated in RGC in experimental models [7,48], resulting in the break-
down of protein substrates. Delineating the role of specific Ca2þ-dependent
neurochemical cascades in neurodegeneration in glaucoma IS important for
future development of interventions [49].
Alterations of autophagy machinery

Autophagy is important for the clearance of intracellular components and recy-
cling of anabolic resources. Excellent reviews have uncovered the emerging
relationship between autophagy and various neurodegenerative diseases,
including AD, PD, HD, ALS, and frontotemporal dementia [50]. Recent liter-
ature has shown that acute IOP elevation can induce a reduction of LC3II and
beclin 1, 2 specific markers of autophagy, suggesting the role of IOP in disrupt-
ing autophagic mechanism [51].
Misfolding of proteins
Error in protein conformation is one of the common features in the pathogen-
esis of neurodegenerative disease. Examples include Lewy bodies in PD and
Pick bodies in frontotemporal dementia. In AD, tau protein is abnormally
phosphorylated to form extracellular b-amyloid plaques, which now are the
current target component for drug development. Amyloid precursor protein
(APP) is the most abundant protein in the optic nerve. Animal glaucoma
models were able to demonstrate abnormal APP processing, and neurotoxic
amyloid accumulation, while directly targeting the formation of amyloid-b,
has shown promise in preserving RGC [52].
Activation of glia
The presence of A large number of activated microglia and astroglia (gliosis) is
a hallmark of neurodegeneration. Over the years, in vivo and in vitro studies
have characterized the changes in quiescent astrocytes that lead to reactive
phenotype in glaucoma. In glaucomatous human eyes, there is immunohisto-
logical and immunohistochemical evidence of retinal glial cells activation
when compared with controls [53]. It has been proposed that activated astro-
cytes at the optic nerve are capable of secreting matrix metalloproteases and
signal a variety of cytokines that may result in optic nerve excavation in glau-
coma [54]. Reactive astrocytes can cause remodeling of the optic nerve head
and result in a nonsupportive environment for the survival of RGC axons
and thus glaucomatous progression.
GLAUCOMA AND CEREBROSPINAL FLUID

Almost a decade ago, a retrospective case control study identified glaucoma pa-
tients to have significantly lower cerebral spinal fluid (CSF) pressure in POAG
and NTG patients, whereas CSF pressure is higher in ocular hypertension. The
investigators suggested a contributory role of CSF pressure in the pathogenesis
of open-angle glaucoma [55]. The low CSF pressure in glaucomatous eyes was
later confirmed in a prospective interventional study, and translamina cribrosa
pressure difference (TLCPD) (IOP minus CSF pressure) was higher in NTG
than POAG patients [56]. The group was able to show a positive correlation
between TLCPD and the extent of glaucomatous visual field loss and neurore-
tinal rim loss [56,57]. A recent meta-analysis has echoed the finding of high
TLCPD in NTG and POAG patients [58]. This topic has been heavily re-
viewed, and it is hypothesized that an elevated TLCPD produces posterior
bowing of the lamina cribrosa and disc excavation in some of the glaucoma pa-
tients [59]. Surely, there are other factors other than TLCPD in the pathogen-
esis of glaucoma, but it is becoming more acceptable nowadays that TLCPD is
a contributory factor in glaucomatous development and progression. Interest-
ingly, CSF pressure was shown to have a positive linear relationship with
body mass index [60]. As low CSF pressure plays a contributory role in glau-
coma, it has then put NTG as a conceptual opposite to idiopathic intracranial
hypertension, which is a neurologic disease.
LOOKING INTO THE FUTURE

An N-methyl-D-aspartate glutamate receptor antagonist was the first drug
approved for use as a neuroprotective agent in moderate and severe Alzheimer
dementia. Despite its protective effect against RGC loss in animal glaucoma
models, unfortunately, a clinical trial in human glaucoma did not show a benefit.
a2-Adrenergic activation was first shown to be neuroprotective in animal models
of focal cerebral ischemia, and patients randomized to monotherapy of brimoni-
dine (a2-agonist) were reported to have less visual field progression than patients
being put on Timolol despite a similar IOP-lowering effect [61]. However, topical
administration of brimonidine is accompanied with high incidence of local side
270 CHAN & CHAN
effects and poor compliance rate. A novel delivery system of brimonidine using a
surgical implant has been developed and was approved by the Food and Drug
Administration for intracameral administration. Several other clinical trials are un-
derway exploring novel therapies to improve RGC survival, protect, or rebuild
RGC connections, and enhancing RGC function [62]. Antioxidant treatment or
gene therapy, such as administration of adenoviral vector modified with neuro-
protective candidate, may become important future adjunctive strategies for cyto-
protection against apoptotic RGC body death in early or advanced glaucoma [63].
No doubt neuroscience-based approaches in understanding the pathogenesis
of glaucoma have opened up the opportunity for new therapies. Upcoming im-
aging techniques for detecting RGC apoptotic cells are important in the evalu-
ation of these new neuroprotective therapies. Cordeiro and colleagues [64]
have reported in vivo visualization of neuronal apoptosis in glaucoma patients
using intravenous injection of an infrared fluorescently labeled dye followed by
retinal imaging using specific wavelengths. This new imaging technique DARC
(detection of apoptosis of retinal cells) can serve as a potential surrogate marker
in detecting and monitoring glaucomatous neurodegeneration.
In the past decade, gene therapy has been represented as a potential tool in
terms of neuroprotection and neuron regeneration via modulation of key mo-
lecular pathways dictating RGC survival. As there are heterogenic factors
contributing to RGC death in glaucoma, gene therapy has the advantage of
tackling multiple pathways simultaneously. Preclinical studies have demon-
strated success in the modulation of neurotrophic factor or antioxidant expres-
sion and blockade of intrinsic apoptotic pathway using recombinant viral
vectors, such as adeno-associated virus. As the list of candidate genes continues
to expand, better patient stratification in future glaucoma practice is expected to
enable more personalized and effective treatment [65].
SUMMARY
Although high IOP is no longer required in the diagnosis of glaucoma, it remains
the only modifiable risk factor proven to decrease risk of onset and progression.
Studies have revealed that despite aggressive IOP lowering, glaucomatous pro-
gression appeared inevitable in some patients. Acknowledging glaucoma as a
neurodegenerative disease and understanding the neuropathological processes
are crucial in the development of complementary glaucoma treatment.
CLINICS CARE POINTS
Early recognition and treatment of glaucoma patients are important in prevent-

ing irreversible neurodegeneration as well as brain insult. Better imaging tech-
niques are needed to detect and monitor apoptosis of retinal ganglion cells.
By acknowledging glaucoma as a neurodegenerative disease, clinicians must

be aware of intraocular pressure as an independent risk factor when managing
a patient with progressive glaucomatous loss despite good intraocular pressure
control.
Clinicians should watch out for the latest developments in neuroprotection and
gene therapy for glaucoma patients.
Disclosure
The authors have nothing to disclose.
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Another random document with
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both upper and lower radial nervules uniting with the posterior branch of
the subcostal. It has been treated as a moth by several entomologists.
Aurivillius considers that it is certainly a butterfly; but as the
metamorphoses are unknown, we cannot yet form a final opinion as to
this curious form. The extraordinary Peruvian Insect, Styx infernalis, is
also placed in this family by Staudinger; it is a small, pale Insect, almost
white, and with imperfect scales; a little recalling a Satyrid. It appears to
be synthetic to Pieridae and Erycinidae.
Fig. 180—Pupation of the Orange-tip butterfly, Euchloe cardamines. A,

The completed pupa; B, the larva, with its girdle, prepared for the
change.
The caterpillars of Pieridae are perhaps the least remarkable or

attractive of all butterfly-caterpillars; their skins are as a rule bare, or
covered only with fine, short down or hair; their prevalent colour is
green, more or less speckled with black and yellow, and they are
destitute of any prominent peculiarities of external structure. Pupation is
accomplished by the larva fixing itself to some solid body by the
posterior extremity, with the head upwards (or the position may be
horizontal), and then placing a girdle round the middle of the body. The
pupa never hangs down freely as it does in Nymphalidae. It has been
ascertained by experiment that if the girdle round the larva be cut, the
pupation can nevertheless be accomplished by a considerable
proportion of larvae. Some of the pupae are of very peculiar form, as is
the case in the Orange-tip (Fig. 180, A) and Brimstone butterflies. The
Orange-tip butterfly passes nine or ten months of each year as a pupa,
which is variable in colour; perhaps to some extent in conformity with its
surroundings. The North American E. genutia has a similar life-history,
but the larva leaves its Cruciferous food-plant, wanders to an oak tree,
and there turns to a pupa, resembling in colour the bark of the tree.
Fig. 181—Newly-hatched larva of Euchloe cardamines. A, The larva in
profile; B, one segment more magnified, showing the liquid-bearing
setae; C, one of the setae still more magnified, and without liquid.
It is not unusual for caterpillars to change their habits and appearance

in a definite manner in the course of the larval life. The caterpillar of
Euchloe cardamines exhibits a larval metamorphosis of a well-marked
character. The young larva (Fig. 181) is armed with peculiar setae,
furcate at the tip, each of which bears a tiny ball of fluid. In this stage
the caterpillar makes scarcely any movement. In the middle of the
caterpillar's life a new vestiture appears after an ecdysis; numerous fine
hairs are present, and the fluid-bearing spines nearly disappear, being
reduced to a single series of spines of a comparatively small size on
each side of the upper middle region of the body (Fig. 182). The colour
is also a good deal changed, and concomitantly there is a much greater
voracity and restlessness.
Fig. 182—Larva of Euchloe cardamines in middle life. A, the larva in

profile; B, one segment more magnified.
Fam. 5. Papilionidae.—All the legs well developed. Claws large,

simple, without empodium. Front tibiae with a pad. The metanotum
free, conspicuously exposed between mesonotum and abdomen. This
series of butterflies includes some of the most magnificent of the
members of the Insect world. It is considered by some authorities to be
the highest family of butterflies; and in one very important feature—
sexual differentiation—it certainly is entitled to the rank. There are
about 700 recorded species, the larger portion of which are included in
the genus Papilio. The great variety of form has led to this genus being
divided; the attempts have, however, been partial, with the exception of
an arrangement made by Felder, who adopted 75 sections, and a
recent consideration of the subject by Haase, who arranges Felder's
sections into three sub-genera. Many of the sections have received
names, and are treated by some authors as genera, so that an
unfortunate diversity exists as to the names used for these much-
admired Insects. The genus is distributed all over the world, but is
perhaps nowhere more numerous in species than in South America.
Fig. 183—Ornithoptera (Schoenbergia) paradisea, male. New Guinea. ×

1. (Colours, velvet-black, golden-yellow and green.)
Wallace informs us that the great majority of the species of the Amazon
valley frequent the shady groves of the virgin forest. In many cases the
sexes are extremely different in appearance and habits, and are but
rarely found together in one spot. The genus Ornithoptera is closely
allied to Papilio, and contains some of the most remarkable of
butterflies, the homes of the species being the islands of the Malay
Archipelago, and outlying groups of islands, there being a smaller
number of species in the neighbouring continents. The females are of
great size, and are so excessively different from their consorts of the
other sex, as to arouse in the student a feeling of surprise, and a strong
desire to fathom the mysteries involved.
Fig. 184—Ornithoptera (Schoenbergia) paradisea, female. × 1. (The wings, on the
right side, detached, showing the under surface. Colours, black, white, and gray.)
It would be difficult to surpass the effective coloration of the males in

many of the species of Ornithoptera; they are, too, very diverse in this
respect; O. brookiana is of an intense black colour, with a band of
angular green marks extending the whole length of its wings, while
behind the head there is a broad collar of crimson colour. Perhaps the
most remarkable of all is the O. paradisea, recently discovered in New
Guinea; in this species the sexual disparity reaches its maximum. The
female (Fig. 184) is a large, sombre creature of black, white and grey
colours, but the male (Fig. 183) is brilliant with gold and green, and is
made additionally remarkable by a long tail of unusual form on each
hind wing.
We may anticipate that these extraordinary cases of sexual total

dissimilarity in appearance are accompanied by equally remarkable
habits and physiological phenomena. In the case of O. brookiana the
female is extremely rare, so that the collector, Künstler, could only
obtain fifteen females to a thousand males. According to Mr. Skertchly,
instead of the crowd of males being eager to compete for the females,
the reverse is the case; the female diligently woos the male, who
exhibits a reluctance to coupling. This observer apparently considered
that the "emerald feathers" of the male are a guide or incitement to the
female.[229]
In Africa Ornithoptera is to a certain extent represented by two

extremely remarkable forms, Papilio zalmoxis and P. (Drurya)
antimachus. There are about a dozen other genera of Papilionidae;
most of them contain but few species. Parnassius, however, is rich in
species inhabiting the mountains and elevated plateaus of the northern
hemisphere in both the Old and New Worlds; it is remarkable for the
small amount of scales on the wings, and for the numerous variations
of the species. The female possesses a peculiar pouch at the end of
the body; although only formed during the process of coupling, it has a
special and characteristic form in most of the species. The curious
Indian genus Leptocircus has parts of the front wings transparent, while
the hind pair form long tails. This genus is of interest in that it is said to
connect Papilionidae to some extent with Hesperiidae. The larvae of
this family are remarkable on account of a curious process on the
thoracic segment called an "osmeterium." It is usually retracted, but at
the will of the caterpillar can be everted in the form of a long furcate or
Y-shaped process; there is a gland in the osmeterium, and as a result a
strong odour is emitted when the exstulpation occurs.
The pupation of Papilionidae is similar to that of Pieridae, the pupa

being placed with the head upwards, fixed by the tail, and girt round the
middle. A very curious diversity of pupation occurs in the genus Thais,
in which the pupa is attached by the tail as usual, and—which is quite
exceptional—also by a thread placed at the top of the head. Scudder
thinks there is also a girdle round the middle, but Dr. Chapman inclines
to the view that the thread attaching the head is really the median girdle
slipped upwards. The pupation of Parnassius is exceptional, inasmuch
as, like Satyrides, it is terrestrial, in a slight construction of silk.
Fam. 6. Hesperiidae (Skippers).—Six perfect legs: metanotum not

free, largely covered by the mesonotum. A pad on the front tibia. Claws
short and thick; empodium present. Although this family has been
comparatively neglected by entomologists, upwards of 2000 species
and more than 200 genera are known, and it is not improbable that it
may prove to be as extensive as Nymphalidae. We have already said
that Hesperiidae is generally admitted to be the most distinct of the
butterfly groups. It has been thought by some taxonomists to be allied
to Papilionidae, but this is a mistake. It is undoubtedly more nearly
allied to Heterocera, and when the classification of Lepidoptera is more
advanced, so that the various natural groups placed in that sub-Order
are satisfactorily distinguished, it is probable that Hesperiidae will be
altogether separated from Rhopalocera. We have already mentioned
that E. Reuter considers the Hesperiidae to be phylogenetically
unconnected with Rhopalocera proper; but though quite ready to admit
that he will probably prove correct in this, we think Lepidopterists will
not be willing to recognise the family as a sub-Order equivalent in value
to all Heterocera.
The body is shorter and thicker than it is in most butterflies, and is

pointed at the tip rather than knobbed or bent downwards; the wings
are less ample; the antennae are not truly knobbed, but are thicker
before the actual tip, which is itself pointed and more or less bent
backwards, so that the antennae are somewhat hook-shaped.
In habits as well as structure the family is markedly distinct from

butterflies; the pupation is peculiar, and the name Skipper has been
applied to the perfect Insects, because so many of them indulge in a
brief, jerky flight, instead of the prolonged aerial courses characteristic
of the higher butterflies.
There is great difference among the members of the family, and some
of them possess a very high development of the powers of locomotion,
with a correspondingly perfect structure of the thoracic region, so that,
after inspection of these parts, we can quite believe Wallace's
statement that the larger and strong-bodied kinds are remarkable for
the excessive rapidity of their flight, which, indeed, he was inclined to
consider surpassed that of any other Insects. "The eye cannot follow
them as they dart past; and the air, forcibly divided, gives out a deep
sound louder than that produced by the humming-bird itself. If power of
wing and rapidity of flight could place them in that rank, they should be
considered the most highly organised of butterflies." It was probably to
the genera Pyrrhopyge, Erycides, etc., that Mr. Wallace alluded in the
above remarks. Although the Hesperiidae are not as a rule beautifully
coloured, yet many of these higher forms are most tastefully
ornamented; parts of the wings, wing-fringes, and even the bodies
being set with bright but agreeable colours. We mention these facts
because it is a fashion to attribute a lowly organisation to the family, and
to place it as ancestral to other butterflies. Some of them have
crepuscular habits, but this is also the case with a variety of other
Rhopalocera in the tropics.
In their early stages the Skippers—so far as at present known—depart

considerably from the majority of butterflies, inasmuch as they possess
in both the larval and pupal instars habits of concealment and
retirement. The caterpillars have the body nearly bare, thicker in the
middle, the head free, and more or less notched above. They make
much greater use of silk than other butterfly-larvae do, and draw
together leaves to form caves for concealment, and even make webs
and galleries. Thus the habits are almost those of the Tortricid moths.
Fig. 185—Pupation of Badamia exclamationis. (After Dudgeon. J. Bombay

Soc. x. 1895, p. 144). A, One side of the leaf-cradle, the other
(nearest to the observer) being broken away; B, transverse section
of entire cradle, a, The pupa; b, fastenings of perpendicular threads
round pupa; c, cross thread retaining the leaf in cradle form; d,
margins of the leaf; e, midrib of leaf.
Pupation takes place under similar conditions; and it is interesting to

find that Chapman considers that the pupa in several points of structure
resembles that of the small moths. Not only does the larva draw
together leaves or stalks to make a shelter for the pupa, but it
frequently also forms a rudimentary cocoon. These arrangements are,
however, very variable, and the accounts that have been given indicate
that even the same species may exhibit some amount of variation in its
pupation. Scudder considers that, in the North American Skippers, the
cremaster is attached to a single Y-like thread. In other cases there is a
silk pad on the leaf for the cremaster to hook on. An interesting account
given by Mr. Dudgeon of the pupation of a common Indian Skipper,
Badamia exclamationis, shows that this Insect exercises considerable
ingenuity in the structure of the puparium, and also that the
arrangements it adopts facilitate one of the acts of pupation most
difficult for such pupae as suspend themselves, viz. the hooking the
cremasters on to the pad above them. Badamia uses a rolled-up leaf
(Fig. 185); the edges of the leaf are fastened together by silk at d; from
this spot there descends a thread which, when it reaches the pupa, a,
forks so as to form an inverted Y, and is fastened to the leaf on either
side; the two sides of the leaf are kept together by a cross thread, cc.
Mr. Dudgeon was fortunate enough to observe the act of pupation, and
saw that "although the anal prolegs of the larva were attached to a tuft
or pad of silk in the usual way, and remained so until nearly the whole
skin had been shuffled off, yet when the last segment had to be taken
out, the pupa drew it entirely away from the skin and lifted it over the
empty skin, and by a series of contortions similar to those made by an
Insect in depositing an egg, it soon re-attached its anal segment or
cremaster to the web, throwing away the cast-off skin by wriggling its
body about."
Series II. Heterocera. Moths.
Although Rhopalocera—if exclusion be made of the Hesperiidae—is

probably a natural group, yet this is not the case with Heterocera. The
only definition that can be given of Heterocera is the practical one that
all Lepidoptera that are not butterflies are Heterocera. Numerous
divisions of the Heterocera have been long current, but their limits have
become more and more uncertain, so that at the present time no
divisions of greater value than the family command a recognition at all
general. This is not really a matter of reproach, for it arises from the
desire to recognise only groups that are capable of satisfactory
definition.
Several attempts have recently been made to form a rough forecast of

the future classification of moths. Professor Comstock, struck by some
peculiarities presented by the Hepialidae, Micropterygidae (and
Eriocephalidae), recently proposed to separate them from all other
Lepidoptera as a sub-order Jugatae. Comstock's discrimination in
making this separation met with general approval. The character on
which the group Jugatae is based is, however, comparatively trivial, and
its possession is not sufficient, as pointed out by Packard,[230] to justify
the close association of Hepialidae and Micropterygidae, which, in
certain important respects, are the most dissimilar of moths. The
characters possessed by the two families in common may be
summarised by saying that the wings and wing-bearing segments
remain in a low stage of development. In nearly all other characters the
two families are widely different. Packard has therefore, while accepting
Comstock's separation of the families in question, proposed a different
combination. He considers that Eriocephalidae should be separated
from all others as "Protolepidoptera" or "Lepidoptera Laciniata," while
the whole of the other Lepidoptera, comprised under the term
"Lepidoptera Haustellata," are divided into Palaeolepidoptera
(consisting only of Micropterygidae) and Neolepidoptera, comprising all
Lepidoptera (inclusive of Hepialidae) except the Eriocephalidae and
Micropterygidae. The question is rendered more difficult by the very
close relations that exist between Micropterygidae and a sub-Order,
Trichoptera, of Neuroptera. Dr. Chapman, by a sketch of the
classification of pupae,[231] and Dyar, by one on larval stages,[232] have
made contributions to the subject; but the knowledge of early stages
and metamorphosis is so very imperfect that the last two memoirs can
be considered only as preliminary sketches; as indeed seem to have
been the wishes of the authors themselves.
Simultaneously with the works above alluded to, Mr. Meyrick has
given[233] a new classification of the Order. We allude, in other pages,
to various points in Mr. Meyrick's classification, which is made to appear
more revolutionary than it really is, in consequence of the radical
changes in nomenclature combined with it.
As regards the various aggregates of families that are widely known in

literature by the names Bombyces, Sphinges, Noctuae, Geometres,
Pyrales, we need only remark that they are still regarded as to some
extent natural. Their various limits being the subject of discussion and
at present undecided, the groups are made to appear more uncertain
than is really the case. The group that has to suffer the greatest
changes is the old Bombyces. This series comprises the great majority
of those moths that have diurnal habits. In it there were also included
several groups of moths the larvae of which feed in trunks of trees or in
the stems of plants, such as Cossidae, that will doubtless prove to have
but little connection with the forms with which they were formerly
associated. These groups with aberrant habits are those that give rise
to the greatest difficulties of the taxonomist.
The following key to the families of Heterocera is taken from Sir G. F.

Hampson's recent work, Fauna of British India—Moths.[234] It includes
nearly all the families at present recognised among the larger
Lepidoptera; certain families[235] not mentioned in this key are alluded
to in our subsequent remarks on the families:—
Key to the Families of Moths[236]
N.B.—This table is not simply dichotomic; three contrasted categories are used
in the case of the primary divisions, A, B, C, and the secondary divisions, I,
II, III.
A. Fore wing with nervule 5 coming from the middle of the discocellulars, or
nearer 6 than 4 (Categories I, II, III = 1-18).
I. Frenulum rudimentary. .......... Fam. 38. Epicopeiidae, see p. 418.
II. Frenulum absent (Categories 1-8).
1. Proboscis present, legs with spurs (Cat. 2-5).
2. Hind wing with nervule 8 remote from 7 (Cat. 3 and 4).
3. Fore wing with nervule 6 and 7 stalked .......... Fam. 39. Uraniidae,
see p. 419.
4. Fore wing with nervules 6 and 7 not stalked .......... Fam. 5.
Ceratocampidae, see p. 375.
5. Hind wing with nervule 8 nearly touching 7 beyond end of cell ..........
Fam. 4. Brahmaeidae, see p. 374.
6. Proboscis absent, legs without spurs (Cat. 7 and 8).
7. Hind wing with one internal nervure .......... Fam. 3. Saturniidae, see
p. 372.
8. Hind wing with two or three internal nervures .......... Fam. 6.
Bombycidae, see p. 375.
III. Frenulum present (Cat. 9-18).
9. Antennae fusiform [spindle-shaped] .......... Fam. 9. Sphingidae, see
p. 380.
10. Antennae not fusiform (Cat. 11-18).
11. Proboscis absent .......... Fam. 7. Eupterotidae, see p. 376.
12. Proboscis present (Cat. 13-18).
13. Hind wing with nervule 8 curved and almost touching 7 after end of
cell; nervure 1a reaching anal angle .......... Fam. 12.
Cymatophoridae, see p. 386.
14. Hind wing with nervule 8 remote from 7 after end of cell (Cat. 15-
18).
15. Tarsi as short as tibia, hairy; stoutly built moths .......... Fam. 11.
Notodontidae,[237] see p. 383.
16. Tarsi long and naked; slightly built moths (Cat. 17 and 18)
17. Fore wing with nervule 7 remote from 8, and generally stalked
with 6 .......... Fam. 40. Epiplemidae, see p. 420.
18. Fore wing with nervule 7 given off from 8; hind wing with
nervure 1a short or absent .......... Fam. 36. Geometridae, see
p. 411.
B. Fore wing with nervule 5 coming from lower angle of cell or nearer 4 than 6
[see figures 161 and 162, pp. 318, 319] (Categories 19-58).
19. Hind wing with more than 8 nervules (Cat. 20, 21).
20. Proboscis absent, no mandibles nor ligula; size not very small ..........
Fam. 23. Hepialidae, see p. 396.
21. Mandibles, long palpi and ligula present; size very small .......... Fam.
47. Micropterygidae, see p. 435.
22. Hind wing with not more than 8 nervules (Cat. 23-58).
23. Hind wing with nervule 8 remote from 7 after origin of nervules 6 and 7
(Cat. 24-51).
24. Frenulum absent (Cat. 25-29).
25. Hind wing with one internal nervure; nervule 8 with a precostal spur
.......... Fam. 31. Pterothysanidae, see p. 406.
26. Hind wing with two internal nervures (Cat. 27 and 28).
27. Hind wing with a bar between nervules 7 and 8 near the base;
nervure 1a directed to middle of inner margin .......... Fam. 30.
Endromidae, see p. 406.
28. Hind wing with no bar between nervules 7 and 8; nervure 1a
directed to anal angle .......... Fam. 29. Lasiocampidae, see
p. 405.
29. Hind wing with three internal nervures .......... Fam. 21. Arbelidae,
see p. 396.
30. Frenulum present (Cat. 31-51).
31. Hind wing with nervule 8 aborted .......... Fam. 15. Syntomidae,
see p. 388.
32. Hind wing with nervule 8 present (Cat. 33-51).
33. Antennae knobbed .......... Fam. 1. Castniidae, see p. 371.
34. Antennae filiform, or (rarely) dilated a little towards the tip (Cat.
35-51).
35. Fore wing with nervure 1c present (Cat. 36-43).
36. Hind wing with nervule 8 free from the base or connected
with 7 by a bar (Cat. 37-42).
37. Proboscis present .......... Fam. 16. Zygaenidae, see
p. 390.
38. Proboscis absent (Cat. 39-42).
39. Palpi rarely absent; ♀ winged; larvae wood-borers ..........
Fam. 20. Cossidae, see p. 395.
40. Palpi absent; ♀ apterous (Cat. 41, 42).
41. ♀ rarely with legs; ♀ and larvae case-dwellers ..........
Fam. 19. Psychidae, see p. 392.
42. ♀ and larvae free[238] .......... Fam. 18. Heterogynidae,
see p. 392.
43. Hind wing with nervule 8 anastomosing shortly with 7 ..........
Fam. 26. Limacodidae, see. p. 401.
44. Fore wing with nervure 1c absent (Cat. 45-51).
45. Hind wing with nervule 8 rising out of 7 .......... Fam. 34.
Arctiidae, see p. 408.
46. Hind wing with nervule 8 connected with 7 by a bar, or
touching it near middle of cell (Cat. 47, 48).
47. Palpi with the third joint naked and reaching far above
vertex of head; proboscis present .......... Fam. 33.
Hypsidae, see p. 408.
48. Palpi not reaching above vertex of head; proboscis absent
or very minute .......... Fam. 32. Lymantriidae, see p. 406.
49. Hind wing with nervule 8 anastomosing shortly with 7 near
the base; proboscis well developed (Cat. 50, 51).
50. Antennae more or less thick towards tip .......... Fam. 35.
Agaristidae, see p. 410.
51. Antennae filiform .......... Fam. 37. Noctuidae, see p. 414.
52. Hind wing with nervule 8 curved and nearly or quite touching nervure 7,
or anastomosing with it after origin of nervules 6 and 7 (Cat. 53-58).
53. Hind wing with nervure 1c absent (Cat. 54-57).
54. Hind wing with nervule 8 with a precostal spur .......... Fam. 24.
Callidulidae, see p. 400.
55. Hind wing with nervule 8 with no precostal spur (Cat. 56, 57).
56. Hind wing with nervure 1a absent or very short .......... Fam. 25.
Drepanidae, see p. 400.
57. Hind wing with nervure 1a almost or quite reaching anal angle
.......... Fam. 28. Thyrididae, see p. 404.
58. Hind wing with nervure 1c present .......... Fam. 41. Pyralidae, see
p. 420.
C. Fore wing with 4 nervules arising from the cell at almost even distances
apart (Cat. 59-66).
59. Wings not divided into plumes (Cat. 60-63).
60. Hind wing with nervule 8 coincident with 7 .......... Fam. 13. Sesiidae,
see p. 386.
61. Hind wing with nervule 8 free (Cat. 62, 63).
62. Fore wing with nervure 1b simple or with a very minute fork at base
.......... Fam. 14. Tinaegeriidae, see p. 387.
63. Fore wing with nervure 1a forming a large fork with 1b at base ..........
Fam. 45. Tineidae, see p. 428.
64. Wings divided into plumes (Cat. 65, 66).
65. Fore wing divided into at most two, hind wing into three plumes ..........
Fam. 42. Pterophoridae, see p. 426.
66. Fore wing and hind wing each divided into three plumes .......... Fam.
43. Alucitidae (= Orneodidae), see p. 426.
Fam. 1. Castniidae.—The Insects of this family combine to a large

extent the characters of butterflies and moths. The antennae are
knobbed or hooked at the tip, there is a large precostal area to the hind
wing. The nervules of the front wing are complex and anastomose so
as to form one or more accessory cells (Fig. 162). This important, but
not extensive, family consists chiefly of forms found in tropical America
and Australia. The diversity of size, form and appearance is very great,
and it is probable that the members of the family will be separated;
indeed, taxonomists are by no means in agreement as to the limits of
the family. The Castniidae are diurnal Insects, and the North American
genus Megathymus is by many considered to belong to the
Rhopalocera. Euschemon rafflesiae (Fig. 186) is extremely like a large
Skipper with long antennae, but has a well-marked frenulum. The
members of the Australian genus Synemon are much smaller, but they
also look like Skippers. Their habits are very like those of the
Hesperiidae; they flit about in the hot sunshine, and when settling after
their brief flights, the fore wings are spread out at right angles to the
body, so as to display the more gaily coloured hind wings; at night, or in
cloudy weather, the Insect rests on blades of grass with the wings
erect, meeting vertically over the back, like a butterfly. Hecatesia,
another Australian genus, is now usually assigned to Agaristidae; its
members look like moths. The male of H. fenestrata is provided with a
sound-producing organ similar to that of the Agaristid genus Aegocera.
Fig. 186—Euschemon rafflesiae. Australia. (After Doubleday.)
The Castnia of South America are many of them like Nymphalid

butterflies, but exhibit great diversity, and resemble butterflies of several
different divisions of the family.[239]
The species are apparently great, lovers of heat and can tolerate a very
dry atmosphere.[240] The transformations of very few have been
observed; so far as is known the larvae feed in stems; and somewhat
resemble those of Goat-moths or Leopard-moths (Cossidae); the
caterpillar of C. therapon lives in the stems of Brazilian orchids, and as
a consequence has been brought to Europe, and the moth there
disclosed. The pupae are in general structure of the incomplete
character, and have transverse rows of spines, as is the case with other
moths of different families, but having larvae with similar habits.[241]
Castnia eudesmia forms a large cocoon of fragments of vegetable
matter knitted together with silk. These Insects are rare in collections;
they do not ever appear in numbers, and are generally very difficult to
capture.
Fam. 2. Neocastniidae.—The Oriental genus Tascina, formerly placed

in Castniidae has recently been separated by Sir G. Hampson and
associated with Neocastnia nicevillei, from East India, to form this
family. These Insects have the appearance of Nymphalid butterflies.
They differ from Castniidae by the want of a proboscis.
Fam. 3. Saturniidae.—This is a large and varied assemblage of moths;

the larvae construct cocoons; the products of several species being
used as silk. These moths have no frenulum and no proboscis. The
hind wings have a very large shoulder, so that the anterior margin or
costa stretches far forward beneath the front wing, as it does in
butterflies. The antennae of the males are strongly bipectinated and
frequently attain a magnificent development. The family includes some
of the largest and most remarkable forms of the Insect-world,
Coscinocera hercules, inhabiting North Australia, is a huge moth which,
with its expanded wings and the long tails thereof, covers a space of
about 70 square inches. One of the striking features of the family is the
occurrence in numerous forms of remarkable transparent spaces on the
wings; these window-like areas usually occur in the middle of the wing
and form a most remarkable contrast to the rest of the surface, which is
very densely scaled. In Attacus these attain a large size. In other
species, such as the South African Ludia delegorguei, there is a small
letter-like, or symboliform, transparent mark towards the tip of each
front wing. We have at present no clue to the nature or importance of
these remarkable markings. In the genus Automeris, and in other
forms, instead of transparent spaces there are large and staring
ocellate marks or eyes, which are concealed when the Insect is
reposing. In Arceina, Copiopteryx, Eudaemonia and others, the hind
wings are prolonged into very long tails, perhaps exceeding in length
those of any other moths.
Fig. 187—Larva of Attacus atlas, India. A, at end of 1st instar, profile; B,

4th instar, dorsal view; C, full-grown larva, in repose. (After Poujade.)
The cocoons are exceedingly various, ranging from a slight open

network to a dense elaborate structure arranged as in our Emperor
moth; in this latter case an opening is left by the larva for its exit after it
has become a moth, but by an ingenious, chevaux-de-frise work, this
opening is closed against external enemies, though the structure offers
no resistance at all to the escape of the moth. Fabre has recorded
some observations and experiments which seem to show that the
instinct predominating over the formation of the cocoon is not
cognoscent. The Insect, if interfered with, displays a profound stupidity.
Its method is blind perseverance in the customary.[242] The cocoon of
Saturniidae is more often continuous, i.e. entirely closed. Packard says
that Actias luna effects its escape by cutting through the strong cocoon
with an instrument situate at the base of the front wing. Other species
were examined and were found to possess the instrument; but Packard
is convinced that the majority of the species possessing the instrument
do not use it, but escape by emitting a fluid that softens the cocoon and
enables the moth to push itself through.[243] The cocoons of the
species of Ceranchia have a beautiful appearance, like masses of
filagree-work in silver. The pupa in Ceranchia is very peculiar, being
terminated by a long, spine-like process. In Loepa newara the cocoon
is of a green colour and suspended by a stalk; looking like the pod, or
pitcher, of a plant. The silk of the Saturniidae is usually coarse, and is
known as Tusser or Tussore[244] silk.
The larvae of this family are as remarkable as the imagos, being

furnished with spine-bearing tubercles or warts, or long fleshy
processes; the colours are frequently beautiful. The caterpillar of
Attacus atlas (Fig. 187) is pale olive-green and lavender, and has a
peculiar, conspicuous, red mark on each flank close to the clasper.
About seventy genera and several hundred species are already known
of this interesting family. They are widely distributed on the globe,
though there are but few in Australia. Our only British species, the
Emperor moth, Saturnia pavonia, is by no means rare, and its larva is a
beautiful object; bright green with conspicuous tubercles of a rosy, or
yellow, colour. It affects an unusual variety of food-plants, sloe and
heather being favourites; the writer has found it at Wicken flourishing on
the leaves of the yellow water-lily. Although the Emperor moth is one of
the largest of our native Lepidopterous Insects, it is one of the smallest
of the Saturniidae.
The family Hemileucidae of Packard is included at present in

Saturniidae.
Fam. 4. Brahmaeidae.—The species forming the genus Brahmaea

have been placed in various families, and are now treated by Hampson
as a family apart, distinguished from Saturniidae by the presence of a
proboscis. They are magnificent, large moths, of sombre colours, but
with complex patterns on the wings, looking as if intended as designs
for upholstery. About fifteen species are recognised; the geographical
distribution is remarkable; consisting of a comparatively narrow belt
extending across the Old World from Japan to West Africa, including
Asia Minor and the shores of the Caspian Sea. Little has been recorded
as to the life-histories of these Insects. The larva is said to have the
second and third segments swollen and armed with a pair of lateral
spines projecting forwards. A cocoon is not formed.
Fam. 5. Ceratocampidae.—This is a small family. They are fine moths

peculiar to the New World, and known principally by scattered notices in
the works of North American entomologists. Seven genera and about
sixty species are known. The chief genus is Citheronia. Some of the
larvae are remarkable, being armed with large and complex spines. A
cocoon is not formed.
Fam. 6. Bombycidae.—In entomological literature this name has a

very uncertain meaning, as it has been applied to diverse groups; even
at present the name is frequently used for the Lasiocampidae. We
apply it to the inconsiderable family of true silkworm moths. They are
comparatively small and uninteresting Insects in both the larval and
imaginal instars; but the cocoons formed by the well-known silkworm
are of great value, and some other species form similar structures that
are of more or less value for commercial purposes. The silkworm has
been domesticated for an enormous period, and is consequently now
very widely spread over the earth's surface; opinions differ as to its real
home, some thinking it came originally from Northern China, while
others believe Bengal to have been its native habitat. The silkworm is
properly called Bombyx mori, but perhaps it is as often styled Sericaria
mori. Besides being of so great a value in commerce, this Insect has
become an important object of investigation as to anatomy, physiology
and development. Its domestication has probably been accompanied
by a certain amount of change in habits and instincts, the creature
having apparently lost its appreciation of freedom and its power of
flight; it is also said to be helpless in certain respects when placed on
trees in the larval state; but the importance of these points has been
perhaps somewhat exaggerated.[245]
Although the family Bombycidae is very widely distributed in the warmer

regions of the world, it includes only 15 or 20 genera, and none of them
have many species. The Mustiliidae of some entomologists are
included here. Like the Saturniidae, the Bombycidae are destitute of
proboscis and of frenulum to the wings, but they possess two or three
internal nervures on the hind wing instead of the single one existing in
Saturniidae.
Fam. 7. Eupterotidae (Striphnopterygidae of Aurivillius).—This family

has only recently been separated from Lasiocampidae; its members,
however, possess a frenulum; while none is present in the larger family
mentioned. Its limits are still uncertain, but it includes several extremely
interesting forms. The larvae of the European processionary moth,
Cnethocampa processionea, are social in habits; they sometimes occur
in very large numbers, and march in columns of peculiar form, each
band being headed by a leader in front, and the column gradually
becoming broader. It is thought that the leader spins a thread as he
goes on, and that the lateral leaders of the succeeding files fasten the
threads they spin to that of the first individual, and in this way all are
brought into unison. The hairs of these caterpillars are abundant, and
produce great irritation to the skin and mucous membrane of any one
unlucky enough to come into too close contact with the creatures. This
property is, however, not confined to the hairs of the processionary
moths, but is shared to a greater or less extent by the hairs of various
other caterpillars of this division of Lepidoptera. In some cases the
irritation is believed to be due to the form of the hair or spine, which
may be barbed or otherwise peculiar in form. It is also thought that in
some cases a poisonous liquid is contained in the spine.
The larvae of other forms have the habit of forming dense webs, more
or less baglike, for common habitation by a great number of caterpillars,
and they afterwards spin their cocoons inside these receptacles. This
has been ascertained to occur in the case of several species of the
genus Anaphe, as has been described and illustrated by Dr. Fischer,
[246] Lord Walsingham,[247] and Dr. Holland.[248] The structures are
said to be conspicuous objects on trees in some parts of Africa. The
common dwelling of this kind formed by the caterpillars of Hypsoides
radama in Madagascar is said to be several feet in length; but the
structures of most of the other species are of much smaller size.
The larvae of the South American genus Palustra, though hairy like
other Eupterotid caterpillars, are aquatic in their habits, and swim by
coiling themselves and making movements of extension; the hair on the
back is in the form of dense brushes, but at the sides of the body it is
longer and more remote; when the creatures come to the surface—
which is but rarely—the dorsal brushes are quite dry, while the lateral
hairs are wet. The stigmata are extremely small, and the mode of
respiration is not fully known. It was noticed that when taken out of the
water, and walking in the open air, these caterpillars have but little
power of maintaining their equilibrium. They pupate beneath the water
in a singular manner: a first one having formed its cocoon, others come
successively and add theirs to it so as to form a mass.[249] Another
species of Palustra, P. burmeisteri, Berg,[250] is also believed to breathe
by means of air entangled in its long clothing; it comes to the surface
occasionally, to renew the supply; the hairs of the shorter brushes are
each swollen at the extremity, but whether this may be in connexion
with respiration is not known. This species pupates out of the water,
between the leaves of plants.
Dirphia tarquinia is remarkable on account of the great difference of

colour and appearance in the two sexes. In the Australian genus
Marane the abdomen is densely tufted at the extremity with hair of a
different colour.
Fam. 8. Perophoridae.—The moths of the genus Perophora have for

long been an enigma to systematists, and have been placed as
abnormal members of Psychidae or of Drepanidae, but Packard now
treats them as a distinct family. The larvae display no signs of any
social instincts, but, on the contrary, each one forms a little dwelling for
itself. Some twenty species of Perophora are now known; they inhabit a
large part of the New World, extending from Minnesota to Buenos

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Advances in Ophthalmology and

Optometry Myron Yanoff (Ed.)

PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO

CONTENTS VOLUME 6  2021

Editorial Board vii

An Update on Neurodegenerative Disease for Eye Care

Efferent visual function in neurodegenerative disease 24

Neuroanatomical Structures in Extraocular Muscles and

Current Management of Pediatric Glaucoma

Systemic Immunomodulatory Therapy in Pediatric

Update on Intravitreal Chemotherapy for

Classification of seeding 104

Ophthalmic Pathology & Ocular Oncology

Applications of Plaque Brachytherapy in Posterior

Intraocular Tumors—Advances in Ophthalmic Pathology

Adenoid Cystic Carcinoma of the Lacrimal Gland

Cataract & Refractive Surgery

Artificial Intelligence in Retina

Retina in the Age of COVID-19

Diagnostic and Treatment Update on Sickle Cell

Glaucoma Surgery: Which Surgery to Pick for Your

Ocular Blood Flow as It Relates to Race and Disease on

Glaucoma as a Neurodegenerative Disease: A Clinician

Is glaucoma a neurodegenerative disease? 264

Neuro-Ophthalmologic Manifestations of Novel

Cornea and External Diseases

Advances in Endothelial Keratoplasty Surgery

Update in the Management of Keratoconus

Update on Refractive Surgery

Refractive Error Changes Associated with Eyelid Weight

Refractive Change after Upper Eyelid Surgery

Canalicular Stenosis Secondary to Chemotherapeutic

Optical Coherence Tomography Angiography in White Dot

DAVID A. CRANDALL, MD – Cataract & Refractive Surgery

PAUL B. FREEMAN, OD, FAAO, FCOVD – Optometry

MORRIS E. HARTSTEIN, MD, FACS – Oculoplastics

RUSTUM KARANJIA, MD, PhD, FRCSC, DABO – Neuro-ophthalmology

RONNI M. LIEBERMAN, MD – Vitreoretinal Disease

ANN-MARIE LOBO, MD – Uveitis

STEPHEN ORLIN, MD – Cornea and External Diseases

JOSEPH M. ORTIZ, MD, FRCOphth – Glaucoma

LEONARD J. PRESS, OD, FAAO, FCOVD – Optometry

APARNA RAMASUBRAMANIAN, MD – Pediatric Ophthalmology

Ó 2021 Elsevier Inc. All rights reserved.

ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY

IN MEMORY OF DR ALAN CRANDALL

E-mail address: myanoff4@gmail.com

He cast an enormous shadow in ophthalmology, one that I long ago accepted I

Wayne State University

ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY

E-mail address: myanoff4@gmail.com

ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY

Noel C.Y. Chan, MBChB, FRCSEda,b,*, Jane W. Chan, MDc

non-intraocular pressure (IOP) -dependent risk factors. Despite the paradigm

IS GLAUCOMA A NEURODEGENERATIVE DISEASE?

SICK EYE COMES WITH A SICK BRAIN

potential ischemic pathophysiological basis in low-tension glaucoma is further

COMMON CLINICAL CHARACTERISTICS BETWEEN GLAUCOMA

OVERLAPPING PATHOPHYSIOLOGY BETWEEN GLAUCOMA

machinery of the mitochondria. There is cumulating evidence to support the

Dysregulation of calcium dependent process

Alterations of autophagy machinery

GLAUCOMA AND CEREBROSPINAL FLUID

CONTENTS VOLUME 6 2021