Current Practices in Ophthalmology

Series Editor: Parul Ichhpujani

Daisy Shu
Rohan Bir Singh
Parul Ichhpujani Editors

Current
Advances in
Optometry
Current Practices in Ophthalmology

Series Editor
Parul Ichhpujani, Department of Ophthalmology
Government Medical College and Hospital
Chandigarh, India
This series of highly organized and uniform handbooks aims to cover the latest
clinically relevant developments in ophthalmology. In the wake of rapidly evolving
innovations in the field of basic research, pharmacology, surgical techniques and
imaging devices for the management of ophthalmic disorders, it is extremely
important to invest in books that help you stay updated. These handbooks are
designed to bridge the gap between journals and standard texts providing reviews on
advances that are now part of mainstream clinical practice. Meant for residents,
fellows-in-training, generalist ophthalmologists and specialists alike, each volume
under this series covers current perspectives on relevant topics and meets the CME
requirements as a go-to reference guide. Supervised and reviewed by a subject
expert, chapters in each volume provide leading-edge information most relevant and
useful for clinical ophthalmologists. This series is also useful for residents and
fellows training in various subspecialties of ophthalmology, who can read these
books while at work or during emergency duties. Additionally, these handbooks can
aid in preparing for clinical case discussions at various forums and examinations.
Daisy Shu • Rohan Bir Singh
Parul Ichhpujani
Editors

Current Advances in
Optometry
Editors
Daisy Shu Rohan Bir Singh
School of Optometry and Vision Science, Department of Ophthalmology, Harvard
Faculty of Medicine and Health Medical School
University of New South Wales (UNSW) Schepens Eye Research Institute of Mass
Sydney, NSW, Australia Eye and Ear
Boston, MA, USA
Parul Ichhpujani
Department of Ophthalmology
Government Medical College and Hospital
Chandigarh, India

ISSN 2523-3807     ISSN 2523-3815 (electronic)

Current Practices in Ophthalmology
ISBN 978-981-97-8139-3    ISBN 978-981-97-8140-9 (eBook)
https://doi.org/10.1007/978-981-97-8140-9

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore
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Preface

We welcome our readers to the fascinating subject of optometry and its dynamic
landscape, which will definitely shape the way you practice today as well as in the
future. This book delves into the intricate science and artistry behind vision care,
exploring the marvels of the intricate mechanisms that provide us sight. Whether
you are an optometry graduate, a seasoned optometrist, or an ophthalmologist seek-
ing to deepen your understanding, or simply an enthusiast curious about the novel
wonders of visual assessment and rehabilitation, this book will illuminate and
inspire you.
Optometry is a discipline at the intersection of ophthalmology, physics, and tech-
nology, continuously evolving with advancements in science and innovation.
Optometry is more than just diagnosing and correcting refractive errors. It encom-
passes a holistic approach to eye health, encompassing preventative care, disease
management, and rehabilitation. Throughout this book, we emphasize the impor-
tance of comprehensive eye examinations, early detection of eye conditions, and the
role of optometrists as primary eye care providers.
Within these pages, we endeavour to capture not only the recent advances in the
field of optometry but also the established fundamentals. Our exploration begins
with the differences in global optometry practices, advances in the management of
ocular surface disorders and cornea, as well as glaucoma. From there, we venture
into the realms of diagnostics, examining the tools and techniques used to assess
colour vision and tailoring precise prescriptions for contact lenses, vision therapy,
and low vision aids. We also delve into the relevant clinical trials for optometrists,
novel ocular drug delivery modalities, and the application of artificial intelligence in
optometry.
As we journey through these pages, it is essential to remember that optometry is
not merely a profession but a calling—a commitment to safeguarding one of our
most precious senses, enriching lives, and empowering individuals to experience
the world with clarity and confidence.
We extend our heartfelt gratitude to all the contributors, researchers, educators,
and clinicians whose dedication and expertise have enriched the field of optometry
and made this book possible. We earnestly hope that this book serves as a valuable
resource, inspiring readers to explore, learn, and contribute to the remarkable field
of optometry.

v
vi Preface

With curiosity as our compass and knowledge as our guide, let us embark on this
illuminating journey into the world of optometric practices.

Chandigarh, India Parul Ichhpujani

Boston, MA, USA  Rohan Bir Singh
Sydney, NSW, Australia  Daisy Shu
Acknowledgments

Alone we can do so little, together we can do so much.–Helen Keller

I would like to extend my deepest gratitude to all those who have contributed to
the creation of this book, from the authors who shared their expertise to the editorial
team who worked tirelessly to ensure its quality and accuracy. It is my sincere hope
that this book will serve as a beacon of inspiration and a valuable resource for those
seeking to explore the advances in the realm of optometry.

Parul Ichhpujani

vii
Contents


Differences in Optometry Practices Across the Globe������������������������������������   1
Shivani Majithia and Sahil Thakur

Advances in Dry Eye Disease Diagnosis and Management���������������������������� 11
Rohan Bir Singh and Parul Ichhpujani

Advances in Diagnosis and Management of Infectious Keratitis������������������ 19
Bharat Gurnani and Kirandeep Kaur
Advances in Glaucoma�������������������������������������������������������������������������������������� 47
Parul Ichhpujani and Shibal Bhartiya

Advances in the Management of Oculomotor Dysfunction
in Adults and Children with Concussion �������������������������������������������������������� 59
Tiong Peng Yap and Cathy Stern
Advances in Color Vision Testing �������������������������������������������������������������������� 77
Sara I. Shoushtari and Rohan Bir Singh
Advances in Low Vision Aids���������������������������������������������������������������������������� 89
Samira Mortazavi and Asha Meloottu

Advances in Contact Lenses for Ophthalmic Drug Delivery ������������������������ 99
Parvin Shokrollahi and Alex Hui

Novel Ocular Drug Delivery Methods�������������������������������������������������������������� 115
Yuan Fang, Chris Hodge, Gerard Sutton, and Jingjing You

Clinical Trials Relevant for Optometrists�������������������������������������������������������� 131
Parul Ichhpujani and Surbhi Kapoor

Artificial Intelligence and Optometry: Transforming Practice
and Patient Care������������������������������������������������������������������������������������������������ 139
Shivani Majithia and Sahil Thakur

ix
Differences in Optometry Practices
Across the Globe

Shivani Majithia and Sahil Thakur

Key Points
• The World Council of Optometry provides the four categories of scopes of
optometry practices.
• These include the optical technology services (OT), visual function services
(VF), ocular diagnostic services (ODx), and ocular therapeutic services (OTx).
• Level 4 services are predominantly concentrated in regions like the UK, USA,
and Oceania, while the majority of global practices are Level 2 or Level 3.

1 Introduction

In the realm of eye care, two distinct yet interdependent professions, ophthalmology,
and optometry, play pivotal roles in safeguarding and enhancing our most treasured
sense: vision. Ophthalmology stands as the medical specialization tasked with the diag-
nosis and treatment of eye diseases, with a focus on surgical interventions. Optometry,
on the other hand, focuses on the assessment and correction of refractive errors and the
prescription of corrective lenses. The collaboration between these two professions is
integral to providing comprehensive eye care, but their individual roles and practices
vary considerably across the globe. Understanding these differences is crucial, as it not
only sheds light on the evolution of healthcare practices but also illuminates the socio-
cultural and economic factors shaping the delivery of eye care services.

S. Majithia
Education and Professional Services, Essilor Luxottica, Singapore
e-mail: [email protected]
S. Thakur (*)
Singapore Eye Research Institute, Singapore, Singapore
Medical Affairs, Mediwhale, Seoul, South Korea

© The Author(s), under exclusive license to Springer Nature Singapore Pte 1

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_1
2 S. Majithia and S. Thakur

This chapter embarks on journey through the diverse landscapes of optometry

practices across different regions, aiming to uncover the nuances that shape the way
we perceive and treat vision-related concerns. As we traverse the landscape of
optometry practices, we will meticulously examine one country from each major
global region to highlight the intricate tapestry of practices, regulations, and chal-
lenges that characterize the optometric field. By delving into these regional dispari-
ties, we aim to enrich the understanding of how cultural, societal, and economic
contexts shape the provision of eye care services. From the educational paths lead-
ing to optometry licensure to the scope of services offered by optometrists, we will
scrutinize the unique facets that define each country’s optometry practices. Through
this chapter, we hope to paint a comprehensive picture of the variations in optome-
try practices across the world. By doing so, we aspire to foster a deeper appreciation
for the diverse ways in which societies address visual health and refractive needs,
ultimately highlighting the need for global collaboration to ensure that the gift of
sight is cherished and preserved universally.
The world is a tapestry of cultures, economies, and healthcare systems, each
contributing to the diverse fabric of optometry practices. Optometry, as a profession
dedicated to preserving and enhancing visual health, manifests in varied ways
across different continents and regions. This section of this chapter thus embarks on
a journey across the globe, exploring the distinct optometry practices that have
evolved in response to unique societal, cultural, and economic contexts.

1.1 World Council of Optometry

The World Council of Optometry (WCO) defines the scope of optometry as, “a
healthcare profession that is autonomous, educated, and regulated (licensed/regis-
tered), and optometrists are the primary healthcare practitioners of the eye and visual
system who provide comprehensive eye and vision care, which includes refraction
and dispensing, detection/diagnosis and management of disease in the eye, and the
rehabilitation of conditions of the visual system [1].” This definition plays a pivotal
role in delineating the parameters of optometry, characterizing it as an independent,
knowledge-intensive healthcare discipline that operates within a regulated frame-
work of licensure and registration. The WCO offers several guidelines, consensus
documents and educational resources that can be used by stakeholders interested in
the profession [2, 3]. The WCO has outlined its 2021–2024 strategic plan, “One
Voice of Optometry” that has outlined four themes: inspiring optometric education;
integrating optometry in broader health sector; membership support and growth; and
future planning and collaborations with international bodies like WHO and IAPB
[3]. In addition to these advocacy activities, the WCO also provides a competency
based model of Scope of Practice in Optometry to assist states and countries around
the world to reconcile the variations in the scope of optometric practice internation-
ally. The competency model includes four categories of services that provide a verti-
cal ladder for individuals seeking to expand their career. The WCO defines four
categories of practice types [3]. They are outlined in Table 1.
Differences in Optometry Practices Across the Globe 3

Table 1 Four categories of scopes of practice by the world council of optometry

Level 1 Optical Technology This includes management and dispensing of ophthalmic
Services (OT) lenses, ophthalmic frames and other ophthalmic devices that
correct defects of the visual system
Level 2 Visual Function This includes investigation, examination, measurement,
Services (VF) recognition, and correction/management of defects of the
visual system. The practitioners at Level 2 are considered to be
optometrists
Level 3 Ocular Diagnostic This includes investigation, examination and evaluation of the
Services (ODx) eye and adnexa, and associated systemic factors, to detect,
diagnose, and manage disease
Level 4 Ocular Therapeutic This includes use of pharmaceutical agents and other
Services (Otx) procedures to manage ocular conditions/disease

The WCO currently has 36 country members and is the leading global body for
advocacy, education, policy development and humanitarian outreach for optome-
trists [4]. For the subsequent chapter, we will use the four levels of practice to cat-
egorize the optometry services in different global regions.

2 Optometry Practices in Different Global Regions

2.1 North America: United States (Level 4)

United States (US), boasts of a well-established optometry practice deeply inte-

grated into the healthcare systems. Optometrists are educated to diagnose and treat
various eye conditions, prescribe corrective lenses, and provide pre- and post-­
operative care. The optometrists in US embark on a comprehensive educational
journey, commencing with 4 years of undergraduate studies followed by 4 years in
Optometry school to get Doctor of Optometry (OD) degree, with some pursuing an
additional fifth year of specialized training. Recently some institutions also offer
combined degrees with MPH, MBA, and PhD [5]. There are 24 schools and colleges
of optometry under the Association of Schools and Colleges of Optometry
(ASCO)—23 are in the continental US, and one is in Puerto Rico. The regulatory
bodies and professional associations play pivotal roles in shaping education and
licensure requirements [5, 6]. The regulations are however governed by state laws
and are thus amenable to constant practice updates [6]. In certain states like
Louisiana optometrists can perform several laser procedures, including YAG capsu-
lotomy, peripheral iridotomy, and selective laser trabeculoplasty [7]. The readers
are thus advised to look at online resources to review the clinical and therapeutic
scope of optometrists in the US [8]. Currently optometrists in all states have oral
medication authority and can treat glaucoma topically [8]. They can also remove
ocular foreign bodies and order blood panels or imaging studies such as CT or
MRI. In some states they can perform refractive procedures and minor lid surgery
[8]. Optometrists in US are also required to obtain continuing education credit hours
to maintain licensure. Organizations like the American Optometric Association
4 S. Majithia and S. Thakur

(AOA) provide regularly updated, high-quality, evidence-based clinical practice

guidelines for common eye diseases [9, 10]. As per the Bureau of Labour Statistics
employment estimates 40,640 optometrists in the US, earning a mean annual wage
of $133,100, with most employed in optometry co-practices [11]. Therefore, in
summary, the US boasts a well-established and highly specialized field of optome-
try, delivering top-tier diagnostic and treatment services for eye health.

2.2 Europe: Europe (Level 3) and United Kingdom (Level 4)

In Europe, optometry practices vary from country to country. The European Council
of Optometry and Optics (ECOO) represents the interests of optometrists and opti-
cians across Europe. The ECOO represent more than 150,000 opticians and optom-
etrists from 22 European Union (EU) countries. The European Diploma accredited
by the ECOO is set at the Bachelor level in European Higher Education and pro-
vides a qualification defined for optometric practice at WCO Category 3 [12]. The
ECOO also provides online resources on education, advocacy and professional con-
duct for use for professionals [13]. The United Kingdom (UK), however, has a sys-
tem where optometrists are trained to diagnose and treat a range of eye conditions,
prescribe medications, and refer patients to ophthalmologists when necessary. They
are regulated by the General Optical Council (GOC) through the Opticians Act
1989, and they are distinct from medical practitioners. Registration with the GOC is
mandatory for practicing optometry in the UK [14]. The optometrists complete a
4-year undergraduate honors degree followed by a 1-year internship. Successful
completion of assessments and supervised practice qualifies them to register with
the GOC and potentially join the College of Optometrists. Members of the College
of Optometrists can use the designation MCOptom. The College of Optometrists
also provides clinical management guidelines [15] for 62 diseases and drug formu-
lary [16] of 71 drugs that the optometrists can prescribe. To sum up, the United
Kingdom also showcases a firmly established and extensively specialized domain of
optometry, providing exceptional diagnostic and therapeutic solutions for maintain-
ing ocular health. Table 2 presents the standards of practice recommended by differ-
ent organizations, the GOC provides the most detailed 19 standards in that list [18].

2.3 Asia: India (Levels 2 and 3)

Asian countries like India reflect a diverse spectrum of optometry practices. In

India, optometry has been rapidly evolving as a standalone profession with a grow-
ing emphasis on primary eye care and refractive correction. Optometrists in India
are trained to diagnose and manage common eye conditions, often working in rural
and urban settings. The Indian Optometry Federation described three types of
optometry cadres: the trained ophthalmic assistants/technicians (2 year), the
diploma trained optometrists (2 year) and the degree trained optometrists (4 year)
[21]. The Ministry for Health and Family Welfare, Government of India has
Differences in Optometry Practices Across the Globe 5

Table 2 The standards of practice/code of conduct for optometrists

Organization Country Standards
World Council of Global 1. Keep your patients’ eye, vision, and general health your
Optometry [17] first priority
2. Respect the rights and dignity of patients regarding their
health care decisions
3. Advise your patients whenever consultation with, or
referral to, another optometrist or other healthcare
professional is appropriate
4. Ensure confidentiality and privacy of patients’ health
and other personal information
5. Strive to ensure that all people have access to eye and
vision care
6. Advance your professional knowledge and skills
7. Maintain your practice in accordance with professional
health care standards
8. Promote ethical and cordial relationships with all
members of the health care community
9. Uphold the dignity, honor, and integrity of the
optometric profession
General Optical United 1. Listen to patients and ensure that they are at theheart of
Council [18] Kingdom the decisions made about their care
2. Communicate effectively with your patients
3. Obtain valid consent
4. Show care and compassion for your patients
5. Keep your knowledge and skills up to date
6. Recognize, and work within, your limits of competence
7. Conduct appropriate assessments, examinations,
treatments, and referrals
8. Maintain adequate patient records
9. Ensure that supervision is undertaken appropriately and
complies with the law
10. Work collaboratively with colleagues in the interests
of patients
11. Protect and safeguard patients, colleagues, and others
from harm
12. Ensure a safe environment for your patients
13. Show respect and fairness to others and do not
discriminate
14. Maintain confidentiality and respect your patients’
privacy
15. Maintain appropriate boundaries with others
16. Be honest and trustworthy
17. Do not damage the reputation of your profession
through your conduct
18. Respond to complaints effectively
19. Be candid when things have gone wrong
Optometry Council India 1. Respect your patient
of India [19]a 2. Provide accessible and suitable setup
3. Maintain privacy and confidentiality
4. Provide relevant and evidence-based management
5. Provide appropriate referrals
(continued)
6 S. Majithia and S. Thakur

Table 2 (continued)
Organization Country Standards
Australian Health Australia 1. Put patients first—Safe, effective, and collaborative
Practitioner practice
Regulation Agency 2. Aboriginal and Torres Strait islander health and cultural
[20] safety
3. Respectful and culturally safe practice for all
4. Working with patients
5. Working with other practitioners
6. Working within the healthcare system
7. Minimizing risk to patients
8. Professional behavior
9. Maintaining practitioner health and wellbeing
10. Teaching, supervising, and assessing
11. Ethical research
The codes and standards are available on the official website of the concerned regulator and advi-
sory bodies
a
The general guideline from the Optometry Council of India have been adopted from the section A
of the best practice in standards of Optometry handbook available at the official website [19]

provided the model curriculum for Bachelors (4 years) and Masters of Optometry
(2 years) courses [22]. It also describes the job scope of optometrists in India. The
scope fits into WCO Category 3 with additional provision to only use diagnostic
medications, namely mydriatics and cycloplegics [22]. Recently, the National
Commission for Allied & Healthcare Professionals Act, 2021 has been passed and
optometry has been recognized as a profession in India [23]. The introduction of
PhD programs in select institutions, such as the Elite School of Optometry in
Chennai, has significantly broadened the prospects and horizons available to optom-
etrists [24]. In summary, Indian optometry is thus poised to align with global coun-
terparts in the collective pursuit of eliminating avoidable blindness and propelling
advancements within various specialized realms of optometry. This transformation
is underscored by recent legislative and regulatory reforms that have streamlined
and fortified the profession’s trajectory.

2.4 Africa: Botswana (Level 3)

The African continent presents a diverse range of healthcare challenges, influencing

optometry practices. Progress is evident, especially with efforts toward a united
African Union, yet significant health issues such as visual impairment and blindness
often persist, due to refractive errors. Optometry thus emerges as a key solution to
address vision impairment on the continent. There are about 17 institutions in 10
countries offering 14 fully accredited programs [25]. The programs include Diploma
in Optometry, Bachelor of Optometry, and Doctor of Optometry degrees. However,
meeting the demand for optometric professionals primarily requires establishing
Differences in Optometry Practices Across the Globe 7

more institutions with uniform curriculum and standards. Significant challenges in

staffing, infrastructure, and training resources also exist. One such example is
Botswana, where the Botswana Optometrists Association (BOA) aims to act as the
voice of optometrists [26]. Most optometrists are foreign trained and work in the
private sector. The organization’s main role is to advance optometry and eye health-
care through advocacy and support. It empowers optometrists in Botswana to excel
in their profession, acting as their representative in engagements with government
bodies, health councils, and relevant organizations [4]. By fostering professional
growth and development, the organization also ensures high-quality care. It collabo-
rates with the Botswana Health Professions Council for peer reviews and continuing
education activity. Securing financial assistance and maintaining transparent com-
munication with stakeholders, members, and the public are also integral functions.
The organization also conducts regular eye camps, spectacle distribution and public
education activities. Ultimately, the organization strives to enhance optometry in
Botswana and undertakes all possible actions to achieve these goals [4, 26].

2.5 Oceania: Australia and New Zealand (Level 4)

In the Oceania region, Australia and New Zealand showcase comprehensive optom-
etry practices. Optometrists in these countries are trained to diagnose, manage, and
co-manage a variety of eye conditions. The Optometry Board of Australia is respon-
sible for registering optometrists and students, establishing profession-related stan-
dards, managing complaints and investigations, evaluating overseas practitioners,
and approving accreditation standards and courses [27]. The scope of optometry
practice includes therapeutic prescribing, enabling optometrists to treat certain eye
diseases. In the “Working Together for Better Eye Care” scope of optometry docu-
ment, Optometry Australia recommends actions that can be implemented to better
utilize the skills of optometrists to enhance patient access and increase the effi-
ciency of Australia’s eye health system [28]. Australia has a total of 6175 registered
optometrists who are actively practicing. These professionals are spread across
1200 communities throughout the country. Their geographic distribution closely
mirrors the overall population, although there are certain underserved areas in rural
and remote regions. Among the optometrists, approximately 56% are women, and
an estimated 72% fall under the age of 50, indicating a relatively youthful demo-
graphic profile [28, 29]. While optometrists in New Zealand are allowed to pre-
scribe oral medications for eye conditions like infections, inflammation, and
allergies, optometrists in Australia are limited to use of topical medications [28].
Advocacy groups are also campaigning for provision of intravitreal drug injection
privileges along with greater role in national screening programs for chronic dis-
eases like cataract, glaucoma, age related macular degeneration and diabetic reti-
nopathy [28].
8 S. Majithia and S. Thakur

2.6 South America: Brazil and Colombia (Level 3)

Optometry practices in South America exhibit varying degrees of development [4].

In Brazil, optometrists have a prominent role in providing primary eye care and
refractive correction, especially in underserved areas. Recently, optometry has been
recognized in the Brazilian Supreme Court [30]. The Brazilian Council of Optics
and Optometry (CBOO) is the main body for advocacy and formulating guidelines
for optometrists. The goal of obtaining legal recognition is to reduce the societal
impact due to diseases affecting the eye. This objective is pursued through a strate-
gic approach that focuses on raising awareness and integrating optometrists into the
public healthcare framework. Similarly in Colombia, the main advisory body is the
Colombian Federation of Optometrists (FEDOPTO: En el Colegio Federación
Colombiana de Optómetras) [31]. There are seven optometry schools in Colombia
[32]. An intriguing report shed light on a significant disparity: although optometrists
are legally permitted to conduct fundus and peripheral examinations with dilation,
this practice remains infrequent and is predominantly carried out by ophthalmolo-
gists [33]. This underscores the urgency for advocacy and heightened awareness,
aiming to harness the available workforce and mitigate the eyecare challenges faced
in Latin America.

2.7 Middle East: Saudi Arabia and Dubai (Level 3)

The Middle East has a diverse range of optometry practices. In Saudi Arabia, the
Saudi Society of Optometry (SSO) is the main advocacy organization [26]. The
SSO plays a pivotal role in establishing a comprehensive scientific and educational
platform that empowers optometrists to acquire knowledge and contribute effec-
tively. It fosters health research in eye care, benefiting both the community and
professionals in the field. The society also drives professional development, paving
the way for a brighter future for the optometry profession in Saudi Arabia. By
equipping optometrists with the skills to provide primary eye health care and com-
bat blindness, the society significantly impacts public health. It leads efforts to
enhance regulatory aspects within the optometry sector and establishes valuable
collaborations with the private sector. Additionally, the society focuses on bolster-
ing financial resources while upholding the best governance and institutional prac-
tices. Through its initiatives, the SSO promotes societal engagement, delivers health
education, and ultimately elevates the public’s perception of the optometry profes-
sion. As of 2021, there were a total of 1886 practicing optometrists in Saudi Arabia
(64% male), with 45% practicing in Riyadh, according to the Saudi Commission for
Health Specialties [34]. While in Dubai, an optometrist is defined as, ‘a primary
healthcare professional for the eye concerned especially with examining the eye for
refractive error problems and prescribing spectacle lenses, contact lenses and low
vision rehabilitation to correct these related problems’ [35]. Thus, optometry ser-
vices in Dubai mainly provide primary eye and vision care, eye examinations to
Differences in Optometry Practices Across the Globe 9

detect vision problems and prescription of corrective lenses to correct those prob-
lems under Level 3 category of the WCO.

3 Summary

Currently, the majority of optometry practices worldwide fall within Level 2 or

Level 3 categories as defined by the World Council of Optometry (WCO). Notably,
Level 4 practices, which offer advanced ocular therapeutic services, are predomi-
nantly concentrated in regions like the UK, US, and Oceania. The future of optom-
etry is anticipated to witness a growth in the number of optometrists providing
ocular therapeutic services, spurred by promising outcomes from studies such as
selective laser trabeculoplasty trials [36, 37]. However, this expansion requires the
establishment of a standardized training scheme and robust governance measures to
ensure the safe and effective delivery of these services across the profession.

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Advances in Dry Eye Disease Diagnosis
and Management

Rohan Bir Singh and Parul Ichhpujani

Dry eye disease (DED) is an inflammatory response of the eye caused by decreased
production of tears, excessive evaporation of tears, or both [1]. It is a very common
disorder in the USA and affects roughly 5% of adults nationally [1].

1 Epidemiology

DED is more common in people aged 50 and older and it is more common in women
than in men [1]. Previous studies have found prevalence rates to vary from 5% to
34% worldwide [2]. The difference in prevalence between men and women is due
to the effect of female hormones on the lacrimal and meibomian glands [3]. Other
studies have estimated DED to affect 3.2 million women and 1.68 million men in
the USA [4].
Global, population-based studies have found prevalence rates to vary from 5% to
50% around the world. This range is due to discrepancies in diagnostic criteria and
what actually classifies as DED [3]. Additionally, for reasons that are unknown,
prevalence is found to be higher in Asian populations as compared to White popula-
tions. Climate, geographic location, and environmental factors may explain these
discrepancies [3]. DED prevalence also increases with age; as one gets older, tear
production naturally decreases to an extent, and impaired tear production is the
underlying issue behind DED [5].

R. B. Singh (*)
Harvard Medical School, Boston, MA, USA
e-mail: [email protected]
P. Ichhpujani
Department of Ophthalmology, Government Medical College and Hospital,
Chandigarh, India

© The Author(s), under exclusive license to Springer Nature Singapore Pte 11

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_2
12 R. B. Singh and P. Ichhpujani

The high prevalence of DED poses a great burden in terms of healthcare costs in
the USA, especially as the population continues to age. The annual cost to the aver-
age patient with DED is estimated to be $783 [2]. This equates to a $384 million
cost to the United States health care system every year [2]. Treatments for DED are
continuing to evolve but as the population continues to age, prevalence levels will
likely remain high nationwide.

2 Pathophysiology

DED is a caused by a variety of factors affecting the ocular surface and its tears. In
a structurally functional eye, the ocular surface is kept lubricated by the lacrimal
gland producing tears superiorly, and the meibomian sebaceous glands producing
oils and lipids inferiorly [1]. Damage to any of these structures can precipitate the
effects of DED. It is thought that external stressors on the ocular surface can trigger
the body’s natural immune response and thereby cause inflammation to these cru-
cial structures of the eye [2]. These external stressors may be environmental, anti-
genic, infectious, or genetic. The inflammatory response of chemokines, cytokines,
matrix metalloproteases, and the recruited T cells will then invade the ocular surface
and its surrounding glands, rendering them nearly nonfunctional [2].
The normal tear film is composed of three main layers: the lipid layer, the aque-
ous layer, and the mucin layer [3]. The lipid layer is the most superficial layer and
is made by the meibomian glands, which sit in the eyelid. The lipid component of
the tear serves to decrease its evaporation, thereby, allowing for adequate lubrica-
tion [3]. Next, the job of the lacrimal gland, along with the accessory lacrimal
glands, is to produce the middle, aqueous layer of the tear film. This layer is the
thickest of the three layers and contributes to an overall film thickness of 2–5 μm
[3]. Lastly, the base mucin layer is composed of glycoproteins, which are produced
by goblet cells of the conjunctiva [3].
In DED, these structures, and therefore the integrity of the tears, are compro-
mised. Inflammation of the lacrimal gland will lead to decreased production of the
aqueous layer, resulting in a thinner tear film and a less hydrated eye [3]. If the
meibomian glands are damaged due to inflammation, there will be no superficial
lipid component of the tear film, making it vulnerable to increased evaporation [3].
These two mechanisms are the basis for the two subtypes of DED.

3 Subtypes

The two main subtypes of DED are defined as aqueous-deficient(ADED) or

evaporative(EDED) [3]. Aqueous-deficient DED is due to reduced tear production,
likely from an impaired lacrimal gland. Evaporative or hyperevaporative DED is
due to impaired lipid production by the sebaceous meibomian glands, causing
increased evaporation of the tear film. Of the patients with DED, about 10% have
just the aqueous-deficient subtype. Most patients (over 80%) have either EDED or
Advances in Dry Eye Disease Diagnosis and Management 13

mixed ADED and EDED [2]. While the mechanism of the two subtypes differs,
both mechanisms result in an impaired tear film, which leads to inadequate lubrica-
tion of the ocular surface. This decreased lubrication is the cause of the symptoms
that patients with DED experience.

4 Symptoms

Many symptoms of DED can be vague and nonspecific; these include redness of the
eye, burning or stinging, grittiness or the feeling of a foreign body in the eye, itchi-
ness, and photophobia. These symptoms while nonspecific can greatly impair a
patient’s quality of life and their ability to carry out everyday activities comfortably;
up to 60% of patients with DED report a reduced quality of life [2]. This can cause
concurrent anxiety and/or depression for many patients. Prevalence of depression in
patients with DED was roughly 5% higher when compared to the control group, one
study found [2]. Additionally, DED can impair vision, affecting a patient’s ability to
drive or read, further impairing their quality of life and contributing to their depres-
sive symptoms. Reduced reading speed and reduced driving reaction time, tested in
a driving simulator, were both notable findings in patients with DED [2].
Additional findings in patients with DED include signs of impaired meibomian
gland function, such as obstruction of the gland by a cloudy, granular excretion [2].
This must be removed by applying significant pressure on the lower eyelid where
the gland is located. This impaired gland function may also result in blepharitis or
meibomitis, or inflammation of the eyelid and the meibomian gland, respectively
[2]. The inflammation of the ocular structures in DED may lead to damage of the
ocular surface. This presents as small epithelial erosions on the ocular surface, also
known as superficial punctate keratitis [2]. Often this is indicated by temporal con-
junctival folds that are parallel to the lid margin.

5 Diagnosis and Treatment

DED can present similarly to allergies or certain infections, therefore, proper diag-
nosis is crucial to insure adequate treatment is provided. The first component of
diagnosis is obtaining a detailed patient history about the symptoms, their severity,
onset, and triggers as well as additional underlying health conditions and medica-
tions [2].
Next, examination of the eyelids can provide information about the condition
and possible severity. Factors such as reduced blink rate (promoting tear evapo-
ration), lid incongruity, and insufficient lid closure can also be seen. Examination
of the lids themselves can provide insight into the functioning, or lack thereof, of
the meibomian glands; a slit lamp can be used to visualize these in greater
detail [2].
Another finding suggestive of DED is temporal lid-parallel conjunctival folds
(LIPCOFs); this is a physical exam finding that is caused by increased friction
14 R. B. Singh and P. Ichhpujani

between the eyelids and the surface of the conjunctiva [2]. This increased friction
can be due to decreased lubrication from tears, therefore, indicating DED.
The slit lamp can also be used to visualize the ocular surface for signs of damage.
One common dye, lissamine green, will stain damaged surface cells with a defective
mucin layer, while fluorescein dye will highlight erosions in the conjunctiva and
cornea [2]. Fluorescein will also stain tear film. In DED, significant staining in the
region near the palpebral fissures will be seen [2].
Lastly, the tear film itself will be examined. The height of the tear film can be
measured during a slit lamp examination and can be indicative of DED. The stabil-
ity of the tear film is also measured via the tear film break-up time (TFBUT) [2]. A
shorter TFBUT is often indicative of some underlying pathology [2]. Additional
tests are present; however, they are subject to high variability and not often required
to make the diagnosis [2].
Treatment for DED is primarily aimed at alleviating symptoms since it is a
chronic disease. Patients should also be educated about their condition and certain
aggravating factors such as dry air, smoke, or use of contact lenses [2]. Artificial
tears are the main treatment for patients with DED; no studies have been done com-
paring different types of artificial tears, however. In general, it is known that artifi-
cial tears reduce ocular surface friction, improve tear film integrity, and increase
patients’ quality of life [2]. For patients with hyperevaporative DED, artificial tears
containing a lipid component have been shown to improve tear film stability and
meibomian gland function [2].

5.1 Tear Film Biomarkers

Tear-soluble factors such as cytokines and chemokines are the best surrogate mark-
ers of DED severity and can help in disease classification and treatment planning.
Increased levels of cytokines, viz., interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-9,
IL-12, IL-17A, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α);
chemokines (CCL2, CCL3, CCL4, C-X-C motif chemokine ligand 8; CXCL8);
MMP-9, FGF, VEGF-A; soluble receptors (sICAM-1, sTNFR1), neurotrophic fac-
tors (NGF, substance P, serotonin) and IL1RA and reduced levels of IL-7, IL-17F,
CXCL1, CXCL10, EGF, and lactoferrin have been found in DED [6].
Anti-inflammatory treatment is also recommended in patients with more severe
forms of DED [2]. This is because the underlying mechanism of DED is thought to
be an innate inflammatory response infiltrating the ocular surface structures. Chronic
inflammatory insult to the ocular surface leads to the invasion of blood and lym-
phatic vessels into the cornea, which contributes to cellular trafficking [6]. During
the inflammatory siege, granulocyte–macrophage–colony-stimulating factor
(GM-CSF) secretion adds fuel to fire by the induction of monocytes/macrophages.
Corticosteroid eye drops are also available for patients with a more severe form
of DED [2]. Again, this is likely due to reduced inflammation within the ocular
surface structures that contribute to the DED symptoms. Lastly, certain immuno-
modulators and antimicrobial agents have shown some efficacy in reducing
Advances in Dry Eye Disease Diagnosis and Management 15

symptoms of DED due to their anti-inflammatory effects [2]. Further research is

being done to understand the specific inflammatory pathways of DED, in hopes of
developing more targeted treatment in the future [7].

6 Risk Factors

There are many potential risk factors for the development of DED, some more sup-
ported than others. Risk factors that are supported by a high level of evidence
include age and female sex, as discussed before, post-menopausal hormone replace-
ment therapy (HRT), and androgen insensitivity syndrome (AIS) [2]. Studies have
shown that the meibomian gland dysfunction (MGD) occurs because of the hor-
mones used in HRT and the lack of hormonal response in AIS [8, 9]. NOV03 (per-
fluorohexyloctane; under review with the US Food and Drug Administration [FDA])
is an emerging therapy for DED associated with MGD. This drug has shown signifi-
cant improvements in both signs and symptoms [10].
Intense pulsed light (IPL) therapy, involving treatment over the eyelids, has
emerged as a potential treatment for MGD by causing liquefaction of meibum,
thrombosis of telangiectatic blood vessels in the eyelids, changes in meibomian
gland architecture and photomodulation. A recent Cochrane review has shown that
LipiFlow performs similarly to other commonly used DED treatment modalities as
regards the DED signs and symptoms. A high level of bias was seen in the best
available evidence, resulting in low certainty evidence [11]. In addition to the rela-
tively high costs, IPL treatment may cause depigmentation or swelling of the peri-
ocular skin, eyelash loss or permanent iris transillumination defects.
Additional highly supported risk factors include anything that may affect the
integrity of the ocular surface, such as collagen vascular disease, corneal refractive
surgery, irradiation, vitamin A deficiency, and stem cell transplantation [2]. Patients
using certain antihistamine drugs may also be at an increased risk of DED due to
their mechanism of action, which decreases tear production as a side effect [12].
Lastly, for reasons that are unknown, patients with Hepatitis C are at a higher risk
for developing DED [13].
Other possible risk factors for DED that are moderately supported by research
include diabetes mellitus, isotretinoin, systemic chemotherapies, keratoplasty, sar-
coidosis, HIV infection, and certain medications such as tricyclic antidepressants,
selective serotonin reuptake inhibitors, and beta blockers [2]. Smoking, alcohol use,
Botox injections, oral contraceptives, gout, and pregnancy are other possible risk
factors for the development of DED, however, they are not well supported [2].
A point-of-care diagnostic kit, Bio-M Pathfinder (NovoMol-Dx, India, a custom-
ized version of the Ella™ Automated ELISA system, Bio-Techne®Corporation,
Minnesota, USA) has been recently introduced in the Indian market for clinical use.
This kit will help to identify the molecular status in patients with DED and addition-
ally, help define the risk of development of DED in clinically healthy eyes planned
for invasive procedures [6]. This will help in tailored management of these individu-
als (“personalized medicine”).
16 R. B. Singh and P. Ichhpujani

7 Complications

Late stages of DED can progress to more severe symptoms, leading to ocular health
complications. The consequences of the surface inflammation and the epithelial ero-
sions can progress to conjunctival scarring, permanent epithelial defects, ulceration,
or in very severe cases, corneal ulceration [2]. These complications may even lead
to vision loss [3]. However, the severe complications listed above are very rare and
often precipitated by underlying health issues and autoimmune syndromes. These
include Stevens-Johnson Syndrome, Sjögren’s Syndrome, xerophthalmia and vita-
min A deficiency, and graft-versus-host disease [2].

8 Disease Progression and Future Direction

All in all, DED is a self-limited disease especially once symptoms are treated. Most
patients see a reduction in symptoms as time progresses with the treatment, with no
major progression of symptoms [4]. Some patients with a severe form of DED ini-
tially may report a worsening severity down the line, as well as patients with a lower
level treatment course [4]. More research is needed to accurately track the progres-
sion of DED in patients with varying degrees of severity, along with the efficacy of
different levels of treatment courses. Additionally, further research on the underly-
ing inflammatory pathways triggered in DED must be conducted in order to develop
more effective therapy for those with severe disease progression [6].

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Advances in Diagnosis and Management
of Infectious Keratitis

Bharat Gurnani and Kirandeep Kaur

1 Introduction

Infectious keratitis (IK) is an acute or chronic infection of the cornea that poses a
significant risk of visual impairment [1, 2]. It is a serious ocular condition that can
result in corneal scarring, thinning, and perforation, potentially leading to blindness
if not correctly managed. The etiology of IK is diverse, with bacterial, viral, fungal,
and parasitic organisms all known to be causative agents [1]. The global burden of
the disease is substantial, particularly in developing countries where access to health
care is limited and risk factors, such as the use of traditional eye medications and
poor hygiene practices, are prevalent [1, 3].
Current research on the occurrence of IK is limited, with most studies being
over a decade old. The incidence rates of IK vary significantly based on geographic
location and research methodology, ranging from 2.5 to 799 cases per 100,000
people annually [3–5]. This variation is particularly notable between high-income
and low-income countries. For instance, past research indicated an incidence of
2.5–27.6 per 100,000 people per year in the USA and 2.6–40.3 per 100,000 people
per year in the United Kingdom. Recent findings from a study in Nottingham, UK,
align with these older studies, showing a steady incidence of 34.7 per 100,000
people per year from 2007 to 2019, suggesting a continuous presence of IK in
developed countries [6].
Similarly, a study in Australia reported a lower incidence of 6.6 per 100,000 people
per year between 2005 and 2015 [7]. However, these figures might be underestimates,

B. Gurnani (*)
Cataract, Cornea, External Diseases, Trauma, Ocular Surface and Refractive Surgery,
Gomabai Netralaya and Research Centre, Neemuch, India
K. Kaur
Cataract, Pediatric Ophthalmology, Strabismus and Neuro-Ophthalmology, Gomabai
Netralaya and Research Centre, Neemuch, India

© The Author(s), under exclusive license to Springer Nature Singapore Pte 19

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_3
20 B. Gurnani and K. Kaur

as they were derived from cases requiring corneal scraping. Conversely, much higher
rates of IK have been reported in less affluent countries. For example, South India
recorded an incidence of 113 per 100,000 people per year, and Nepal reported a stag-
gering 799 per 100,000 people per year [8]. The increased incidence in these areas can
be attributed to factors like poor environmental and personal hygiene, lower educa-
tional levels, the prevalence of agricultural work, heightened risk of work-related cor-
neal injuries, and limited access to sanitation and healthcare facilities [1].
The risk factors for infectious keratitis can be varied and are often associated
with conditions that compromise the integrity or immune defense of the eye [9].
Some of the primary risk factors include contact lens use, ocular trauma, compro-
mised immune function, exposure to contaminated water, poor eyelid hygiene, pre-
vious eye infections or surgeries, use of topical corticosteroids, dry eye syndrome,
wearing decorative contact lenses, and environmental factors [10]. Addressing these
risk factors through proper eye care, hygiene, and caution in potentially hazardous
environments can significantly reduce the likelihood of developing infectious kera-
titis [2]. The diagnosis of infectious keratitis is primarily clinical but requires a high
index of suspicion, especially in individuals presenting with risk factors such as
contact lens use, recent ocular trauma, pre-existing ocular surface diseases, or sys-
temic immunodeficiency [11]. Clinically, patients with infectious keratitis may
present with a range of symptoms, including ocular pain, redness, photophobia,
decreased vision, and discharge. A thorough ophthalmic examination using a slit-
lamp microscope may reveal an epithelial defect, focal infiltrate, stromal edema,
and, in some cases, an overlying hypopyon [12].
The management of IK must be aggressive and tailored to the type of pathogen
suspected. Bacterial keratitis, often caused by Staphylococcus, Streptococcus, and
Pseudomonas species, is typically treated with broad-spectrum topical antibiotics,
which are later refined based on microbial culture and sensitivity results [9]. Viral
keratitis, predominantly due to the herpes simplex virus, requires antiviral therapy
[13]. Fungal keratitis, caused by organisms such as Fusarium or Aspergillus, is
managed with topical antifungal agents [14]. Parasitic infections like Acanthamoeba
keratitis, although less common, are particularly challenging to treat and necessitate
the use of topical anti-amoebic medications [15].
Laboratory testing plays a pivotal role in diagnosing and managing infectious
keratitis. Cultures from corneal scrapings can identify the causative organism and
guide targeted therapy. Molecular techniques like polymerase chain reaction (PCR)
offer rapid and sensitive detection of microbial DNA [16]. In vivo, confocal micros-
copy and anterior segment optical coherence tomography (ASOCT) are valuable
non-invasive imaging modalities that can provide detailed visualization of the cor-
neal layers and assist in diagnosing and monitoring treatment response [16].
The depth and severity of the infection also influence the choice of management
strategy. For superficial keratitis, topical medications may suffice. However, forti-
fied antibiotics or combination therapy may be necessary for deeper infections. In
cases where there is no response to medical therapy or in the presence of complica-
tions such as impending perforation, surgical intervention becomes essential.
Advances in Diagnosis and Management of Infectious Keratitis 21

Surgical options include corneal debridement, therapeutic keratoplasty, and, in

severe cases, corneal transplantation [17].
Preventive strategies are equally important in the management of infectious kera-
titis. These include patient education on contact lens care, avoidance of contact lens
wear in high-risk environments such as swimming, and immediate evaluation of any
ocular trauma. Public health measures, including improved access to clean water
and sanitation, are critical in reducing the incidence of infectious keratitis in suscep-
tible populations [18].
Overall, infectious keratitis requires a coordinated approach to management,
encompassing accurate diagnosis, prompt initiation of therapy, and regular follow-
up to monitor treatment efficacy and detect any complications. Advances in diag-
nostic technology and antimicrobial therapy continue to improve the prognosis for
patients with infectious keratitis, but challenges remain, particularly in resource-
limited settings where the disease burden is highest [19].

2 Pathophysiology

Infectious keratitis is a pathophysiological process where the cornea becomes

inflamed due to an infection. This condition is initiated when pathogens such as
bacteria, viruses, fungi, or parasites breach the protective barriers of the eye, often
through a disruption in the corneal epithelium [11]. This disruption can occur due to
factors like contact lens wear, eye trauma, or compromised immune defense. Once
the pathogen invades the stromal tissue of the cornea, it triggers an inflammatory
response [20]. This response involves the activation of the immune system, leading
to an influx of inflammatory cells and mediators into the cornea. These cells work
to eliminate the pathogen but can also cause collateral damage to corneal tissues.
The resulting inflammation and tissue damage manifest as the symptoms of kerati-
tis—pain, redness, blurred vision, and sensitivity to light. The host’s immune sys-
tem responds to this invasion with an inflammatory response aimed at eliminating
the pathogen. This response includes the activation of innate immune cells, like
neutrophils and macrophages, and the release of cytokines and chemokines, which
help in fighting the infection but can also contribute to corneal damage [12].
In some cases, an excessive or prolonged immune response can lead to further
corneal injury and scarring, exacerbating the severity of the disease. The balance
between the virulence of the pathogen and the effectiveness of the host’s immune
response ultimately determines the progression and severity of infectious keratitis
[21]. Effective management of the condition thus requires not only targeting the
pathogen with appropriate antimicrobial therapy but also managing the inflammatory
response to prevent excessive tissue damage. In severe cases, the infection and the
associated immune response can lead to corneal ulceration, scarring, and even perfo-
ration, potentially causing significant vision impairment or loss. The specific patho-
physiological mechanisms can vary based on the type of pathogen involved. For
instance, bacterial infections often result in rapid, acute inflammation, whereas fungal
infections might lead to more chronic and indolent processes. The severity and
22 B. Gurnani and K. Kaur

progression of infectious keratitis are influenced by factors such as the pathogen’s

virulence, the host’s immune status, and the treatment’s timeliness and effective-
ness [19].

3 Clinical Presentation

Infectious keratitis is a serious eye infection that affects the cornea, often caused by
bacteria, viruses, fungi, or parasites. The symptoms of infectious keratitis can vary
depending on the underlying cause but generally include severe eye pain, redness,
and irritation [2]. Patients may also experience blurred vision or sensitivity to light
(photophobia) as the infection progresses. It is common for the affected eye to pro-
duce excessive tears or a thick, sticky discharge. The cornea may appear cloudy or
have visible white spots in more advanced cases, indicating an ulcer or severe infec-
tion [22]. These symptoms can reduce vision quality and, if left untreated, might
result in permanent vision loss. Early detection and treatment are crucial to prevent
complications. If any of these symptoms are present, especially following an eye
injury or contact lens use, seeking immediate medical attention is advised [9].
Differentiating between bacterial, viral, fungal, acanthamoeba, and Pythium
keratitis is crucial for effective treatment, as the signs and symptoms vary between
these infections. Bacterial keratitis typically presents with a rapid onset of pain, red-
ness, and discharge, with the cornea showing a dense, central, white infiltrate that
may develop into an ulcer (Fig. 1). Staphylococcus and Pseudomonas are common
culprits, and they often cause a ‘hypopyon,’ a visible layer of white blood cells in
the anterior chamber of the eye [9].
Viral keratitis, often caused by the herpes simplex virus, may start with a less
aggressive presentation, including redness, tearing, and blurred vision. The key sign
is a dendritic ulcer, which can be seen on corneal staining with fluorescein and pres-
ents as branching lesions on the cornea (Fig. 2) [23].

Fig. 1 Diffuse slit-lamp

image of a patient with
Pseudomonas keratitis
depicting a full-thickness
corneal infiltrate with a
stromal melt
Advances in Diagnosis and Management of Infectious Keratitis 23

Fig. 2 Diffuse slit-lamp

cobalt blue illumination
image of a patient
depicting multiple
dendrites in a case of
herpes simplex keratitis

Fig. 3 Diffuse slit image

of a patient with
Curvularia keratitis
depicting healing
pigmented corneal
infiltrate with hypopyon

Fungal keratitis, which can be due to various fungi like Fusarium or Aspergillus,
typically has a slower onset. It presents with a grayish, feathery infiltrate and may
include satellite lesions—small, separate opacities that surround the main infiltra-
tion. Patients may also experience a more significant sensation of a foreign body in
the eye [21]. Hypopyon is usually immobile and maybe convex (Fig. 3).
24 B. Gurnani and K. Kaur

Fig. 4 Diffuse slit image

of a patient with Pythium
keratitis depicting cotton
wool-like fluffy full-
thickness corneal infiltrate
with rapid inferior limbal
spread 5 days post-trauma
with vegetative matter

Acanthamoeba keratitis is often associated with contact lens wear, especially

when exposed to contaminated water. Symptoms may mimic bacterial or viral kera-
titis initially but persist despite treatment. A key distinguishing feature is severe
pain out of proportion to clinical findings. Ring-shaped stromal infiltrates may
eventually appear [18].
Pythium keratitis, a rarer condition, resembles fungal keratitis but tends to be
more aggressive. It features rapidly progressive ulcers and may show a tentacular
projects, peripheral furrowing and early limbal spread with guttering, which is quite
distinctive (Fig. 4). It is more prevalent in tropical regions and often requires aggres-
sive treatment [24, 25]. In all cases, specialized laboratory tests are required for an
accurate diagnosis, and an eye care professional should evaluate any of these signs
promptly to avoid complications and loss of vision.

4 Diagnostic Approach

The diagnostic approach for IK is multifaceted, with an emphasis on the importance

of accurate and timely diagnosis to prevent complications such as vision loss or
corneal scarring. The process typically involves:

• Clinical Examination
Initial assessment includes a patient history to identify risk factors such as con-
tact lens use, recent eye trauma, or exposure to contaminated water. Symptom
evaluation will focus on pain, redness, discharge, and visual changes [26].
• Slit-Lamp Biomicroscopy
This is a critical tool in the evaluation of keratitis. A slit lamp allows for a detailed
examination of the cornea, conjunctiva, and anterior chamber. It helps to identify
the location and depth of the corneal lesion, epithelial defect, depth and extent of
Advances in Diagnosis and Management of Infectious Keratitis 25

infiltrate, endothelial plaques, and anterior chamber reactions, including hypo-

pyon [27].
• Fluorescein Staining Patterns
The application of fluorescein dye during slit-lamp examination can reveal dis-
tinct patterns. For example, dendritic ulcers are indicative of herpes simplex
virus keratitis, whereas diffuse staining might suggest a more widespread epithe-
lial breakdown, as seen in bacterial or fungal infections [28]. The staining is
useful to locate the epithelial defect, check for seidels test in case of a perforation
and also to assess the healing of epithelial defect.
• Sample Collection
Optimal specimen acquisition is pivotal and must occur during the initial clinical
evaluation before the commencement of antimicrobial treatment. Empirical ther-
apy may be instituted contingent upon the outcomes of the smear analysis. The
following are the specimens pertinent to the etiological determination of corneal
ulcerations [29]:
• Eyelid Swab: Generally yields limited diagnostic utility.
• Conjunctival Swab: Typically of marginal diagnostic value.
• Corneal Scraping: This is the paramount specimen for diagnostic assessment,
providing critical microbiological insights.
• Contact Lens: The procurement of the contact lens, its storage case, and the
solution are mandatory for individuals who use contact lenses, as they can be a
repository of pathogens [18].
• Anterior Chamber Paracentesis (Hypopyon Aspirate): This procedure is
reserved for cases with profound ulceration or when there is an insufficient sam-
ple from corneal scraping to conduct an adequate analysis.

4.1 Laboratory Diagnosis

4.1.1 Corneal Scraping and Smear Analysis

The foundational approach for identifying corneal ulcers involves scrutinizing cor-
neal scrapings and culturing tissue from the cornea. The Gram stain method is effec-
tive for bacterial infections, yielding 60–75% identification rates. For fungal
infections, its effectiveness is noted to be between 35% and 50%. The use of a
potassium hydroxide (KOH) preparation is recognized for its 76.3% sensitivity rate
in pinpointing fungal keratitis. When dealing with fungal, Acanthamoeba, and
Microsporidial keratitis, Calcofluor white stain proves to be beneficial. Standard
culture media for bacterial growth include blood and chocolate agar. For fungal
growth, media such as Sabouraud’s dextrose agar or potato dextrose agar are
preferred.
Meanwhile, acanthamoeba is typically cultivated on a non-nutrient agar that has
been supplemented with Escherichia coli. In cases of fungal keratitis that do not
respond to standard treatments, it is advisable to consider the possibility of Pythium
insidiosum infection. The hyphae of this organism typically show a positive reaction
to stains such as calcofluor-KOH, acridine orange hydrochloride, potassium
26 B. Gurnani and K. Kaur

Table 1 Jones criteria for a confirmed positive culture in infectious keratitis

1 Clinical signs of infection and the cultivation of bacteria amounting to a count of 10 or
greater colonies on a single solid medium and bacterial presence on a secondary medium
2 Recovery of an organism, with any level of growth observable, on two separate solid media
3 Identification of an organism in a single medium, supported by a positive result from a
smear test
4 Should initial culture results return negative, there is a protocol to pause antibiotic therapy
for a 24-h interval. After this hiatus, a new corneal scraping should be performed.
Subsequently, samples are recultured and revaluated

iodide-sulphuric acid, and lactophenol blue. The Tzanck smear is a cytological

diagnostic test that has been traditionally used to detect herpes simplex virus (HSV)
infections, which are a common cause of ocular viral keratitis. Under microscopic
examination, a positive Tzanck smear would show multinucleated giant cells and
epithelial cells with characteristic cytopathic effects, such as ballooning degenera-
tion. These findings can suggest a herpesvirus infection.

4.1.2 Culture Techniques

Samples from corneal scrapings are cultured on different media to isolate bacteria,
fungi, or amoeba. Blood agar (aerobic bacteria, facultative anaerobic bacteria,
fungi), chocolate agar (aerobic bacteria, facultative anaerobic bacteria, Neisseria,
Haemophilus, Moraxella), Thioglycolate broth (aerobic bacteria, anaerobic bacte-
ria), Sabouraud’s dextrose agar (Fungi, Nocardia), brain heart infusion broth plate
with antibiotic (Fungi, Nocardia), Cooked meat broth (anaerobic bacteria), Thayer
martin blood agar plate (Neisseria species), Lowenstein–Jensen media (Mycobacteria
species), Middlebrook-Cohn agar (Mycobacteria species, Nocardia), and non-nutri-
ent agar with E. coli overlay for Acanthamoeba are commonly used. Jones criteria
for confirmed positive culture cases in IK are given in Table 1.

4.1.3 Corneal Biopsy in Infectious Keratitis

A corneal biopsy may become necessary when infectious keratitis is strongly sus-
pected, yet there is an absence of positive findings after two consecutive smear
analyses and culture attempts. This step is considered especially when no discern-
ible clinical response to initial empirical broad-spectrum antibiotic treatment exists.
Additionally, corneal biopsy is advised for specific conditions, such as extensive
fungal keratitis and stromal abscesses where the infection is situated deep within the
corneal tissue.

4.2 Procedure for Corneal Biopsy

The biopsy procedure typically involves partial-thickness trephination using an

appropriately sized trephine. This ensures the collection of a sufficient sample for
diagnostic analysis. During the procedure, it is critical to steer clear of the visual
axis to the greatest extent possible. A biopsy may be performed beneath a lamellar
Advances in Diagnosis and Management of Infectious Keratitis 27

flap for lesions situated mid-stromal, such as those seen in infectious crystalline
keratopathy, or for deeper stromal infections like fungal keratitis. This approach
helps in obtaining a sample from the precise depth of the lesion.

4.2.1 Anterior Chamber Paracentesis

Anterior chamber paracentesis is an infrequently required diagnostic measure in the
assessment of corneal ulcers. Nevertheless, it may be warranted in cases where
there is a high clinical suspicion of keratomycosis but where corneal scrapings and
biopsies have not yielded positive results. This procedure is particularly considered
when there is observed advancement in corneal damage and when there is the pres-
ence or exacerbation of a hypopyon [30].

4.2.2 Molecular Diagnostics (PCR)

Polymerase chain reaction (PCR) testing can rapidly detect microbial DNA or RNA
from small samples, offering a more sensitive and faster diagnosis, particularly for
viral keratitis and atypical pathogens like Acanthamoeba or Pythium insidio-
sum [31].

4.2.3 In Vivo Confocal Microscopy

This non-invasive in vivo imaging technique provides high-resolution images of the
cornea. It is beneficial for diagnosing fungal and acanthamoeba keratitis as it can
visualize the characteristic structures like hyphae or double-walled cysts within the
corneal stroma. The latest advancements in In Vivo Confocal Microscopy (IVCM)
technology can aid in the early commencement of antifungal treatments and provide
valuable insights into the patient’s response to the therapy. Additionally, IVCM is
emerging as a preferred diagnostic tool due to its non-invasive nature, speed, and
high sensitivity. IVCM excels in detecting sizable and deeply embedded organisms
that conventional corneal scraping might miss, such as filamentous fungi,
Acanthamoeba, and Nocardia [32].

4.2.4 Anterior Segment Optical Coherence Tomography (ASOCT)

Techniques like ASOCT can provide detailed cross-sectional images of the cornea
and are useful for assessing the depth of corneal infiltrates and ulcers. Furthermore,
ASOCT is increasingly utilized for quantifying the extent of corneal infiltrates or scar-
ring and tracking corneal thinning throughout treatment. This imaging provides an
objective assessment that can be invaluable for managing the condition effectively [33].

4.2.5 Contemporary Approaches

The imperative for swift diagnostic capabilities has fostered enhancements to
traditional methodologies and the emergence of novel techniques, including
immunohistochemistry, fluorescence microscopy, enzyme-linked immunoas-
says, radioimmunoassay, and advanced molecular biology techniques like
PCR. These cutting-edge methods have significantly reduced the diagnostic
timeline for most ocular infections, with results now achievable within a span of
1–6 h [34].
28 B. Gurnani and K. Kaur

4.2.6 Genomic Sequencing

Sequencing of the internal transcribed spacer (ITS) region of the fungal genome is
a technique that significantly hastens the diagnosis of fungal keratitis, particularly
in stubborn cases. This method’s efficacy is well-documented in the identification of
Pythium and other molds that do not form spores. Moreover, this molecular approach
facilitates the identification of uncommon fungal pathogens. Examples include
Beauveria bassiana, noted for its formidable resistance to antifungal medications,
as well as Colletotrichum gloeosporioides and Trametes betulina. Each diagnostic
tool has its strengths and may be used in conjunction with others to confirm the type
of IK. Early and accurate diagnosis is essential to guide appropriate and effective
treatment, reduce the risk of complications, and improve the outcomes for the
patient. It is imperative that these diagnostic steps are performed promptly and
interpreted by an eye care professional experienced in managing corneal dis-
eases [35].

5 Differential Diagnosis

The differential diagnosis of infectious keratitis is crucial to ensure proper manage-

ment and treatment. Here is a detailed approach:

5.1 Distinguishing Infectious from Non-infectious Keratitis

Infectious keratitis typically presents with pain, photophobia, reduced vision, and
signs of infection like corneal infiltrates, edema, and ulceration. Non-infectious
keratitis may have similar symptoms but often lacks purulent discharge or marked
anterior chamber reaction. A history of trauma, contact lens wear, or prior ocular
surgery may suggest an infectious etiology, whereas autoimmune conditions or dry
eye syndrome might point toward non-infectious causes [36].

5.2 Other Causes of Red-Eye

• Conjunctivitis: Can be viral, bacterial, or allergic. It usually presents with dif-

fuse redness, itching, and a watery or mucopurulent discharge, but the cornea is
typically clear.
• Episcleritis: Involves inflammation of the episclera, causing localized or diffuse
redness with minimal pain and no discharge.
• Scleritis: More severe, deep-seated eye redness and pain, often associated with
systemic autoimmune diseases.
• Acute Glaucoma: Can mimic infectious keratitis but is distinguished by a mid-
dilated pupil, high intraocular pressure, and a history of halos around lights [2].
Advances in Diagnosis and Management of Infectious Keratitis 29

5.3 Corneal Dystrophies and Degenerations

Mimicking Infection

• Corneal Dystrophies: Genetic conditions such as Fuchs’ endothelial dystrophy

or lattice dystrophy might present with corneal changes, including haze and
deposits, which can be confused with infection.
• Corneal Degenerations: Conditions like band keratopathy and Salzmann’s nod-
ular degeneration can cause corneal opacities and surface irregularity that may
resemble infectious keratitis [1].

5.3.1 Management Strategies

The management of infectious keratitis involves a combination of medical and, if
necessary, surgical strategies. Here is an outline of the various management
approaches:

6 General Management Principles

Immediate commencement of treatment is critical to prevent corneal scarring or

perforation.
Adjust therapy based on clinical response and laboratory results. Frequent moni-
toring of the corneal lesion is necessary. In severe cases, hospitalization may be
required for close observation and intensive care [12].

6.1 Medical Management

6.1.1 Antibacterial Therapy

• Empiric Therapy: Broad-spectrum topical antibiotics like fluoroquinolones are
often initiated while awaiting culture results.
• Culture-Directed: Once pathogens are identified, more specific antibiotics are
chosen based on sensitivity patterns.

Bacterial Keratitis
It is a critical ocular condition that must be treated promptly due to its potential for
rapid progression and severe complications. Immediate initiation of empirical anti-
biotic therapy is essential. This often involves a combination regimen covering a
broad spectrum of Gram-positive and Gram-negative organisms. The standard treat-
ment protocol typically includes:

• A fortified antibiotic solution such as cefazolin at 5% or 10% concentration com-

bined with tobramycin at 1.3%.
• A fluoroquinolone such as moxifloxacin 0.5% or gatifloxacin 0.3% is also used
in conjunction with tobramycin 1.3% [9].
30 B. Gurnani and K. Kaur

When comparing fluoroquinolones with fortified eye drops, several factors are
considered:

• Cost: Fluoroquinolones are generally less expensive than fortified drops.

• Availability: Fluoroquinolones are readily available, whereas fortified drops
must be specially prepared.
• Stability: Fluoroquinolones are stable at room temperature, whereas fortified
drops often require refrigeration to maintain potency.
• Shelf Life: Fluoroquinolones typically have a shelf life of up to 1 month, com-
pared to 1 week for fortified drops.
• Toxicity: Fortified drops are generally more toxic than fluoroquinolones.
• Efficacy: Older generations of fluoroquinolones may have poor coverage against
Gram-positive organisms, whereas fortified drops tend to have better coverage
overall.

In clinical practice, the choice between fluoroquinolones and fortified antibiotics

is made based on the severity of the infection, bacterial culture results, patient toler-
ance, and the potential for toxicity. Regular monitoring and adjustments to therapy
may be required to ensure the best outcome for the patient [9].
The dosing frequency of eye drops is typically dictated by the severity of the
condition. Standard practice involves initiating treatment with half-hourly
administrations around the clock for the majority of patients. In cases of severe
corneal ulcers, an initial loading dose may be employed, consisting of drops
every 5 min for the first half-hour. The dosing intervals are then adjusted accord-
ing to the clinical improvement observed [11]. For fortified drops, aminoglyco-
sides such as gentamicin and tobramycin are utilized, providing robust coverage
against gram-negative bacteria and efficacy against certain strains of staphylo-
cocci and streptococci, although they are less effective against pneumococci.
Cefazolin is the cephalosporin most frequently employed in fortified drops,
offering substantial activity against gram-positive bacteria that do not produce
penicillinase.
Symptom management may include ancillary treatments such as cycloplegic
medications, anti-glaucoma agents, artificial tears, and potentially topical
corticosteroids.
Systemic antibiotics are considered in bacterial keratitis under specific circum-
stances such as:

• Corneal ulcers with actual or imminent perforation.

• Post-traumatic perforations.
• Involvement of the sclera.
• Development of endophthalmitis.
• Infections are caused by highly virulent pathogens like Neisseria and
Haemophilus.
Advances in Diagnosis and Management of Infectious Keratitis 31

The Steroid for Corneal Ulcer Trial (SCUT) did not demonstrate a significant
difference in the best-corrected visual acuity at 3 months between patients treated
with topical corticosteroids versus placebo as an adjunctive therapy in the manage-
ment of bacterial corneal ulcers. Additionally, the use of corticosteroids did not
show an increased risk of corneal perforation [9].

Viral Keratitis; Herpes Simplex Keratitis

Antiviral Therapy
Topical antivirals such as trifluridine or ganciclovir are standard. Oral antiviral med-
ications like acyclovir, valacyclovir, or famciclovir can be used, particularly for
deep stromal involvement or for prophylaxis against recurrence. Available antiviral
agents for treatment include acyclovir at a 3% concentration in ointment form, vida-
rabine also at 3%, trifluorothymidine at 1%, and idoxuridine at 1% [23]. It is crucial
to reassess the condition if ulceration remains active beyond a 14-day treatment
period. This evaluation is necessary to differentiate between a neurotrophic ulcer
and ongoing infectious epithelial keratitis. A neurotrophic ulcer typically presents
with smooth margins, in contrast to the irregular, scalloped edges often seen in
infectious epithelial keratitis. In cases where infectious epithelial keratitis is ongo-
ing, the possibility of antiviral resistance should be considered. Under these circum-
stances, initiating an alternative antiviral therapy may be warranted [13].

Fungal Keratitis
Antifungal Agents
Agents like natamycin, amphotericin B, or voriconazole are used depending on the
type of fungus. Treatment duration is typically longer than for bacterial infections.
The principal categories of antifungal agents encompass:

• Polyenes: This class includes Natamycin, Nystatin, and Amphotericin B.

• Azoles: This group features Fluconazole, Itraconazole, Voriconazole,
Posaconazole, and Ravuconazole.
• Fluorinated Pyrimidines, such as Flucytosine.
• Echinocandins: Including Caspofungin and Micafungin.

The typical treatment regimen for fungal infections follows a stepwise approach:
Topical Antifungals: The preferred choice is 5% Natamycin, administered
every hour during the day and every 2 h at night. Based on the clinical response, the
frequency is gradually reduced after 4–7 days [14].
Surface Debridement: This procedure aims to eliminate slough and reduce the
infection load. Though its benefits are debated, it is still widely used by clinicians.
Adjustments for Worsening Conditions: If there is no improvement after
14 days, options include adding 0.15% Amphotericin B drops or 1% Voriconazole
and revisiting the culture report.
Duration of Therapy: Treatment typically spans 3–4 weeks, with complete
resolution often taking 4–8 weeks [21].
32 B. Gurnani and K. Kaur

Antifungals, unlike antibacterials, have limitations such as reduced ocular pen-

etration, limited bioavailability, potential epithelial toxicity, and availability issues.
Indications for systemic antifungals in fungal keratitis include:

• Perforated or imminent perforation of the corneal ulcer.

• Severe, deep ulcers involving more than two-thirds of the stromal depth.
• Large ulcers exceeding 6 mm in diameter.
• Cases following penetrating keratoplasty.
• Scleral involvement.
• Endophthalmitis.

Common systemic antifungals include Ketoconazole (200 mg twice daily),

Fluconazole (200 mg twice daily), Itraconazole (100 mg twice daily), and
Voriconazole (200 mg twice daily). Monitoring for adverse effects is crucial, includ-
ing regular blood glucose, blood pressure, and liver function checks [22].

6.1.2 Targeted Drug Delivery

For approximately 20% of fungal ulcers resistant to medical therapy, targeted drug
delivery is a viable option before considering surgery. This method ensures that the
drug is delivered directly to the affected area. Techniques include intracameral,
intracorneal, or intrastromal drug delivery. The agents used in these methods are
Amphotericin B (5–7.5 μg per 0.1 mL in 5% dextrose) and Voriconazole (50–100 μg
per 0.1 mL) [29].

Acanthamoeba Keratitis
Anti-amoebic Drugs
Combination therapy, including topical chlorhexidine, polyhexamethylene bigua-
nide (PHMB), and propamidine isethionate, is effective. Oral agents like itracon-
azole or miltefosine may be added for severe cases.
The treatment of Acanthamoeba keratitis is challenging and often involves a
combination of medications:

• Biguanides: The primary agents used are PHMB and chlorhexidine. These
agents are effective against both the cystic and trophozoite forms of Acanthamoeba.
• Aminoglycosides: Drugs like neomycin may be used in combination with bigu-
anides due to their efficacy against the trophozoite form [15].
• Azole Antifungals: Ketoconazole, fluconazole, or voriconazole can be effective
due to their anti-acanthamoeba properties.
• Propamidine Isethionate and Hexamidine: These are effective against the tro-
phozoite form and can be used as adjunctive therapy.
• Topical Steroids: The use of steroids is controversial and typically avoided in
the initial phase due to the potential exacerbation of the infection. Steroids may
be considered in later stages to control inflammation after infection control.
• Pain Management: Cycloplegics can be used for pain relief and to manage
photophobia. Oral analgesics may also be necessary.
Advances in Diagnosis and Management of Infectious Keratitis 33

• Debridement of Infected Tissue: In some cases, removal of the infected corneal

epithelium can enhance drug penetration [18].

Pythium Insidiosum Keratitis

Antifungal Drug
Historically, Pythium Insidiosum Keratitis (PIK) was treated with antifungals such
as 5% Natamycin, 1% Voriconazole, 1% Itraconazole, and 2% Ketoconazole under
the assumption that they were typical fungal ulcers. However, further understand-
ing of Pythium’s unique cell wall structure, which lacks ergosterol, has revealed
the limited efficacy of these antifungals against it. Studies by Bagga et al. have
shown that antibacterials are more effective than antifungals for PIK, indicating
them as the preferred first-line treatment. Even though Gurnani et al. recognized
some role for antifungals in PIK, particularly in initial treatments before culture
confirmations, their success is limited. In cases presenting clinical features sugges-
tive of fungal keratitis but with negative cultures for Pythium, antifungals are rec-
ommended until fungal keratitis is ruled out. Caspofungin, an inhibitor of
beta-glucan synthase, shows some effectiveness against PIK but with transient
results [37].

Antibacterial Drug Therapy

In vitro studies and rabbit models have indicated the efficacy of 0.2% Linezolid and
1% Azithromycin as first-line antibacterials for PIK. These drugs demonstrate supe-
rior effectiveness compared to antifungals. Linezolid, prepared from IV formula-
tions or crushed capsules, and Azithromycin, either as an eye ointment or oral
medication, have been used with a high degree of success. Monitoring for clinical
improvement, such as reduction in ulcer size and inflammation, is crucial.
Combination therapy with Linezolid and Azithromycin is recommended for larger,
vision-affecting ulcers. Other effective antibiotics include tetracyclines, lincos-
amides, and oxazolidinones, among others [38].

Adjuvant Therapy in PIK Treatment

• Anti-glaucoma Medications: Beta-blockers and adrenergic agonists are used to
manage secondary glaucoma or hypopyon, reducing intraocular pressure and
alleviating pain.
• Cycloplegic Medications: Agents like atropine and cyclopentolate relieve
pain from ciliary muscle spasms and prevent complications like synechiae
formation.
• Anti-inflammatory Medications: In PIK and post-keratoplasty cases, oral anti-
inflammatory drugs such as diclofenac and ibuprofen are crucial for managing
inflammation and pain.

In summary, the treatment of PIK has evolved with a greater emphasis on anti-
bacterials over antifungals, supported by recent research. Adjuvant therapies play a
significant role in managing symptoms and preventing complications. Regular
34 B. Gurnani and K. Kaur

monitoring and adjustments based on clinical response are key to successful treat-
ment outcomes [24].

Surgical Management
Indications for Surgical Intervention
• Unresponsive to medical therapy.
• Progressive corneal thinning or perforation.
• Significant visual axis opacification after the resolution of infection.

Procedures
• Debridement: Removal of infected or necrotic tissue to promote healing.
• Keratoplasty: Corneal transplantation may be necessary for tectonic support or
visual rehabilitation.
• Amniotic Membrane Transplantation: Used for promoting healing, reducing
inflammation, and as a temporary patch for small perforations [39].

Surgical intervention in cases of infectious keratitis is considered under specific

circumstances, such as impending or actual perforation and non-healing corneal
ulcers, particularly when there is a high microbial load. The decision to proceed
with surgery should be based on a thorough evaluation of the patient’s clinical prog-
ress. Surgical options aim to reduce microbial burden and provide structural support
to the eye, especially in cases where corneal integrity is compromised due to thin-
ning or perforation. Various surgical techniques are available, including:

• Epithelial Removal and Anterior Lamellar Keratectomy: Useful in fungal ker-

atitis, this procedure involves regular debridement to remove organisms and
necrotic material, thus enhancing antifungal drug penetration. Anterior lamellar
keratectomy targets the removal of dense fungal filaments from the cornea and can
be combined with phototherapeutic keratectomy for anterior stromal infiltrates [40].
• Conjunctival Flaps: This method is beneficial for stabilizing the epithelial sur-
face in cases of persistent epithelial defects or progressive ulceration, especially
in viral keratitis. Gunderson’s flap, covering the entire surface with conjunctival
tissue, is used in advanced cases to preserve the integrity of the globe [40].
• Tissue Adhesives: Cyanoacrylate adhesives are used for supporting areas of cor-
neal thinning and sealing perforations up to 2 mm in diameter. A bandage contact
lens (BCL) is applied post-adhesive application, and the adhesive is maintained
until it spontaneously loosens or further surgical intervention is necessary [39].
• Patch Graft: Techniques include Tenon’s patch graft for peripheral ulcers,
multi-layered amniotic membrane grafts for severe thinning or small perfora-
tions, and tectonic patch grafts for 3–5 mm perforations [39].
• Therapeutic Penetrating Keratoplasty: A full-thickness graft is indicated for
larger perforations (>5 mm). Postoperative management includes continued anti-
microbial treatment and cautious use of steroids in fungal keratitis. Smaller
grafts tend to yield better outcomes [40].
Advances in Diagnosis and Management of Infectious Keratitis 35

• Collagen Cross-linking (CXL): CXL is effective in refractory cases due to its

bactericidal activity and the increased resistance of crosslinked corneas to enzy-
matic degradation by pathogens. In all surgical procedures, thorough preopera-
tive assessment and careful postoperative follow-up are crucial for optimal
outcomes. The choice of surgery depends on the ulcer’s size, location, and the
patient’s overall eye health. Surgery is particularly crucial when conservative
treatments fail or in cases of severe infection where preserving ocular integrity is
a priority. Regular follow-up and potential modification of the management plan
are essential based on the clinical course of the disease. It is important to manage
patient expectations regarding the healing process and visual recovery, as corneal
healing can be prolonged, and vision improvement may be gradual.
Multidisciplinary care involving an infectious disease specialist, a microbiolo-
gist, and a cornea specialist may be beneficial in complex cases [41].

7 Complications and Prognosis

Infectious keratitis, a serious eye infection affecting the cornea, can have various
complications and a varied prognosis depending on several factors, including the
cause of the infection, the patient’s overall health, and the timeliness and effective-
ness of treatment.

7.1 Complications of Infectious Keratitis

• Corneal Scarring: This is one of the most common complications. The infec-
tion can lead to scarring, which may cause permanent vision impairment or even
blindness if the scar is centrally located.
• Corneal Ulceration: The infection can progress to create ulcers on the cornea.
Deep ulcers can lead to corneal perforation, a severe condition that can result in
vision loss.
• Secondary Infections: If the primary infection is not adequately treated, it can
lead to secondary infections in the eye or other parts of the body.
• Chronic Eye Pain: Some patients experience ongoing eye pain, even after con-
trolling the infection.
• Hypopyon is the accumulation of white blood cells in the anterior chamber of
the eye, indicating a severe infection.
• Spread of Infection: In rare cases, the infection can spread to other parts of the
eye, leading to conditions like endophthalmitis, which is an inflammation of the
interior of the eye and can be sight-threatening [42].

7.2 Prognosis of Infectious Keratitis

The prognosis for infectious keratitis varies:

36 B. Gurnani and K. Kaur

• Early Diagnosis and Treatment: If diagnosed and treated early, many patients
recover completely without any permanent vision loss [11].
• Type of Infectious Agent: The causative organism affects the prognosis.
Bacterial keratitis generally has a better prognosis than fungal or parasitic kera-
titis, which are often more challenging to treat [11, 12].
• Underlying Health Conditions: Patients with pre-existing eye conditions or
systemic health issues, like diabetes or a compromised immune system, may
have a poorer prognosis.
• Adherence to Treatment: The patient’s adherence to treatment protocols,
including the use of prescribed medications and follow-up appointments, signifi-
cantly impacts the outcome.
• Severity at Presentation: More severe infections at the time of presentation
tend to have a worse prognosis, particularly if the central cornea is involved or if
there is a deep corneal ulcer.
• Recurrence: Some forms of keratitis, particularly those caused by herpes sim-
plex virus, can recur, potentially worsening the long-term prognosis [11].

In conclusion, infectious keratitis can lead to serious complications, including

vision loss, if not promptly and effectively treated. The prognosis varies widely
based on the causative organism, the severity of the infection at diagnosis, the
patient’s overall health, and the effectiveness of treatment. Regular follow-up and
adherence to treatment are crucial for a favorable outcome.

8 Prevention and Public Health Strategies

Preventing infectious keratitis involves several public health strategies and personal
hygiene practices, particularly for individuals who wear contact lenses, are exposed
to environmental risks, or have pre-existing ocular conditions [17]. Here is a detailed
write-up on the prevention of infectious keratitis under the specified heads:

8.1 Contact Lens Hygiene

• Proper Hand Washing: Always wash hands with soap and water and dry them
with a lint-free towel before handling contact lenses.
• Disinfect Contact Lenses: Use only the recommended type of disinfecting solu-
tion to clean and store contact lenses. Never use tap water, saliva, or non-sterile
solutions [20].
• Replace Lenses as Directed: Follow the eye care professional’s recommenda-
tions for replacement intervals for contact lenses and cases.
• Avoid Sleeping in Contact Lenses: Unless specifically designed for overnight
wear, do not sleep in contact lenses to reduce the risk of infection [20].
• Respect Water Exposure Guidelines: Do not swim or shower while wearing
contact lenses to prevent exposure to waterborne pathogens.
Advances in Diagnosis and Management of Infectious Keratitis 37

• No Lens Sharing: Never share contact lenses with others. This can spread
microorganisms that may lead to infection.

8.2 Protective Eyewear

• Use of Safety Glasses: In environments with dust, chemicals, or potential for

injury, protective eyewear should be used to prevent corneal abrasions, which
can become infected.
• Sports Eyewear: Wear protective eyewear during sports to shield the eyes from
injury and possible subsequent infection.
• UV Protection: Use sunglasses that block UV rays to protect the cornea and sur-
rounding ocular tissues from UV damage, which can compromise the ocular
surface [11].

8.3 Prompt Treatment of Ocular Surface Disease

• Regular Eye Examinations: Routine eye check-ups can help in the early detec-
tion and treatment of ocular surface diseases, preventing the progression to
keratitis.
• Manage Dry Eye: Adequate treatment of dry eye syndrome is crucial as it can
compromise the ocular surface and make it more susceptible to infections.
• Treat Lid Margin Diseases: Conditions such as blepharitis should be managed
promptly to maintain a healthy ocular surface.
• Control Inflammation: The use of anti-inflammatory medications, as prescribed,
can help control ocular surface inflammation and reduce the risk of infection [12].

8.4 Public Health Strategies

• Education Campaigns: Public health campaigns to educate about the risks

associated with poor contact lens hygiene and the importance of protective
eyewear.
• Access to Eye Care Services: Ensuring that communities have access to quality
eye care services for promptly diagnosing and treating ocular surface diseases.
• Surveillance Systems: Establish surveillance systems to monitor the incidence
of infectious keratitis and to identify outbreaks related to contact lens products or
solutions.
• Regulation of Contact Lens Solutions: Ensuring that contact lens solutions on
the market are safe and effective and recalling products associated with increased
risk of infection.
• Research and Development: Supporting research into better materials for con-
tact lenses and more effective antimicrobial contact lens solutions [2].
38 B. Gurnani and K. Kaur

By implementing these strategies, it is possible to reduce the incidence of infec-

tious keratitis significantly. Public health initiatives combined with individual prac-
tices can contribute to improved ocular health and decrease the burden of this
potentially serious eye infection.

9 Recent Advances

Recent advances in the management of IK have shown promising developments

across various aspects of treatment and prevention. Here is a detailed overview
under the specified headings:

9.1 Novel Pharmacotherapeutics

• Targeted Antimicrobial Therapy: Advances in pharmacotherapeutics include

the development of newer antimicrobial agents that are more specific to the caus-
ative organisms of keratitis. These agents aim to reduce the resistance seen with
traditional antibiotics [24].
• Antimicrobial Peptides: Research is exploring the use of antimicrobial peptides
as potential therapeutic agents due to their broad-spectrum activity and reduced
likelihood of developing resistance [43].
• Collagen Cross-Linking (CXL): Though originally developed for keratoconus,
CXL is being investigated for its ability to increase corneal rigidity and halt the
progression of corneal melting in bacterial keratitis [41].
• Drug Delivery Systems: Improvements in drug delivery, such as contact lenses
with embedded medications or slow-release corneal inserts, ensure that thera-
peutic levels of drugs are maintained over a longer period, improving effi-
cacy [44].

9.2 Advances in Surgical Techniques

• Phototherapeutic Keratectomy (PTK): This laser surgery technique can be

used to remove superficial corneal scars caused by keratitis and is increasingly
precise with recent technological advancements [45].
• Lamellar Keratoplasty: Advancements in partial-thickness corneal trans-
plants allow for the selective replacement of diseased corneal tissue while pre-
serving healthy parts, resulting in better outcomes and reduced rejection
rates [46].
• Amniotic Membrane Transplantation: This surgical technique is used more
frequently in the treatment of persistent epithelial defects and as a biological
bandage after debridement for infectious keratitis [47].
Advances in Diagnosis and Management of Infectious Keratitis 39

9.3 Biomarkers for Early Detection

• Genetic Markers: Research into genetic markers that may predispose individu-
als to certain types of keratitis could allow for earlier identification and targeted
prevention strategies.
• Tear Fluid Analysis: The analysis of tear fluid for specific enzymes or inflam-
matory markers associated with infection can facilitate early detection and treat-
ment [48].
• In Vivo Confocal Microscopy: This imaging technique allows for the
non-­invasive examination of the cornea at a cellular level, which can help in
the early diagnosis of microbial keratitis before clinical signs become
apparent [32].

9.4 Vaccination for Prevention of Viral Keratitis

• Herpes Simplex Virus (HSV) Vaccine: While still under development, there is
ongoing research into vaccines for HSV, which is a common cause of viral kera-
titis. The aim is to reduce the incidence and severity of HSV-related ocular dis-
ease [49].
• Adenovirus Vaccine: Research is also being conducted into vaccines for adeno-
virus, which causes epidemic keratoconjunctivitis and can lead to keratitis [50].
• Public Health Vaccination Programs: The implementation of widespread vac-
cination programs could significantly reduce the incidence of viral keratitis, par-
ticularly in regions where it is endemic.

These recent advances represent a multifaceted approach to the management of

infectious keratitis, focusing on improved treatment modalities, surgical interven-
tions, early detection, and preventative measures. Continued research and develop-
ment in these areas hold the promise of better outcomes for patients affected by this
condition.

10 Future Directions

The future directions in managing and understanding infectious keratitis are driven
by ongoing research and the evolving landscape of microbial resistance. Addressing
research gaps, exploring the potential of gene therapy, and the need for new antibi-
otics are at the forefront of this field. Here is a detailed write-up on these aspects:

10.1 Research Gaps

• Pathogen-Specific Data: There is a need for more comprehensive data on the

prevalence and virulence of specific pathogens in different geographic and
40 B. Gurnani and K. Kaur

demographic populations. This information would help in developing targeted

therapies.
• Disease Mechanisms: The exact mechanisms by which different pathogens
affect the cornea and cause varying levels of damage are not fully understood.
Research is needed to elucidate these processes at the molecular level.
• Host Response: A better understanding of the host immune response to corneal
infections could lead to improved treatment strategies that minimize inflamma-
tion and scarring.
• Long-Term Outcomes: There is a scarcity of data on the long-term outcomes of
infectious keratitis, particularly regarding visual acuity, recurrence rates, and
quality of life.
• Prevention Strategies: Research into effective prevention strategies, especially
in regions with high incidence rates, is needed to reduce the disease burden [51].

10.2 Potential for Gene Therapy

• Genetic Vulnerabilities: Identifying genetic factors that make individuals more

susceptible to keratitis could lead to gene therapies that strengthen the cornea’s
defenses against infection.
• Gene Editing: Techniques like CRISPR/Cas9 offer the potential to edit genes
that may be involved in the pathogenesis or progression of keratitis, possibly
preventing the disease before it manifests.
• Delivery Mechanisms: Research into efficient and safe delivery methods for
gene therapy to the cornea is ongoing. Viral vectors, nanoparticles, and mechani-
cal methods like electroporation are being explored.
• Regenerative Medicine: Gene therapy might be used 1 day to promote corneal
healing and regeneration, reducing the risk of scarring and vision loss following
infection.

10.3 Development of Resistance and Need for New Antibiotics

• Surveillance Programs: Global surveillance programs are needed to monitor

trends in antibiotic resistance among pathogens causing keratitis. This data can
inform the development of new antibiotics.
• Novel Antibiotics: There is an urgent need to develop new antibiotics that work
through different mechanisms to overcome resistance. Research is focused on
finding compounds with unique targets in bacterial, fungal, and viral pathogens.
• Antibiotic Stewardship: Programs that promote the judicious use of antibiotics
are essential to slow the development of resistance. Education for both health-
care providers and patients is a crucial component.
• Alternative Therapies: Exploring non-antibiotic therapies, such as bacterio-
phage therapy, antimicrobial peptides, and host-defense modulators, is crucial as
resistance continues to grow.
Advances in Diagnosis and Management of Infectious Keratitis 41

10.4 Combination Therapies

Using combinations of antibiotics or other types of treatments may help overcome

resistance and improve outcomes [52].
The future directions in the battle against infectious keratitis involve a multi-
pronged approach that encompasses filling research gaps, harnessing the potential
of gene therapy, and developing new antimicrobial agents to overcome resistance.
These strategies require a global effort and collaboration across scientific disci-
plines to ensure that progress continues in preventing and treating this vision-­
threatening condition.

10.5 Importance of a Multidisciplinary Approach

A multidisciplinary approach is crucial in managing infectious keratitis effectively.

This involves:

• Ophthalmologists: Leading the diagnosis and treatment efforts, including surgi-

cal interventions.
• Microbiologists: Providing expertise in identifying the causative pathogens and
their sensitivity patterns.
• Pharmacists: Assisting with the optimal selection and dosing of antimicro-
bial agents.
• Infectious Disease Specialists: Offering guidance on systemic infections and
complications.
• Primary Care Physicians: Participating in early recognition and referral, espe-
cially in community settings.
• Public Health Professionals: Implementing prevention strategies and surveil-
lance for outbreaks.

Collaboration across these disciplines ensures comprehensive patient care, from

initial presentation to long-term management, including the rehabilitation of vision
if impairment occurs.

10.6 Call for Further Research

Despite advancements, significant challenges remain, and further research is

essential:

• Understanding Pathogen Behavior: More research is needed to understand the

evolving patterns of pathogen behavior, particularly in the context of climate
change and global travel.
• Host Immunity: Investigating the host immune response to corneal infections
could yield insights into new therapeutic targets.
42 B. Gurnani and K. Kaur

• Resistance Mechanisms: Understanding how resistance develops and spreads

among pathogens is critical to developing new antimicrobial strategies.
• Gene Therapy and Regenerative Medicine: Exploring the potential of gene
therapy and stem cell-based regenerative medicine could offer novel treatment
avenues.
• Vaccines: Research into vaccines for preventing viral keratitis, particularly for
herpes simplex virus, requires ongoing investment and innovation.
• Public Health Interventions: Evaluating the effectiveness of public health
interventions on the incidence and severity of infectious keratitis can guide future
prevention efforts.
• Global Health Disparities: Addressing disparities in the incidence and out-
comes of infectious keratitis across different regions is essential, necessitating
research sensitive to diverse populations’ needs [53].

11 Conclusion

Infectious keratitis remains a significant cause of ocular morbidity and potential

visual loss worldwide. Our current understanding of infectious keratitis has
expanded considerably, yet the condition continues to pose a threat to vision health.
A unified, multidisciplinary approach coupled with an ongoing commitment to
research is paramount to continue improving prevention, diagnosis, and treatment
strategies, with the ultimate goal of preserving sight and improving patient outcomes.

12 Summary of Current Understanding

Infectious keratitis is an infection of the cornea caused by bacteria, viruses, fungi,

or parasites. The severity of the infection can range from mild irritation to severe
inflammation, leading to corneal scarring and vision impairment. Key factors in the
pathogenesis of infectious keratitis include the pathogen’s virulence, the integrity of
the ocular surface, and the host immune response.
The standard of care involves prompt antimicrobial treatment, often guided by
laboratory cultures and sensitivity testing. However, the rise of antimicrobial resis-
tance has complicated treatment strategies. The introduction of newer pharmaco-
therapeutics, advancements in corneal transplantation, and the development of
molecular diagnostic tools have improved outcomes for many patients [54].

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Advances in Glaucoma

Parul Ichhpujani and Shibal Bhartiya

1 Introduction

Glaucoma management is at the cusp of monumental change. While there are excit-
ing possibilities emerging for its diagnosis, and therapeutic interventions, clinical
scientists across the globe are looking increasingly at the quality of life of glaucoma
patients. Research is being focused at not only genetics and gene therapy for glau-
coma, but also at technologies that will enable better patient compliance with con-
ventional anti glaucoma medications (AGMs); as well safer, and more effective
surgical options [1, 2].
The clinical experience with respect to these technologies, expectedly, is lim-
ited, and so, their acceptability for both patients and glaucoma practitioners alike
is a barrier for their early adoption. It is therefore imperative that a concerted
effort be made towards education of patients and caregivers, as well as the health
care team comprising of optometrists, general ophthalmologists, and glaucoma
surgeons. It is only then that the patient will be able to benefit from the latest
advances in glaucoma management. This chapter will cover the recent advances
in glaucoma diagnostics, newer drugs as well as visual rehabilitation for glau-
coma management.

P. Ichhpujani (*)
Department of Ophthalmology, Government Medical College and Hospital,
Chandigarh, India
S. Bhartiya
Department of Ophthalmology, Marengo Asis Hospitals, Gurugram, Haryana, India

© The Author(s), under exclusive license to Springer Nature Singapore Pte 47

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_4
48 P. Ichhpujani and S. Bhartiya

2 Glaucoma Diagnostics

Home Tonometry: Glaucoma treatment is currently based on a snapshot of an “in-

office” intraocular pressure (IOP) measurement, twice or thrice a year. Recent lit-
erature has shown that the “at-home” tonometry can significantly alter IOP
management. It allows measurement of diurnal fluctuations in IOP by providing a
more holistic view of the IOP profile outside the clinic, which can help understand
disease progression and therefore guide change in treatment strategy. The Icare
Home (Icare Inc., USA) tonometer, which uses rebound tonometry, is easy to use as
it does not require the administration of a topical anaesthetic. The patient needs to
rest the instrument against his or her forehead and align the device in front of the
cornea with the help of a light ring surrounding the probe. After correct positioning,
when the ring turns green, a button needs to be pressed for the measurement. This
tonometer records six consecutive IOP measurements and the average IOP along
with the date and time of measurement are saved to a cloud database. However,
nearly 10% of glaucoma patients are not able to operate this tonometer properly [3].
Nearly 9% of readings vary by more than 3 mm Hg from the gold standard,
Goldmann applanation tonometry (GAT) and 2% of readings vary by more than
5 mm Hg [4]. A recent study has shown that patients can be taught to perform self-
tonometry remotely using a remote video link [5].
Home tonometry can aid in the detection of IOP spikes, especially in patients
with pigmentary or pseudoexfoliative glaucoma (PEXG), angle closure glaucoma
(ACG) or in paediatric or postoperative patients.

A. Implantable sensors: The development of implantable sensors for continuous

IOP monitoring has been possible due to the technological advances in the
microelectromechanical systems (MEMS) and microfluidics. These sensors are
being embedded in a contact lens or integrated into a tonometry device or
embedded intraocularly [6]. Currently available continuous pressure monitoring
systems include the EYEMATE® (Implandata Ophthalmic Products GmbH,
Germany) and Triggerfish® (Sensimed AG, Switzerland). These are yet to be
used routinely in clinical practice.
Triggerfish Contact Lens Sensor (CLS): The SENSIMED Triggerfish is a
soft silicone, contact lens with a circumferential sensor consisting of two plati-
num titanium strain gauges, which measure the changes in the radius of curva-
ture of the cornea. The contact lens is available in three base curves sizes, 8.4,
8.7, and 9 mm. A wireless antenna adherent on the periocular surface receives
an output signal transmitted by a microprocessor. The strain gauge takes 300
readings over a 30-s period every 5 min, giving 86,400 data points over a 24-h
period (Fig. 1). Bluetooth connection allows this data to be transferred to a com-
puter for analysis. The data points are measured in millivolt equivalents and are
relative to the first reading (zero). The Triggerfish CLS does not give an estimate
of absolute IOP.
Eyemate-IO intraocular version: The Eyemate (Implandata; Hannover,
Germany) is a new implantable device for continuous, long-term IOP monitor-
Advances in Glaucoma 49

-21000
Zoom A Zoom B
-21500
-22000
IOP Profile [a.u.]

-22500
-23000
-23500
-24000
-24500
10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 19:00 20:00 21:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00 06:00 07:00 08:00 09:00 10:00 11:33
Time

Fig. 1 A 24 h pressure profile obtained using Triggerfish

ing. It was CE-certified in 2017 for commercial use in the European Union
(EU). Eyemate has eight pressure and temperature sensors, designed for implan-
tation in the ciliary sulcus at the time of cataract surgery [7].
Each pressure sensor has two parallel plates, the base plate is rigid while
the plate that indents with changes in IOP is flexible. The distance between
these two plates varies with fluctuations in IOP, generating an analog signal,
which is then converted to a digital signal, that is transmitted to a small hand-
held mesograph by radiofrequency. For the reader to activate the electromag-
netic coupling sequence and the units to correspond with each other, the reader
and the intraocular transponder unit must be within 5 cm of each other. The
device can obtain up to 10 IOP measurements per second. The Eyemate (with
a GSM module) data can be shared with the physician using an internet
database.
EYEMATE-SC when implanted in patients with primary open-angle glau-
coma (POAG) undergoing simultaneous nonpenetrating glaucoma surgery
(NPGS) was found to be safe and well tolerated through 12 months [8].
Literature reassures that the Smart IOP sensors hold promise for redefining
glaucoma treatment strategies.
Digital photography:
Remote or rural areas have limited access to good ophthalmic care with the
state-of-the-art diagnostic equipment, especially for detecting preperimetric or
early glaucomatous damage [9]. Smartphone-based teleglaucoma screening can
help in early detection and treatment.
Affordable adapters that convert a smartphone camera into a miniature ante-
rior segment and fundus camera have flooded the markets globally.
Some of the adapters used in community studies include the Peek (Peek
Vision; https://www.peekvision.org) from England, the D-Eye system (Si 14;
https://www.d-­eyecare.com) from Italy, and the IExaminer (Welch Allyn),
EyeGo (Stanford University and DigiSight Technologies), and Ocular CellScope
(University of California, Berkeley) from the United States.
These smart devices are being used to capture “direct” images or video of the
posterior pole (in an undilated state, without the condensing +20 D lens) not
only by the ophthalmologists and optometrists but also by the neurologists and
paediatricians. These images can be shared for expert assessment (HIPPA com-
pliant) and saved to a patient file for future reference [10, 11].
50 P. Ichhpujani and S. Bhartiya

Results from Smartphone ophthalmoscopy has shown good agreement with

slit lamp examination for the estimation of optic nerve head cupping or glau-
coma detection [12].
B. Perimetry:
Tablet Perimetry: Mobile applications that allow visual field (VF) charting
have opened up options for a small clinical setup or even home-based perimetry
where standard automated perimetry (SAP). Several tools are available for VF
charting on tablets, laptops, and desktop computers [13].
Melbourne Rapid Fields (MRF): MRF is an iPad tablet application (iPad 3
or later) that allows in-office or remote VF testing [14].
Recently, an Online website version of MRF has been made available that
has a web-cam technology to monitor viewing distance as well as gaze stability.
Online version can be accessed at the webpage, www.visioninhome.com.
MRF Glaucoma detects VF abnormalities both centrally as well as peripher-
ally (up to 30° from central fixation point). At the end of each test, longitudinal
comparison of test results is performed. Stored test results can be accessed
through an online portal, exported as comma separated values (.CVS) format
and imported into Excel for detailed point-to-point analysis. User experience
using MRF has been positive [15].
Prea SM et al. have shown that MRF correlated strongly with SAP using
Humphrey visual field analyser (HFA), over a 6-month period across four visits,
with good test-retest reliability [16].
It is important to remember that although the average mean deviation (MD)
values from MRF or a Smart Visual Function Analyzer (SVFA) such as
IMOvifa™ provide similar results to the HFA, point-by-point comparisons show
notable deviations [17]. These differences could partly be due to the different
normative databases as well as the difference in MD calculation. The tablet
design itself may also account for variations in the local sensitivities.
Tablet perimetry has garnered interest during COVID and in the post COVID
era as it can be done at home or in the waiting room, thus saving time [18].
C. Contrast Sensitivity Testing:
The Spaeth Richman Contrast Sensitivity Test (SPARCS): SPARCS helps
assess both central as well as peripheral contrast sensitivity (CS) using the
Weber contrast. The test requires internet access on a standard computer with
monitor set to 1024 × 768 resolution, 256 grey levels and a size of at least 22 cm
width and 26.5 cm height. The test is available at https://www.sparcscontrast-
center.com. The website provides instructions on how to take the test. Each
patient gets a unique identification number. At a testing distance of 50 cms, the
test occupies 30° of vision horizontally and 23.5° of vision vertically. The cen-
tral test area subtends 3.5° vertically and 5° horizontally. Patient has to fixate on
the central area of the testing screen and identify the areas, which appears dif-
ferent. When patient is ready, they click on the central area. In one of the five test
areas, vertical square wave gratings with a spatial frequency of 0.4 cycles per
degree randomly appear for 0.3 s. Temporarily, patients break fixation to select
the area with the grating. Patient fixates again on the central area and clicks on
Advances in Glaucoma 51

the screen to activate the programme to show the next area with grating. Correct
and incorrect responses are recorded until the software determines the contrast
threshold in each area. The test takes 5–10 min per eye [19].
The contrast threshold is determined using a staircase strategy with reversals.
Initial correct responses advance four levels until the patient gives an incorrect
response. After the incorrect response, a contrast level two levels easier than the
previous one is presented. The algorithm advances or regresses one level at a
time until two incorrect responses are made at a specific level, which establishes
the contrast threshold. If a patient stops trying to guess the correct area and
clicks the same location repeatedly, the test terminates. Patient is instructed to
attempt to choose the location where the gratings appear. The range of contrast
tested is from 100% to 0.45% (log contrast sensitivity 0.00–2.35) and decreases
by approximately 0.15 log units between levels. The central area (CC) and four
peripheral areas (SN, ST, IN, IT) each receive separate scores. A total SPARCS
score is summated from each of the five areas (20 per area), resulting in a perfect
score of 100.
Richman et al. studied the performance of SPARCS for glaucoma patients,
and found that a total SPARCS score of <70 had a sensitivity of 79.7% and
specificity of 92.8% in the identification of glaucoma in Caucasian population
[19]. Thakur et al. have also found SPARCS to be a sensitive and reliable indica-
tor of glaucomatous damage [20]. SPARCS has also been used to test CS in
patients with refractive errors, cataract, age-related macular degeneration and
idiopathic intracranial hypertension [21–23].
D. Electrophysiology:
nGoggle™: The nGoggle™ is a “virtual reality” (VR) goggle with embed-
ded EEG sensors. It is a brain–computer interface platform (BCIP) for detecting
and monitoring neurodegenerative diseases of eye and brain. It allows detection
of steady-state visual evoked potentials (SSVEP) corresponding to pattern
reversal visual stimuli [24].
A trial (NCT03760055) is ongoing to assess the ability of the nGoggle to
detect VF loss in patients with glaucoma, as well as to differentiate different
severity stages of glaucoma, its repeatability and reliability for patient self-­
testing and patient satisfaction compared to SAP, optical coherence tomography
(OCT) metrics and Diopsys NOVA (Diopsys, Inc.).
Pattern Electroretinogram (PERG):
PERG measures the activity of retinal ganglion cells (RGCs) and possibly
detects the early functional abnormalities in glaucoma. Available commercial
devices include Diopsys’ Nova and Argos Vision Testing Systems and Konan
Medical’s EvokeDx [25].
Steady-state PERG amplitude has been shown to progressively decrease over
time in a subset of glaucoma suspects, with relatively steeper slope in treated
compared to untreated glaucoma suspects [26]. EvokeDx device has been found
to be useful to help assess central vision and evaluate damage to magnocellular
(MC) pathway, however it is noncontributory in mapping specific structural
changes or peripheral defects [27].
52 P. Ichhpujani and S. Bhartiya

3 Newer Drugs

A. Rho Kinase Inhibitors: The two Rho kinase isoforms (ROCK 1 and ROCK 2)
are the effectors for the Rho A, B, and C. These G proteins get activated after
binding to guanosine triphosphate (GTP). Rho kinase inhibitors have a dual
mechanism of action, increase in aqueous outflow, along with decrease in aque-
ous outflow resistance by increasing the pores formed by the endothelial cells in
the Schlemm’s canal (SC). They also increase the outflow by relaxing smooth
muscle fibres of the trabecular meshwork (TM). In addition, Netarsudil has nor-
epinephrine transporter (NET) inhibitor activity further lowers aqueous humour
production as well as the episcleral venous pressure. Rho kinase may also be
neuroprotective, possibly via increased optic nerve head perfusion, and may
decrease postsurgical scarring. The latter action is because ROCK inhibitors
inhibit fibroblasts activation via TGF-beta [2, 28].
The two commonly used ROCK inhibitors are Ripasudil and Netarsudil.
Ripasudil hydrochloride hydrate (Glanatec®) 0.4% which requires twice a day
dosing and Netarsudil (Rhopressa®) 0.02% which is used once at bedtime [2].
They are both known to effective in lowering IOP in POAG and OHTN alike, with
the most common side effects being conjunctival hyperaemia (75%), blepharitis
(20%), and cornea verticillata (15%), with the latter being unique to Netarsudil.
The fixed drug combination (FDC) of netarsudil 0.02% and latanoprost
0.005% (ROCKLATAN®) once daily has been found to resulted in greater
mean IOP reduction as compared to monotherapy with either drug [29].
The newest ROCK inhibitor in pipeline, Fasudil, has shown good IOP lowering
even in end-stage glaucoma [30]. Use of depot formulation of Fasudil loaded
polylactide-co-glycolide (PLGA) microspheres have been proposed in the form of
intravitreal injection for glaucoma patients with coexistent retinal disease [31].
Rho kinase inhibitors hold great promise as an adjunctive therapy, since their
mechanism of action is different from the existing AGMs. Although adverse
events, especially conjunctival hyperaemia and subconjunctival haemorrhages,
may impact compliance in the long term, this class of AGM is a significant addi-
tion to the glaucoma practitioners armamentarium.
B. Latanoprostene Bunod: Latanoprostene bunod 0.024% (Vyzulta®) is a pro-
drug, which has the unique property of donating nitric oxide (NO). The drug
metabolizes into latanoprost acid, and butanediol mononitrate; and the latter is
further metabolized to 1,4-butanediol and NO.
Latanoprost acid increases uveoscleral outflow via the Prostaglandin F receptor.
Like all other prostaglandin agonists, it modulates the remodelling of the extracel-
lular matrix of the ciliary muscle via matrix metalloproteinases. Nitric oxide, the
second active metabolite of the prodrug, causes vasodilation and smooth muscle
cell relaxation in the TM and SC by decreasing cell contractility and volume, thus
increasing outflow facility [32]. LBN has shown to increase both, optic nerve head
capillary blood volume and oxygen saturation more than latanoprost [33].
The once daily dosing of LBN has been found to be more effective than both
latanoprost and timolol. The most common side effects include conjunctival
Advances in Glaucoma 53

hyperemia (17%), eyelash growth (16%), irritation and pain (10%). LBN has
been found to be as effective as netarsudil as an adjuvant therapy [34].
C. Novel Methods of Drug Delivery
Nanotechnology: Nanotechnology-based treatments may improve patient
quality of life, and consequently adherence, because of targeted drug delivery,
better bioavailability, sustained release of the AGM or anti-metabolite (in case
of glaucoma surgeries), and better therapeutic efficiency [35].
Additionally, nanomedicine formulations may have decreased side effects
due to less frequent dosing [36]. These include liposomes, nanogels, nanopar-
ticles, micelles, nanosuspensions, dendritic polymers, microneedles, etc., all of
which have a particle size ranging from 1 to 100 nm, have shown to have signifi-
cantly better therapeutic safety and efficacy than conventional ophthalmic for-
mulations in animal studies. Even though this is yet to be a part of clinical
practice, nanomedicine formulations of several AGMs that have been tried
include supraciliary injection of brimonidine-laden microspheres, subconjuncti-
val injection of dorzolamide nanoparticles and intravitreal injection of brimoni-
dine, travoprost, and bimatoprost-laden nanosponges [2, 37, 38].
Implants:
Antiglaucoma drugs dispensed as injectable systems and undertrial punctal
plug delivery systems are enlisted in Table 1.
(a) Bimatoprost implant: The bimatoprost implant (Durysta™) is a sustained
release, biodegradable implant uses the NOVADUR drug delivery system.
A 28-gauge, prefilled applicator releases this implant intracamerally. The
biodegradable polymers of the implant disintegrate within the anterior
chamber into carbon dioxide and water. The main adverse event noted was
conjunctival hyperemia in almost one in three patients, and a more than

Table 1 Antiglaucoma drugs dispensed as Injectable systems and Undertrial Punctal plug deliv-
ery systems
Drug delivery Placement of Current stage
system Drug Material location of development
ENV515/PGA or Travoprost – Anterior Phase 2 clinical
Travoprost XR chamber angle trial
Bimatoprost SR Bimatoprost – Subconjunctival Phase 3 clinical
space trial
Graybug Various – Ocular surface Preclinical
OTX-TP Travoprost Polyethylene Puncta Phase 2 clinical
glycol-based trial
hydrogel with
loaded PLA
Evolute Latanoprost – Puncta Phase 2 clinical
trial
Latanoprost Latanoprost – Puncta Phase 2 clinical
punctal plug trial
delivery system
(L-PPDS)
54 P. Ichhpujani and S. Bhartiya

20% reduction in endothelial cell density in 10% and 21% of the 10 and
15 mcg groups. About 4% and 10% of eyes in each of the two groups,
respectively, needed implant removal because of the corneal oedema, in
order to prevent further endothelial loss. Better formulations are currently
under review [39, 40].
(b) BIM ring: The bimatoprost ocular ring (Bimatoprost HELIOS™ insert,
Abbvie) is a silicone—polypropylene ring impregnated with bimatoprost
(24–29 mm in diameter) which is inserted in the fornices. It provides sus-
tained IOP control over 6 months, eluting 6–35 microns of the drug per day.
The device does not have FDA approved yet [41].
(c) Travoprost punctum plugs: Recently, Polyethylene glycol resorbable
hydrogel punctal plugs impregnated with travoprost, OTX-TP (Ocular
Therapeutix, Inc.) have been developed. The retention rates of these plugs
were 90% at 2 months, but less than 50% at 3 months. The other major
adverse event reported was foreign body sensation in almost 40% patients,
with the tolerability increasing over time [42].
Precise targeted delivery will minimize drug wastage by preventing drug loss
due to systemic absorption and first-pass metabolism. High prevalence of ocular
surface disease in patients instilling AGMs with added preservatives may be
overcome with the newer devices [43].

4 Visual Rehabilitation

(a) Virtual reality based low vision aids: For patients with advanced glaucoma
using low vision aids, augmented reality magnification can be done with devices
such as Microsoft HoloVision Hololens and a camera worn on the finger [44].
Electronic head-mounted low vision aid (e-LVA) SightPlus (GiveVision,
UK, givevision.net) improves visual function in people with low vision [45].
(b) Smartphone applications for people with low vision: Several smartphone
apps are available that can make day-to-day tasks easier for people with visual
impairment to improve their quality of life [46].
• NavCog: This iPhone based app is helpful for indoor navigation, inside
complex building spaces such as an airport or hospital. (https://www.cs.cmu.
edu/~NavCog/navcog.html)
• Seeing AI: This app gives a narration of the surrounding world around the
patient through their phone’s camera. It can help to identify and describes
people, objects (e.g., currency) and documents (reads them aloud).
Additionally, it can describe features such as colour, light, and handwriting.
• In future, patients can get customized digital devices and apps to address
their low vision.
• We are hopeful that the emerging technologies will not only help mitigate
the disease but also improve the quality of life of those with advanced or end
stage glaucoma.
Advances in Glaucoma 55

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Advances in the Management
of Oculomotor Dysfunction in Adults
and Children with Concussion

Tiong Peng Yap and Cathy Stern

1 Vision and Concussion

Mild traumatic brain injury (TBI) arising from a bump, blow, shake or jolt to the
head or body is often referred to as a concussion [1]. Approximately, 70–80% of all
TBIs are classified as mild in the absence of lesions from brain imaging and/or loss
of consciousness. This may arise from road traffic accidents, falls, sports injuries,
assaults, recreational activities, or children’s playground accidents. For example,
sudden rapid changes in movement during whiplash can cause the brain to bounce,
stretch or twist within the skull. This neurological event may result in focal and/or
diffuse damage to neuronal dendrites, axons, and astrocytes, disrupting cellular
membranes and releasing neurotransmitters. This invariably affects the intracellular
and extracellular ionic equilibrium which consequently cause neuroinflammation
and cell loss [2].
Concussion patients may suffer from a wide range of issues, given the pervasive-
ness of the injury. This includes sensory, motor, perceptual, cognitive, attentional,
behavioral, somatic, academic, linguistic, and social well-being issues. Oculomotor,
vestibular, and visual processing disorders are frequently experienced. Thus, it is
necessary to investigate each of these functions carefully so that the appropriate
treatment, therapy, and rehabilitation can be rendered to the patient.
The terms ‘oculomotor’ and ‘ocular motor’ tend to be used interchangeably in
the literature despite their contextual differences in terms of nerve innervations and
eye movements respectively. Although the latter is more accurate, it is more com-
mon to use the term ‘oculomotor’ to describe eye movement function or disorders.

T. P. Yap (*)
IGARD Vision Therapy Center, Singapore, Singapore
e-mail: [email protected]
C. Stern
Pappas Rehabilitation Hospital for Children, Canton, MA, USA

© The Author(s), under exclusive license to Springer Nature Singapore Pte 59

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_5
60 T. P. Yap and C. Stern

Fig. 1 Clinical management of concussion patients

1.1 Acute Care of the Concussion Patient

Acute care of the concussion patient typically involves management of symptoms

(Fig. 1) and evaluating the likelihood of an intracranial injury based on the symp-
toms reported by the patient and/or brain imaging. To satisfy the diagnostic criteria
of concussion, the Glasgow coma score should be 13–15, or any loss of conscious-
ness should be less than 30 min and/or amnesia should be less than 24 h.
Given the high risks during sports, any symptoms, physical signs, and/or altera-
tions of cognitive functioning may indicate a concussion in athletes [3]. In pediatric
patients, age-appropriate concussion symptom scales are available [1] and addi-
tional signs should be taken into consideration, such as loss of appetite, refusal to
engage in routine activities, and/or increased dependence on parents.

1.2 Recovery of the Concussion Patient

Relative Rest is important for brain injury recovery. Rest during the recovery phase
allows inflammation to reduce and the brain to recover. If the condition is not wors-
ening, concussion patients are often discharged from hospitals and encouraged to
rest at home with limitations of activities involving mental concentration (e.g.,
video games and reading) and physical exertion (e.g. sports) to allow the symptoms
to subside. After the first few days, one should gradually increase physical activity
to a level that does not provoke symptoms. The duration for recovery depends on
age [4], gender [5], severity [6], and presence of comorbid conditions, such as
migraines, mood, learning, and attention-deficit disorders [1].
While full recovery is generally expected within weeks or up to 3 months, activi-
ties within the next 2–3 days should be light and kept to a level that does not pro-
voke symptoms especially when returning-to-work (or school). To avoid the risk of
a repeat concussion, return-to-sports (or play) should be conducted in a safe manner
and guided using a graduated return-to-sport strategy [7] along with baseline
Advances in Management of the Oculomotor Dysfunction… 61

measurements of neurocognitive function. However, patients with prolonged or per-

sistent symptoms lasting weeks, months, or years [8] may require intervention as
they are likely to have post-concussion syndrome.

1.3 Post-concussion Syndrome and Vision

Post-concussion syndrome refers to concussive symptoms that have lasted longer

than expected. These may include headaches, blurred vision, double vision (diplo-
pia), photosensitivity, nauseousness, dizziness, fogginess, and/or disequilibrium in
busy environments.
Patients with oculomotor and/or vestibular dysfunction tend to be overwhelmed
and cannot navigate in complex visual environments. They may present with visual
motion sensitivity, visual-attentional deficits or visual field deficits. Some patients
may present with gait or neurocognitive impairment. They may feel more emotional
than usual or find it difficult to concentrate [7] and they may have heightened sensi-
tivity to light or noise.
Post-concussion oculomotor dysfunction carries a four-times risk of developing
chronic post-concussion syndrome [9]. Those who are symptomatic for 30 days or
more tend to have significant challenges in vision and concentration [10]. Particularly
in children and adolescents, nearly 14% remain symptomatic after 3 months [6]
which adversely impacts reading, daily work, school or play activities.
Long-term repetitive concussion may contribute to mood or personality
changes (e.g., depression), attention-deficit, hyperactivity, and anxiety disorders
[11] and can potentially result in chronic traumatic encephalopathy. Therefore, it
is essential to investigate oculomotor and vestibular functions carefully in order to
facilitate the appropriate referral for vision therapy or Neuro Optometric
Rehabilitation Therapy.

2 Oculomotor Dysfunction in Concussion

Oculomotor dysfunction affects more than 60% of concussed children and adoles-
cents [12] and more than 90% of concussed adults [13]. Deficits in saccades, smooth
pursuit, vergence, and accommodation are frequently observed [14]. In the absence
of symptoms or in situations where patients are unable to recall the concussion,
oculomotor function may be used as an objective biomarker in early detection [15]
and for monitoring recovery [14].
The propensity for the visual system to be affected may be related to the large
extent of the human brain involved in visual processing. As discussed previously,
‘ocular motor function’ describes the overall quality of eye movement but ‘oculo-
motor dysfunction’ is the term more commonly used in the literature to describe eye
movement disorders. Thus, oculomotor function can be defined as the ability of the
visual system to accurately fixate and track a moving target or when the person is
moving; and to keep the target clearly in focus at all times. This entire process relies
62 T. P. Yap and C. Stern

Fig. 2 Schematic representation of the neurological elements that mediates oculomotor function

on the visual system’s capacity to align the eyes accurately in relation to the vestibu-
lar and proprioceptive systems.
Screening tools, such as the Vestibular Ocular Motor Screening (VOMS), King-­
Devick test or computerized eye tracker protocols can be used for initial diagnosis
of oculomotor dysfunction but should by followed by a complete neuro optometric
evaluation. The evaluation provides more detailed information about the oculomo-
tor dysfunction, including the fixation, accommodation, vergence, saccadic eye
movements, smooth pursuit eye movements and vestibular-oculomotor func-
tion (Fig. 2). Each of these visual functions may be considered as a neurological
element that mediates oculomotor function, where each of them tend to interact
with another. For example, vergence and the accommodative systems are tightly
coupled in the process in maintaining accurate fixation, while pursuit eye move-
ments entails steady and accurate fixation in relation to the vestibular system in
order to hold the gaze. Each of these neurological elements needs to be assessed
carefully during the neuro optometric evaluation, so any deficits can be diagnosed
and properly managed in a treatment plan.

2.1 Fixational Disorders

Fixational disorders can occur after a concussion, resulting in an inability to main-

tain a stable image on the fovea. Fixation or visual fixation refers to the ability to
voluntarily maintain a steady and accurate eye position that is focused on a target in
order to prevent attention from fading away.
As the foveal field covers only 2° of the visual fields of each eye, precise fixa-
tional eye movements are needed to prevent the visual images from “slipping” away
from the fovea. Small slow drifts (amplitudes ranging 1.5–4 arc minutes), tremors
(rapid oscillatory movements of approx. 200 Hz with amplitudes ranging 5–30 sec
Advances in Management of the Oculomotor Dysfunction… 63

arc), and microsaccades (fast jerky involuntary eye movements with amplitudes
ranging 10–12 arc minutes) are actively occurring to fine-tune and ensure an accu-
rate fixation.
As interactions between fixational eye movements and directed visual attention
are mediated in the median cingulate gyrus, frontal eye fields (FEFs) and supplemen-
tary eye fields (SEFs) [16], fixational disorders post-concussion can affect a person’s
visual attention in a similar way to the poor fixation linked to attention deficit hyper-
activity disorder (ADHD) traits [17]. Previous experiments found that microsaccades
can result in a gaze shift from a target to another location of interest if the fixation is
poorly engaged [18], thus affecting visual attention, visual perception and cognition.
In addressing fixational disorders, two major neurological elements in the pro-
cess of fixation must be considered—vergence and accommodation. These systems
actively align and adjust the focus of each eye synchronously to maintain the fixa-
tion. Similarly, any microsaccades during each fixation are typically conjugate eye
movements with equal velocity and amplitudes, so both accommodative and ver-
gence systems are tightly coupled in the process of fixation. Therefore, both systems
need to be carefully examined in concussion patients.

2.2 Accommodative Disorders

Accommodative disorders are estimated to affect nearly 50% of post-concussion

adolescents and children [12, 19, 20]. Accommodation is the neurological process
in maintaining a clear and sharp image on the retina while the distance of objects may
vary anywhere from distance (infinity) to as close as approximately 6 cm from the
eye depending on the patient’s age and in the absence of presbyopia.
As part of a complex neural control system, the accommodative system responds
to retinal image blur through a neural feedback mechanism and constantly fine
tunes itself in order to maintain a clear image on the retina. The autonomic innerva-
tion of the ciliary smooth muscles during accommodation is principally mediated
by a fast reflexive parasympathetic (~1 s) and a slow adaptive sympathetic nervous
system (~10 s) which produces dynamic changes and sustained steady-state
responses, respectively.
Patients with accommodative disorder may report headaches, blurred vision,
eyestrain, nauseousness, dizziness, and visual fatigue. These symptoms are similar
to the symptoms experienced by patients with convergence insufficiency. Both con-
ditions can be present in patients demonstrating receded near point of convergence
(NPC) [20]. In one study of 74 patients with receded NPC, 95% had oculomotor
dysfunction, 41% accommodative disorders only, 28% convergence insufficiency
and accommodative disorders, and 8% convergence insufficiency alone. Therefore,
a thorough examination of the vergence and accommodative systems is essential for
accurate diagnosis [20].
Accommodative disorders can be broadly classified into accommodative insuf-
ficiency and accommodative excess. There may also be cases of aniso- or unequal
accommodation in both eyes after brain injury which results in differential deficits
64 T. P. Yap and C. Stern

between the two eyes. Accommodative insufficiency refers to premature weakening

or paralysis of the accommodative system that is not within age expected norms,
whereas accommodative excess occurs when a disproportionately large magnitude
of accommodation is used during a near task. In the latter situation, the actual
accommodative response during a particular task tends to exceed the accommoda-
tive demand, leading to an overexertion of the ciliary muscles.
Accommodative excess may be seen with a vergence disorder where excessive
accommodation may be exerted to reduce diplopia [21] or it may occur following a
brain injury in the absence of vergence disorder resulting in an accommodative
spasm [22]. Thus, the visual system may fail to relax accommodation readily and
patients may complain of headaches after prolonged near work or experience
blurred vision in the distance after prolonged periods of near work. In school-aged
children, accommodative infacility may contribute to slowness in adjusting focus
from distance to near or vice versa and may affect tasks such as copying from the
board in school.
The extent of the accommodative insufficiency or excess can be assessed by
measuring the amplitude of accommodation, determining if there is a lag or lead of
accommodation and evaluating the speed taken in exerting and relaxing the ciliary
muscles. Amplitude of accommodation should be measured by moving an accom-
modative target, e.g., a paragraph of N5 print, at 1–2 cm/s toward the eye with the
endpoint being the first sustained blur. The neuro optometric evaluation entails
quantitative and qualitative measures of accommodation with careful interpretation
in relation to vergence and oculomotor function. For example, dynamic retinoscopy
can be used to assess accommodative lead or lag with additional observation to
determine if the accommodation is oscillating or is accurate and sustainable.
Accommodative facility can be measured with alternation of ±2.00 lenses while
viewing an accommodative target and noting the number of cycles per minute taken
to regain clear vision.
To probe the accommodative response, positive and negative relative accommo-
dation (PRA, NRA) can be measured to determine how the visual system would
respond to changes in the accommodative demand while vergence remains
unchanged.

2.3 Vergence Disorders

Vergence disorders refer to a wide range of sensorimotor and visual perceptual

abnormalities in relation to differences in the position of the two eyes. Convergence
insufficiency is the most commonly reported vergence abnormality, ranging 38–49%
in children [20, 23] and 44–47% in adults [19, 24]. Other common vergence disor-
ders include convergence excess, divergence insufficiency, divergence excess and
decompensated horizontal or vertical phorias.
Vergence adjustments are dynamic and can be horizontal, vertical, or torsional.
The proper coordination and alignment of the eyes enables the visual system to
accurately locate targets at different distances. Slight difference in the position of
Advances in Management of the Oculomotor Dysfunction… 65

the two retinae (or retinal disparity) must be readily reconciled by an adequate ver-
gence response in order to achieve sensory fusion. While viewing objects that are
nearer or further away, convergence or divergence of the two eyes works synchro-
nously with accommodation at all distances under the influence of the propriocep-
tive system which gives the internal awareness of space. Failure to maintain vergence
can result in unstable binocular vision, diplopia, asthenopia and visual discomfort.
Approximately half of those affected by a receded NPC post-concussion tend to
recover without intervention in 4.5 weeks [25], but some patients experience persis-
tent abnormalities lasting several months or longer [26]. In children with persistent
post-concussive symptoms lasting longer than 28 days, a receded NPC was observed
in 89% of them [20].
In sports-related concussion, receded NPC (>6 cm) appears to be a reliable bio-
marker for prolonged recovery (e.g. 50 days) [27]. Symptoms of convergence insuf-
ficiency tend to be similar to that reported in patients with accommodative disorder
[20]. Since vergence disorders can influence accommodation, both conditions are
often present in patients demonstrating a receded NPC. Hence, patients should ide-
ally receive a neuro optometric evaluation 4–5 weeks post-concussion when
other conditions will have abated.
Typically, the NPC breakpoints are measured as the distance from the point of
diplopia to the nasion (bridge of the nose) and the recovery point is when single
vision is re-established as the target is backed away. However, NPC measurements
can be confounded by the patient’s poor misinterpretation of blur versus diplopia.
Receded NPC tends to be more apparent using a line target on the RAF rule (e.g.
Grafton Optical, Berkhamsted, UK) compared to a pencil tip or fingertip [28], or
when the target speed is increased [29]. NPC measurements alone may not be suf-
ficient when evaluating vergence disorders but should be used as a screening test
prior to a referral for neuro optometric evaluation.
Other diagnostic factors of convergence insufficiency include a larger exophoria
at near than far and inadequate positive fusional vergence at near. Exophoria refers
to the tendency for the eyes to deviate outwards and is a common observation after
a concussion; whereas fusional vergence measurements determine if the patient has
the capacity to sustain binocular single vision as the examiner increases negative
and positive vergence demands while the patient maintains a constant level of
accommodation. This is collectively also known as binocularity, which has to be
assessed carefully by a clinician with the relevant training in optometry. While these
heterophoria measurements will determine the relative deviation of the eyes when
the two eyes are dissociated, such as during the cover test, an experienced clinician
must also consider the interplay and influence of accommodation, refractive correc-
tion, spectacle lens design, head posture, vestibular input, and the patient’s vestibu-
lar status.
Stereopsis can be measured using commercially available tests, such as the
Frisby stereotest (Stereotest Ltd., Oxfordshire, UK). Typically, positive and nega-
tive fusional vergence (PFV and NFV) ranges are measured at a fixed distance of
40 cm using a prism bar (base-out and base-in, respectively) by increasing its mag-
nitude until the blur and break (diplopia) points are found and reducing the prism
66 T. P. Yap and C. Stern

until the recovery (single vision) point. In a full binocular vision work-up, vergence
facility can be measured by alternating a 3Δ base-in/12Δ base-out prism while fix-
ating on an accommodative target at 40 cm in order to determine the number of
cycles per minute the patient can achieve while gaining single and clear vision dur-
ing each alternation of the prisms.

2.4 Saccadic Disorders

Saccadic disorders are estimated to occur in 20–30% of concussion patients [12, 13]
and its associated impairments tend to be more apparent under conditions of high
cognitive load, such as reading or when watching fast moving objects. For example,
patients may lose their place when reading, skip or re-read lines of print, face diffi-
culty with eye contact, and academic learning may be affected [10]. Other symp-
toms of saccadic disorders may include asthenopia, headaches, and dizziness.
Saccadic eye movements (or saccades) involves rapid changes in fixation while
shifting the gaze. In general, the process of reading tends to involve small ampli-
tudes of saccades whereas large amplitudes would typically be used during visual
scanning tasks. Following a concussion, these tasks tend to become more difficult
due to poorer accuracy (hypo- or hypermetric), slower velocities, increased laten-
cies, longer duration, and smaller peak accelerations in the saccadic eye movements.
Vergence disorders often occur together with saccadic dysfunction because these
two systems tend to interact during eye movements and may affect attention after
concussion [30].
The normal function of saccades is to scan the visual environment (e.g., visual
search or free viewing) in order to capture the image of interest as quickly as pos-
sible onto the fovea where photoreceptor density and visual resolution are the high-
est. Saccades can be voluntary or reflexive to visual, auditory, memory, and tactile
stimuli. In response to changes in fixations, the eyes shift rapidly with a velocity of
400–800°/s from one object of fixation to another. This movement is brief (short
duration of 10–100 ms), conjugate (i.e., parallel and same direction), and ballistic
(i.e., unable to change the course of the eye movement without making a separate
saccade).
Clinical examination typically evaluates the accuracy, latency, and velocity of
the saccadic eye movements by asking the patient to alternately fixate between
two targets 30–40° apart at a viewing distance of 40 cm. Latencies of 180–200 ms
are normally observed at the beginning of a saccade, then it tends to be slightly
hypometric (i.e., undershoot the target) by approximately 10% less than the
amplitude of the intended target and is fine-tuned by a microsaccade. Reading-
related eye movement can be examined using standardized rapid number naming
tests, such as the Developmental Eye Movement (DEM) test (Bernell Corp.,
Mishawaka, Indiana, USA), or the King-Devick test (King-Devick Technologies
Inc., Downers Grove, Illinois, USA). The latter is increasingly used in baseline
testing and for sideline testing when subclinical concussions are suspected among
athletes [31].
Advances in Management of the Oculomotor Dysfunction… 67

2.5 Smooth Pursuit Eye Movement Disorders

Smooth pursuit eye movement (SPEM) disorders are estimated to affect 43–60% of
patients with concussion [14]. They tend to induce visual motion sensitivity, dizzi-
ness, and nausea when viewing objects in motion. This is largely because the eyes
tend to lose track when unable to keep up with their speed, thus putting an addi-
tional load in the saccadic, vestibular, and optokinetic systems. This tends to elicit
involuntary conjugate saccades that interrupt fixation knows as saccadic intrusions
or a combination of eye and head movements in order to compensate or reduce that
target error.
The fundamental purpose of SPEM is to assist with gaze holding where the two
eyes produce conjugate movements (in the same direction) so the target remains
accurately fixated on the fovea without head movement. While the neural process of
gaze holding also involves the vestibular and optokinetic systems, SPEM maintains
gaze accurately together with the fixational and vergence systems keeping it to a
speed of 30–40°/s before shifting the gaze or moving the head. However, post-­
concussion SPEM can prove to be difficult for some patients as observed by their
frequent fixations and saccades when tracking slow moving targets [32]. This affects
their attention given that the prefrontal cortex is involved in both processes. For
example, visual attention tends to be hindered when tracking multiple moving
objects due to the increased tracking load and distraction [30].
Clinical evaluation of SPEM involves observing for smoothness, amplitude,
velocity, and direction when the patient is following a 10–20°/s moving target, such
as the tip of a pencil, at a distance of approximately 1 m. The patient should be
instructed not to move his or her head, and the target should be moved in the vertical
and horizontal planes. To track a moving object, a very quick “catch-up” saccade
normally precedes the fixation and SPEM. Longer lags, smaller amplitudes,
increased eye position errors, and variabilities in gaze positions may be observed
post-concussion and SPEM may appear jerky due to saccadic intrusions and re-­
fixations. Alternatively, an optokinetic drum can be used to examine the patient’s
horizontal SPEM by following the alternating white and black vertical stripe pat-
terns on the rotating drum. As the eyes moves toward the end of each excursion, a
corrective saccade would be observed in the opposite direction—this normal phe-
nomenon is known as optokinetic nystagmus and it relies on intact SPEM and sac-
cadic systems in order to produce this normal rhythmic reflex response.

2.6 Vestibular-Ocular Disorders

Vestibular-ocular disorders are estimated to affect up to 71% of concussion patients

[33]. This occurs when there is mismatched sensory-motor feedback from eye and
head movements due to a disruption to the normal sensory integration of the visual
and vestibular systems. This may produce a false sense of movement within the
individual (internal vertigo), in the surroundings (oscillopsia or external vertigo), or
a heightened sensitivity to head movement when shifting gaze. For example, a room
68 T. P. Yap and C. Stern

may appear to be spinning, or there may be a sensation of falling, tilting or bounc-

ing. These symptoms tend to exacerbate when there is an overreliance on the visual
system or in visually complex environments, resulting in visual motion sensitivity
and balance deficits in 40–68% of concussed patients [34]. Other symptoms include
nausea, imbalance, dizziness, movement-related blurry vision, unsteadiness or anx-
iety in busy environments [34].
Vestibular brain injuries are generally classified as central (affecting the brain or
central nervous system) or peripheral (pathology of inner ear vestibular structures
and/or the vestibular portion of the eighth cranial nerve). Central vestibulopathy
may result in disequilibrium and ataxia, which lead to difficulties in balance, coor-
dination and walking. Peripheral vestibulopathy is most often due to benign parox-
ysmal positional vertigo (BPPV) which occurs when calcium carbonate crystals
(otoconia) migrate from the utricle into the semi-circular canals. Some concussed
patients develop temporary hearing loss due to labyrinthine concussion which
occurs with or without BPPV.
While >90% of BPPV are successfully treated within weeks with canalith
repositioning maneuver [35], patients with central vestibulopathy and/or
vestibular-­ocular disorders tend to have prolonged symptoms involving dizziness
and visual instability which necessitates oculomotor and vestibular rehabilitation.
This is because the vestibular system and the oculomotor functions are closely
related. For example, the vestibulo-ocular reflex (VOR) is when the vergence and
SPEM systems interact with the vestibular system during head movements in
order to stabilize the eyes on a target relative to the external environment. Deficits
in VOR can be accompanied with nystagmus. For example, patients with oscil-
lopsia after moving the head often have positional nystagmus, whereas patients
with oscillopsia unrelated to moving the head often acquire downbeat or pendular
nystagmus which is characterized by slow upward followed by a fast downward
drift of the eyes, or a fast sinusoidal oscillatory movement of the eyes respectively
[36]. Therefore, it is important to examine the VOR in concussed patients with
prolonged symptoms.
The VOR is mediated through the labyrinth of the inner ear (including the semi-
circular canals), vestibular nuclei and cerebellar flocculonodular lobe. There are two
types of VORs: Firstly, angular VOR stabilizes vision during rotational acceleration
using the semicircular canals. Secondly, translational VOR stabilizes vision during
linear acceleration of the head and body using the otoliths (utricles and saccules). In
the process of VOR, brief changes in head position would direct the eyes to move
opposite the direction of head movement with equal amplitude in order to quickly
correct the target error. This would allow the images to remain on the fovea and to
process visual motion and motion parallax. In contrast, the VOR tends to be sup-
pressed during large saccades as the head and eyes move in the same direction
simultaneously. As the VOR may not respond to slow constant velocity motion and
persistent rotation of the head, this situation then relies on the proprioceptive inputs
from the neck.
In clinical practice, the head impulse test is used to evaluate VOR. While
fixating on the examiner’s nose or a distance target, the patient’s head is quickly
Advances in Management of the Oculomotor Dysfunction… 69

and unpredictably moved horizontally 20–30° by the examiner. The expected

normal finding is a conjugate eye movement opposite direction of the head
movement. The eyes should remain steadily fixated on the target during the neck
rotation. Any refixation saccades would suggest that the VOR is abnormal. The
patient’s ability to suppress the VOR can be evaluated by asking the patient to
fixate on the thumb of their outstretched arm while the chair is rotated, so any
refixation saccades suggest an impaired ability to suppress the VOR. In addi-
tion, the patient should have their dynamic visual acuity examined after refrac-
tion and static visual acuity testing. This can be assessed by rotating the patient’s
head back and forth by 20–40° in the horizontal plane at approximately 2 Hz. As
this head movement exceeds the ability of the pursuit system to compensate, a
reduction of <2 lines in dynamic visual acuity is expected as compared to static
visual acuity.

3 Treatment of Oculomotor Dysfunction in Concussion

It is essential for eye doctors to be able to initiate clinical management of visual

symptoms given the prevalence of oculomotor dysfunction following a concussion.
While estimates vary, a recent publication by the American Academy of
Ophthalmology (AAO) referred to 69% of children and adolescents with a concus-
sion having at least one associated vision disorder. The most common presenting
vision disorders are convergence insufficiency, accommodative insufficiency, and
saccadic dysfunction [37].
Treatment should be directed at full rehabilitation of the specific type of oculo-
motor dysfunction and the specific type of visual disorder affecting the patient.
When a full recovery is not possible, compensatory or therapeutic interventions that
reduces the symptoms should be included in the treatment plan.
The following are the most common interventions:

• Refractive correction
• Therapeutic lenses for symptom relief, or to assist focus flexibility or
binocularity
• Prism lenses for spatial orientation, binocular compensation, balance, or pos-
tural control
• Spectral filters (color or tint) for light sensitivity or reading disability
• Selective occlusion for strabismus or diplopia
• Neuro Optometric Rehabilitation Therapy to remediate oculomotor dysfunction,
inclusive of fixation, pursuits, saccades, accommodation, vergence, and
binocularity.

While not being covered here, patients may also benefit from visual field expand-
ing devices for visual field constriction or loss, optical devices for sight loss, non-­
optical aids for low vision or reading disability, and proper management or
monitoring of eye disease.
70 T. P. Yap and C. Stern

The use of lenses, prisms, selective occlusion, and spectral filters or tints is inte-
gral to treating post-concussion syndrome. The goal of the treatment is to alleviate
symptoms, achieve desired visual outcomes, meet the patient’s needs, and improve
the patient’s quality of life.
Neuro Optometric Rehabilitation Therapy may be considered at the same time as
the use of lenses, prisms, selective occlusion, and tints but may be needed alone or
after a trial of these other more passive treatments. Here, the reasons or rationale of
using each of these treatment modalities will be discussed.

3.1 Refractive Correction

Brain injury may change a patient’s refractive status. A patient may need a change
in spectacle prescription or a first prescription when they had no apparent prescrip-
tive visual need prior to their injury. A patient wearing contact lenses may no longer
be able to insert or remove the lenses and may not have a current eyeglasses pre-
scription. They may have only worn spectacles for brief periods of time for many
years and will therefore need a careful refraction that they can tolerate.
The prescription should consider both maximizing sight and patient comfort. If
there is a significant difference in the spherical or cylindrical components between the
two eyes, consider reducing the prescription in one eye to better balance the prescrip-
tion. In clinical practice, if at least one meridian of the astigmatic prescription is equal
between the two eyes, the patient can better tolerate wearing the prescription and there
is little to no compromise of binocular eyesight or binocular vision status [38].
Trial frame testing should be considered with every patient. If the refraction is
done in a phoropter, the desired prescription should be placed into a trial frame and
the patient allowed to walk around with it on for a few minutes. Giving them the
experience of near and far viewing along with body movement can be very helpful
in knowing if the patient is likely to tolerate the new prescription in everyday
activities.

3.2 Therapeutic Lenses

Therapeutic lenses can be prescribed for symptomatic relief, focus flexibility or to

assist binocularity. Accommodative disorders are common after brain injury and a
patient may benefit from a lens prescription for near-centered work, such as while read-
ing or working at their computer. This is especially true for patients in their mid to late
30s who are approaching presbyopia. Brain injury places additional stress on a patient’s
system often leaving them stuck in a state of sympathetic fight or flight. Thus, these
patients often benefit from low plus lenses of +0.25 to +0.50 OU during near-centered
work. This not only reduces accommodative lag and accommodative demand, but can
alter the perception of space to allow more “focalized” patients to better use their ambi-
ent vision and it helps to increase the VOR gain for those with vestibular issues.
Advances in Management of the Oculomotor Dysfunction… 71

3.3 Prism Lenses

Prism lenses can be prescribed to improve spatial orientation, binocular compensa-

tion, or postural control. The purpose is to bend the light entering the eye so that the
image can be shifted in the direction of the prism apex, which may be more desir-
able for the neurological process. To reduce the convergence stress, small magni-
tude of bases in prisms (e.g., 1Δ before each eye) can be used for near-centered
work to improve binocular stamina and stability.
Brain injured patients often compensate for visual information overload by con-
stricting peripheral awareness (or ambient vision). Visual field testing often shows
an overall constriction with no pathological pattern. Reduced peripheral awareness
contributes to inaccurate eye movements, poor depth perception, convergence dif-
ficulty and poor eye-hand coordination. Thus, prescribing 1–2Δ bases down prism
in each eye (yoked prism) can help to expand the patient’s visual awareness which
leads to greater binocular stability and increased patient safety as they go about their
daily activities.
A third application of prisms can be for postural control. Given the non-uniform
magnification of space across the visual field, prisms are able to produce spatial
changes neurologically by countering the expansion or compression of space that is
occurring in the ambient visual process. When a patient presents with limited head
control, a head turn, or abnormal egocentric localization, vertical or horizontal
yoked prism that is generally 3–4Δ per eye, may help the patient better center their
visual world and therefore present with their head aligned and with improved head
control.

3.4 Spectral Filters (Color or Tint) for Light Sensitivity or

Reading Disability

Clinicians should be aware that a significant number of patients experience photo-

sensitivity following brain injury, and some patients experience visual snow syn-
drome where tiny flickering dots can appear across the visual field. Spectral filters,
or tinted lenses, can selectively eliminate visible wavelengths that are causing per-
ceptual discomfort, visual snow, and reading disability [39].
While the exact hue and saturation level of these spectral filters can be precisely
determined to ameliorate the symptoms of photosensitivity using an intuitive colorim-
eter (Cerium Visual Technologies Limited, Tenterden, Kent, UK), there is a series of
recommended tints known as the Polytrauma Brain Injury Filter Kit available from
Chadwick Optical (Pennsylvania, USA) (Table 1). Chadwick Optical surveyed clini-
cians from Veterans Affairs Polytrauma Centers as well as experienced doctors from
the Neuro Optometric Rehabilitation Association (NORA, noravisionrehab.org) to
develop the kit. While clinicians have had success with most of these tints, E-15, and
FL 41 50% tend to be the ones most frequently chosen for indoor use and FL 27%
(73% tint) for outdoor use.
72 T. P. Yap and C. Stern

Table 1 List of tinted ophthalmic lenses from the Polytrauma Brain Injury Filter Kit (Chadwick
Optical: www.chadwickoptical.com)
Green/Blue Plum
 • Green/Blue 20%  • Light Plum (Noir 88)
 • Blue/Green 20%  • Medium Plum (COI Plum)
Blue  • Dark Plum (Noir 81)
 • E-15 Blue (Light Blue) Rose
 • E-30 Blue (Medium Blue)  • Light Rose (FL-41 75%)
 • E-50 Blue (Dark Blue)  • Medium Rose (FL-41 50%)
 • z1 Blue (Noir 26)  • Dark Rose (FL-41 27%)

3.5 Selective Occlusion

Patients do sometimes report diplopia that may be constant or intermittent. When

lenses alone are not successful in relieving the diplopia, temporary occlusion may
be needed. Contrary to traditional methods of occlusion, dark black “pirate” patches
should not be used to cover one eye as they limit peripheral vision and therefore
present a safety risk. Instead, occlusion that is opaque and only as broad as needed
to reduce the diplopia is preferred. For example, even if a patient is highly sensitive
to diplopia in all fields of gaze, consider placing opaque occlusion covering ¾ of
one lens of a pair of spectacles, leaving the temporal portion of the lens clear, then
adding nasal occlusion to the other spectacle lens if the patient still complains of
diplopia when looking to the side of the lens that is already occluded.
Another approach commonly used in neuro optometric rehabilitation is to pre-
scribe binasal occlusion, which can be useful in dampening the visual confusion
that often arises in the area of greatest binocular overlap. In clinical practice, the
authors’ preference is to use Scotch® Removable Magic™ Tape or LP Bangerter
occlusion foil which can be cut to size.

3.6 Neuro Optometric Rehabilitation Therapy

While many believe that neuro optometric rehabilitation is quite new, the concept of
being able to rehabilitate or enhance oculomotor, accommodative and binocular
vision skills has been in the literature since the nineteenth century. A French oph-
thalmologist, Louis Émile Javal, wrote his Manual of Strabismus in 1896 and is
considered the father of orthoptics, a precursor to modern vision therapy and neuro
optometric rehabilitation [40].
Neuro Optometric Rehabilitation Therapy is an individualized treatment pro-
gram for patients with oculomotor deficits that either do not respond to other inter-
ventions or where the other interventions mentioned still leave them with residual
deficits. There is evidence supporting vision therapy as an effective strategy for
rehabilitation. For example, Ciuffreda, et al. found that treatment with eye tracking,
accommodation and convergence exercises expedited recovery and completely alle-
viated symptoms in almost 90% of patients with mild TBI who have persistent
oculomotor defects [41].
Advances in Management of the Oculomotor Dysfunction… 73

This therapy typically involves weekly in-office sessions with supportive home
activities over an 8-month period until symptoms resolved [41]. This includes activi-
ties or techniques that are carefully planned and guided by eye doctors who are accred-
ited or board certified in vision therapy and neuro optometric rehabilitation, so as to
remediate the underlying neural deficits that limit oculomotor function. International
accreditation bodies include the Neuro Optometric Rehabilitation Association
(NORA), College of Optometrists in Vision Development (COVD)/Optometric
Vision Development and Rehabilitation Association (OVDRA), Optometric
Extension Program Foundation (OEPF), Australasian College of Behavioural
Optometrists (ACBO), British Association of Behavioural Optometrists (BABO),
and the Binocular Vision, Perception and Pediatric Optometry (BVPPO) Section of
the American Academy of Optometry (AAO).
Typically, the therapy activities begin at a level where the patient can perform the
activities without exacerbating their symptoms, and the level of the training activi-
ties is gradually increased according to the patient’s response to the treatment. This
helps in reducing the positional error of the eyes, reducing retinal slippage and
improving gaze stability. The target distances and conditions of each activity are
varied according to the treatment plan for the patient, with the goal being to normal-
ize the sensorimotor deficits of binocular vision, improve visual perceptual skills,
and integrate the oculomotor and vestibular systems. Techniques applicable to a
neuro optometric rehabilitation program are available from resources, such as the
Optometric Extension Program Foundation (OEPF) [42].

4 Summary

Oculomotor dysfunction affects more than 60% of concussed children and adoles-
cents and more than 90% of concussed adults. Deficits in saccades, smooth pursuit,
vergence, and accommodation are frequently observed. With proper refractive cor-
rection taking into account visual–vestibular interaction and the use of therapeutic
lenses, prism lenses, spectral filters, selective occlusion, and/or a program of Neuro
Optometric Rehabilitation Therapy, these patients will have their symptoms signifi-
cantly or fully resolved and be able to return to their previous daily activities. Today,
the eye and vision care community should recognize these post-concussion or mild
brain injury visual issues and treat or refer these patients for what is considered the
best medical care.

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Advances in Color Vision Testing

Sara I. Shoushtari and Rohan Bir Singh

1 Introduction

Alterations in color vision have been recognized for almost three centuries, and
since their discovery, there have been attempts to qualify and quantify changes in
color vision perception. The theory of color vision deficiency (CVD) was first pro-
posed by John Dalton in the late eighteenth century, and reflected the recent discov-
ery of red, green, and blue as primary colors [1, 2]. The earliest tests of color vision
were developed to test vocational capacity in transportation careers [1]. Eventually,
as understanding of the perceptual changes present in CVD grew, tests were
designed to leverage the unique physiology of color vision for determination of
perceptual deficiencies.
In this chapter, we will review the basic mechanisms of color perception, the
deviations which cause CVD, and the traditional as well as the newer testing modal-
ities for screening, diagnosing, and evaluating color perception.

2 Color Vision

2.1 Physiology of Color Vision

Vision is processed in the retina, and cone type photoreceptor cells are responsible
for color vision perception. Cones contain photopigments, comprised of an opsin
molecule and a retinol derivative [3, 4], which are capable of activating signaling
cascades upon reaction with photons. To be able to perceive complex color patterns,

S. I. Shoushtari · R. B. Singh (*)

Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye
Research Institute, Massachusetts Eye and Ear Institute, Boston, MA, USA
e-mail: [email protected]; [email protected]

© The Author(s), under exclusive license to Springer Nature Singapore Pte 77

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_6
78 S. I. Shoushtari and R. B. Singh

the retina employs three cone types, that when combined, include most of the UV
light spectrum. Short (peak sensitivity ~419 nm), medium (peak sensitivity
~530 nm), and long (peak sensitivity ~560 nm) wavelength cones correspond to
blue, green, and red wavelengths, respectively. Activation of cone photopigments
therefore depends on the UV wavelength of the source. The relative signaling pat-
tern of cones is interpreted by the brain to form color vision perception.

2.2 Color Vision Deficiency

CVD has traditionally been considered a congenital disease caused by alteration or

absence in one or more cone types. More commonly though, CVD occurs due to
retinal or optic nerve damage from chronic disease or ocular toxic medications,
leading to acquired changes in color vision, which do not usually result in chromatic
patterns of loss as seen in inherited CVD.

2.2.1 Congenital Color Vision Deficiency

Congenital CVD arises from dysfunction or nonfunctional photopigments, resulting
in changes or limitations in the perceived color spectrum. The prefixes protan-, deu-
tran-, and tritan, refer to red, green, and blue, respectively, and are used when
describing CVD type (Fig. 1).
Dysfunction without complete loss of photopigment causes anomalous trichro-
macy, and individuals will demonstrate altered hue matching patterns [3–5].
Depending on the affected cone type, individuals can be described as protanoma-
lous, deuteranomalous, or tritanomalous. In the cause of protanomaly and deuter-
anomaly, individuals inherit defective long and medium wavelength sensitive
photopigments with altered lengths of peak sensitivity [4]. Mutations in the short
wavelength sensitivity photopigment result in tritanomaly [6].
Dichromatic vision is similarly chromatically categorized, and results from com-
plete absence of one photopigment type, with possible associated loss in cone type
within the retinal cell population [7, 8].
Monochromatism is extremely rare and results in achromatopsia, complete loss
of color discrimination. Rod monochromatism is the most severe form and is due to
an autosomal recessive mutation causing total absence of cone function [9]. The
more common form of monochromatism is X-linked recessive blue monochroma-
tism, where individuals only possess blue pigment cones [10]. Vision is mostly reli-
ant on rods in blue monochromats, therefore resulting in decreased overall
visual acuity.
“Red-green color-blindness” is the most common X-linked recessive vision defi-
ciency, and includes protanomaly, deuteranomaly, protanopia, and deuteranopia, of
which deuteranomaly is the most common deficiency [3]. Red-green color defi-
ciency has a global prevalence estimated to between 2–8% in males and 0.5% in
females [3]. Comparatively, “blue-yellow color blindness” consists of the “tritan
deficiencies” tritanopia and tritanomaly. Tritanopia has an autosomal dominant
inheritance pattern with an estimated 1 in 500 prevalence [3, 4, 6].
Advances in Color Vision Testing 79

Fig. 1 Normal color

vision (top) as compared to
deuteranopic (middle) and
proanopic (bottom) vision
80 S. I. Shoushtari and R. B. Singh

2.2.2 Acquired Color Vision Deficiency

Acquired CVD is more common than the congenital form, especially in individuals
over 40 years old [11]. Acquired CVD can also be associated with changes in other
areas of visual perception, such as spatial discrimination and visual acuity [12].
There is some evidence of a relationship between visual perception changes and
specific color deficiency patterns [12]. Most forms of acquired CVD result from
damage to the retina or optic nerve, and thus there is no distinct chromatic pattern
of cone loss as seen in congenital CVD [5]. Additionally, there are some medica-
tions with a known side effect of dyschromatopsia, many with unclear mechanisms
of acting on the color vision system [5].

3 Color Vision Assessment

There are multiple methods for assessing CVD, and thorough clinical evaluation
often relies on utilizing more than one test. The most recognized test uses the pseu-
doisochromatic plates (PIP) used in screening for CVD. More complex tests, such
as the hue arrangement testing (Farnsworth D15) and anomaloscope evaluation, are
used to diagnose specific deficiency patterns. There are also several occupationally
oriented tests used by various professional institutions to determine an individual’s
ability to complete work specific tasks. Importantly, all testing methods utilize the
unique physiology of color perception to isolate and evaluate the function of indi-
vidual cone types.

3.1 Routine Screening Tests

The basis of most CVD screening tests is the PIP. PIP tests are made by placing
randomly sized dots of varying color patterns to draw out numbers or shapes only
visible to individuals with color vision. The variations of the color patterns can dif-
ferentiate specific deficiencies [1, 3, 4, 13]. The first PIP test was developed by
German ophthalmologist, Dr. Jakob Stilling in the late nineteenth century [1, 4], and
in the subsequent century variations of these original tests have been made. The
straightforward nature of CVD testing using PIPs makes them ideal for screening.

3.1.1 Ishihara Plates

Dr. Ishihara first published his “tests for color blindness” in 1917, where he debuted
the Ishihara plates, his adaption of Stilling’s PIP [14]. Today, the Ishihara plate test
is the most commonly administered CVD test. The original Ishihara test consists of
38 plates, one introductory plate in which the pattern is visible to all individuals
regardless of cone function (Fig. 2), following by a series of testing plates [4, 13,
15]. Subsequent abbreviated 24 and 16 plate versions have also been published [4,
13]. Each version contains scoring guideline indicating how many errors can be
made before anomalous vision should be suspected [4]. This is important to note as
individuals will full color vision are prone to errors when tested [16]. The Ishihara
Advances in Color Vision Testing 81

Fig. 2 Ishihara plate #1 (left), the test plate, would show “12” in all individuals regardless of color
vision. Ishihara plate #9 (right) which would show “74” for normal trichromats and “21” for
dichromats

plates are considered reliable screening tests for congenital red-green deficiency,
with over 95% sensitivity and almost 100% specificity [17–19]. Ishihara plates are
unable to determine severity of deficiency though [1, 13, 20]. Additionally, the
Ishihara plates do not contain tritan sensitive plates, and therefore cannot be used to
detect tritan deficiency [1, 4].

3.1.2 Hardy-Rand-Rittler (HRR) Plates

The HRR plates employ pseudoisochromatic theory to test both red-green and blue
color vision deficiency, and have the ability indicate potential severity of CVD. HRR
plates utilize changes in saturation of figure dots as compared to background dots to
determine mild, moderate, or severe deficiency [1, 4, 13, 15, 21]. Additionally, HRR
plate figures are symbols, rather than numerals, making it capable of testing younger
children or those without education [1]. HRR plates are equally sensitive (1.0) and
specific (over 0.97) in determining CVD [19, 21, 22].
Additional variations of PIP tests have been developed throughout the years in
attempt to address the diagnostic shortcomings of the Ishihara tests and better evalu-
ate tritan deficient and illiterate individuals [23].

Diagnostic Tests
Diagnostic tests have been developed for administration following screening tests to
further classify the deficiency present. Because of this, they are inclusive of all color
deficiencies, acquired and congenital, across the chromatic spectrum [1]. The most
common diagnostic test is a form of an arrangement test, in which an individual
arranges small caps filled with hues into their perceived natural order. The subjec-
tive order is then plotted to determine the specific CVD [4]. Variations of the tests
allow for more sophisticated determination of deficiency as well as recognition of
acquired variances.
82 S. I. Shoushtari and R. B. Singh

3.1.3 Hue Tests

The original hue test developed by Dean Farnsworth included 100 caps with a uni-
form increase between hues (based on Albert Henry Munsell) that encompassed the
entire color spectrum [1, 24–26]. The location of each cap in an individual’s arrange-
ment is compared to the correct order, and deviation in the pattern corresponds to
perceptual deficiencies. Administration of the F-M D100 and scoring of the response
is a very tedious process, so hue arrangement tests are not suitable for screening.
They can diagnose subtle anomalous vision changes that cannot be identified on PIP
testing [4, 22].
Shortened versions of the hue test, like the F-M D15, include fewer caps and
therefore are more useful in determining severe and acquired CVD [1, 4, 13, 27].
Alternative hue tests, such as the Lanthony, Adams, and City University tests were
designed for children and acquired CVD [1, 4, 13, 15, 27–30]. Hue test are consid-
ered extremely specific, however due to their limited sensitivity, they are considered
more effective as follow-up tests to PIP screening [17, 19, 31].
Online hues tests are also available such as, https://www.color-­blind-­test.com/
d15-­color-­blind-­test-­more, https://www.color-­blindness.com/color-­arrangement-­
test/. The online test consists of 15 color squares and one reference color square
(Fig. 3). The patients are asked to be seated at 50 cm from computer monitor as then
it subtends an angle of 1.5°. The patients begin with the reference color and arrange
the others in a progression of hue and 2 minutes are given to complete the test. They
are allowed to review their ordering and make any necessary changes.
For scoring, color difference vector (CVD) analysis is done. Quantifiable square
arrangements include the confusion angle, which identifies the type of color vision
deficiency. An angle above +0.7 degrees points toward a protan defect, between
+0.7 and −65 a deutan defect and below that a tritan defect. Other parameters
include the major and minor radius which is ratio of those two numbers results in
the S-index. The total error score (TES) which combines the two radii into a score
of total error. TES ranges from around 11 up to about 40 for strong vision deficien-
cies. The confusion index (C-index) quantifies the ratio between major radius and
the major radius of a perfect arrangement. People with normal color vision or
slightly colorblind persons have a ratio below 1.2. The higher this number (grows
up to above a ratio of 4), the more is severity of color blindness.

Fig. 3 Output of an online protan deutan

hue test (https://www. P 1 2 3 4 5
color-­blindness.com/
6
color-­arrangement-­test/).
(Image courtesy: Dr. Parul 7
Ichhpujani) tritan

8
15

14 9
13
12 11 10
Advances in Color Vision Testing 83

3.1.4 Anomaloscope
The anomaloscope is considered the gold standard of CVD diagnostic testing. An
anomaloscope is an instrument to test color matching. An individual mixes two light
beams to adjust the proportion of each light until they feel it matches a given sample
[4, 15, 32, 33].
The results of the test are interpreted using various equations to assess the degree
and type of color deficiency. The original anomaloscope was created for evaluation
of red-green color deficiency using the Rayleigh equation, which dictates the tests
wavelength parameters [4, 32]. The Moreland test was subsequently created to
allowing for tritan deficiency testing, and similarly provides parameters and evalu-
ation criteria [32, 34]. Alternative versions, such as the Pickford-Lakowski or
Besancon test similarly can be used to assess tritan deficiency [4].
As every color on a computer display is essentially made from the base colors
red, green, and blue, an anomaloscope cannot be reproduced online. Therefore, a
simplistic reproduction, based on a different operating principle has been attempted
on portals such as, www.color-­blind-­test.com/anomaloscope-­more.html.

3.2 Occupational Testing

The origins of CVD tests are in occupational testing, and the first standardized color
vision tests were developed to assess rail and naval employees’ abilities to safely
complete work duties [4]. Today various professional organizations continue to
include CVD testing in employee assessments to determine the ability of an indi-
vidual to perform occupational tasks [10, 31, 35].

3.2.1 Lantern
The most common occupational test in use dates to the nineteenth century, devel-
oped in response to repeated railway accidents at the time [4]. Lantern tests
involve showing various color signals and patterns to individuals and asking them
to state what they have been presented. The colors, speed, and spatial patterns of
the test should reflect relevant occupational distinction requirements and mimic
real signals the individuals would encounter [4, 27]. Thus, the lantern tests are not
reliable for screening or diagnosis of CVD and should only be used to determine
potentially hazardous visual defects [1, 4].Additionally, performance on lantern
test cannot be easily associated with performance on other CVD tests and accord-
ingly should not be used as a means of independent clinical diagnosis of CVD [13,
36, 37].

3.3 New Testing Modalities

With the development of technology and understanding of color perception, new

testing modalities have been developed to attempt to improve the CVD screening
and diagnosis process.
84 S. I. Shoushtari and R. B. Singh

Fig. 4 Author’s own test taken online, https://colorblind-­test.io/cambridge-­color-­test

3.3.1 Digital Testing

The major innovation in CVD testing has been in the creation of various digital tests
with the goal of standardizing test administration and results. Examples of digital
tests include the Cambridge color test (CCT), the portal color sort test (PCST), color
assessment and Diagnosis (CAD) test, and Martin Lantern test [15, 19, 27, 35, 38].
The CCT is an adaptive digital PIP test that randomizes plate order as individuals
answer (Fig. 4) [15, 27]. The CCT can also be adapted for use with children, further
expanding its accessibility for CVD screening [39]. The PCST offers a digital ver-
sion of the hue arrangement test that allows for both screening and diagnosis [38].
The CAD test utilizes HRR plate style coloring to detect red-green deficiency [19].
Digital lantern tests, such as the Martin Lantern test, have also been developed to
more easily test potential job candidates [27]. These digital tests demonstrate simi-
lar reliability to physical tests [17, 19, 31, 38].

3.3.2 Developments to PIP

Physical PIP tests also remain useful, and there have been developments in plate
design to reduce variability and deterioration of plates overtime. Dalton’s PIP uti-
lizes polymer print, rather than ink to produce hues, reducing the effects of aging on
testing reliability [40].

3.3.3 Electroretinography
Electroretinography (ERG) utilizes measurements of electrical signaling in the ret-
ina in response to light flashes to determine anomalies in color vision [27, 41]. ERG
offers an opportunity to further objectify CVD testing and decrease reliance on
subjective response to visual prompts for diagnosis [42, 43].

4 Limitations of Testing

The sensitivity and specificity of various CVD tests have been evaluated numerous
times and are extremely high across testing modalities and subsequent test versions
[13, 17–19, 21, 22, 31, 32, 40, 44]. However, there remains several limitations to the
currently available CVD testing methods.
Advances in Color Vision Testing 85

The most common issue with physically administered tests is the possibility for
variation. This can be a result of differences in ambient lighting during testing or
hue quality on plates and caps. Tests contain instructions on standard lighting condi-
tions to effectively administer the test [4]. There have been several studies that dem-
onstrate that changes in lighting source during testing can either improve anomalous
performance or increase failures in trichromats [45–50]. Additionally, physical
plates and hue caps have the potential to deteriorate over time, also affecting perfor-
mance of both normal and anomalous individuals. However, these limitations can
also apply to digital test, which must be similarly standardized to reduce the effect
of display screen variance on test efficacy [27].
Another limitation of current CVD testing methods is the lack of standardization
across tests [15]. Scores between modalities are not comparable and therefore grad-
ing of CVD severity is not uniform. Furthermore, there is no current procedure for
testing that allows for complete screening and diagnosis within one test. It is fre-
quently recommended that more than one test be utilized to ensure diagnose [4, 15].
A concern for many institutions that administer tests for occupational evaluation
is attempts to memorize test to ensure passing despite CVD [31]. This is especially
common with plate and lantern tests that have limited ability to randomize or adapt
to individual responses [31]. Digital tests that adapt to individual response, or more
complex tests such as hue arrangement, can provide a more reliable assessment of
color vision [15, 27, 38].
Improvement has been made to make CVD screening more accessible to indi-
viduals with intellectual disability, poor literacy, and children, however, many tests
remain inaccessible. Hue sorting test require physical mobility, and many PIP tests
require recognition of numerals [4].

5 Future Directions

Augmented reality and virtual reality technologies are being explored to create
immersive color vision testing environments. These platforms offer novel ways to
simulate real-world color discrimination tasks and evaluate color vision under vari-
ous lighting conditions, potentially improving the ecological validity of assessments.
Machine learning algorithms and AI techniques are being applied to analyze
large datasets of color vision test results [51]. These approaches can identify pat-
terns and correlations that may not be apparent to human observers, potentially
leading to new insights into color vision disorders and more accurate diagnostic
algorithms.

6 Conclusion

Color vision deficiency testing utilizes the unique physiology of human color per-
ception to isolate the function of cone types and assess their function and the prin-
ciples of color vision testing have remained the same for centuries. Developments
have been made recently to improve test administration and increase test
86 S. I. Shoushtari and R. B. Singh

accessibility, however, many issues with standardized test experiences remain.

Progress also needs to be made to create tests that are better able to screen, diag-
nose, and offer useful evaluation of an individual’s functional and occupational abil-
ity. As our understanding of retinal cell development increases, there will be great
opportunities to apply this knowledge to better understand color vision and offer
new methods for testing and predicting CVD.

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Advances in Low Vision Aids

Samira Mortazavi and Asha Meloottu

1 Introduction

An article published in 1964 by optometrist Dr. John Zettel discusses official ter-
minology for patients with partial vision loss, determining a need for classifying
the degree of blindness due to changes in social standards at the time. Visually
impaired patients were initially labeled as people with “subnormal vision,” how-
ever, Zettel recommended using the term “partially sighted individuals.” He also
made an outline of recommendations for these patients, including examination
techniques and low vision aids to prescribe [1].These aids included high add power
bifocals and base out prism glasses with increased power to aid in convergence and
fusion [1]. Today, “visually impaired” is the accepted terminology for this popula-
tion, and the specialty in caring for these individuals can be referred to as low
vision or vision rehabilitation. While high-power lenses are still widely prescribed,
updated technology has diversified and increased clinicians’ options in prescrip-
tion low vision aids.
The goal of low vision devices is to augment or maximize the remaining vision
that the patient has. When weighing appropriate devices for low vision patients, it is
necessary to consider their level of visual function, the type of vision loss, the
patient’s cognitive function, and the visual goal they are trying to accomplish.
Additionally, this decision-making process must consider the principle of least
effort, where options that are easier to implement and require less labor are more
favorable. Therefore, to prevent device abandonment and unnecessary patient costs,
a stepwise approach is necessary for choosing low vision devices.

S. Mortazavi (*) · A. Meloottu

Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
e-mail: [email protected]; [email protected]

© The Author(s), under exclusive license to Springer Nature Singapore Pte 89

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_7
90 S. Mortazavi and A. Meloottu

2 Low Vision Devices

Below are the general categories of devices used in low vision rehabilitation, listed
in increasing complexity.

• Spectacle correction
–– High reading adds
–– Microscopes
• Magnifiers
–– Handheld magnifiers
–– Stand magnifiers
• Telescopes
–– Handheld telescopes (Galilean, Keplerian)
–– Spectacle mounted (binocular vs. monocular)
• Electronic devices
–– Desktop CCTV (with or without OCR)
–– Portable CCTV
–– Head-mounted
–– Applications for smartphones/tablets
• Non-optical devices
–– Optical Character Recognition (OCR)
–– Tactile (e.g., Braille)
–– Audio devices (e.g., Talking watches, Siri, etc.)

2.1 Devices for Mild Low Vision

These patients will fall into the visual acuity range of 20/20–20/70 (Table 1) and
will easily find improvement to their visual impairments through simple optical
devices. These include:

• Spectacle or contact lens correction

• High reading adds
• Microscopes
• Magnifiers
• Telescopes

Table 1 Grading of Visual Impairment [2]

Category Worse than Equal to or better than
Mild visual impairment 20/70
Moderate visual impairment 20/70 20/200
Severe visual impairment 20/200 20/400
Blindness 20/400 No light perception
Advances in Low Vision Aids 91

2.2 Devices for Moderate Low Vision

These patients will fall into the visual acuity range of <20/70–20/200. The patient’s
overall visual function becomes dependent on how both eyes work together. For exam-
ple, if the acuity of one eye still falls into the category of mild low vision, they may still
benefit from simple optical devices alone. However, if vision loss is complicated
by central scotomas or visual confusion the visual potential is limited and these patients
may function more similarly to someone with severe low vision. In such cases, elec-
tronic devices and smartphone applications may be more efficient at improving visual
function (See Sect. 2.3). Similarly, when patients have a hemianopsia following a
stroke or traumatic brain injury, their visual function is greatly impeded, though central
visual acuity is spared. In these scenarios, patients may benefit from a peripheral prism
(ex: Peli Prisms) to expand their awareness of the missing field.

2.3 Devices for Severe Low Vision—Blindness

These patients will fall into the visual acuity range of <20/200-no light perception.
At this stage, optical devices are often dependent on the acuity of both eyes indi-
vidually (as stated above). Patients will likely gain some benefit from optical devices
and will rely more on devices that augment their vision, such as electronic devices.
When the visual impairment is very severe to total blindness, the patient must rely
on other senses to function. This may mean using auditory cues from optical char-
acter recognition devices or tactile cues.

2.4 Current and Emerging Low Vision Aids

In the early 1800s, a young Louis Braille was introduced to night writing, a tactile
writing system that uses 12 raised dots in various arrangements. While night writing
was originally invented by Charles Barbier for soldiers to communicate in the dark,
Braille simplified and perfected the system by reducing the 12 dots arrangements to
6 dots and changing the symbols to stand for letters rather than sounds [3]. The
braille system is a well-­known adaptation still used for visually impaired individu-
als and can be implemented presently as an accommodation. While braille is still
taught to children with vision impairment, adults are encouraged toward low vision
aids that can be seamlessly integrated into their life. Older individuals may not want
the extensive training required to learn a new way of reading or may struggle with
using tactile cues due to other comorbidities. Other available accommodations, such
as magnification, do not require learning a new language and allow patients to con-
tinue enjoying reading material they are familiar with.
Magnification-Optical magnifiers such as handheld, dome, and stand magnifiers
are commonly prescribed, due to being user-friendly, affordable, and often portable.
Traditionally, the potential magnification to read standard size print (1M) can be
determined with the patient’s recorded working distance and acuity. Based on this
92 S. Mortazavi and A. Meloottu

calculation, a low vision specialist can provide the patient with a demonstration and
a prescription for an optical magnifier. The magnification of a handheld or stand
magnifier cannot be adjusted; therefore, if vision continues to decline, a magnifier
with a lower power may be deemed useless to the patient. Video magnification, on
the other hand, such as portable digital magnifiers and CCTVs (closed circuit televi-
sions), can adjust magnification strength while providing other vision-enhancing
possibilities such as adjusting contrast and brightness. Video magnifiers can offer
magnification from 2× to 60×, providing patients the flexibility not offered by opti-
cal magnifiers. Another added benefit of digital magnifiers is comfort, primarily
through having a larger screen and a more natural reading position. Digital and
video magnifiers often include built-in stands that allow the screen to face the
patient at an angle or, in the case of desktop CCTVs, straight ahead. Unlike dome
and stand magnifiers, patients are not required to hover over the device to read on a
flat surface.
Electronic Magnification-Currently, there is a shift toward prescribing digital
magnification, such as desktop CCTVs, portable video magnifiers, and magnifying
smartphone applications. As mentioned, in addition to the possibility of adjusting
the magnification provided by the video magnifier, another substantial benefit of
such devices is the ability to change the text’s contrast. Contrast sensitivity is a
measure of visual function that describes the ability to differentiate the target lumi-
nance from the background luminance [4]. This measurement can be done with a
Pelli-Robson Chart or a MARS chart to find the logarithmic value of the contrast
sensitivity of the patient. Different values are assigned for different age groups and
are categorized as normal, moderate loss, severe loss, and profound loss. Contrast
sensitivity impairment is less commonly reported than visual acuity but may better
represent real-world goals and situations [4]. Visual acuity charts used in the exam
room are known to have 100% contrast with black letters on a white background.
However, the patient will likely encounter everyday circumstances that require high
contrast sensitivity, which become more critical on cloudy days, indoors, and in
other low lighting settings. A sign of reduced contrast can be difficulty seeing faces
or reading a newspaper, as both have a relatively low target to background
luminance ratio compared to a standard visual acuity chart. There are numerous
studies regarding the decrease in contrast sensitivity for various ocular diseases, and
even a study showing that glaucoma patients may have impaired contrast sensitivity
while having good visual acuity [5].
There are several methods to help patients with reduced contrast sensitivity.
Some digital magnifiers can increase contrast by changing the color of the reading
material or object being viewed. These color combinations can include an increased
contrast of white background with black writing, black background with white writ-
ing, yellow background with black writing, blue background with yellow writing,
and others—up to 14 different color combinations to increase the contrast of the
targeted material (e.g., See Fig. 1).
Tints-A decrease in contrast sensitivity can also be addressed with light filters or
tinted lenses. A tint assessment can be an element of a low vision examination,
depending on the patient’s vision loss and the pathology causing the loss. For
Advances in Low Vision Aids 93

a b

Fig. 1 (a and b) Textbook being magnified using a digital magnifier with “False Colors” setting
to increase contrast

Fig. 2 Tint evaluation kit

commonly used for
polytrauma conditions

instance, a patient with decreased contrast sensitivity due to advanced glaucoma

may express that yellow and orange tints increase contrast. This can be measured
objectively by repeating contrast sensitivity testing to see if there is a notable
increase in score. Tints can also be used for nontraditional vision impairment, such
as traumatic brain injury or extreme photophobia. Particularly, lenses that block
480 nm wavelengths, like the rose-colored FL-41 tint, have been proven to aid
migraine headaches and the photophobia caused by it. In one study, 37 individuals
with chronic migraines were asked to trial seven different lens tints and choose the
most comfortable ones [6]. The results showed that 71% of participants preferred
FL-41 tinted lenses to aid in their migraine symptoms [6].
Tints can also be used for glare sensitivity caused by ocular pathology. In-office
tint assessments can be done with tint kits (Fig. 2). These tints can be prescribed to
be placed in habitual glasses or as an addition to glasses, such as a fit-over frame or
a clip-on. Corning, a large glass company, introduced corning protective color filter
(CPF) lenses in the 1980’s, and these have been the industry standard for tinted
lenses [7]. Currently, many companies offer corning inspired lenses, offering
94 S. Mortazavi and A. Meloottu

interpretations of the same colors as well as other light filters scientifically proven
to be effective [7]. In addition to light filtering tints, glare reducing tints, like NoIR,
filter 99% of short wavelength light as well as infrared light to help reduce excess
glare [8].
Wearable Devices-Virtual reality (VR) headsets enable augmentation of a
patient’s visual acuity or expansion of their visual field through a wearable elec-
tronic device. Devices such as the IrisVision, Vision Buddy, eSight, and PatriotVision
all employ a camera that feeds a video image onto the internal device screen. The
head-mounted displays have a similar advantage to traditional binocular telescopes
as digital magnifiers have with optical magnifiers—flexibility. The hands-free
nature of the device affords the patient a more natural experience. The screen within
the headset allows for variable magnification using digital zoom, contrast enhance-
ments, and minification. While older VR devices are reportedly uncomfortable due
to the weight placed on the patient’s head, newer devices such as the IrisVision
Inspire and eSight Go are designed to fit more ergonomically, similar to glasses
[9–11]. While VR devices work for visual needs at all distances, they are more ben-
eficial for distance viewing. Many versions include OCR (Optical Character
Recognition) capabilities for reading, a live feed from the patient’s cable box for TV
viewing, phone connectivity for smartphone use, and voice control settings. The use
of VR devices while mobile is discouraged, as proprioception changes with magni-
fication and minification [12].
Optical Character Recognition (OCR)-Not all patients with visual impairment
can read comfortably with magnification alone. If vision reduction is more severe,
or scotomas and field loss interrupt the natural flow of reading, attempting to
increase reading ability may be frustrating and cumbersome for the patient. In these
circumstances, devices that utilize audio instead of visual support may be more
appropriate. Traditionally, patients with severe vision loss were limited to prere-
corded audiobooks and prerecorded object identification using barcode scanning.
This restricted identification to objects that had barcodes, and often would only
identify the object without providing more helpful information. For example, these
devices may be able to correctly identify a can of food but not read cooking instruc-
tions written on the back. Optical character recognition, also known as text recogni-
tion, deciphers printed text and converts it to a digital format. This technology aids
patients in reading virtually anything, including bills, newspapers, magazines, and
even text on everyday items. Devices with OCR capabilities range from desktop
CCTVs to wearable technology. Desktop devices such as Lyric or Eye-Pal Solo can
be a simple option for older patients or patients who don’t require the portability of
alternative aids. The primary benefit of these devices is the oversized tactile buttons,
which many patients find easier to utilize.
Smartphone Technology-There are many smart device applications for visually
impaired individuals, such as SeeingAI, EnVision, and Lookout-Assisted Vision.
These applications may be equipped with OCR technology, artificial intelligence to
describe a scene, options to help patients find an object in a room, and various other
features. OCR features within a smartphone application have the benefit of being an
inexpensive, more simplistic, and more immediate option when compared to
Advances in Low Vision Aids 95

desktop OCR devices Smartphones also have built-in accessibility options for visu-
ally impaired individuals that can be customized in the phone’s settings. Apple
iPhones have features such as zoom, magnifier, audio descriptions, and dictation, to
name a few [13]. Android phones are also equipped with similar accessibility
options, including customizing screen contrast, “talk back” or the screen’s ability to
be read aloud, and text magnification [14]. Both smartphone companies have tutori-
als that are available for patients and family members to make these accessibility
changes as an initial step toward independence with visual impairment. These
accessibility options allow a more seamless transition for patients to continue using
a device they are already familiar with. This also allows visually impaired individu-
als to not draw attention to their impairment should that be a concern to them.
Clinicians should familiarize themselves with these accessibility options to help
patients set up their phones for their low vision assessment in the clinic.
Similar to smartphone use described above, not all technology beneficial to visu-
ally impaired individuals was originally made for that purpose. Voice assistants
such as Apple’s Siri, Microsoft’s Cortana, Amazon’s Alexa, and Google Assistant
are available on smartphones or speaker devices. Siri and Google Assistant can send
and read texts, make phone calls, answer basic questions, set timers, and carry out
many other commands. Individuals without vision impairment use these voice
assistants regularly, but they also prove to be highly beneficial for low vision indi-
viduals. Smart home automation using Google Home and Alexa may also support
low vision individuals. Installing commands such as turning lights or appliances on/
off make previously difficult tasks for low vision individuals achievable with a few
spoken words. The thermostat may even be set to a specific temperature, rather than
manually adjusting it, negating the need for a handheld magnifier to see the small
numbers.
Mobility Aids-People with vision impairment face mobility challenges with
navigating indoor and outdoor settings [15]. For this specific functional challenge,
white canes and seeing-eye dogs continue to be commonly used among this popu-
lation. White canes provide the user beneficial feedback for obstacles in front of
them to encourage more independence while ambulating. However, learning to
use a white cane takes multiple training sessions from orientation and mobility
specialists to ensure confidence in the user. Newer technology aims to decrease
the training needed for traditional mobility aids as much as possible to encourage
seamless integration in the user’s life. This aspect is especially crucial for older
patients whose vision loss occurs later in life. Ultrasound devices on the market,
such as the Buzz clip, are designed for use with the white cane. This device uses
ultrasound to detect obstacles in the user’s path and alert them with vibrations.
The WeWALK smart handle can attach to any long cane and provides additional
mobility support, including vibration to inform the patient of low-hanging obsta-
cles that a cane alone would miss, such as a sign or tree branch. Additionally, the
patient can pair their cane to the WeWALK app on iOS or Android devices via
Bluetooth to make use of its public transportation features and other audio
alerts [16].
96 S. Mortazavi and A. Meloottu

With the rise in artificial intelligence use, wearable devices to aid in mobility,
such as the Biped, are entering the market for testing. The Biped is a harness worn
on the shoulders and is equipped with cameras, offering audio feedback to the
wearer, alerting them of any obstacles. This device advertises itself to function as a
“self-driving car” but for pedestrians, offering guidance to the wearer in real time
[17]. The Biped is currently being used in the USA and Europe and has plans to
include GPS (Global Positioning System) capabilities in upcoming updates [17]. As
mentioned earlier, these wearable devices can benefit patients because of the
reduced training required to utilize these devices.
Psychology Services-It is important to note that even with the devices and
accommodations available for visually impaired individuals, there is not a lack of
mental health difficulties associated with the loss of sight. Blindness is reported to
be one of the most feared health complications, greater than cancer or paralysis.
Loss of vision may cause anxiety, worry, embarrassment, and social withdrawal due
to negative self-perceptions [18]. Overall, vision loss can cause emotions similar to
bereavement, due to the loss of a heavily relied-on sense. Some mental health dif-
ficulties may stem from visual hallucinations that often occur with vision loss 20.
Patients may not report these hallucinations in fear of being perceived as having a
psychiatric disorder and are, therefore, less likely to receive support. In addition to
having an examination with a low vision provider, it is important to inquire about
the patient’s adaptation to their condition and offer a supportive space to share their
concerns. Providing resources available in the community, support groups, and a
referral to a psychiatric provider can offer patients with tools to better navigate the
emotional and social changes that accompany vision loss [17]. Currently there is
limited data to support the positive effects on mental health that support groups can
provide [18]. As research continues, there is a high likelihood of more data to sup-
port mental health interventions in patients with vision loss.

3 Case Scenario

A 51-year-old female presented for a low vision examination with a known history
of Stargardt Disease. The patient presented to the inherited retinal disease depart-
ment after 4 years with no reported change to her vision. She denied any issues with
her peripheral vision or night vision. Her visual acuity was 20/500 in the right eye
and 20/400 in the left eye—with a slight decrease in acuity in the right eye since last
seen. A battery of testing was performed, including a Goldman Visual Field of both
eyes, which revealed stable, dense central scotomas. Her last low vision evaluation
was several years prior and was now being referred back to the vision rehabilita-
tion department, as she had reported some difficulty with her activities of daily living.
As a previous patient of vision rehab services, she had received several devices
prior to this visit; however, she still found herself having difficulty seeing small
objects around the house. She also reported increased difficulty with reading, even
while using her current devices.
Advances in Low Vision Aids 97

The following is a review of her current devices when she presented for her low
vision evaluation:

1. Prism Magnifier Reading Glasses (+10D): Used for quick reading around the
house (e.g., reading labels in the kitchen), however found that this device
was not enough.
2. Desktop CCTV: Working well, used mostly for reading.
3. Computer enlargement software: Used for reading emails, and other computer
work - working well.
4. Ruby XL HD portable electronic magnifier: Working well, however, used infre-
quently as it was cumbersome to carry around the house or outside the house.
5. Smartphone accessibility settings: Patient is using all the accessibility settings
on her phone without difficulty. Not using any apps for magnification.
6. Eschenbach 7× handheld optical magnifier: Uses occasionally, working fine.
7. Long cane: No difficulty, no new mobility goals.
8. Beecher 5.5× binocular telescope: Working well uses this device most frequently
for distance viewing needs.
9. IrisVision head-mounted device: Using infrequently in the garden, watching TV,
reading.

Her main goal with this exam was to improve reading, and so while the above
devices did not adequately meet this need, the following devices were shown to her:

1. iPhone apps such as SeeingAI and Magnifier

2. +16 prism readers—custom made

3.1 Case Take Aways

• The simpler devices were what the patient tended to use more frequently (e.g.,
Beecher binocular telescope, prism readers), following the principle of
least effort.
• Where the portable handheld CCTV (Ruby XL HD) was cumbersome to trans-
port, smartphone applications provided similar features with the addition of
other app features and ease of access (considering how consistently the patient
had her phone on her person).

4 Conclusion

Low vision device technology has advanced rapidly in recent years. To keep up with
the ever-increasing low vision population, it is necessary to have a good understand-
ing of the available devices and related resources for these patients. While optical
devices such as handheld magnifiers and telescopes remain within our baseline bat-
tery of low vision devices, newer technology such as VR headsets, OCR, and
98 S. Mortazavi and A. Meloottu

smartphone applications can give patients the most visual functional benefit and
with the most ease. Though many devices are available for patients to use, patients
are often unaware of all the tools at their disposal. Given this, it is ideal for clini-
cians to have a good knowledge of at least a few of these devices to better support
their visually impaired patients.

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KJ. Generational differences in the 10-year incidence of impaired contrast sensitivity.
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Advances in Contact Lenses
for Ophthalmic Drug Delivery

Parvin Shokrollahi and Alex Hui

1 Traditional Eye Drug Dosage Forms

In contemporary practice, more than 90% of ocular drug formulations used are eye
drops [1]. Despite their popularity, eye drops are generally inefficient drug delivery
systems due to rapid drainage of instilled drops from the ocular surface as well as
nonproductive absorption through routes leading away from the eye, resulting in
short precorneal residence time and less than 5% bioavailability, respectively [1].
This inefficiency in drug delivery necessitates multiple instillations of eye drops to
reach and maintain therapeutic concentrations, all of which can be significantly
impacted by patient compliance. Compliance is further compounded in chronic
conditions, with indefinite drug use and potential for multiple drugs being used
simultaneously. Multi use formulations also contain preservatives to protect against
microbial contamination but are known to have detrimental effects on the ocular
surface due to their cytotoxicity [2]. Nonproductive absorption systemically can
also cause detrimental side effects, with heart related complications after usage of
topical beta blockers for the treatment glaucoma a ready example [3].
It is within this context that researchers have investigated other means of deliv-
ering drugs to the eye, including use of medicated or therapeutic contact lenses
(TCLs). The field of drug delivery from contact lenses has seen important develop-
ments within the past decade, including the release of commercially available
products. This chapter will present an overview regarding the chemistry and

P. Shokrollahi
Centre for Ocular Research and Education, University of Waterloo, Waterloo, Canada
A. Hui (*)
School of Optometry and Vision Science, UNSW Sydney, Sydney, Australia
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Singapore Pte 99

Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_8
100 P. Shokrollahi and A. Hui

material science behind contact lenses before detailing some of the methods and
means through which contact lenses have been investigated to deliver drugs to
the eye.

2 Contact Lenses: Overview

2.1 Types of Contact Lenses and Their Classification

Contact lenses have traditionally been classified and considered by practitioners

according to their mechanical properties and water content. Durable, rigid corneal
lenses (RCLs) (previously more commonly known as rigid gas permeable (RGP)
lenses were contrasted primarily with soft contact lenses (SCLs) as the two primary
contact lenses prescribed. This has been changing more recently, with other types of
lenses outside of these two groups becoming more common, including large, rigid
scleral lenses to treat more advanced conditions. While rigid contact lenses are
mainly composed of hydrophobic poly methyl methacrylate (PMMA), siloxy meth-
acrylate, cellulose acetate butyrate, or more recently, fluoro-siloxy methacrylates,
soft contact lenses are based on flexible hydrophilic polymers such as poly hydroxy-
ethyl methacrylate (pHEMA) and polyvinyl alcohol (PVA). pHEMA-based SCLs
are the most popular CLs used in practice due to a combination of water content,
oxygen permeability, and comfort of use [4]. Oxygen transmission through contact
lenses is also a significant factor to their long-term biocompatibility. The lens thick-
ness has a significant influence on oxygen permeability of SCLs, thus, as the lens
thickness approaches 0.1 mm, oxygen transmissibility decreases sharply which can
cause hypoxia, particularly during extended wear overnight when the eye is closed.
The incorporation of silicone into both RCLs and SCLs has been important for
physiological compatibility to try to address this issue, resulting in design of sili-
cone hydrogel soft contact lenses in which poly dimethyl siloxane, tris-­
trimethylsiloxy silyl, or tris(trimethylsiloxy)-methacryloxy propyl silane are
copolymerized with hydroxyethyl methacrylate, N,N-dimethylacrylamide, or
N-vinyl pyrrolidone [4]. Incorporation of silicone allows for the fabrication of con-
tact lenses with higher oxygen permeability, making them suitable for extended
wear. Without silicone, oxygen transmissibility in soft contact lenses is solely
dependent on the water content. pHEMA, PVA and silicone hydrogel contact lenses
currently account for approximately 88% of the contact lens market worldwide,
with silicone hydrogel CLs holding the largest share at around 64% [5, 6]. Depending
on the composition, SCLs offer a wide range of physical and mechanical properties.
For example, while silicone hydrogels are typically very oxygen permeable, and
pHEMA shows good oxygen permeability, PVA is of low oxygen permeability.
pHEMA and PVA are also hydrophilic, but silicone-based contact lenses are hydro-
phobic. At the same time, silicone CLs are of high modulus and durable, pHEMA is
flexible and PVA is of high tensile strength. Also, pHEMA is prone to protein
absorption, but PVA CLs are known to be antibiofouling [7]. pHEMA can also be
copolymerized with other highly hydrophilic monomers such as N-vinyl
Advances in Contact Lenses for Ophthalmic Drug Delivery 101

Table 1 Food and Drug Administration classification of the soft contact lenses
Low water content (<50%) Nonionic
High water content (>50%)
Low water content (<50%) Ionic
High water content (>50%)
— Silicone hydrogel

pyrrolidone and methacrylic acid to modify properties such as surface friction or

lens tribology to further customize desired lens parameters [8].
In general, as SCLs are more popular and provide better patient comfort com-
pared to RCLs, they have been the focal point of TCL research [9–11]. The Food
and Drug Administration (FDA) classifies SCLs in five groups as identified in
Table 1 [12].
The purpose of this classification scheme is to inform the practitioners of protein
deposition behavior as well as compatibility with care and cleaning solutions. They
also appear to also be useful in explaining some drug delivery behavior when mate-
rials encounter different types of pharmaceuticals. For example, incorporation of
components such as methacrylic acid leads to overall negative ionic charged lenses
and increases the loading of cationic drugs through ion-ligand interactions. Other
drugs may interact mainly with the hydrophilic or hydrophobic components in a
therapeutic soft contact lens, leading to certain drug-lens combinations being more
favorable for drug loading and potential for sustained drug release [8].

2.1.1 Material Criteria and Selection for CLs and TCLs

Selection of the component mixture for SCL fabrication is critical to ensure proper
physical and mechanical properties. Optical transparency, glass transition tempera-
ture, oxygen permeability, wettability, and water content are among the most influ-
ential physical properties which are required to be optimized for successful contact
lens application. Mechanical properties such as the friction of the surface, structural
hardness or modulus, and mechanical stability, also need to be considered for effi-
cient synthesis on a mass scale as well as to ensure lenses can maintain the curva-
tures needed to correct refractive error [4, 7]. To this, additional polymers or
oligomers may need to be added when considering drug delivery applications and
the challenge is for these additions to not compromise the essential properties of the
contact lens while also achieving desired pharmaceutical delivery [13]. For exam-
ple, a contact lens is required to be placed on the ocular surface, so any additions in
pursuit of drug delivery purposes must also be biocompatible without exception.
When selecting both the primary components and the drug carriers for a therapeutic
contact lens, biocompatibility of the materials and their degradation products (in the
case of biodegradable materials) is a crucial factor to consider. A drug delivering
contact lens continues to need to be comfortable to wear, stable at physiological
temperature and optically clear, and all of these must be taken into consideration by
researchers in this area as they try to add in pharmaceutical delivery. Selection of the
therapeutic molecules also must be done with care. Some biologically active mole-
cules or drugs may not be stable or may lose their desired function when exposed to
102 P. Shokrollahi and A. Hui

physiological temperature or pH, or when exposed to light, or if they are required to

go through the contact lens synthesis process which may involve higher tempera-
tures or shorter frequencies of light [14].
For instance, ciprofloxacin, an antibiotic, is poorly soluble in water but soluble
in other solvents. Unfortunately, utilization of an appropriate ciprofloxacin solvent
can cause significant swelling and damage to the contact lens if they are added
together. To address this issue, Liu Z. et al. used a water/ethanol solvent system and
demonstrated that adding up to 25 vol/vol% of water to ethanol significantly con-
trolled swelling of the lens. Furthermore, this approach improved the loading and
release profile of the drug, and demonstrated the type of troubleshooting, which is
inherent to adding drug delivery properties to lenses [15]. Challenges related to
material selection for therapeutic contact lens design may vary depending on the
intrinsic properties of the contact lens, such as solvent vulnerability and hydrophi-
licity and may preclude specific combinations of lens materials and certain drugs. In
addition, other considerations include durability of the components with respect to
length of wear and manufacturing cost, which collectively impact commercializa-
tion of the therapeutic contact lens [7].
Consideration also must be made on how the TCL will be used. The delivery of
different drugs may require appropriate timing and dosing profiles, ranging from
continuous, ‘zero-order’ delivery for short-lived drugs such as pilocarpine, to high
initial doses followed by a sustained lower dose for anti-inflammatory drug applica-
tions such as corticosteroids [14]. The delivery time course also impacts selection of
contact lens materials and replacement frequencies. Daily disposable contact lenses
may not be the best option for long-term drug release if they need to be worn con-
tinuously. Furthermore, physical properties of the contact lenses used for drug
delivery have a significant effect on amount of drug loading based on the power
dependent thickness of the lens. For instance, incorporating active monomers into a
contact lens may result in excessive cross-linking and thus alter the optical and
swelling behavior of the lens [16].
Designing TCLs that are safe, comfortable, and meet demands of a specific appli-
cation often requires combining properties of two or more components. For example,
Maria Vivero-Lopez et al. attempted to combine the antibiofouling property of phos-
phorylcholine with the antioxidant and prebiotic effects of resveratrol in a CL by
copolymerizing 2-hydroxyethyl methacrylate (HEMA) with 2-­methacryloyloxyethyl
phosphorylcholine (MPCAs). They showed that homogeneous distribution of MPC
along the pHEMA hydrogel depth caused a remarkable increase in free water content
and decreased Young’s modulus. Interestingly, MPC did not show any adverse effect
on the uptake of resveratrol by the CLs and had network/water partition coefficients
of >100. The resulting pHEMA contact lens showed reduced growth colonies of
P. aeruginosa and S. aureus, anti-inflammatory properties, and biocompatibility as
evidenced by in vivo studies in rabbit tests [6].

2.1.2 Drug Loading Strategies for Sustained Release from CLs

Various loading strategies have been developed to incorporate drugs in contact
lenses for therapeutic purposes, each with its own advantages and limitations and
Advances in Contact Lenses for Ophthalmic Drug Delivery 103

will be presented in this section. Some research groups have designed specific lens
formulations to fabricate TCLs [11, 12], while others have focused on developing
drug loading methods for commercially available lens formulations (with slight
modifications). The latter approach could potentially be more feasible for commer-
cialization as they use materials which are already available on the market.

2.1.3 Soaking
One of the simplest drug loading methods used in the preparation of therapeutic
contact lenses is soaking, which is a cost-effective, and widely used approach, par-
ticularly for hydrogel contact lenses. This method involves immersing a pre-formed
contact lens in a drug solution, allowing for drug diffusion into the lens via a con-
centration difference (known as osmotic pressure). Alternatively, eye drop instilla-
tion on a contact lens worn by the patient can also be used, although, sustained
release from the lens via this method is questionable [17]. When a therapeutic con-
tact lens is worn by a patient, drug release occurs via diffusion through pathways in
the contact lens to the tear film, both in the pre and post lens tear space. The overall
loading capacity of the contact lens in soaking depends on several factors, such as
drug concentration in the loading medium, lens thickness, hydrophilicity of the
drug, presence of hydrophilic/hydrophobic components in the lens, molecular
weight/size of the drug, lens incubation time, and water content [10]. However, it
should be noted that loading drugs can cause alteration of the lens critical properties
including increased swelling and decreased optical transparency, and in general,
soaking methods suffer from low drug loading and an uncontrolled, large initial
burst release of the drug of interest [10]. Chemical and environmental conditions,
such as concentration, pH, and temperature, can be adjusted to optimize loading
capacity, to some degree [10]. Innovative methods have been developed to address
some of the shortcomings of soaking, to try and increase drug loading or extend its
release. For example, Pluronic® F-68, a nonionic surfactant, has been used to dis-
solve gatifloxacin precipitates in the contact lens matrix, leading to improved drug
uptake. This approach resulted in acceptable swelling ratios (92.36%) and optical
transparency (92.84%) at carefully optimized levels and ratios of gatifloxacin to
Pluronic [18]. The presence of the surfactant also supported sustained release of
gatifloxacin for up to 72 h from these lenses, as evidenced both by in vitro and
in vivo experiments in a rabbit model [18].

2.2 Modified Materials and Soaking Techniques

2.2.1 Pre-loading with Graphene Oxide or Gold Nanoparticles

Pre-loading of nanoparticles into the lens material itself has been found to be an
effective strategy for increasing drug loading, reducing burst release, and prolong-
ing the sustained release period [19]. Maulvi et al. used nanotechnology to address
the issues associated with loading hydrophobic drugs through soaking.
Bimatoprost: The researchers added bimatoprost and graphene oxide (GO) to a
silicone hydrogel contact lens formulation during the polymerization step. This led
104 P. Shokrollahi and A. Hui

to a significant increase in the drug loading capacity and a sustained release period
of bimatoprost. The GO-containing contact lenses were also transparent, with over
92% transparency, after loading with bimatoprost through soaking. This was attrib-
uted to the efficient dispersion of the drug molecules on the GO surface within the
lens matrix. Additionally, the water retention power of the GO nanoparticles
improved the swelling property of the drug-loaded composite contact lens [19].
Timolol: A similar strategy has been seen using gold nanoparticles. Silicone
hydrogel contact lenses were pre-loaded with gold nanoparticles (GNPs) during
manufacturing (GNPs-CL) and through soaking (GNPs-SS). The contact lenses
were then soaked in timolol solutions of two different concentrations (2 and 4 mg/
ml). The addition of the gold nanoparticles did not affect the swelling and optical
transmittance of the contact lenses, but the timolol loading significantly increased
using GNPs using both approaches. In vitro release profiles of timolol remained
almost unchanged for both methods, but in vivo measurements in rabbit tear fluid
showed higher timolol concentration with the GNPs-laden contact lenses at all time
points compared to those without GNPs. In vivo pharmacodynamic studies showed
a remarkable decrease in intraocular pressure (IOP) over 72 h using the GNPs-laden
contact lenses, whereas soaked contact lenses without GNPs and eye drop solutions
(0.5%w/v) only showed a decrease of 2 mmHg that lasted for only 12 h. Furthermore,
the drug deposition in the ciliary body significantly increased with the GNPs-laden
contact lenses, suggesting that incorporation of nanoparticles into these lenses may
lead to more of the timolol being bioavailable at the desired sites of action [20].

2.2.2 Incorporation of Vitamin E

Pre-loading of Vitamin E on to the surface of lenses is another potential strategy to
address the short release time associated with soaking. By pre-loading hydrogel
contact lenses with Vitamin E, a hydrophobic molecule with antioxidant properties,
the release duration of both hydrophobic and hydrophilic drugs can be increased
through different mechanisms. The drug can dissolve into the Vitamin E to form a
“drug depot” or diffuse through an increased pathway created by the Vitamin E bar-
rier. It has also been reported that Vitamin E pre-loading enhances the stability of
the loaded drugs. Both drug loading and release time (ranging from a few hours to
a few days) can be adjusted as a function of Vitamin E loading and the solvent sys-
tem used for pre-loading, while transparency of the loaded contact lenses remains
only minimally affected for a range of ophthalmic agents, including timolol, cyclo-
sporine, and dexamethasone [15].

2.2.3 Host–Guest Inclusion Complexes

The generation of host–guest inclusion complexes, where specific molecules such
as cyclodextrins are used to interact with drugs of interest, increasing both their
loading and solubility, has also been utilized to enhance the efficiency of soaking in
ocular drug delivery. These can be particularly useful in allowing for meaningful
loading of drugs which have poor aqueous solubility such as many of the antifungal
agents. For instance, econazole/hydroxypropyl-alpha-cyclodextrin and econazole/
hydroxypropyl-beta-cyclodextrin inclusion complexes were prepared and loaded
Advances in Contact Lenses for Ophthalmic Drug Delivery 105

into soft hydrogel contact lenses through soaking, and then applied to freshly enu-
cleated porcine eyeballs. The hydrogel contact lenses and the hydrogel contact
lenses loaded with the cyclodextrin inclusion complexes delivered 2.8 and 5 times
more drug across the corneas, respectively, compared to econazole nitrate eye drops
at the same concentrations. Furthermore, while the eye drop led to concentrations
below the minimum inhibitory concentration (MIC) of the drug against test agents
of Fusarium semitectum and Fusarium solani (141 μg/mL) and Scolecobasidium
tshawytschae and Bipolaris hawaiiensis (283 μg/mL), the hydrogels containing the
inclusion complexes demonstrated efficient antifungal activity against these fungi,
suggesting a potential application in the treatment of keratitis [21].

2.2.4 Molecular Imprinting

Molecular imprinting enables chemical or physical interactions between specific
sites on the hydrogel and the drug through generation of molecular memory within
the final polymer. This is achieved through incorporation of molecules in the syn-
thesis process which are similar to the target drug of interest, creating both size and
functional group specific areas within the materials and have been used for a variety
of studies with contact lenses [10]. High degrees of cross-linking are necessary for
this technique to be successful, as there is some degree of mechanical strength
required for the final polymer to be able to efficiently and effectively interact with
the drug of interest [10]. Molecular imprinting techniques have begun to consider
the known chemical structures of drugs or receptors in the selection of components
to be included in the mixtures. Inspired by the activity of statins as 3-hydroxy-
3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors, Pereira-da-Mota et al.
designed pHEMA hydrogel lenses using ethylene glycol phenyl ether methacrylate
(EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-
aminopropyl) methacrylamide hydrochloride (APMA) as the comonomers with
functional groups to resemble those of HMG–CoA. Copolymerization with AEMA
and APMA increased the loading capacity of the contact lenses for atorvastatin, and
atorvastatin accumulation in these materials reached levels sufficient for the treat-
ment of ocular surface diseases, as evidenced by permeability studies using porcine
cornea and sclera tissues [22]. Similarly, González-Chomón C. et al. developed a
contact lens with an affinity to olopatadine, an antihistaminic drug, by mimicking
the composition of the natural H1-receptor to which olopatadine behaves as an
antagonist. They used acrylic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid,
and benzyl methacrylate as comonomers to fabricate a hydrogel CL with a high
capacity for olopatadine. The drug-loaded CL passed both the biocompatibility test
with mast cells and the HET-CAM test of ocular irritancy successfully [23] It should
be noted however, the high degree of cross-linking in molecular imprinting can
sometimes alter the optical and physical characteristics of the contact lenses [16].

2.2.5 Supercritical Fluid Impregnation and Deposition

The supercritical fluid impregnation (SFI) method utilizes a supercritical solvent,
such as carbon dioxide, to carry the drug into a pre-formed polymeric matrix such
as a contact lens. The supercritical solvent plasticizes the polymeric matrix and
106 P. Shokrollahi and A. Hui

causes it to swell, which allows for the mobile phase containing the drug to diffuse
more quickly. When pressure is released, the drug is deposited into the polymer via
two main mechanisms: by dispersing molecularly in the contact lens material (SFI)
or by precipitating within the hydrogel (supercritical fluid deposition or SFD).
Addition of small amounts of cosolvents can enhance the process by increasing
solvent polarity, promoting drug solubility, or by increasing polymer swelling and
pliability. Therefore, the amount of impregnated or dispersed drug can be regulated
by altering process conditions such as pressure and temperature, selecting suitable
cosolvents, and varying their compositions. While SFI results in a release profile
similar to that of soaking, SFD enables elongated and sustained release of the
drug [8].
A recent study showed that it is possible to create therapeutic contact lenses with
acetazolamide and timolol maleate using solvent mixtures of supercritical carbon
dioxide with ethanol or water (scCO2 + EtOH and scCO2 + H2O). The amount of
impregnated drug can vary depending on the type and concentration of cosolvent
used (in addition to operational conditions such as temperature and pressure), which
can be useful for controlling drug amounts for drugs with different hydrophilic/
hydrophobic character [24]. This technology has shown promise in improving drug
loading capacity and release duration for both hydrophilic and hydrophobic drugs.
However, the process can be expensive and time-consuming [25].

2.2.6 Drug-Loaded Nanocarriers

Nanoparticles have a large surface area-to-volume ratio, which enables them to
efficiently encapsulate drugs and release them over an extended period. In contact
lenses, drug-loaded nanoparticles can be incorporated into the lens material or
coated onto the surface, leading to prolonged release. The size and drug loading
of the nanoparticles are crucial factors in determining the drug release rate and
duration. Additionally, various types of nanoparticles, such as polymeric, colloi-
dal, or lipid-based, can be utilized to optimize drug delivery in contact lenses.
Figure 1 illustrates the structures of nanoparticles commonly utilized in therapeu-
tic contact lenses. Additionally, the nanocarriers themselves can play a protective
role against biological conditions, potentially leading to increased drug stability
under various conditions encountered in storage or on the ocular surface. This
property, along with high bioavailability and extended residence time make nano-
carriers attractive candidates for drug-eluting contact lenses. Different nanopar-
ticle carriers have been prepared and evaluated as delivery systems for a broad
range of eye complications using a variety of agents. Table 2 summarizes the most
common nanoparticle systems in TCLs, along with a schematic display of struc-
tural features of each group.

2.2.7 Cyclodextrin Inclusion Sites

Cyclodextrins (CDs) are cyclic oligosaccharides widely used in the pharmaceutical
industry. Biologically safe CDs consist of 6–8 glucose units that form a hydropho-
bic interior cavity with a hydrophilic exterior, known as α-CD (6 glucose units),
β-CD (7 glucose units), and γ-CD (8 glucose units). CDs are excellent candidates
Advances in Contact Lenses for Ophthalmic Drug Delivery 107

Fig. 1 Drug-loaded nanostructures incorporated into therapeutic contact lenses

for drug reservoirs/carriers due to their structural specifications. Hydrophobic and

water-insoluble drugs can form complexes with CDs to create release systems of
high loading capacity that support an extended-release period into hydrophilic envi-
ronments such as the ocular surface (Fig. 2a) [31]. For drug delivery and tissue
regeneration purposes, CDs can be chemically conjugated to the contact lens mate-
rial, applied as a coating through self-assembly, or simply mixed with drug-
loaded CDs.
Recently, an antibacterial coating was applied to the surface of a CL through
layer-by-layer (LBL) electrostatic self-assembly was combined with host−guest
inclusion to treat bacterial keratitis. The LBL self-assembly method is commonly
used for surface modification and creating multilayer films with precise control over
thickness, making it an eco-friendly manufacturing process. It can be used to mod-
ify almost any substrate surface, including CLs, and has been used to create sus-
tained release CLs.
To combine these two techniques, the polyanionic copolymer P(AA-co-AdA)
(PAcA) was synthesized by radical copolymerization of acrylic acid (AA) and
1-adamantan-1-ylmethyl acrylate (AdA) and combined with poly(ethyleneimine)
(PEI) to enable layer-by-layer (LBL) self-assembly on the surface of the CLs. Next,
β-cyclodextrin-levofloxacin (β-CD-LEV) was used to prepare an antibacterial coat-
ing through AdA/β-CD-LEV host–guest interaction. The antibacterial and germi-
cidal efficacy were shown in vitro and in vivo in an animal model of staphylococcal
keratitis. Also, the coated contact lens showed optical transparency, in vitro. The
drug loading capacity and thickness of the coating layer can be controlled through
the host–guest recognition time and number of the layers. The authors believe that
Table 2 Examples of nanoparticle systems used as drug carrier in TCLs
108

NP preparation
Nanoparticle method Lens material Drug(s) Disease Results and significance Ref.
mPEG-PLA Thin film pHEMA; free radical Timolol and Glaucoma In vivo (in rabbits) release was sustained for [26]
Micelle hydration polymerization of latanoprost timolol (120 h) and latanoprost (96 h); micelles
HEMA+NPs exhibited ultra-small size/narrow particle size
distribution and optical transparency; 9.8× higher
IOP reduction compared to eye drops.
PEGylated Solvent pHEMA(+DMA); free Latanoprost Glaucoma In vitro 120 h, and in vivo in rabbits 96 h; [27]
SLN evaporation radical polymerization; pegylated SLNs improved loading capacity and
soaked in NPs suspension sustained latanoprost release without
in STF, for 10 days compromising swelling, transmittance, and
oxygen permeability of the CLs. Lower protein
adherence than non-pegylated laden SLN lens.
Silica shell Microemulsion pHEMA(+MAA); free Ketotifen Ocular 240 h in vitro, and 240 h in vivo in rabbits’ eyes; [28]
nanoparticle- radical polymerization; Allergy extended drug delivery even with initial loading
laden monomers+ NPs (65 μg). In contrast to direct drug loading, NPs
laden CLs did not alter optical and swelling
properties, and ion permeability of CLs.
Drug-loaded Quasi- pHEMA(+MAA, NVP); Cyclosporine Chronic dry No drug loss was reported during monomer [29]
Eudragit emulsion CLs consisted drug laden eye syndrome extraction, 168 h drug release in vitro, 336 h
S100 NPs solvent ring and drug free center release, in vivo in rabbits’ eyes, remarkably longer
laden diffusion than in vitro, due to binding of drug to lipid (e.g.,
technique cholesterol) in tear fluid.
Poloxamer40/ Controlled Two CLs: 1. pHEMA Triamcinolone Ocular NSs with a mean particle size of 147 nm and a [30]
PVA precipitation (+MAA) radical solution acetonide inflammation drug load of 0.8 mg/ml using PVA/poloxamer
stabilized polymerization, 2. stabilizer, had no blurring effect on the CLs.
nano- Hilafilcon B (pHEMA Increased concentration of TA in the NSs improved
suspensions (+NVP) the drug-loaded dose significantly. Controlled TA
(NSs) release profiles for a period of 12 and 48 h for
Hilafilcon B and pHEMA-MAA, respectively.
P. Shokrollahi and A. Hui

PEG poly(ethylene glycol), pHEMA poly(2-hydroxyethyl methacrylate), IOP intraocular pressure, SLN solid lipid NPs, NPs nanoparticles, DMA N,N-dimethyl
acrylamide, MAA methacrylic acid, NVP N-vinylpyrrolidone, NSs nanospheres, TA Triamcinolone acetonide, PVA poly(vinyl alcohol)
Advances in Contact Lenses for Ophthalmic Drug Delivery 109

Fig. 2 (a) Host–guest inclusion complex formation between CDs ad hydrophobic drugs; (b)
Contact lens with drug-loaded implants

the adhered dead bacteria can be release and reloading of β-CD-LEV can be
achieved through immersion in a LEV solution [32].

2.2.8 Drug Loading Based on Electrostatic Interactions

Electrostatic interactions have also been tapped to improve drug loading and extend
delivery, so long as there are appropriate charged species of the drug of interest to
interact with an oppositely charged lens material. García-Millán et al. conducted a
study on how modifying the chemical and structural properties of pHEMA contact
lenses affect the loading and release of triamcinolone acetonide, a corticosteroid
drug. They investigated two types of lenses, one made with NVP as a comonomer
and the other with MAA as a comonomer. They used saline solution and PBS buffer
solution (pH of 7.4) for drug loading and found that the lenses had similar swelling
properties in saline solution, but in PBS buffer, the contact lens with MAA as a
comonomer had enhanced swelling compared to the one with NVP. This was due to
the carboxylic groups in MAA, which become ionized at pH 7.4, causing the hydro-
gel to swell. The use of comonomers increased the amount of drug loaded in the
lens, and the swelling properties affected the drug loading in PBS buffer. The lens
with 40% MAA (200 mM) showed the most efficient drug loading when PBS buffer
was used as the loading solution. The release profiles showed that all the lenses,
110 P. Shokrollahi and A. Hui

regardless of the concentration of comonomers, had similar release kinetics when

placed in artificial lachrymal fluid. There was no lag phase in the drug release, and
more than 80% of the drug was released within the first 24 h, suggesting that using
40% MAA (200 mM) as a comonomer with pHEMA could be a potential formula-
tion for triamcinolone acetonide, with PBS buffer at pH 7.4 being an ideal medium
for loading the drug [33].

2.3 Implanted Drug-Loaded Sheet(s)

Simple drug dispersion (during fabrication), soaking, or coating on the surface

has the potential to compromise critical properties such as mechanical proper-
ties, oxygen or ion permeability and may be limited in drug loading capacity and
ultimate drug release. Drug-loaded implant-laden strategies, in contrast, hold
promise to address some of the drug loading and release limitations, however,
they are not without their own downsides. Drug-loaded implants are polymer
films or sheets loaded with drug carriers that are implanted in the outer periphery
of contact lenses, leaving the critical properties of the central area (over the cor-
nea) intact. As these films allow for a significantly greater amount of drug to be
loaded, reaching even the posterior segment of the eye is beginning to become
possible. For example, in a recent study, a composite film was made by adding
dexamethasone to poly (lactic-co-glycolic acid) (PLGA-DEX) and implanted in
the outer periphery of a pHEMA methafilcon-based soft contact lens. By incor-
porating a large amount of dexamethasone into this composite film, in vivo appli-
cation of these lenses on rabbits led to a 200-fold increase in drug concentration
at the retina compared to the intensive hourly eye drop instillation, all while
having significantly lower with a lower drug concentration in the blood serum
suggesting a superior systemic safety profile. Additionally, an efficacy study in
rabbits revealed the inhibitory effect of the worn contact lenses on retinal vascu-
lar leakage induced by intravitreal injection of vascular endothelial growth factor
(VEGF). A 4-week follow-up confirmed the safety of the drug-eluting contact
lenses in healthy rabbits [34].
Drug-loaded sheets also have the capacity for multiple drug delivery (Fig. 2b). In
some patients with glaucoma, single drug therapy may not effectively control intra-
ocular pressure (IOP), and some combination of IOP lowering eye drops is often
prescribed. A multiple implant-laden silicone hydrogel contact lens (IM) has been
developed to passively deliver timolol, bimatoprost, and hyaluronic acid. During
dry radiation sterilization and hydration for 24 h prior to use, the drugs showed a
loss 16.87%, 47.95%, and 24.41% for timolol, bimatoprost, and HA, respectively.
In vitro experiments showed a significantly lower burst of drug release as well as an
elongated sustained release of the drugs (up to 72 h) compared to soaked and direct
drug-included contact lenses, with the authors suggesting that the decrease in burst
could reduce the risk of side effects. The implanted contact lenses led to a prolonged
reduction in IOP for 120 h, in contrast to the peak and valley profile seen with mul-
tiple eye drop instillations [35].
Advances in Contact Lenses for Ophthalmic Drug Delivery 111

3 Current Commercialization and Future Application

of Therapeutic Contact Lenses in the Management
of Ocular Diseases

The arguments for the development and research into drug-eluting contact lenses
center on the ubiquity of CLs having been safely worn by millions of users world-
wide over the last decades and the presumed pharmacokinetic advantages of such a
system compared to eye drops. In addition, therapeutic contact lenses can function
as a reservoir of preservative free drug that can remain in contact with the cornea
and thus facilitate ocular treatment of the drug so long as it is worn. The first drug
releasing contact lens has reached the market, specifically targeting the manage-
ment of ocular allergy with a daily disposable ketotifen releasing contact lens [23].
A vast group of commercial silicone hydrogels, conventional hydrogels, and daily
disposable contact lenses have been demonstrated to support sustained release of
ketotifen fumarate at a clinically relevant amount compared to conventional eye
drops when tested in vitro [36]. Ultimately, etafilcon A, which is a HEMA-based
soft contact lens, was utilized by Johnson & Johnson Vision Care to produce a daily-
wear, disposable, vision-correcting soft contact lens loaded with 0.019 mg ketotifen
and released to the market as Acuvue Theravision. This formulation became the first
drug-eluting contact lens to pass different phases of clinical trials successfully and
received FDA approval for the prevention of ocular itch due to allergic conjunctivi-
tis [37, 38]. Glaucoma releasing contact lenses are also in clinical trials. LLT-BMT1,
a contact lens printed with bimatoprost, has shown promising results in a Phase IIb
clinical study conducted by MediPrint™ Ophthalmics’ SIGHT-1 clinical program.
The product was well-tolerated by patients, and there was a lower incidence of
hyperemia compared to bimatoprost drops. The company has initiated [5] a Phase
IIb study for dosage optimization called SIGHT-2 and hopes to obtain dose results
by the first half of 2023, which will take the clinical study to the Phase III trial. As
further contact lens drug delivery devices become commercialized, acceptance of
these forms of alternative methods of treatment will become more of a reality for
prescribing practitioners and patients and will hopefully lead to improved patient
outcomes in treating these diseases [39, 40].

4 Conclusion

The potential for soft contact lenses, due to their water content in comparison with
rigid contact lenses, to deliver drugs was identified in the original patents for the
materials in the 1960s [41]. Research has continued in this area to demonstrate the
potential of these drug delivery devices within the laboratory with a variety of drugs,
materials, and testing conditions as well as work in vivo in animals or humans.
Matching of a material, drug, drug release kinetics, and disease to be treated will be
crucial things to identify for the future success of these devices, and the hope is that
the work published in the field will allow for this to be a successful means of ocular
drug delivery.
112 P. Shokrollahi and A. Hui

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Novel Ocular Drug Delivery Methods

Yuan Fang, Chris Hodge, Gerard Sutton, and Jingjing You

1 Introduction

There are many challenges involved in ocular drug delivery because of the unique
anatomical and physiological factors in the eye. Currently, 90% of all ophthalmic
drug formulations are applied as eye drops [1]. However, because of the static bar-
riers (including the cornea, conjunctiva, and sclera) and dynamic barriers (including
blinking reflex, high tear turnover rate, and rapid restoration of eye film), less than
5% of the applied dose can penetrate and reach intraocular tissue, leading to low

Y. Fang
School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
e-mail: [email protected]
C. Hodge
Vision Eye Institute Chatswood, Sydney, NSW, Australia
Save Sight Institute, The University of Sydney, Sydney, NSW, Australia
Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
NSW Tissue Bank, Sydney, NSW, Australia
e-mail: [email protected]
G. Sutton
Vision Eye Institute Chatswood, Sydney, NSW, Australia
Save Sight Institute, The University of Sydney, Sydney, NSW, Australia
NSW Tissue Bank, Sydney, NSW, Australia
e-mail: [email protected]
J. You (*)
School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
Save Sight Institute, The University of Sydney, Sydney, NSW, Australia
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Singapore Pte 115
Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_9
116 Y. Fang et al.

bioavailability of approximately 1–3% [1, 2]. In the initial stages of the application
of eye drops, the majority will be washed away by tear production and blinking of
the eyes. The remaining drugs will be delivered through the corneal route and non-
corneal route as described below (Fig. 1).
The innate structure of the cornea negatively impacts drug penetration.
Anatomically, the cornea consists of five layers, from anterior to posterior; corneal
epithelium, Bowman’s layer, corneal stroma, Descemet’s membrane, and corneal
endothelium. Each layer has different priorities and potential rate-limiting structures
for drug permeability. Among the five structures of the cornea, epithelium and stroma
are considered two major drug diffusion barriers. The lipoidal epithelium cells num-
ber account for 90% of the total cornea cells, causing a significant resistance to
hydrophilic drug permeability. Furthermore, the junctional complex network of epi-
thelium also acts as a barrier to the diffusion of drugs [1]. Corneal stroma constitutes
90% thickness of the cornea that contains aligned cells guided by parallel hydrated
collagen lamellae [1]. The hydrophilic nature of stroma makes it a significant barrier
for hydrophobic drugs. Although relatively uncommon in practice, if the drugs are
targeting the posterior part of the eye, the drug will need to penetrate the cornea,
move into the anterior chamber and then through the iris, to the posterior chamber
and into posterior tissue. Among these structures, it is mainly the iris-ciliary body
and the aqueous humor that prevent further penetration of the drug from corneal

Fig. 1 The routes and barriers in topical administration

Novel Ocular Drug Delivery Methods 117

absorption. When the drug is distributed in the vascularized iris and ciliary body, it
can permeate into the blood vessels and move into the systemic circulation [3]. Drugs
in the anterior chamber may also be eliminated through aqueous humor outflow [3].
Understandably therefore, achieving therapeutic concentration levels in the pos-
terior segment is challenging through this long route. The non-cornea drug delivery
pathway involves the conjunctiva and sclera. Human conjunctiva is a highly vascu-
lar structure with approximately 17 times the surface area of the cornea, which
allows macromolecules (with a molecular weight ranging from 1000 to 20,000 Da)
to pass through with a permeability coefficient negatively related to solute size [4].
However, a large portion of the drug is absorbed by conjunctival blood capillaries
and lymphatics, and entry into system circulation before penetration into the ocular
tissue [1]. The sclera is made of connective tissue containing collagen fibers to pro-
tect and support the eye, which has comparable drug permeability with corneal
stroma and is more permeable for molecules with a smaller radius [1].
The low drug bioavailability of eye drops delivery mandates frequent administra-
tion. The highly frequent dosing schedule results in poor patient compliance and
may cause side effects in a long term. Although an extreme example, corneal micro-
bial keratitis patients need to instill eye drops every 30 min in the first 24–36 h in
mild to moderate cases [5]. Routinely, topical medication for reducing intra-­
operative pressure may demand instillation between 2 and 4 times per day. The
frequent dosing schedule results in poor patient compliance and result in an extended
treatment period. Frequent instillation can lead to ocular surface disruption and irri-
tation or stinging on further application. Practically, frequent instillation has been
known also cause joint and muscle pain in the application finger, albeit in patients
with pre-existing conditions such as arthritis which may limit movement.
Many novel drug delivery systems have been explored to overcome the limita-
tions related to the topical ophthalmic formulation. The ideal drug delivery system
requires easy administration, long residence time, high biocompatibility, and does
not interfere with vision and normal eye function [2]. In this context, novel hydrogel
and nanoparticle drug delivery techniques will be discussed, as they are the most
frequently analyzed ocular drug delivery platforms that can be applied for both
anterior and posterior segment eye diseases.

2 Hydrogel

To overcome the low bioavailability of topical administration and prevent quickly

being washed away from the ocular surface, the hydrogel drug delivery method has
been researched. By definition, the hydrogel is a three-dimensional crosslinked
polymer network that contains at least 10% water content. Hydrogel can be fabri-
cated from natural polymers such as alginate, collagen, and chitosan, or synthetic
polymers such as poly(vinyl alcohol) and poly(hydroxyl alkyl methacrylate) [6].
Natural polymers have the advantages of high biocompatibility and non-toxicity
subunits, while potentially limited by their weak mechanical properties [7]. The syn-
thetic polymers are beneficial in the higher batch-to-batch reproductivity and
118 Y. Fang et al.

stability, but they are limited by inflammation response and cytotoxic by-products
after degradation. Hydrophilic polymers can be chemically or physically crosslinked
from liquid to gel to allow a longer residence time and show a sustained drug-releas-
ing profile representing a further possible advantage. Chemical crosslinked gels are
formed by covalently crosslinking chemical agents including N-hydroxysuccinimide
(NHS) and N,N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(EDC), which results in a stable structure [7]. Drug release in the covalent linkage is
usually achieved by enzyme degradation. However, the chemical crosslinker is usu-
ally cytotoxic and has potential biosafety concerns. Physically crosslinked hydrogel
is normally formed by forces including van der Waals, hydrogen bonding, and elec-
tronic bonding. Hydrogels formed by physical interactions are typically less stable
and are known to be thermally reversible [7].
High initial drug release, also known as burst release of drug molecules, has been
a challenge in hydrogel drug delivery (Fig. 2). The typical hydrogel biomaterial has
a mesh size range from 5 to 100 nm, which is larger than most small drug molecules
(molecular dimensions of 0.5–1.5 nm) [8]. Therefore, after being transferred to the
hydrogel drug delivery system in an aqueous environment, small drug molecules
can quickly diffuse from the hydrogel network in the swelling process, resulting in
an initial burst release. Burst release can result from other reasons such as the
desorption of the drug attaching to the surface of hydrogel and the poor distribution
of the drug in the network [9]. Silicone hydrogel and Poly(hydroxyethyl methacry-
late) (pHEMA) hydrogel show burst release profiles for most ophthalmic drugs with
release lasting for a few hours [10]. The burst release phenomenon usually has nega-
tive effects, including cause cytotoxicity and tissue irritation in the human body
[11]. Therefore, a constant rate of drug release, also referred to as zero-order sus-
tained drug release, is usually the preferred method of drug delivery [9]. For exam-
ple, the Retisert implant is a zero-order drug delivery system made from silicone
polymer and has been approved by Food and Drug Administration (FDA). It is used
to treat chronic non-infectious uveitis in the posterior segment of the eye, providing
a continuous release of fluocinolone acetonide for about 30 months after surgical
implantation at the back of the eye.

Fig. 2 The illustration of drug release with initial burst and zero-order kinetics
Novel Ocular Drug Delivery Methods 119

To enhance drug absorption and accomplish sustained and regulated drug release
in the hydrogel, it may be necessary to enhance molecule interactions and binding
mechanisms within the delivery system. There are various chemical, physical, and
biological factors that have been researched to improve drug delivery. Covalent con-
jugation between the hydrogel polymer and drug can allow a stable binding, which
is cleavable through enzyme degradation to allow drug release [6]. The mucoadhe-
sive effect induced by the physical interaction between polymer and mucin can also
improve drug delivery. As an example, the mucoadhesive property of chitosan poly-
mer makes it one of the most widely used drug delivery materials [12]. Applying a
chitosan-based drug delivery system to the mucosal surface results in an interaction
between chitosan and mucin, creating a strong and long-lasting adhesion that facili-
tates sustained drug release at the site. The physical factors including swelling char-
acteristics and mechanical deformation of the hydrogel can also impact the drug
delivery of hydrogel. For instance, encapsulating cyclodextrin in pHEMA hydrogel
can lead to an increase in swelling behaviors, resulting in improved drug uptake
[13]. With the ability of mechanical deformation from liquid to solid in response to
environmental changes, the in situ hydrogel has become one of the most important
hydrogel systems. A liquid formation in most cases provides an easier application
however transformation to a solid gel increases the potential time in situ further
leveraging the sustained release properties [14]. In addition to in situ hydrogel, con-
tact lenses with high bioavailability and collagen shields with high biocompatibility
have also frequently been investigated as ocular drug delivery systems and will be
discussed in the following sections.

2.1 In Situ Hydrogels

One of the most important types of hydrogels is in situ hydrogels. In situ gelling
systems are stimuli-responsive hydrogels, which can be applied to the eye as liquid
and then mechanically transformed into gels. The in situ reversible hydrogels can
swell, or de-swell based on the change in ion concentration, temperature or pH. All
these types of stimuli-responsive hydrogels have been widely researched in
ophthalmology.
Since in situ hydrogel exists in liquid form prior to mechanical transformation, it
has been applied as a topical instillation on the corneal surface or injection into
intraocular tissues, as discussed, the transformation leads to a significant increase in
precorneal drug contact time, and consequently, an increase in bioavailability [14].
A combination of polyacrylic acid (Carbopol® 980NF) and hydroxypropyl methyl-
cellulose (Methocel® K100LV) was utilized to prepare a pH-triggered hydrogel
system for delivering ciprofloxacin [14]. To prevent any potential incompatibility
between the drug and polyacrylic acid, ciprofloxacin was complexed with an ion
exchange resin. The optimized product sustained drug delivery for 24 h in vitro,
although the release kinetics followed a zero-order pattern for only up to 10 h.
Important for both application and sustainability, it can maintain its stability for
3 months without any changes in clarity, drug content, pH, or gelling ability.
120 Y. Fang et al.

Moreover, in a rabbit model, no irritation was observed upon application of this in-
situ hydrogel.
The injectable in situ hydrogels are especially appealing to be adapted in poste-
rior eye diseases through intravitreal injection as liquid and transformed into solid
form in vivo. This process serves to not only minimize the invasive effect but will
prolong the time required for the drug to be released. Lai et al. developed an in situ
hydrogel delivery system by utilizing gelatin grafted with carboxylic end-capped
poly(N-isopropylacrylamide) to administer pilocarpine for glaucoma treatment
[15]. The hydrogel underwent a phase transition from 25 to 34 °C and exhibited a
cumulative drug release over 14 days, with an initial burst release in the first 30 min.
In a rabbit model, the hydrogel was administered intracamerally and showed excel-
lent bioadhesion, no inflammatory response, and degradation by MMP-2 over time.
The hydrogel showed three times higher drug concentration in the aqueous humor
compared to eye drop instillation after 4 h of treatment, indicating higher bioavail-
ability. This represents a potential tangible difference with practical benefits to the
patient and the treatment of the ocular condition.

2.2 Contact Lenses

The contact lens has also been proposed as a drug delivery system showing signifi-
cantly improved bioavailability than topical formulations. Contact lens delivery sys-
tems achieve an extended residence time of more than 30 min, which is significantly
higher than the normal residence time of only 1–3 min in eye drop delivery [2]. As
expected, the longer residence time increased the drug bioavailability by up to 50%,
suggesting the possibility of less frequent therapy, leading to higher patient compli-
ance and potentially a faster healing process [2]. Against this, contact lens insertion
will often require trained personnel for application. In 2022, FDA approved the first
drug-eluting contact lenses, the ACUVUE® Theravision™ made of etafilcon A
with ketotifen to prevent the itched eye induced by allergic conjunctivitis and cor-
rection of refractive ametropia [16]. Every lens contains 19 mcg of ketotifen, how-
ever, the process for how ketotifen combined with etafilcon A remains proprietary.
Containing almost 2/3 water content (59%), it is expected to have an excellent
safety profile [16]. Wetting agents such as polyvinylpyrrolidone are used in Etafilcon
A lenses to mimic natural tear films and further improve comfort through both ini-
tial and extended wear [17]. Its clinical study showed less than 2% of participants
experienced eye irritation or pain as a result of the procedure [17]. This initial prod-
uct validated the promising effect of using contact lenses as a drug delivery system.
This section will discuss various novel designs for encapsulating drugs in therapeu-
tic contact lenses.

2.2.1 Soaking Method

The soaking method is the most simple and cost-effective way to encapsulate drugs
in contact lenses. The contact lens has internal cavities/channels that can accom-
modate drug molecules. The drug reservoir ability is strongly dependent on the
Novel Ocular Drug Delivery Methods 121

hydrophilic/hydrophobic components of contact lenses, the thickness of contact

lenses, the molecular weight of drugs, the soaking time, and the concentration of
drugs [2]. However, for most ophthalmic drugs, the contact lens has a low affinity,
resulting in poor retention and burst release of drug encapsulated through the soak-
ing method [2]. In an experiment of drug release following soaking in contact
lenses, ophthalmic drugs including cromolyn sodium, ketorolac tromethamine, and
dexamethasone sodium phosphate showed a quick release of less than 1 h, and keto-
tifen fumarate displayed a slower release of approximately 5 h [10]. For drugs
including dexamethasone sodium phosphate, ketorolac tromethamine, and ketotifen
fumarate, higher uptake was observed in materials with higher water content and
higher pHEMA composition suggesting continued variability [10].
Several techniques have been developed to increase the drug loading efficacy
of the soaking method and to achieve sustained and controlled drug delivery.
Ryan et al. developed a rapid drug loading method for the hydrophobic drug
latanoprost for only 4 min by soaking the drugs in n-propanol [18]. The amount
of drug loading remains controllable and can reach up to 450ug per lens, and the
drug release was proportional to the drug-loaded with a duration of up to 4 days.
Cyclodextrin’s structure consists of a hydrophilic outer surface and a hydropho-
bic cavity, which can form inclusion complexes with a variety of hydrophobic
molecules. This property makes it particularly effective in delivering hydropho-
bic drugs [13]. To enhance the uptake of puerarin and achieve controlled and
sustained release of the drug, β-cyclodextrin (β-CD) was encapsulated in pHEMA
hydrogel [13]. When tested in a rabbit trial, the drug-eluted pHEMA lens with
β-CD showed a higher average drug residence time of over 100 min compared
with the drug-eluted pHEMA lens (81 ± 11 mins) and the 1% puerarin topical
eye solution (13 ± 7 mins). Although the optimal balance remains to be eluci-
dated, it would appear higher β-CD content would be more appropriate for suc-
cess with a slower drug release.

2.2.2 Molecular Imprinting

Molecular imprinting refers to a technique using functional monomers imprinted to
create artificial recognition sites in contact lenses, which can tailor the drug loading
and release pattern (Fig. 3) [2]. The molecularly imprinted polymers are generated
by free-radical polymerization, which involves the interaction between functional
monomers and the target drug [19]. After polymerization, the target drug was
removed from the imprinted material, leaving behind specific cavities that are com-
plementary to the size and shape of the target drug. Macromolecular memory in
contact lenses results in extended drug release over weeks [19, 20].
Negin et al. developed HEMA contact lenses for delivering antimicrobial pep-
tides polymyxin B and vancomycin using the molecular imprinting method [20].
Acrylic acid-functionalization with imprinting increased the affinity of polymyxin
B and vancomycin more than ten-fold on lenses, while nearly no uptake was
observed in non-imprinted lenses. This affinity is proportional to the percentage of
template molecules on lenses. In acrylic acid-imprinted lenses, both polymyxin B
and vancomycin were released over a 2-week period, whereas in non-imprinted
122 Y. Fang et al.

Fig. 3 The illustration of molecular imprinting drug loading method

lenses, the drug is released within a few hours. A recent study used molecular
imprinting to deliver multiple drugs simultaneously. Diclofenac sodium (DS) and
dexamethasone sodium phosphate (DMSP) or bromfenac sodium (BS) and moxi-
floxacin (MOX) were molecularly imprinted to contact lens [19]. Both DS + DMSP-
loaded lenses and BS + MOX-loaded lenses showed sustained release of loaded
drugs over 1 week. The stability of the mesh size before and after molecular imprint-
ing confirms that the controlled release is attributed to macromolecular memory
rather than a tighter structure or smaller mesh size.

2.2.3 Other Techniques

Other methods have been developed to enhance the drug’s absorption and to
achieve a sustained release of the drug from the contact lens. Supercritical fluid
technology dissolves the drug in supercritical fluid and diffuses it into contact
lenses, showing high loading efficiency. Supercritical fluids represent fluids whose
temperature and pressure are greater than their critical temperature and critical
pressure, allowing them to assume the properties of both a liquid and a gas. CO2 is
commonly used as a solvent in this technique due to its non-toxicity, high diffusiv-
ity, and low surface tension [21]. However, the cost of supercritical fluid technol-
ogy is high. Furthermore, the drug loading and release behavior is strongly
influenced by the operating conditions, such as temperature, pressure, and depres-
surization during drug impregnation, resulting in poor reproducibility [21]. The
drug-loaded film coating for contact lenses has also been developed. To achieve the
zero-order kinetics of drug delivery, Ciolino et al. created the drug-polymer film by
mixing ciprofloxacin and PLGA (poly[lactic-co-glycolic acid]) (PLGA) polymer
using the solvent casting method, followed by film coating on pHEMA contact
lenses using ultraviolet (UV) polymerization [22]. The drug-polymer-coated lenses
showed a sustained drug release with zero-order kinetics over 4 weeks. The
increased barrier of drug diffusion was found in film with a higher ratio PLGA:
drug ratio. The use of supercritical fluid technology and drug-loaded film coating
is rapidly expanding and represents an option for drug delivery across numerous
biomedical applications.
Novel Ocular Drug Delivery Methods 123

2.3 Collagen Shield

With high biocompatibility and biodegradability, collagen shield has also been
explored as an ocular drug delivery system [23]. The collagen shield usually con-
tains type I and type III collagen and is reserved in dehydrated form, which needs to
be rehydrated before use [23]. The FDA has approved several collagen shields on
the market, including Biocora®, MediLens®, and ProShield®, but there is no clear
information about their composition or patient feedback. Collagen shields usually
start to dissolve after 12, 24, and 72 h [23]. After the designed dissolution period,
the collagen shield will lose 1/2 to 1/3 of its mass. By this point, its geometry will
have changed, and it will become loose on the surface of the eye, allowing it to be
easily removed.
Collagen shields can increase the drug contact time and maintain the concentra-
tion by serving as a reservoir and gradually releasing the drug as the shield dis-
solved [24]. Collagen shield has shown comparable or superior ability in the
delivery in rabbit models of many antibiotics including vancomycin, gentamicin,
tobramycin, and prednisolone acetate [25]. A 12-h collagen shield was soaked in
prednisolone acetate for 15 mins prior to application in rabbit eyes. As compared
to topical application, the drug concentration levels in the aqueous and cornea were
4–5 times higher after 30 mins and 100–200 times higher after 120 min [24].
Another study evaluated the drug delivery of dexamethasone with a 24-h collagen
shield in both the anterior and posterior segments of rabbit eyes [25]. Compared
with the single drop instillation, a 2–5-fold higher drug level was observed in the
20-min pre-soaked shield in the cornea, aqueous, iris, and vitreous over a 6-h
period. This study further compared the treatment of hourly eye drop alone to a
pre-soaked collagen shield plus hourly eye drop. The results showed collagen
shields with supplementary hourly eye drops can maintain twofold higher drug
levels in the cornea, aqueous, iris, and vitreous compared with hourly eye drops
alone over 6 h highlighting a significant potential additive impact. Despite the col-
lagen shield’s advantages over topical eye drops, it is limited by its requirement of
professional installation [23]. Similar to contact lenses, the burst release phenom-
enon still exists in the collagen shield drug delivery [26]. Furthermore, although
the collagen shield has high tolerance with regard to comfort in the eye, it has low
transparency, resulting in a reduction in visual acuity to 6/36–6/60 [23]. Although
there are some collagen shields have been approved by FDA, they are still not fre-
quently used in the clinic.

3 Nanosystems

The use of nanosystems in drug delivery has attracted increasing attention to

enhance the penetration of ophthalmic drugs and prolong drug release. They also
showed benefits to protecting the unstable drug from premature degradation by
inhibiting the premature interaction of the drug with the biological environment
[27]. Nanosystems can actively incorporate into cell membranes via different
124 Y. Fang et al.

endocytic pathways and can be used to deliver poorly permeable small molecules
and proteins [28]. In general, nanocarriers with smaller sizes remain preferred
because of lower irritation and better bioavailability [27]. Several factors affect the
mechanism of drug release from these nanocarriers, including the stability of the
carrier, drug–carrier interaction, and drug diffusion [27]. A variety of nanocarriers
have been studied for use as ocular drug delivery systems. The three most widely
studied nanocarriers are liposomes, dendrimers, and polymeric nanoparticles
including nanospheres and nanocapsules.

3.1 Liposome

The liposome is a spherical vehicle made of a double layer of phospholipids with an

aqueous core (Fig. 4). Liposomes can have single or multiple phospholipids double
layers, resulting in a wide size range from 10 nm to 1 μm [29]. It is a biodegradable
and biocompatible carrier for both hydrophilic and hydrophobic drugs [29].
Hydrophilic drugs can be encapsulated in the aqueous core and hydrophobic drugs
can be encapsulated in the lipid membrane (Fig. 4).
The use of liposomes in ocular drug delivery has been demonstrated by several
researchers in the last few decades, and some liposomal drugs are currently avail-
able in clinics. For example, Visudyne®, a liposomal intravenous drug system has
been approved by FDA and utilized successfully for many years for treating choroi-
dal neovascularization caused by macular degeneration, pathologic myopia, and
ocular histoplasmosis.

Fig. 4 Structure of liposomes for drug delivery application

Novel Ocular Drug Delivery Methods 125

Drugs in the liposomal formulation have shown higher biocompatibility than

commercial eye drop formulation [30]. Different materials have been explored to
improve the mucoadhesive property of liposomes. It is reported that positively
charged liposomes have higher affinity on the ocular surface compared with neg-
atively charged or neutral liposomes because they can bind to negative-charged
mucin on the corneal epithelium [29]. In a rabbit model, dioctadecyldimethylam-
monium bromide (DODAB) and stearyl amine (SA) have been used as positive
charge-inducing agents to generate cationic liposomal ciprofloxacin, which has
shown more than threefold higher bioavailability compared with commercially
available eye drops [31]. Coating bioadhesive polymers such as chitosan and
carbomer can also be used to modify liposomes for mucoadhesive properties.
Carbomer with good bioadhesive properties and good ocular tolerability has also
been used to synthesize carbomer-coated liposomal ciprofloxacin [29]. The
in vivo drug-­releasing test in rabbit eyes showed an approximately fourfold
higher bioavailability in the carbomer-coated liposome formulation compared
with the commercial ciprofloxacin eye drop [29]. To improve the mucoadhesive
property, it is preferable to coat liposomes with natural polymers rather than
using charge-inducing chemicals like SA and DODAB due to their potential
cytotoxicity. Furthermore, it has been demonstrated that polymeric liposomes
coated with natural polymers, such as chitosan, even if charged negatively with
dicetylphosphate (DP), are more mucoadhesive than liposomes that have been
cationized with SA [30].

3.2 Dendrimers

Dendrimers are nanovehicles made of high-branching “tree-like” structured poly-

mers with well-defined shapes and sizes [27].The shape of dendrimers consists of a
central core and “radically concentric layers” known as “generations” (Fig. 5).
Dendrimer has extraordinary structure control of linear increase in diameter with
the increase in generation [32].While many dendrimer families have been synthe-
sized, polyamidoamine (PAMAM) dendrimer is the most widely studied. In
PAMAM dendrimers, ammonia or ethylenediamine core binds with the amine
groups of branches and amides [32].
Dendrimers can deliver lipophilic drugs through direct encapsulation in the inner
oily cavity. It can carry hydrophilic drugs by bonding them on the surface through
covalent or electrostatic interaction [32]. There are also terminal groups in den-
drimers that can be employed to make drug-dendrimer conjugation. For example,
DenTimol developed to treat glaucoma was synthesized by conjugating timolol in
PAMAM G3 dendrimer surface through the polyethylene glycol (PEG) terminal
group [33]. This system shows increased efficiency in penetrating the cornea, lead-
ing to a quick reduction of an important risk factor, elevated intraocular pressure
(IOP), by 30% in less than 30 min in rabbit eyes [33]. However, dendrimers have
raised concerns due to their potential cytotoxicity. Scientists have demonstrated that
the cytotoxicity of dendrimers is highly linked with the generations and properties
126 Y. Fang et al.

Fig. 5 Structure of dendrimer for drug delivery application

of terminal groups [34]. In general, those dendrimers with higher generation and
positive charges on their surface exhibited greater cytotoxicity [34].

3.3 Polymeric Nanoparticles

Polymeric nanoparticles can be made of biodegradable natural polymers including

alginate, chitosan, gelatin, and albumin, or synthetic polymers including poly(lactide)
(PLA), poly(lactide-co-glycolide) (PLGA), and poly (ɛ-caprolactone) (PCL) [35].
Biodegradable nanoparticles are frequently utilized due to their higher biocompat-
ibility. Nanoparticles are divided into two main categories based on the inner struc-
ture: nanosphere and nanocapsule (Fig. 6) [35]. Nanosphere, ranging in size from
100 to 1000 nm, is defined as a matrix system, in which the drug is dispersed evenly
in the matrix or is absorbed on the surface (Fig. 6a). The nanocapsule, ranging in
size from 10 to 1000 nm, is composed of a hydrophobic core and polymeric enve-
lope, in which the hydrophobic drug can be entrapped into the cavity or absorbed on
the surface (Fig. 6b).
Polymeric nanoparticles have been extensively studied to improve drug contact
time and increase bioavailability. A nanoparticle consisting of two polymers,
namely mucoadhesive hyaluronic acid and biocompatible zein, has been synthe-
sized to enhance the bioavailability and stability of ciprofloxacin [36]. The poly-
meric nanoparticle system exhibited an initial burst release followed by a sustained
release over 24 h while maintaining high biocompatibility and encapsulation effi-
ciency. Positively charged polymeric nanoparticles have demonstrated enhanced
drug delivery properties due to their bioadhesive nature to negatively charged
ocular surfaces [12]. Cationic nanoparticles composed of Eudragit RLPO® poly-
mer were employed to deliver the antifungal drug terconazole (TCZ), which
Novel Ocular Drug Delivery Methods 127

a b

Fig. 6 Structure of (a) nanosphere and (b) nanocapsule for drug delivery application

exhibited mucoadhesive properties and sustained drug delivery over 24 h in vitro

and a 2.3-fold higher antimycotic activity compared with plain TCZ solution [12].
However, despite the demonstrated effectiveness of these polymeric nanoparticles
in drug delivery, potential cytotoxicity resulting from the release of toxic mono-
mers during degradation and residual material associated with them remains a
concern [37].

4 Comparison of the Delivery of Ciprofloxacin

in Different Systems

Ciprofloxacin is used as a case to discuss the differences between various drug

delivery systems. The fluoroquinolone antibiotic ciprofloxacin has a broad use in
both Gram-positive and Gram-negative bacterial infections [38]. This hydrophilic
drug has been widely explored in a variety of novel drug carriers including contact
lenses, in situ hydrogel, liposomes, and polymeric nanoparticles, to achieve sus-
tained and controlled drug delivery with zero-order kinetics. In the application of all
these carriers, longer ciprofloxacin contact time and higher biocompatibility have
been achieved when compared with commercial eye drop instillation. Polymeric
nanoparticles, liposomes, and in situ hydrogel showed 8–24 h of ciprofloxacin
releasing, with burst releasing remaining a challenge in these systems [14, 30, 36].
Contact lens soaking in the ciprofloxacin showed quick release in a few hours.
However, when other techniques including molecular imprinting were employed, it
showed extended releasing time, even over weeks representing a significant poten-
tial clinical advantage [19, 20].
Sustained drug delivery can be achieved when these techniques were used in
combination. Nanocarriers, because of their small size, are usually investigated
to be encapsulated in other macro-sized carriers such as hydrogel and contact
lenses for sustained drug delivery and have shown improved efficacy in drug
delivery. Compared with liposomes alone, the liposome in hydrogel form
showed retarded and more extended ciprofloxacin release as well as higher drug
128 Y. Fang et al.

permeation on cornea tissue [39]. For example, liposomes containing soybean

phosphatidylcholine (PC), cholesterol (CH), and SA in a 5:3:1 molar ratio were
developed to deliver ciprofloxacin, and the liposomes were further dispersed in
1.5% (w/w) carbopol gel to form liposomal hydrogel [39]. The results indicated
that liposomal hydrogel formation had the most sustained release of ciprofloxa-
cin, with 75% released in 10 h, as opposed to 6 h in liposomal suspension and
2 h in 0.3% aqueous formation. In this example, the high viscosity of liposomal
hydrogel can act as an extra barrier to drug release, and the improved mucoad-
hesive property in hydrogel form can prolong drug retention at the administra-
tion site providing an additive response. Soaking polymer nanoparticles made
from copolymer composed of pullulan and polycaprolactone in contact lenses
also showed sustained ciprofloxacin release over 24 h, with a concentration
higher than the minimal inhibition concentration of S. aureus and P. aeruginosa
[38]. In addition, it has been shown that drug release behavior is affected not
only by the properties of drug carriers but also by drug release systems. Drug
release systems in a physiological flow exhibit a slower and more consistent
release rate than in a vial system [40]. In fixed-volume vials, the release of cip-
rofloxacin from contact lenses typically takes approximately 2 h, whereas under
physiological flow conditions, a gradual and steady release of the drug over 24 h
was observed [40].

5 Discussion and Conclusion

Improving the efficacy of drug delivery in the ocular system is a long-standing

challenge. The topical administration has many limitations, especially the low
bioavailability and short drug contact time. Novel alternative drug delivery sys-
tems have been generated to overcome these limitations including using hydro-
gel and nanocarrier systems. These techniques have also been used individually
or combined for a more sustained and controlled drug release, resulting in a
reduced dose frequency and leading to potentially higher patient compliance. A
number of these techniques have been approved by FDA and are currently avail-
able in the clinic, including the most recently approved drug-eluting contact lens
ACUVUE Theravision by FDA in 2022. These successes indicate the promising
direction in using hydrogel and nanocarriers as alternatives to topical eye drops.
However, challenges including the burst release still need to be addressed.
Furthermore, more research needs to be carried out on the potential cytotoxicity
of nanocarriers in ocular drug delivery and the clinical impact on the patient.
Research interests also focus on other factors such as drug loading efficiency and
drug penetration efficiency to improve bioavailability. Combining nanocarriers
and hydrogel systems has demonstrated increased drug contact time and higher
bioavailability when compared to drug delivery with either nanocarriers or
hydrogel alone. Therefore, this approach holds significant potential for further
investigation.
Novel Ocular Drug Delivery Methods 129

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Clinical Trials Relevant for Optometrists

Parul Ichhpujani and Surbhi Kapoor

The landmark clinical trials in Ophthalmology provide an inside look at the thera-
peutic pipeline and how the standardized treatment protocols can objectively guide
patient care, which strategies to adopt and which to discontinue. This chapter enlists
a few landmark clinical trials which may help optometry practitioners and students
to uncover better ways to prevent, diagnose, treat, and understand common ophthal-
mic disorders. For ease of the readers, the trial results and conclusions have been
tabulated.

1 Pediatric Eye Disease Investigator Group (PEDIG)

Amblyopia, or lazy eye, refers to a unilateral or bilateral decrease of vision, caused

by abnormal vision development in infancy or childhood. It is the leading cause of
decreased vision among children.
Spectacle correction with occlusion or penalization therapy using atropine eye
drops is generally considered the first treatment options for amblyopia. Clinically
effective health care requires informed decisions based on evidence-based treat-
ment. Over- or underutilization of the prescribed therapy often leads to poor visual
recovery [1]. For children with amblyopia, evidence-based treatment has been made
possible by the landmark Pediatric Eye Disease Investigator Group (PEDIG)
research. This study compared the result of patching and atropine as treatments for
moderate amblyopia in children younger than 7 years [2].

P. Ichhpujani (*) · S. Kapoor

Department of Ophthalmology, Government Medical College and Hospital,
Chandigarh, India

© The Author(s), under exclusive license to Springer Nature Singapore Pte 131
Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_10
132 P. Ichhpujani and S. Kapoor

Disease entity Study group Results Conclusion

Amblyopia 3–7 years 3–7 years old group: Visual Atropine and patching
with visual old group: acuity improvement: 3.16 in produce improvement of
acuity from 1. Patching patching group vs. 2.84 in similar magnitude, and both
20/40 to 2. Atropine atropine group are appropriate modalities
20/100 7–17 years 7–17 years old group: for the initial treatment of
* 419 patients old group: Patching and near vision moderate amblyopia in
(3–7 years old) 1. Patching + exercise can improve visual children aged 3 to <7 years.
* 507 patients atropine acuity from 7 to 12 years For kids 7–12 years old, a
(7–17 years 2. Optical even if previously treated. combined program of
old) correction This is less effective for the patching and near vision
alone 13–17 years age group exercise can improve visual
acuity. This is less effective
in age 13–17 year olds

2 Infant Aphakia Treatment Study (IATS)

Unilateral congenital cataracts lead to deprivation amblyopia, which can be severe,

unless early surgical intervention is done [3]. The answer as regards the best type of
optical correction for the monocular aphakia resulting from cataract extraction
came from IATS. This study compared the visual outcomes and adverse events of
contact lens (CL) to primary intraocular lens (IOL) correction of monocular aphakia
during infancy.
IATS found that good visual acuity and stereopsis could be achieved in some
patients in both the CL and IOL groups. Early cataract surgery, appropriate optical
correction, and part-time occlusion of the fellow eye are important to achieve good
vision [4]. However, excessive occlusion of the fellow eye may disrupt the develop-
ment of stereopsis. Additionally, IOL implantation may be associated with adverse
effects such as the visual axis opacification. A 10-year follow-up study showed that
glaucoma-related adverse events occurred in 40% of eyes, unrelated to IOL implan-
tation. More research is needed to provide a perfect visual outcome for these
children.

Disease entity Study group Results Conclusion

• Unilateral Group 1: IOL Median Caution should be exercised when
congenital cataract implantation logMAR: 0.80 in performing IOL implantation in
undergoing cataract Group 2: CL CL group vs. children 6 months of age or younger
surgery between 1 correction 0.97 in IOL given the higher incidence of
and 6 months of group (p = 0.20) adverse events and the absence of an
age Additional improved short-term visual outcome
• 114 patients surgeries: 12% compared to CL use
in CL group vs.
63% in IOL
group
Clinical Trials Relevant for Optometrists 133

3 Low-Concentration Atropine for Myopia Progression

(LAMP) Study

Most infants are born hyperopic, and their hyperopia reduces as the eyeball elon-
gates alongwith flattening of cornea. Both genetic and environmental factors influ-
ence the onset and progression of myopia. Increased near work, less outdoor
activities, and lifestyle ruled by smartphones/tablets are responsible for the early
development of myopia at a younger age. The prevalence rate of myopia is increas-
ing worldwide, and as per WHO, it is projected to increase to 52% by 2050 [5]. The
available treatment options for the control of myopia include spectacle correction,
contact lenses, keratorefractive surgery, and pharmaceuticals agents such as low
dose atropine. However, there are no perfect therapeutic modalities that effectively
halt and slow down the development of myopia without causing significant side
effects.
LAMP study evaluated the efficacy and safety of low-concentration atropine eye
drops at 0.05%, 0.025%, and 0.01% compared with placebo over a 1-year period.
[6] The study was a double-blinded, randomized, and placebo-controlled therefore
it provided robust evidence. It has delineated a concentration-dependent response,
both as regards efficacy and side effect profile in the low-atropine concentration
range from 0.05% to 0.01%. Higher concentration of low-concentration atropine
0.05% is most efficacious among the three concentration.
The LAMP phase 2: In a follow-up study, over 2 years, the efficacy of 0.05%
atropine observed was double that of 0.01% atropine, and it remained the optimal
concentration among the studied atropine concentrations in slowing myopia pro-
gression [7].

Disease entity Study group Results Conclusion

438 children Randomly assigned * After 1 year, the mean SE * The 0.05%,
aged in a 1:1:1:1 ratio to change was 0.025%, and 0.01%
4–12 years. with receive 0.05%, significant(P < 0.001) in the atropine drops
myopia of at 0.025%, and 0.01% 0.05%, 0.025%, and 0.01% reduced myopia
least −1.0 atropine eye drops, atropine groups, and placebo progression along a
diopter (D) and or placebo eye groups, with a significant concentration-
astigmatism of drop, respectively, (P < 0.001) mean increase in dependent response
−2.5 D or less once at bedtime to AL * Of the three
both eyes for 1 year * Accommodation amplitude concentrations,
was also significantly reduced 0.05% atropine was
(P < 0.001) most effective in
controlling SE
progression and AL
elongation over a
period of 1 year
134 P. Ichhpujani and S. Kapoor

4 Atropine for the Treatment of Myopia 1 (ATOM 1)

The ATOM 1 study was a randomized, placebo-controlled trial designed to assess

the safety and efficacy of topical atropine in controlling the progression of myopia
in children [8].

Disease entity Study group Results Conclusion

400 children aged * Randomly assigned * At 1 year, mean Atropine 1% helped
6–12 years with with equal probability myopia progression in in controlling
myopia of –1 D to to receive either 1% the placebo-control childhood myopia
−6 D and atropine eye drop or eyes was −0.76 progression and
astigmatism of Isoptotears once D ± 0.44 D axial elongation
−1.50 D or less nightly * In atropine-treated
* Followed-up at eyes, however, there
4-monthly intervals for was a regression of
2 years myopia by +0.3
D ± 0.50 D
(p < 0.0001)

5 Atropine for the Treatment of Myopia 2 (ATOM 2)

ATOM 2 was carried out to compare efficacy and visual side effects of three lower
doses of atropine: 0.5%, 0.1%, and 0.01%. [9]

Disease entity Study group Results Conclusion

400 children Randomly assigned Mean myopia progression at Atropine 0.01% has
aged 6–12 years in a 2:2:1 ratio to 2 years was −0.30 ± 0.60, minimal side effects
with myopia of 0.5%, 0.1%, and −0.38 ± 0.60, compared with
at least −2.0 D 0.01% atropine to and −0.49 ± 0.63 D in the atropine at 0.1 and
and astigmatism be administered atropine 0.5%, 0.1%, and 0.5%, and retains
of −1.50 D or once nightly to 0.01% groups, respectively comparable efficacy
less both eyes for (P = 0.02 between the 0.01 in controlling
2 years and 0.5% groups; between myopia progression
other concentrations
(P > 0.05)

A rebound phenomenon was seen following the cessation of atropine 1%, 0.5%,
0.1%, and 0.01%, in ATOM 1 and ATOM 2 studies.
LAMP phase 3 study plans to look more into the rebound phenomenon by ran-
domizing each of the three groups 0.05%, 0.025%, and 0.01% into wash out group
and treatment-continued group, to evaluate the efficacy of 0.05%, 0.025%, and
0.01% atropine group during 3 years; whether treatment should be stopped after
2 years of atropine.
Clinical Trials Relevant for Optometrists 135

6 Zhongshan Angle Closure Prevention (ZAP) Trial

Primary angle closure disease constitutes a spectrum that includes primary angle
closure suspects (PACS), primary angle closure (PAC, occludable angles with signs
suggestive of outflow obstruction in absence of glaucomatous optic neuropathy) and
primary angle closure glaucoma (PACG; occludable angles with glaucomatous
optic neuropathy).
Most practitioners routinely offer prophylactic laser peripheral iridotomies (LPI)
to PAC and PACG patients and only to a select few PACS ones. The ZAP trial was
conducted to assess the efficacy and safety of LPI prophylaxis for Chinese patients
with PACS [10]. The study found that although the LPI is effective in preventing
progression from PACS to PAC, given the low incidence of development of PAC
both in untreated and treated groups, LPI is not mandatorily recommended in glau-
coma screening programs. However, the low rates of progression of PACS could be
unique to Chinese population and this must be kept in mind when making clinical
decisions regarding LPI for patients with PACS.

Disease entity Study group Results Conclusion

PACS n = 889 Incidence of PAC occurred in
defined as Group 1 = Laser PAC = 4.19/1000 eye years significant more untreated
angle closure PI (in one eye) in treated eyes compared eyes (30 vs. 19) mostly
 • ≥6 h Group with 7.97/1000 eye years in due to development of
 • No PAS 2 = Observation untreated eyes PAS
 • IOP < 21 (in other eye)

7 Ocular Hypertension Treatment Study 1

Ocular Hypertension (OHT) is defined as elevated intraocular pressure (IOP) more

than 21 mmHg on two or more occasions in the presence of open angles with no
glaucomatous optic neuropathy or visual field defects. OHT is a significant risk fac-
tor for development of primary open angle glaucoma, and it is imperative that these
patients be considered as glaucoma suspects and kept under follow up.
The landmark OHTS can guide who to observe and who to treat [11]. The first
goal of this study was to determine if early treatment of people with elevated intra-
ocular pressure (IOP) with topical antiglaucoma medication, would prevent them
from developing POAG. The second goal was to determine baseline clinical and
demographic factors that predict which people were more likely to develop glau-
coma, and benefit from treatment. The study found that the predictive factors for
developing POAG included increasing age, elevated IOP, thin corneas, and increased
cup/disc ratio.
136 P. Ichhpujani and S. Kapoor

Disease entity Study group Results Conclusion

1636 ocular Group 1 = topical Cumulative Topical antiglaucoma
hypertensive hypotensive eye probability of medication was effective in
participants drops developing POAG was preventing or delaying the onset
Group 4.4% in medication of POAG in individuals with
2 = observation group and 9.5% in elevated IOP and associated
observation group at risk factors such as black race,
60 months thin CCT, male gender

The conclusion was that some individuals with OHTN might benefit from receiv-
ing early treatment, whereas most others were at such low risk that they did not need
antiglaucoma treatment.

8 Ocular Hypertension Treatment Study 2

Both of the original randomization groups received medication during the OHTS 2
[12]. In OHTS phase 2, participants previously randomized to treatment for a mean
of 7.5 years remained on treatment for a mean of 5.5 additional years. The data was
analyzed to determine if the cumulative incidence of POAG was greater in the
delayed treatment group and if the subsequent course after diagnosis is worse in the
delayed treatment group. OHTS 2 found that the incidence of POAG was generally
equal in the two randomization groups (HR, 1.06).
Delaying treatment in the observation group during the OHTS 1 did not initiate
a process of irreversible deterioration in most participants. Most OHT patients are
at low risk could be followed at less frequent intervals without treatment.

Disease entity Study group Results Conclusion

1636 ocular 1572 * Cumulative proportion of * There is a modest
hypertensive surviving participants who developed penalty for delaying
participants participants; POAG from randomization to treatment in OHT
from out of which 13 years of follow-up was subjects which is minimal
OHTS 1 1385 were 0.22 in original observation for low risk patients and
“active” group and 0.16 in original more substantial for
participants medication group (P = 0.009) high-risk patients
* Median time to develop * High-risk patients may
POAG was 6 years in the benefit from more
observation group and 8.7 years frequent examinations
in the medication group and from early treatment

9 Ocular Hypertension Treatment Study 3

The OHTS Phase 3 built up on the groundwork done by the previous two studies. It
aimed to determine the incidence and severity of POAG in the cohort and develop a
20-year prediction model including the previous factors identified and potential new
risk factors [13]. In the OHTS 3, more than 70% of patients were receiving topical
Clinical Trials Relevant for Optometrists 137

ocular hypotensive treatment, and some patients had undergone glaucoma surgery.
It was noted that only one-fourth of participants in the OHTS developed visual field
loss in either eye over long-term follow-up. The cumulative incidence of POAG at
20 years, adjusted for exposure time, was 45.6%. The incidence of POAG appeared
to be generally linear over 20 years, with a possible modest increase in the rate of
conversion after 15 years. The study developed a model that identified slow versus
fast visual field progressors.

10 Laser in Glaucoma and Ocular Hypertension

(LiGHT) Trial

Not all OHT patients who need treatment for IOP control prefer antiglaucoma med-
ications. Selective laser trabeculoplasty (SLT) could offer an efficacious and adverse
effect free temporary solution. The answer came from the Laser in Glaucoma and
Ocular Hypertension (LiGHT) Trial, which has shown that SLT is a cost-effective
solution for both OAG and OHT at 3 years [14]. This trial reported that the health-
related quality of life (HRQoL) and clinical effectiveness of initial treatment with
SLT compared with IOP-lowering eye drops after 6 years of treatment.

Disease
entity Study group Results Conclusion
718 Group 1 = SLT * 652 (91%) returned SLT is a safe treatment for OAG and
patients group the primary outcome OHT, providing better long-term
Group questionnaire at disease control than initial drop
2 = antiglaucoma 36 month therapy, with reduced need for
drops * Average EQ-5 D incisional glaucoma and cataract
score: SLT: 0.89; eye surgery over 6 years
drops: 0.90

References
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amblyopia recurrence after cessation of treatment. J AAPOS. 2004;8(5):420–8.
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domized trial of patching regimens for treatment of moderate amblyopia in children. Arch
Ophthalmol. 2003;121(5):603–11.
3. Louison S, Blanc J, Pallot C, Alassane S, Praudel A, Bron AM, et al. Visual outcomes and
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2022;67(5):1476–505.
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6. Yam JC, Jiang Y, Tang SM, Law AKP, et al. Low-concentration atropine for myopia progres-
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and 0.01% atropine eye drops in myopia control. Ophthalmology. 2019;126(1):113–24.
7. Yam JC, Li FF, Zhang X, Tang SM, et al. Two-year clinical trial of the low-concentration atropine
for myopia progression (LAMP) study: phase 2 report. Ophthalmology. 2020;127(7):910–9.
8. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, Tan D. Atropine for the treat-
ment of childhood myopia. Ophthalmology. 2006;113(12):2285–91.
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the treatment of myopia 2). Ophthalmology. 2012;119(2):347–54.
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(ZAP) trial. Eye (Lond). 2021;35(12):3185–6.
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Johnson CA, Keltner JL, Huecker JB, Wilson BS, Liu L, Miller JP, Quigley HA, Gordon
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Artificial Intelligence and Optometry:
Transforming Practice and Patient Care

Shivani Majithia and Sahil Thakur

1 Introduction

Artificial intelligence (AI) has emerged as a transformative force in the field of

optometry, revolutionizing the way practitioners diagnose, treat, and manage ocular
conditions. At the heart of AI lies machine learning (ML) and its subset, deep learn-
ing (DL), which have demonstrated remarkable capabilities in analyzing vast
amounts of data to extract meaningful patterns and insights. In the realm of optom-
etry, the advent of AI-driven technologies has been particularly notable in leverag-
ing medical imaging data, such as retinal images and optical coherence tomography
(OCT) scans. These imaging modalities provide rich information about ocular
health and pathology, making them ideal inputs for AI algorithms. Moreover, the
availability of large-scale datasets, such as those from initiatives like the UK
Biobank, combined with advancements in computing power and chip development,
has significantly lowered the barrier for developing sophisticated AI models. These
datasets serve as invaluable resources for training and validating AI algorithms,
enabling researchers and developers to create robust and accurate models for vari-
ous optometric applications. Briefly, the development of AI models typically
involves several stages, including data preprocessing, model selection, training, tun-
ing, and testing. This iterative process aims to optimize the model’s performance
and generalizability across diverse datasets. Evaluating the performance of AI mod-
els then requires robust metrics that assess their accuracy, sensitivity, specificity,
and predictive value. Common metrics include area under the receiver operating

S. Majithia
Education and Professional Services, Essilor Luxottica, Singapore
e-mail: [email protected]
S. Thakur (*)
Singapore Eye Research Institute, Singapore, Singapore
Medical Affairs, Mediwhale, Seoul, South Korea

© The Author(s), under exclusive license to Springer Nature Singapore Pte 139
Ltd. 2024
D. Shu et al. (eds.), Current Advances in Optometry, Current Practices in
Ophthalmology, https://doi.org/10.1007/978-981-97-8140-9_11
140 S. Majithia and S. Thakur

characteristic curve (AUC-ROC), precision, recall, and F1-score. This chapter aims
to provide a focused exploration of the impact of AI on optometry, with a particular
emphasis on FDA-approved AI products, the transformative potential of early detec-
tion and screening, and the evolving scope of optometric practice in the AI era.
While acknowledging the vast landscape of AI applications in optometry, this chap-
ter prioritizes key themes and developments relevant to practitioners and stakehold-
ers. It serves as a concise overview, offering insights into the current state of AI
integration in optometry and outlining future directions for research and practice.

2 FDA-Approved Eye Related SaMD (Software as Medical

Device) and Their Impact

In recent years, the FDA has granted approval to several AI-driven technologies
designed to enhance diagnostic accuracy and streamline patient care within the field
of optometry and ophthalmology. These innovations harness the power of AI, par-
ticularly ML/DL algorithms, to analyze medical imaging data and detect ocular
abnormalities with high precision and efficiency. Notably, these FDA-approved AI
products represent a significant milestone in the integration of AI into clinical prac-
tice, offering optometrists valuable tools for early detection and management of
various ocular conditions. Notable examples include:

2.1 IDx-DR by Digital Diagnostics Inc.

IDx-DR is an autonomous AI diagnostic system authorized by the FDA for the

detection of more than mild diabetic retinopathy (mtmDR) and diabetic macular
edema (DME). A pivotal trial enrolled 900 subjects without a history of diabetic
retinopathy (DR) at primary care clinics, comparing the system’s performance to
Wisconsin Fundus Photograph Reading Center (FPRC) standards. Median age was
59 years (range, 22–84 years); among participants, 47.5% were male; 16.1% were
Hispanic, 83.3% were not Hispanic; 28.6% were African American, and 63.4%
were not. The AI system demonstrated high sensitivity of 87.2% and specificity of
90.7%, exceeding pre-specified superiority endpoints. Furthermore, the imageabil-
ity rate was 96.1%, thus showing AI’s ability to bring specialty-level diagnostics to
primary care settings [1].

2.2 EyeArt Automated DR Detection System by Eyenuk, Inc.

The EyeArt system has been designed to detect DR and vision-threatening diabetic
retinopathy (vtDR) autonomously. A prospective multicenter cross-sectional diag-
nostic study, conducted from April 17, 2017, to May 30, 2018, evaluated its safety
and accuracy in detecting mtmDR and vtDR in individuals with diabetes. Out of
942 consenting individuals aged 18 years or older, 893 patients (1786 eyes) met the
inclusion criteria and completed the study protocol across 15 primary care and eye
Artificial Intelligence and Optometry: Transforming Practice and Patient Care 141

care facilities. The system demonstrated high sensitivity and specificity in detecting
both mtmDR (sensitivity: 95.5%, specificity: 85.0%) and vtDR (sensitivity: 95.1%,
specificity: 89.0%) without dilation. After correction for enrichment, the specificity
for mtmDR increased to 87.8%, and both sensitivity (97.0%) and specificity (90.1%)
improved for vtDR [2, 3].
These FDA-approved AI products and similar country specific derivatives have
had a profound impact on the screening and diagnosis of ocular conditions, particu-
larly DR. Their deployment in screening programs has significantly enhanced the
efficiency and effectiveness of DR screening, leading to early detection and inter-
vention in at-risk populations [4]. In many countries, AI-based solutions are starting
to become integral components of national DR screening programs, offering scal-
able and cost-effective approaches to managing this sight-threatening complication
of diabetes [4–8]. Moreover, some countries, such as Singapore and Turkey, have
developed their own AI solutions tailored to their population samples, further illus-
trating the versatility and adaptability of AI across diverse scenarios [9–11].

3 Scope of Practice and Salient Examples of Potential

AI Solutions

Optometrists serve as essential primary healthcare providers specializing in the

assessment and management of the eye and visual system. Their scope of practice
encompasses a wide range of services, including the evaluation of visual acuity,
correction of refractive errors through prescription of glasses or contact lenses, as
well as the detection, diagnosis, and treatment of various eye diseases. Additionally,
optometrists play a crucial role in rehabilitating conditions affecting the visual sys-
tem, offering interventions to enhance visual function and quality of life for their
patients. In light of this scope of practice, this section will deal with some salient
examples of AI applications that can be potentially adopted into the workflow for
optometrists.

3.1 Vision Impairment

In the realm of community vision screening, there exists a pressing need for an
efficient and accurate method to detect individuals requiring referral to specialized
eye care centers due to vision loss associated with various eye conditions. The
advent of AI and especially DL presents a promising avenue to transform this clini-
cal referral pathway. Tham et al., in their study aimed to evaluate the efficacy of a
newly developed DL algorithm in detecting disease-related visual impairment using
retinal fundus images [12]. Drawing from a dataset comprising 15,175 eyes with
complete data on visual acuity from the Singapore Epidemiology of Eye Diseases
(SEED) Study, researchers embarked on a proof-of-concept endeavor. Initially, a
single-modality DL algorithm was crafted solely from retinal photographs to dis-
cern any disease-related visual impairment, defined as eyes with major eye diseases
and best-corrected visual acuity of less than 20/40, as well as moderate or worse
142 S. Majithia and S. Thakur

disease-related visual impairment, indicated by eyes with disease and best-corrected

visual acuity of less than 20/60. Following algorithm development, its performance
was internally tested on a fresh set of 3803 eyes from the same study. Subsequently,
external validation was conducted using data from three population-based studies
and two clinical studies, encompassing a total of 16,993 eyes. The findings from the
internal test dataset were promising, with the algorithm exhibiting an AUC of 94.2%
for the detection of any disease-related visual impairment and 93.9% for moderate
or worse impairment. External validation across the five test datasets demonstrated
AUCs ranging from 86.6% to 93.6% for any disease-related visual impairment and
between 85.9% and 93.5% for moderate or worse impairment. These results under-
score the potential of this function-focused tool in promptly identifying visual
impairment stemming from major eye diseases. Ultimately, such a tool holds prom-
ise for facilitating targeted and timely referrals of individuals with disease-related
visual impairment from community settings to specialized eye care facilities,
thereby enhancing the efficiency and effectiveness of vision care delivery.

3.2 Cataract

In the realm of optometry, where practitioners serve as primary healthcare providers

for the eye and visual system, the detection and management of age-related cataracts
stand as a crucial component of comprehensive eye care. Age-related cataracts,
known to be the leading cause of visual impairment among older adults globally,
present a significant challenge in many communities due to issues related to acces-
sibility and availability of screening services. Despite being easily treatable through
surgical intervention, a considerable number of individuals with visually significant
cataracts often go undiagnosed or neglected, particularly in underserved areas where
resources are limited. Traditional methods of cataract diagnosis heavily rely on slit-
lamp biomicroscopy conducted by trained ophthalmologists, a process that may not
be readily accessible in many communities, especially those in rural or low-income
settings. This poses a significant barrier to early detection and intervention, empha-
sizing the need for innovative approaches to expand the reach of cataract screening.
The emergence of deep learning technology and retinal photograph-based algorithms
presents a promising opportunity to address these challenges, offering a more effi-
cient and accessible means of detecting visually significant cataracts. The develop-
ment and validation of a retinal photograph-based, deep learning algorithm for
automated detection of visually significant cataracts were reported in a study that
utilized more than 25,000 images from population-based studies [13]. In the internal
test set, the AUC was 96.6%. External testing performed across three studies showed
AUCs ranging from 91.6% to 96.5%. In a separate test set of 186 eyes, the algo-
rithm’s performance was compared with evaluations by four ophthalmologists. The
algorithm demonstrated comparable, if not slightly superior, performance, with a
sensitivity of 93.3% compared to 51.7–96.6% by ophthalmologists and a specificity
of 99.0% compared to 90.7–97.9% by ophthalmologists. These findings underscore
the potential of a retinal photograph-based screening tool for visually significant
Artificial Intelligence and Optometry: Transforming Practice and Patient Care 143

cataracts among older adults. The algorithm’s high accuracy and sensitivity suggest
its efficacy in providing more appropriate referrals to tertiary eye centers, thereby
facilitating timely interventions for individuals with cataract-related visual impair-
ment. Another study demonstrated the effectiveness of the universal AI platform that
uses anterior segment photos and multilevel collaborative pattern in diagnosing and
managing cataracts [14]. The research also explored an AI-based medical referral
pattern aimed at enhancing collaborative efficiency and resource coverage in cataract
management. The training and validation datasets were sourced from the Chinese
Medical Alliance for Artificial Intelligence, covering diverse healthcare facilities and
capture modes. The datasets underwent a three-step labeling process, which involved
recognizing capture modes, diagnosing cataracts, and detecting referable cataracts
based on etiology and severity. Additionally, the study integrated the cataract AI
agent with a real-world multilevel referral pattern that involved self-monitoring at
home, primary healthcare, and specialized hospital services. The results demon-
strated the robust diagnostic performance of the universal AI platform and multilevel
collaborative pattern across three key tasks. These tasks included capture mode rec-
ognition, cataract diagnosis (normal lens, cataract, or postoperative eye), and detec-
tion of referable cataracts. The AI platform achieved impressive AUC values ranging
from 91% to over 99% in all tests. In the real-world tertiary referral pattern, the AI
agent suggested referrals for 30.3% of individuals, significantly increasing the doc-
tor-to-population service ratio by 10.2-fold compared to the traditional pattern. The
findings suggest that this AI-based medical referral pattern could be extended to
other common disease conditions and resource-intensive situations, offering poten-
tial benefits for public health initiatives.

3.3 Multiple Disease Detection

In recent years, deep learning systems (DLSs) have emerged as powerful tools for
screening various eye diseases, including DR, glaucoma, age-related macular
degeneration (AMD), and other fundus abnormalities. Several studies have evalu-
ated the performance of DLS in detecting these diseases, highlighting their potential
utility in optometry practice for early diagnosis and intervention. Ting et al., in a
pioneering study, evaluated the diagnostic performance of a DLS for detecting
referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible
glaucoma, and AMD in multiethnic populations with diabetes [15]. Using a vast
dataset of retinal images, the DLS demonstrated high sensitivity and specificity for
identifying these conditions, paving the way for efficient screening and referral
strategies. Expanding upon this research, subsequent studies have developed DL
models capable of screening multiple abnormal findings in retinal fundus images.
These models were trained and validated using large datasets from diverse sources,
achieving high accuracy in detecting 12 major findings, including hemorrhage, hard
exudate, cotton-wool patch, drusen, and glaucomatous disc changes [16]. The DL
algorithms exhibited performance comparable to human experts, demonstrating
their potential as automated screening systems for various retinal abnormalities.
144 S. Majithia and S. Thakur

Further advancements in DL technology have led to the development of a deep

learning platform (DLP) capable of detecting a broader range of fundus diseases
and conditions [17]. This platform, trained on a comprehensive dataset of over
200,000 fundus images, demonstrated remarkable accuracy in detecting 39 classes
of common fundus diseases, including DR, AMD, RVO, RAO, glaucoma, and reti-
nal detachment. The DLP’s performance rivaled that of retina specialists, suggest-
ing its potential for use in clinical settings and population screening programs. In a
real-world clinical environment, an AI-based fundus screening system also exhib-
ited superior diagnostic effectiveness for DR, RVO, and pathological myopia (PM),
achieving high sensitivity, specificity, accuracy, and predictive values [18]. This sys-
tem demonstrated its clinical utility in the early detection of ocular fundus abnor-
malities, highlighting its role in preventing blindness through timely intervention.
Collectively, these studies underscore the potential of deep learning technology in
optometry practice for the comprehensive screening and detection of multiple eye
diseases. By leveraging AI-based tools, optometrists can enhance their diagnostic
capabilities, streamline screening processes, and improve patient outcomes through
early detection and intervention.

4 Key Insights from Recent Resources

4.1 Optometry 2040

The Optometry 2040 initiative from Optometry Australia, launched in 2018, pres-
ents three distinct scenarios envisioning the future of optometry, alongside key
trends shaping the profession given in Table 1.
These scenarios highlight potential trajectories for the profession, emphasizing
the need for adaptation to technological advancements. Scenario 2, identified as
optimal, underscores the importance of embracing collaborative and technology-
enabled care delivery. Key trends identified in the report include consistently-­
evolving technology, enlarged scope of practice, and consumer-centric care,
underscoring the importance of embracing AI and adapting practice models.

Table 1 Scenarios discussed under optometry 2040 initiative by Optometry Australia [19]
Scenario Description
1. Optometry fails to Technological and clinical advancements render much of optometry’s
adapt diagnostic work redundant, leading to underemployment and
decreased salaries
2. The eye care you Optometrists become trusted guides through the eye care system,
want—As well as facilitated by collaborative professional-patient relationships and
the eye care you technology-enabled care delivery. This scenario is considered optimal
need for the profession
3. Optometry beyond Optometrists lead technological innovation, becoming ‘optical
the dark room and scientists’ and integrating with other disciplines to optimize
out of the box healthcare
Artificial Intelligence and Optometry: Transforming Practice and Patient Care 145

4.2 American Academy of Optometrists Survey

The American Academy of Optometry (AAO) survey provides insights into optom-
etrists’ perspectives on AI integration in eye care [20]. The study was conducted
among 400 optometrists who completed a survey assessing perceived advantages
and concerns regarding AI using a 5-point Likert scale. The majority of respondents
indicated that they were familiar with AI, with approximately 66.8% reporting such
familiarity. However, approximately half of optometrists expressed concerns regard-
ing the diagnostic accuracy of AI, with around 53.0% expressing such reservations.
Despite these concerns, a significant majority, accounting for 72.0% of respondents,
believed that the integration of AI would enhance the practice of optometry.
Furthermore, optometrists’ willingness to integrate AI into their practice showed a
notable increase, rising from 53.3% before the COVID-19 pandemic to 65.5% fol-
lowing the onset of the pandemic (p < 0.001).
The convergence of insights from Optometry 2040 and the AAO survey under-
scores the transformative potential of AI in optometric practice. While Optometry
2040 provides a visionary outlook on the future of the profession and identifies key
trends shaping its trajectory, the AAO survey offers a snapshot of current percep-
tions and attitudes toward AI integration among optometrists. Together, these
resources offer valuable perspectives on the opportunities and challenges associated
with AI adoption in optometry, highlighting the importance of strategic planning,
education, and collaboration to navigate the evolving landscape of eye care delivery.
As optometry moves toward an AI-enabled future, it is essential for practitioners to
embrace innovation while upholding core principles of patient-centered care and
professional excellence.

5 LLMs and Foundation Models: The Next Frontier

Large language models (LLMs) have emerged as powerful tools with significant
potential to transform various aspects of optometry practice. These models, such as
ChatGPT, Google Bard (now Gemini), and Bing Chat, are trained on vast datasets
and possess human-like text generation capabilities. In the context of optometry,
LLMs can play a crucial role in enhancing diagnosis, treatment, patient care, and
expanding the scope of practice. One area where LLMs demonstrate promise is in
aiding during optometric exams and consultations. For example, eye-specific LLMs,
specifically designed for ophthalmic applications, have been evaluated for their per-
formance in assisting with the Fellowship of Royal College of Ophthalmologists
(FRCOphth) exams [21]. These models have shown varying degrees of accuracy in
answering multiple-choice questions related to ophthalmology, with differences
observed among different LLM-chatbots. This underscores the importance of con-
tinued research and refinement to optimize the performance of LLMs in supporting
eye related education and assessment. In addition to assisting with clinical decision-
making, LLMs can also facilitate patient communication and education [22].
ChatGPT, for instance, can be integrated into virtual consultations, allowing patients
146 S. Majithia and S. Thakur

to ask questions and receive personalized responses regarding their eye health con-
cerns. This not only enhances patient engagement but also promotes proactive man-
agement of ocular conditions.
Moreover, foundation models like RETFound represent a significant advance-
ment in leveraging AI for eye care. RETFound, developed by Moorfields Eye
Hospital and University College London, is an AI foundation model specifically
trained 1.6 million unlabeled retinal images by means of self-supervised learning
[23]. This model has demonstrated the ability to detect sight-threatening eye diseases
and even predict systemic health challenges such as heart attacks, stroke, and
Parkinson’s disease. One notable advantage is their ability to reduce the need for
extensive dataset collection. Unlike conventional AI models that require massive
amounts of labeled data for training, foundation models leverage self-supervised
learning techniques to learn from unannotated or minimally labeled data. This means
that RETFound can extract valuable insights from a relatively small dataset of retinal
images, thereby streamlining the data collection process and reducing the burden on
healthcare institutions to amass large datasets. Moreover, foundation models enable
faster and more customized development of AI solutions through techniques such as
few-shot and zero-shot learning. Few-shot learning allows models like RETFound to
adapt to new tasks or domains with minimal labeled examples, making it possible to
tailor the model to specific clinical applications rapidly. For example, RETFound can
be fine-tuned to detect rare or emerging eye diseases using only a handful of anno-
tated images, accelerating the development of novel diagnostic tools. Zero-shot
learning takes this concept further by enabling the model to generalize to tasks it has
never encountered before. This capability is particularly valuable for rare diseases,
where clinicians may not have enough data or samples to train models. With
RETFound, optometrists can leverage the model’s pretrained knowledge to address
new challenges without the need for additional data collection or model retraining.
Furthermore, foundation models like RETFound democratize AI by making state-of-
the-art technology accessible to a broader audience. Traditionally, AI development
has been confined to research labs and tech giants with the resources to collect and
process massive datasets [24]. However, with the advent of foundation models, even
smaller clinics or research institutions can harness the power of AI to improve patient
care. By providing open access to pretrained models and resources for model adapta-
tion, solutions like RETFound empower clinicians and researchers to innovate and
develop AI solutions tailored to their unique needs and patient populations.
However, the integration of LLMs and foundation models into current practice
necessitates upskilling and adaptation among optometrists. Continuous learning
and development programs are essential to ensure that practitioners are proficient in
leveraging and using AI tools effectively. Strategies for embracing AI, such as
incorporating LLM-driven chatbots into practice workflows and collaborating with
technologists to develop specialized models, are vital for optimizing the benefits of
AI integration. Overall, the impact of LLMs and foundation models in vision sci-
ence extends beyond conventional diagnostic and treatment paradigms. These mod-
els hold the potential to revolutionize the way we deliver care, interact with patients,
and contribute to advancements in ocular health.
Artificial Intelligence and Optometry: Transforming Practice and Patient Care 147

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