Strabismus is a well-known diagnostic challenge for eyecare practitioners, and diagnosing it in an adult patient is particularly demanding due to the potential etiologies, including neurological dysfunction, orbital disease, binocular vision disorders or central nervous system injury.¹ An observational study analyzed the prevalence of binocular diplopia and its associated causes, identifying vasculopathy (28%), trauma (24.6%), decompensating heterophorias (11.25%), tumors (4%), and inflammatory conditions (4%) as common contributors.² A thorough ocular examination with targeted ancillary testing is essential to accurately diagnose and manage strabismus, determine the need for immediate referral, and assess whether the condition poses a vision- or life-threatening risk. Long-standing phorias may present with intermittent diplopia due to decompensation triggered by factors such as fever, trauma or stress.² In this case, the patient’s history and symptom timeline suggest a decompensated phoria following a stressful event. Recognizing the distinguishing features of pathological vs benign strabismus is critical for establishing an accurate and effective treatment plan.

This case report is intended for third- and fourth-year optometry students and eyecare clinicians.

Case Description

On August 15, 2023, a 39-year-old female presented with a chief complaint of intermittent, binocular diplopia at distance, particularly when driving. She described the diplopia as horizontal without vertical disparity, noticing it in both left and right peripheral gazes, with resolution upon closing one eye. Her symptoms worsened at the end of the day or when she was fatigued.

The patient reported that her symptoms began in her teenage years and believed her eye turn was undiagnosed in childhood. The diplopia remained manageable until her pregnancy in 2020, which she described as an intense, stressful event, leading to a noticeable increase in the frequency of her diplopia.

In 2020, at the age of 36, she was officially diagnosed with strabismus by her primary optometrist. She was prescribed her first pair of prism glasses, which alleviated the distance diplopia. She had received her first glasses for myopia at age 14 and had since preferred wearing contact lenses full-time, as she disliked wearing glasses. Her current contact lens prescription was right eye -4.00 diopter sphere (DS) and -3.50 in the left. Her prism glasses had a total of eight prism diopters base out, which she wore over her contact lenses as needed for driving.

The patient’s medical history was unremarkable for disease or significant conditions. However, she was involved in a car accident at age nine, going through the back of a car window. There was no reported diagnosis of concussion, eye injury or overnight hospital stay.

On examination, her corrected visual acuities at both distance and near were 20/20 in both eyes with contact lenses alone. Extraocular movements were full in both eyes. Pupils and confrontation fields were unremarkable. A cover test without prism glasses revealed a constant 12 prism diopter left esotropia in all nine gazes, demonstrating comitancy.

Randot stereopsis testing showed no global stereopsis and local stereopsis of 200 arc seconds, with no improvement when wearing her prism glasses. Worth 4 Dot testing without her prism glasses demonstrated uncrossed diplopia at 40 cm. With the prism glasses, she achieved fusion at 20 cm but experienced intermittent alternating suppression at 4-5 feet. Bagolini lens testing indicated normal correspondence, and visuoscopy showed no eccentric fixation in either eye. See Appendix A for Worth 4 Dot and Bagolini test procedures and interpretation guidelines.

Step vergence ranges, performed with her prism glasses, produced the following results:

• Distance: base out (BO): 16/18/16, base in (BI): X/4/2
• Near: base out (BO): X/35/30, base in (BI): X/6/2

Anterior and posterior segment examinations were unremarkable.

Treatment options were discussed, and the patient opted to begin in-office vision therapy as soon as possible.

Due to her strong aversion to wearing glasses, she was highly motivated to reduce her dependence on prism glasses. The initial vision therapy protocol focused on monocular ocular motor and accommodative activities to equalize visual skills between both eyes. By Week 4, anti-suppression activities were introduced, with an emphasis on peripheral fusion and binocular skills.

At Week 9, the patient underwent an exercise using an optokinetic drum in both left and right gazes, which triggered diplopia while the patient maintained primary gaze. The drum was placed on the patient’s right and left fields, while maintaining fixation in primary gaze. To address this peripheral trigger, binasal occlusion taping was applied to her habitual spectacle prescription without prism. This method was intended to alleviate the onset of diplopia, offering an alternative to wearing prism glasses over her contact lenses. After the application of the binasal taping, the optokinetic drum was spun again, and the patient no longer experienced diplopia in primary gaze. Table 1 provides the pre- and post-examination findings after 12 sessions of vision therapy. See Appendix B for details of the in-office vision therapy activities for the first 12 weeks.

Table 1. Pre- and Post-Examination findings After 12 Vision Therapy Sessions. Click to enlarge

Around Week 19, the patient started experiencing constant, distance blur with her habitual contact lenses and an updated refraction showed a decrease in her myopia: right eye: -2.50 -1.00 x 015 DS, left eye: -3.00 DS with 20/20 acuities at distance and near.

After Week 21, the patient was due for a comprehensive annual examination. She mentioned that her current habitual contact lenses and spectacle glasses were making her distance vision constantly blurry. The patient wore the glasses while driving when necessary.

Dry refraction with primary optometrist before vision therapy was the following:

• Right Eye: -4.00 – 1.00 x 010
• Left Eye: -3.75 DS

Dry subjective refraction with us after 21 weeks of vision therapy was the following:

• Right Eye: -2.50 – 1.00 x 015, 20/20
• Left Eye: -3.00 DS, 20/20
• Add: +1.25, 20/20

The add power was determined based on the fused cross cylinder and subjective findings during the refraction.

Table 2. Pre- and Post-Examination findings After 24 Vision Therapy Sessions. Click to enlarge

After 24 weeks of in-office vision therapy, the patient graduated from the program, having successfully achieved her therapy goals. The patient was able to control her diplopia and did not have to wear the prism glasses nor the binasal occlusion taping while driving. She was able to drive with only her contact lens prescription. The patient’s main primary goal was to not have to wear glasses, and she has been able to drive without her prism glasses since completing vision therapy. She does still note diplopia onset when she is tired at the end of a long day, but she is able to control it and it is much more manageable. Table 2 provides the examination findings after 24 therapy sessions. See Appendix C for details of the in-office vision therapy activities by week for the remaining 12 sessions. She was advised to continue maintenance home therapy 2-3 times per week to preserve her visual skills. She was given two exercises to practice at home: Clear and Opaque Eccentric Circles and Brock String in nine gazes. The patient was to taper the home maintenance exercises to 1-2 times per week after 6 months. A 6-month progress evaluation was scheduled to monitor her symptom resolution and overall progress.

Education Guidelines

Key Concepts

1. 1. Possible causes of unilateral esotropia in adults
   2. Special ancillary testing in sensorimotor evaluations
   3. Management and treatment strategies for strabismus in adults
   4. Individualized Vision Therapy programming with specific goals

Learning Objectives

After this case discussion, participants should be able to:

1. 1. Differentiate unilateral esotropia from other types of strabismus based on ocular alignment and associated features.
   2. Explore the various etiological factors contributing to esotropia, such as refractive errors, accommodative factors, neurological dysfunctions, vasculopathies and space-occupying lesions.
   3. Demonstrate proficiency in using diagnostic techniques and special ancillary testing to assess and diagnose the different types of esotropia.
   4. Develop effective communication skills to counsel patients about the diagnosis, treatment options and expected outcomes associated with esotropia.
   5. Explain the impact of an individualized in-office vision therapy program for strabismic patients and its significance in improving their quality of life.

Discussion Questions

Knowledge and Concepts

1. 1. How is esotropia classified?
   2. What is the difference between adult esotropia and pediatric esotropia?
   3. What tests are used to evaluate esotropia?

Differential Diagnosis

1. 1. What are the differential diagnoses for adult onset esotropia?
   2. What are the key history questions to ask?
   3. What are the key diagnostic tests for evaluation?

Management

1. 1. How do you determine if prism is indicated?
   2. How do you determine the amount of prism to prescribe?
   3. What is the role of binasal occlusion?
   4. How do you determine if vision therapy is indicated?
   5. How do you determine when a surgical consult is warranted?
   6. How do you assess the prognosis for success?

Creating an Individualized In-Office Therapy Program

1. 1. How do you determine the duration of treatment?
   2. What is the sequence of therapy?
   3. How do you select therapy activities?
   4. What is the role of home therapy?
   5. How do you determine when to graduate the patient?

Assessment of learning objectives

1. 1. Students can be asked to classify the types of esotropia in both a classroom and clinical setting.
   2. Facilitate case discussions to conduct components of patient history and pertinent questions relative to the significance of the case, in addition to creating a management strategy.
   3. Evaluate students on how to rule out each differential diagnosis for adult esotropia by listing correlating ancillary testing. 

Discussion

Teaching Methodology

The clinician and students can facilitate a case discussion in either a small-group clinical setting or a classroom setting, with students divided into small groups of two to four. To enhance understanding, provide students with case findings and ask them to formulate the likely diagnosis. Have students create a table listing the differential diagnoses of esotropia, including major symptoms, signs and key diagnostic findings for each type.

To facilitate history-taking skills, students can role-play as clinicians asking pertinent history questions for a patient with adult-onset esotropia. For developing ancillary testing skills, students can alternate between being the student clinician and the simulated patient, with simulated responses provided by the instructor. Student clinicians should be asked to explain the reasons for selecting specific tests and to interpret the simulated findings.

Based on the provided test findings and patient goals, students can write a 12-week individualized therapy plan that appropriately addresses the patient’s needs. To enhance communication skills, student clinicians can practice providing patient education, explaining the diagnosis, elements of the prescribed treatment plan and anticipated treatment outcomes.

History Questions and Key Findings to Differentiate Between Adult-Onset vs Childhood Esotropia

When conducting a strabismus evaluation on a patient with the chief complaint of diplopia, the first step is a detailed, comprehensive ocular and medical history. A thorough assessment of the patient’s current diplopia symptoms will assist the clinician in developing a systematic approach to determine the nature of the strabismus throughout the evaluation. Gathering answers to as many history-of-present-illness (HPI) questions related to the diplopia will help rule out differential diagnoses.

The patient characterized her diplopia as binocular, since it was resolved by monocular occlusion. Since the deviation was only horizontal without a vertical disparity, involvement of certain ocular muscles responsible for elevation or depression of the eye (e.g., superior rectus, superior oblique) was ruled out. Importantly, the patient noted that the onset of her diplopia occurred during her childhood years, though she experienced double vision infrequently at that time. Given the childhood onset of the diplopia, pathological etiologies such as neurological dysfunction, space-occupying lesions and vasculopathies are less likely, moving them toward the bottom of the differential diagnosis list.

Significantly, the patient reported that the diplopia was intermittent and worsened toward the end of the day, with fatigue as a common trigger. This variability in symptoms suggests a potential decompensated phoria, myasthenia gravis or any condition that worsens with exhaustion.

There are several categories of esotropia, including infantile, accommodative, non-accommodative, mechanical, decompensated phoria and microesotropia. Since the patient’s eso-deviation is greater than 10 prism diopters, it does not qualify as micro-esotropia. Infantile esotropia typically presents around 6 months of age, with characteristics such as a large (greater than 40 prism diopters) angle, dissociated vertical deviation, amblyopia and latent or manifest nystagmus—none of which were present during testing in this patient.

The patient did not report any other symptoms associated with her diplopia, which supports a diagnosis of decompensating phoria. Her ocular history revealed myopia during her teenage years, which rules out any accommodative component to her esotropia. Additionally, her medical history was unremarkable for signs of vascular or thyroid issues.

Sensorimotor Evaluation with Ancillary Testing: Key Diagnostic Tests to Evaluate Esotropia

A comprehensive testing protocol is essential to fully assess the nature of esotropia. Extraocular movements will help determine if there is any restriction in the ocular muscles. The cover test in all nine gazes will assess the comitancy of the eye posture and its magnitude. A cranial nerve palsy would typically show a higher magnitude of deviation in the direction of the affected ocular muscle, while a decompensated phoria will generally demonstrate comitancy and no abnormal head posture.

Visuoscopy is used to evaluate eccentric fixation, which is often associated with decreased visual acuity and deep amblyopia. Bagolini testing allows clinicians to test for anomalous retinal correspondence (ARC), a brain issue in which one eye uses an extra-foveal location and the other eye uses its foveal location; it is a sensory maladaptation to avoid diplopia. The development of eccentric fixation, anomalous retinal correspondence or amblyopia suggests that the strabismus has been long-standing.

Randot stereopsis and Worth 4 Dot testing assess the patient’s sensory fusion ability and its range. Understanding the distance at which the patient can achieve fusion is crucial for therapy, as binocular activities are typically initiated at the distance where the patient can fuse the images correctly. Motor fusion testing through step vergence ranges evaluates the patient’s response to prism. Step vergences are performed over smooth vergence ranges because this testing method is conducted in free space, allowing the patient to perform in a more natural setting as opposed to being behind a phoropter, which can block peripheral vision and alter the testing environment.

Differential Diagnoses for Adult-Onset Esotropia

After completing the necessary testing protocol and obtaining a comprehensive history, the clinician can begin ruling out certain pathologic etiologies. Since the patient did not exhibit any ocular muscle restrictions, a cranial nerve palsy or mechanical dysfunction is unlikely. Additionally, the patient’s unremarkable medical history and absence of neurological symptoms help rule out a space-occupying lesion, vasculopathy-related deficits or inflammatory causes.

One differential diagnosis to consider is Sagging Eye Syndrome (SES), which involves deterioration of the band tissue of the superior rectus and lateral rectus muscles, leading to an inability to diverge when looking at distant objects.⁶ This condition is typically associated with specific facial features, such as a deep superior sulcus and upper eyelid ptosis, and generally has an average onset age of 70 years. However, this patient did not present with any abnormal facial features nor fit the demographic criteria for SES.

Figure 1. Algorithm for the Assessment of Diplopia in a Patient with Esotropia and Differential Diagnoses. Click to enlarge

Another potential diagnosis is myasthenia gravis, as diplopia is a common initial symptom in adult patients with ocular myasthenia gravis, particularly when it affects the lateral rectus muscle.⁷ Ocular myasthenia gravis is reported to affect Caucasian patients with frequent symptoms of fluctuating ptosis, diplopia and fatigability with sustained upgaze.⁸ While the patient is Caucasian, she did not demonstrate any fluctuating ptosis or twitching during the assessment of extraocular motilities, making myasthenia gravis less likely in this case. Figure 1 provides a summary of the differential diagnoses based on test findings.

Treatment Options

Determination of Vision Therapy vs Surgery

The decision to pursue in-office vision therapy depends on the type of strabismus and the patient’s sensorimotor fusional capabilities.¹⁴ The prognosis is generally more favorable when the strabismus is intermittent, and when the patient has first or second-degree fusion ability. In this patient’s case, although her strabismus was constant, she demonstrated second-degree fusion with Worth 4 Dot testing and showed local stereopsis on Random Dot testing. These findings indicated that vision therapy was a viable option despite the absence of global stereopsis initially.

In contrast, a surgical consultation is recommended for patients with a cosmetically significant strabismus, particularly if the esotropia deviation exceeds 15 prism diopters at both distance and near, even when the patient is fully corrected with glasses.¹⁴ Since the patient’s deviation was 12 prism diopters, surgery was not recommended at that time. Specifically, patients with constant diplopia that exceeds 15 prism diopters may warrant a surgical consultation due to the magnitude of the strabismus.

Determination of Prism Correction

Prism glasses were recommended due to the patient’s intermittent horizontal diplopia, which occurred while driving and significantly impacted her functionality and daily life. If the diplopia had been rare and only occurred due to fatigue at the end of her day, prism glasses would not have been recommended, as it would not have affected her daily routine.

The prescribed prism amount is based on the patient’s subjective responses and fusional ability. The goal is to resolve the patient’s diplopia while enhancing binocularity at all distances, using the lowest amount of prism that satisfies both criteria. However, there is a potential for prism adaptation—a phenomenon in which the patient’s eye alignment shifts in response to the prism. In such cases, the initial adaptation can result in a recurrence of the original strabismic deviation, effectively negating the corrective effect of the prism. Consider performing a prism adaptation test if the patient has suppression to assess for the presence of prism adaptation. For these patients, prism would not be beneficial. The patient had already been using prism glasses provided by her primary optometrist, which resolved her diplopia and improved her binocular fusion ability from 40 cm to around 4 ft, indicating progress.

To determine the optimal prism prescription, the patient focused on a single letter in the distance while the examiner used a prism bar and gradually increased the compensatory prism until the patient reported fusion. If suppression is suspected, a similar method could be used but with a Worth 4 Dot target while the patient wears red/green glasses as the compensatory prism is used. Ideally, the required prism amount is confirmed across different tests before prescribing it. After determining the appropriate prism, the patient’s random dot stereopsis should be re-tested. Since there was no improvement in either local or global stereopsis for this patient, the prism glasses were recommended only when diplopia occurred while driving, rather than full-time.

Determination of the Prognosis for Treatment Success

Given that the strabismus likely stemmed from a decompensated phoria, in-office vision therapy was recommended as the primary treatment. The patient’s ultimate goal was to avoid wearing glasses throughout the day and to regain depth perception. The patient understood that the length of the therapy program would depend on weekly progress, but it was estimated to take approximately 24 weeks, consisting of 2 units of therapy with both in-office and home-based exercises.

Since the patient did not exhibit eccentric fixation or anomalous retinal correspondence, the prognosis for improvement was optimistic. At the beginning of vision therapy, the recommendation was for the patient to continue wearing her contact lenses for full correction and to use the prism glasses only as needed while driving.

Vision therapy sessions were scheduled for 1 hour per week, with homework assignments provided to be completed at home for at least 15 minutes each day. After 12 office sessions, progress was evaluated by repeating previously abnormal tests for comparison. Case reports have demonstrated that adult patients undergoing vision therapy can develop an appreciation for global stereopsis.⁹ These patients were highly motivated and compliant with in-office therapy supported by home exercises.

Although there are limited studies showing the efficacy of in-office vision therapy for long-standing strabismus, due to the belief that neuroplasticity only has a significant effect during the critical period, there is growing evidence suggesting that binocularity improvement is possible even outside the critical period.⁹ Additionally, the adult visual system has been shown to retain residual plasticity beyond this critical period through sight restoration therapies.^10,11 The patient in this case was highly motivated to begin vision therapy and expressed a strong desire to regain control over her eyes to alleviate the binocular diplopia she experienced, especially toward the end of the day.

The Role of Binasal Occlusion

Binasal occlusion (BNO), a passive vision therapy technique, involves placing opaque tape or similar material on the inner third of eyeglass lenses to reduce visual stress and improve binocular vision, particularly for conditions like esotropia or following mild traumatic brain injury (mTBI). While the patient was never officially diagnosed with a traumatic brain injury, she experienced a severe car accident during childhood in which she fell out of the back of a car window. Although the details of the incident are vague, it is likely that the event resulted in a mild traumatic brain injury. Studies have shown that patients with a history of TBI may have a decreased ability to process and organize spatial information, which in turn reduces the focal system’s processing capability. Binasal occlusion aims to reduce visual stress and improve binocular vision by blocking parts of the image seen by both eyes. This taping method provides an opportunity for the brain to process visual information in a different way, thereby improving eye coordination and reducing visual motion sensitivity.¹² Appendix D provides instructions for the application of binasal occlusion.

Individualized Vision Therapy Programming: Treatment Duration, Therapy Sequencing and the Role of Home Therapy

The approach to programming this particular therapy protocol was designed to be as efficient as the patient would allow. In other words, the patient’s improvement in visual skills each week determined the pace of the therapy program. Since the patient was an adult with remarkable motivation, the pace of therapy was enhanced and centered around the patient’s visual goals. Additionally, activities performed in the office were provided as home exercises, requiring at least 15 minutes per day of practice. The patient practiced exercises every day for at least 20 minutes. Home vision therapy is a crucial component of the patient’s progress and success in the program. Performing the activities daily at home provided the necessary repetition of the preferred sensorimotor pathways with specific, directed attention. The more consistent the repetition, the more likely the correct habit would be formed and utilized subconsciously, without additional mental effort.

Initially, monocular visual efficiency skills, including accommodation, saccades and pursuits, were emphasized. However, by Week 4, the patient demonstrated equal visual skills between both eyes and was able to begin peripheral fusion activities and anti-suppression techniques. After the first progress evaluation, the patient experienced global stereopsis for the first time, meaning that she was finally bi-foveal and using both eyes simultaneously. The anti-suppression phase was particularly lengthy but necessary for the patient to advance to binocular skill-building. As the anti-suppression phase showed limited progression each week, the therapy schedule was adjusted to bi-weekly visits instead of weekly. The patient needed additional time to practice anti-suppression activities at home before returning for another in-office session.

Understanding the patient’s motivation and the likelihood of compliance with home therapy can help the clinician design a therapy protocol that allows for efficiency and progress at a comfortable pace. An individualized therapy program enhances efficacy and productivity in reaching the patient’s visual objectives. A patient is essentially ready to graduate from vision therapy when all visual goals have been met and the patient is satisfied with their progress. While there is always potential for further improvement in the visual system, understanding and acknowledging the patient’s visual goals and initial purpose for vision therapy will guide the clinician in determining the appropriate time to conclude the therapy program.

Conclusion

When evaluating or diagnosing a patient with strabismus, clinicians and students must understand the significance of the patient’s medical and ocular history, as well as the nature of the diplopia onset. A thorough sensorimotor evaluation, supplemented by pertinent ancillary testing, can help determine the cause of the strabismus presentation and provide essential information for constructing an effective treatment and management plan.

Appendices

Appendix A. Test Procedure and Interpretation for Worth 4 Dot and Bagolini Testing. Click to enlarge

Appendix B. In-Office Vision Therapy Programming (Sessions 1-12). Click to enlarge

Appendix C. In-Office Vision Therapy Programming (Sessions 13-24). Click to enlarge

Appendix D. Binasal Occlusion Procedure. Click to enlarge

The executive certificate program offered by Southern California College of Optometry, Marshall B. Ketchum University (MBKU) and the Tokyo Optometric College (TOC) was a collaboration between the two programs to meet the future needs of patients in Japan. With a rapidly aging population, there was a growing demand for access to proper eye care in a timely manner.^1,2 This program was also developed to help strengthen the drive to create a uniform national Japanese optician license which Japan lacked compared to other Asian countries at that time. This helped standardize the requirements to become an optician and ensure that patients would receive the highest care possible. In addition, this program was designed to showcase the scope of practice that American and Canadian optometrists enjoyed compared to colleagues in Japan as a possible future evolution of the profession. The aim of this paper is to highlight and share knowledge of a successful collaboration between international optometric/optician programs to foster growth in this field and provide resources to expand the profession of optometry in other countries.

In Japan there were three levels of eyecare professionals: ophthalmologists, orthoptists and certified optical eyeglass manufacturing technicians (opticians). Ophthalmologists were medical doctors providing medical and surgical eye care. Orthoptists worked alongside ophthalmologists, performing a wide range of procedures including visual fields, imaging, follow-ups and low vision care. Orthoptists needed to complete a training program and pass a national exam to be recognized. According to the Japanese Association of Certified Orthoptist, as of 2019 there were 10 universities, one junior college and 18 training colleges providing the required training program that was a prerequisite to sit for the national exam. There were 16,171 certified orthoptists in Japan.³ As of April 2024, however, there were nine universities, one junior college and 17 training colleges providing the required training program. There were approximately 20,000 certified orthoptists. There was a decrease in the number of training programs during those 5 years, demonstrating little interest in expanding the field.

Opticians, or certified optical eyeglass manufacturing technicians, became a designated occupation in 2021 by Japan’s Ministry of Health, Labor and Welfare, requiring a licensing certification exam. Before then, it was not classified by the government. According to the All Japan Optometric and Optical Association, optical eyeglass manufacturing technicians conducted “tests on tasks such as visual acuity measurement, lens processing and frame fitting that are performed at optical stores.”⁴ Licensure required a written test and a practical exam. Passing both parts awarded the title of “Eyeglass Manufacturing Technician”, first grade or second grade, depending on the results.

Optometry, as a term in Japan, was much more nebulous to define. Optometry, as defined in American (US) and Canadian scopes of practice, did not exist in Japan. In 1966 Greenspoon noted that although there were no optometrists, there were opticians and refracting opticians.⁵ At the time, there were no laws controlling the eyecare professions. He stated that out of approximately 12,000 opticians, about 1,000 refracted. Nearly 30 years later, Kimbara explained that there was a growing movement in Japan to provide optometric education and qualifying examinations comparable to international standards.⁶ Lastly, in 1986 and 2003 respectively, Bailey and Bailey and Hayashi documented similar findings over a period of years.^7,8 There is a growing global demand for eye care provided by optometrists to prevent blindness.⁹ However, since 2003, there has been little evidence in literature discussing the need specifically in Japan. Despite that, with a growing need for eye care and a decrease in training programs for orthoptists, opticians or certified optical eyeglass manufacturing technicians, programs will eventually need to provide for this shortfall.

The learning objective of the executive certificate program was to increase the knowledge of the students by introducing topics not covered in the Japanese opticianry program and potentially expand their career potential by initiating growth in the industry to medical eye care. Meetings were initiated at the Asia Pacific Optometric Congress in 2013. In partnership with TOC Chairman of the Board Ikuzo Okamoto, a University of California, Berkeley graduate, MBKU President Kevin Alexander OD, PhD initiated the executive certificate program.

The 2-year program consisted of 11 courses and four laboratories (Table 1) split between two 24-week semesters per year. Each lecture credit hour consisted of 50 minutes of material delivered in lecture format. Each lab credit hour consisted of 60 minutes of hands-on, in-person workshop training on equipment and optometric techniques. The program had a total of 122 credit hours, of which 74 hours were lecture-based and 48 hours lab-based.

Table 1. MBKU-TOC Executive Certificate Program curriculum. Click to enlarge

The topics chosen comprised of up-to-date contemporary optometric material not taught or emphasized in Japanese optician curriculum but taught in an accredited optometry degree program in the US or Canada. Each course was prerecorded by select MBKU faculty specializing in a particular area of study. Lectures were transcribed in English then translated and transcribed into Japanese by the two designated TOC executive certificate faculty members. The two designated TOC executive certificate faculty members were fluent in both English and Japanese as well as graduates of accredited American colleges or universities of optometry. Japanese subtitles were embedded into the lectures. Each topic within a lecture course included multiple choice assessments, written by the MBKU faculty and translated into Japanese, that students would take to demonstrate comprehension of the material.

The lectures were made available to the registered students, at the beginning of the requisite semester, through the learning management software, Moodle. The students were able to learn the material asynchronously and at their own pace. Course material and assessments needed to be completed by the end of the semester to move on to the next. All students in a particular cohort began and ended each semester at the same time.

Interested students were enrolled in the program through TOC. Recruitment came from word of mouth to alumni, outreach to independent optical shops and support from corporate optical chains. Enrolled students came from throughout Japan. Didactic material in lecture courses was provided online and the students accessed the coursework through Moodle. Students were from differing backgrounds; some were concurrent students at TOC. Others were opticians working in optical shops with varying degrees of experience, from newly graduated to decades of working. A few students were professors at TOC. Class sizes varied from eight to 30 in different cohort years.

Every student was required to attend a 2-day in-person 12 hour laboratory each semester, provided on the TOC campus. Each laboratory emphasized a different topic. (Table 2)

Table 2. MBKU-TOC Executive Certificate Program In-Person Laboratory topics. Click to enlarge

MBKU faculty members traveled to Japan to teach each of the four laboratories in person at TOC. The MBKU professors taught the labs in English while TOC executive certificate program professors Hayashi and Kimbara provided live translation of the lesson into Japanese. Students had varying levels of English proficiency, from none to semi-conversational. Students also had varying levels of previous knowledge and skill in the laboratory topics, with the majority having no experience or knowledge.

Labs started with introductory lectures and initial demonstration of the equipment and optometric procedures. Students were then instructed to perform the procedures on each other. All professors assisted as the students practiced on the equipment and performed the procedures. At the conclusion of each segment, case studies were presented highlighting the equipment or procedure in the diagnosis and management of patients. At the conclusion of the 2-day laboratory, students returned home. Equipment not available at TOC was shipped from MBKU, brought over to Japan by visiting MBKU faculty members when teaching the labs, or was in other locations. For example, TOC had slit lamps and automated visual field instruments available on site for lab use. Retinoscopes and VT equipment were brought over from MBKU. Ocular Coherence Tomography (OCT) instruments were made available at a manufacturer’s showroom.

One caveat to the in-person lab was during the height of the COVID-19 pandemic. Due to Japanese travel restrictions, accommodations were made to adapt to the public health crisis. In-person labs were presented virtually. Introductory material and demonstration of the equipment was performed live by the MBKU professor on the campus of MBKU. Students in the executive program attended the lab program either from their own home or on the campus of TOC through the Zoom video conferencing platform. The TOC professors were on the campus of TOC with students who could attend in person, under strict preventive COVID-19 protocols. The TOC professors translated live for the MBKU professor.

Also, due to the 17-hour time difference between Japan Standard Time (JST) and Pacific Standard Time (PST), further modifications were made to the lab. The MBKU professor demonstrated equipment and procedures for a total of 2 hours in the evening, while the students concurrently attended online during the morning the next day. As this was presented live, questions could be answered immediately. This completed the portion of the lab by the MBKU professor. The TOC professors, having participated in past labs and being graduates of American optometry schools, had the training to continue the lab session on their own starting with practice sessions. Case study materials, usually presented after laboratory practice sessions by the MBKU professor, were sent in advance of the lab to the TOC professors, who taught and discussed the cases in Japanese in place of the MBKU professor. Cases were discussed both in person for those on the TOC campus and online those attending virtually. Hands-on training of procedures and use of equipment were only for those on the TOC campus. The lab was also shortened to 1 day. This affected student cohorts from spring 2020 to fall 2022.

The MBKU-TOC Executive Certificate Program commenced in the spring of 2016. The last class to matriculate was in April 2023 for a total of seven cohorts. At that point, the program went into hiatus at the request of TOC.

Methods

To assess the impact of the program and to predict if course objectives were met, surveys were sent via email to 96 alumni from all cohorts in December 2023 (Appendix 1). The questions were initially written in English with Japanese translation provided by one of the TOC professors. Alumni were able to see the questions in the original English and Japanese translation. There was a total of 33 questions, broken into different sections. The first 10 questions were in relation to general course administration. The next 10 questions (questions 11-20) were related to the quality of course topics covered. Questions 21-24 asked about the quality of the laboratories. Questions 25-27 asked about the level of impact it had on the alumnus’ knowledge and career. Type of current employment was asked in Question 28. Questions 29-33 were open ended questions where the alumni were able to freely answer in short answer form. Questions 1-27 were given five options to respond: (1) poor, (2) fair, (3) good, (4) very good, (5) excellent.

Researching with our biostatistician, there were no validated surveys available that met the specifics to our program, a joint international optometric program that was delivered online and in person. The survey was generated at MBKU to determine overall satisfaction and value of the program. A scientific statistician aided in creating the survey including development of the types of questions asked, wording, scale used in multiple choice questions and statistical analysis.

Results

Alumni were given 2 weeks to respond. Twenty-eight responses were returned at a response rate of 29.167%. Not every question was answered by all responders (Appendix 2) . Multiple choice survey questions had a response rate between 25-27 students. Twenty-eight students responded to the free response questions.

To determine if more than 70% of the responses selected “4” (“very good”) or “5” (“excellent”) for each question, the one sample proportional statistical test was performed for this purpose. Positive statistically significant results will be noted.

General Course Administration

Questions 1-10 dealt with general course administration such as the ease of use of the Moodle platform, lecture videos, assessments, sequencing and content of the curriculum, instructors and laboratories. Of the first 10 questions in the survey regarding general course administration quality, only Question 2 (curriculum topics) and 9 (in-person laboratory instruction) had an observed sample proportion of 23/27 (p-value = 0.06).

Course Topics

The next set of questions, 11-20, asked alumni to generally evaluate the course topics in the curriculum. Material from these courses would not be found in a standard optician curriculum in Japan. For these questions, which pertained to the course topic ratings, Questions 14 (pediatric optometry), 16 (ocular disease) and 18 (sports vision) had a sample proportion of 23/27 (p-value = 0.06), Questions 15 (geriatric optometry) and 19 (ocular health procedures) had a sample proportion of 24/27 (p-value = 0.02), Question 12 (binocular vision) had a sample proportion of 26/27 (p-value = 0.001) and Question 17 (low vision) had a sample proportion of 27/27 (p-value < 0.001).

Laboratory

Questions 21-24 were related to the in-person laboratories delivered once a semester. Students enrolled in the program would gather at TOC from throughout Japan for the 2-day laboratory jointly taught by visiting MBKU professors and TOC professors. Hands-on use of equipment was the primary purpose of these gatherings. There was a total of four laboratory sessions. Regarding the four laboratory quality rating questions, Question 21 (Lab 1: retinoscopy; binocular & accommodative testing) had a sample proportion of 23/27 (p-value = 0.06) and Question 24 (Lab 4: ocular health procedures) had a sample proportion of 25/27 (p-value = 0.005).

Knowledge and Career

The last of the questions using a scaled response was Questions 25-27 regarding outcomes from participating in the joint MBKU-TOC program. Questions included improvement in knowledge of optometric care, interprofessional collaboration with other health care professionals and possible career advancement from participating in the program. Regarding the questions on program impact on knowledge and career, Question 25 (overall improvement in knowledge of optometric care) had a sample proportion of 25/27 (p-value = 0.005).

Mode of Practice and Free Response Questions

There were six free response questions (Appendix 3). On free response Question 28, which asked the alumnus what type of practice they are currently employed, 20/28 respondents reported working in in a corporate or commercial setting. Five reported working in a privately owned practice and one each in a research, hospital or educational setting.

Question 29 asked about the strengths of the didactic program. The general trend in response was variations of “gaining additional knowledge”. Question 30 asked about weaknesses regarding the didactic program. There were multiple answers, but the general comments were mostly regarding the language barrier. Question 31 was in relation to the strengths of the laboratory portion of the program whether it was in-person or virtual. The consensus responses included the “ability to interact with professors from MBKU” and the “use of equipment not available to the students in the general program”. Question 32, regarding weaknesses in the laboratory portion of the program, showed a general consensus of either “no weaknesses” or that the “amount of time spent in the labs were limited”. Lastly, Question 33 asked for comments and recommendations, whether they were positive or negative about the overall program. There were a few comments, but most were regarded as positive. Not all students answered every free response question asked.

Discussion

The executive certificate program offered by MBKU and TOC was considered a positive experience for the alumni. In particular, the curriculum topics chosen and the in-person experiences were found to be statistically significant and scored well. The executive certificate program was designed with an emphasis on a curriculum of advanced topics that would enhance and go beyond current practice in Japan. The program met its goal objective. Also highlighted in the surveys was the importance of face-to-face in-person experiences. This helped to “humanize” the program as most of the learning was done virtually. Students appreciated the ability to interact with all the professors, have questions answered immediately, and utilize equipment demonstrated and/or perform techniques discussed in lectures.

Course topics that scored particularly high included specialty clinical care courses such as low vision, geriatric optometry, ocular health procedures, pediatric optometry, ocular disease and sports vision. Introduction and emphasis on clinical care beyond refraction and visual care was a critical component in the development of the curriculum. Delivery of this information made a significant impact on the alumni. This gained knowledge and strong response may eventually lead to an evolution of the profession in the future. Also garnering strong positive responses was the binocular vision course, of which MBKU has been recognized in the optometry program.

For the in-person laboratories, Lab 1: retinoscopy, binocular and accommodative testing; and Lab 4: ocular health procedures scored statistically high. Lab 1 emphasized techniques used in the MBKU optometry program for evaluating refractive, binocular and accommodative conditions. The lab also illustrated case studies using information gathered from these procedures in the actual care of patients. Although many techniques are similar between what is taught at MBKU and the training for opticianry in Japan, presentation of material in a different perspective may have been helpful and valuable to the alumni in applying their new knowledge to their current practices and patient care, one of the objectives of the program. Lab 4 scored high as it demonstrated and trained the alumni on procedures, techniques and equipment used in the evaluation of ocular health. Evaluating the eye itself, rather than its visual components, added something they had never done before. The lab also gave the alumni the opportunity to use cutting edge technology such as the OCT and Optical Coherence Tomography Angiography (OCT-A). Survey comments regarding in-person laboratories were considered positive, especially noteworthy were comments highlighting the ability to interact with TOC and MBKU professors. Unfortunately, the limited amount of time devoted to this portion of the program was noted as well.

Lastly, the question of overall improvement in knowledge of optometric care was statistically significant for the “very good” and “excellent” categories. It helped to accomplish the overall objective of the program, which was to provide knowledge and skill above and beyond those presently found in practice.

Upon reflection, the strengths of the program stem from the enthusiasm of the administration and faculty at MBKU and TOC, as well as the students’ desire to learn beyond their scope of practice. All students were active opticians. They were able to learn at their own pace asynchronously within a semester. Using Moodle, students were able to interact with faculty regarding course material, including answering questions and discussions on projects. Assessments on Moodle also allowed the faculty to track progress in the program. The greatest strength was the face-to-face meetings in Japan by one of the MBKU faculty every semester. The four 2-day sessions (with the exception of COVID-19 modified 1-day sessions) allowed for both schools to jointly teach the students in person. It also enabled the students to interact with each other, to share ideas and perspectives. During these gatherings the students had hands-on experience with equipment and skills they had never performed before; including but not limited to vision therapy equipment and techniques, low vision devices, and ocular health procedures such as the slit lamp biomicroscope, automated visual field instruments and optical coherence tomography. As students with experience in the use of vision care equipment, they were adept at learning new equipment quickly on each other and interpreting the results. With continued training similar to an accredited optometry program in North America, they could perform these skills on patients more like North American licensed optometrists.

Most of the internally identified weaknesses of the program were logistical. Creation of curriculum materials for this program was done outside of regular faculty hours for the MBKU optometry program. Thus, lectures, labs, discussions and assessments were created based on available time by the instructor of record, which varied. All materials needed to be transcribed for the faculty at TOC to translate, which also added to the delay. The technology for auto captioning or artificial intelligence did not exist at the time. Time zone differences made it difficult to have live sessions as evenings in the US were early mornings of the next day in Japan. The logistics of finding creative ways to bring equipment into Japan to deliver labs in-person was also a challenge. Initial investment in time and costs was a difficult task. Despite these obstacles, the program was a success in delivering an expanded scope of practice curriculum to Japanese opticians for potential expansion of scope of practice for their profession.

From the survey, multiple alumni stated that the language barrier affected their ability to learn effectively and efficiently in the didactic portion of the program. They also stated there was a learning curve to using the online platform, and some also noted that learning the material through remote learning was not the most ideal. Regarding the in-person laboratory component, the language barrier was considered an obstacle as none of the MBKU laboratory instructors were fluent in Japanese. Instructions and topics had to be translated into Japanese by the TOC professors. Other comments included the limited time together for the laboratories and the distance students had to travel to participate in the mandatory laboratories.

Although the program was considered a success by both schools, the program was placed on hiatus at the request of TOC. There were three main reasons. First, the COVID-19 pandemic fundamentally changed how the program was presented. Due to travel restrictions, live in-person 2-day labs were transformed into one 2-hour live demonstration of equipment and skills without students accessing any of the equipment or feedback on their skills. Indefinite postponement of the program was not an option like all other educational programs around the globe. This affected multiple cohorts over multiple years and there was concern regarding the effectiveness of the program without the live component. Second, there has been a petition in Japan for national licensure of opticians in the national Diet, the national legislature. TOC was a proponent of the bill. Thus, priority, energy and time were directed at its passage. Lastly, TOC had a new head administrator and MBKU, a new university president. Both administrations had other priorities regarding their primary programs. Thus, the current hiatus in the program. The relationship between both programs remains positive.

Finally, the authors were disappointed with the limited number of articles related to optometry in Japan or collaboration between ophthalmology with opticians and orthoptists in Japan. Also, the limited number of articles available were not recently published. Multiple attempts using different library resources, and with the assistance of reference librarians, yielded the results used in this article. Although this paper concentrated on the MBKU-TOC executive certificate program, success of other collaborative multinational curricula should be published to highlight the growing global need for eye care and how these contemporary programs address that need. It is with hope that this article will stimulate future papers on the topic of collaborative international optometry programs.

Conclusion

Currently, most program alumni practice in corporate or commercial practice. This is not surprising as it is the custom in Japan for graduates of opticianry programs to work in this mode of practice. Only one works in a healthcare environment. The current perspective in Japan is that opticians are not healthcare providers. Alumni of this program have noted how people who visit optical shops are addressed as customers or clients, not patients. There is no healthcare component. There is no need for continuity of care. There is no doctor-patient relationship. Unfortunately, the Japanese population does not see opticians as healthcare providers. By creating this program and presenting vision and eye care provided by North American optometrists, there may be a spark of inspiration for current Japanese opticians to aspire for an expansion of scope of practice, like the US in the past century. The challenges in Japan today are similar to those of the US regarding the perception of the role of opticians and to their relationship to ophthalmologists. With an increase in the aging Japanese population, the demand for health care increases.¹⁰ If the demand is not met by the current level of healthcare providers, there exists an opportunity for opticians to fill the void by performing ocular health procedures as an optometrist. This program shows there is potential for future growth in Japan and other countries to expand and provide proper eye care through expanded training programs in formal education. Despite language barriers, time zone variances and traveling great distances, these are not major deterrents for international collaboration. A demonstration of expanded scope of practice in the US and Canada to other countries may serve as a model for their evolution. An emphasis on person-to-person interaction in the home country enhances the delivery of the curriculum and success in the program.

Acknowledgements

The authors would like to acknowledge and thank Diana Dicdican-Nguyen for her contributions to the program.

Conflicts of Interest

The authors have no conflicts of interest to report.

Appendices

Appendix 1. Survey. Click to open PDF

Appendix 2. Multiple Choice Results Click to open PDF

Appendix 3. Free Response Results (Summarized)Click to open PDF

Microbial keratitis (MK) is an infectious corneal condition which can lead to corneal scarring and potentially serious visual impairment.¹ Overnight contact lens wear is a leading cause for MK, especially in younger patients. In 1989, Poggio et al introduced the first large scale study of contact lens ulcers which revealed that ulcerative keratitis was five times more likely among extended wear soft contact lens users compared to daily wear soft contact lens users (20.9/10,000 patients and 4.1/10,000 patients, respectively.)² Pseudomonas aeruginosa is an aerobic gram-negative, rod-shaped bacterium, which accounts for approximately 63% of contact lens-related ulcers (CLRUs), making it the most common cause.^3,4 The hallmark of P. aeruginosa keratitis is a ring abscess, a ring-shaped accumulation of polymorphonuclear leukocytes surrounding a central corneal lesion.⁵ P. aeruginosa keratitis can ultimately lead to suppurative infiltration, corneal perforation, corneal melt or endophthalmitis.⁵ Even when properly treated, a central corneal ulcer can leave patients with visually significant corneal scarring.

Patients with a previous history of MK may want to return to contact lens wear once their infection has resolved. However, soft contact lenses may not provide functional vision if the MK has resulted in central corneal scarring. Scleral gas permeable contact lenses can be used as a visual correction of refractive errors in normal eyes as well as patients with irregular corneas such as keratoconus, pellucid marginal degeneration, post-LASIK ectasia, corneal scarring and ocular surface diseases. Benefits of scleral lenses include improved comfort and stable vision compared to corneal gas permeable and other contact lenses.⁶

Case Description

History

A 19-year-old African American female was referred for a “hard” contact lens fit. She was previously diagnosed and treated for a corneal infection of the right eye secondary to “Pseudomonas” that left permanent scarring in the center of the visual axis. The patient had a prior history of wearing unknown soft contact lenses overnight. Her previous contact lenses were ordered from an online vendor. The patient’s medical history is otherwise unremarkable. She reported taking no medications and she had no known drug allergies. The patient was a college student and enjoyed track and field as well as basketball.

Previous records revealed that a year before her examination, she presented with irritation and light sensitivity in the right eye for 4 days that was first thought to be iritis by her previous eyecare provider. However, her symptoms were worsening even with the prescribed eye drops. She was diagnosed with a corneal ulcer in her right eye, severe inflammatory reaction with a 1 mm hypopyon and a 7×8 mm region of corneal edema, likely bacterial in nature. Cultures were ordered and treatment was initiated with fortified vancomycin, tobramycin, ciprofloxacin every hour in the right eye, topical Cyclogyl 3 times a day and oral minocycline and vitamin C.

Records showed at the 1-day follow-up, the hypopyon had resolved and the epithelial defect was slightly smaller. The area of edema and infiltrate was stable, so all medications were continued.

Records showed at the 4-day follow-up, final cultures and sensitivities were received. Gram stain showed no white blood cells seen, with many Gram-negative rods. Culture showed “many pseudomonas aeruginosa”. Sensitivities were positive for amikacin, aztreonam, cefepime, ciprofloxacin, gentamicin, imipenem, levofloxacin, meropenem, piperacillin, piperacillin /tazobactam and tobramycin. Evaluation revealed no hypopyon and decreased density of infiltrate with symptomatic improvement. Vancomycin was discontinued. Fortified tobramycin and ciprofloxacin were tapered to every 2 hours. Cyclogyl was continued. Oral minocycline and ciprofloxacin were continued for the 10-day course.

Records show at the 7-day follow-up, there was continued symptomatic improvement, no hypopyon and decreased density of infiltrate. Topical Cyclogyl was discontinued. Topical Pred Forte was added every 4 hours. Topical fortified tobramycin and ciprofloxacin were tapered to every 4 hours.

Records show at the 8-day follow-up, the patient was diagnosed as a resolved pseudomonas keratitis with a large central scar. The patient was advised to continue topical ciprofloxacin 4 times daily for 3 days, then discontinue. Pred Forte was continued 4 times daily for 1 week then tapered over 3 weeks. At the 1-year evaluation, patient was diagnosed with resolved pseudomonas keratitis in the right eye with large central scar. Patient was highly interested in surgery for cosmetics; however, she was advised against penetrating keratoplasty surgery due to the thinned cornea, her young age and the extent of the surgery. Following that ophthalmology visit, she presented to Nova Southeastern University for a specialty contact lens examination.

Examination findings

Unaided acuities were Count Fingers at 6 feet for the right eye and 20/400 in the left eye. Corrected acuities with her current glasses were 20/80 for the right eye and 20/20 for the left. Manifest refraction in the right eye was: -5.00 sphere and left eye: -5.00 sphere with best-corrected visual acuities of 20/80 (right) and 20/20 (left). Pinhole offered no improvement in the right eye. The right pupil was partially obstructed by a white central corneal scar. The left pupil was round and reactive. There was no afferent pupillary defect using reverse method. Confrontation visual fields and extraocular motilities were full in each eye. Slit lamp examination revealed clear lids and lashes in both eyes. Bulbar conjunctiva were white and quiet in both eyes as well. The right cornea had a 4-5 mm central, opaque white scar (Figure 1). The left cornea was clear (Figure 2). Corneal topography revealed an irregular anterior corneal surface (Figure 3).  Corneal topography in the left eye revealed no irregularities (Figure 4).

Figure 1. Corneal evaluation revealed a 4-5 mm central, opaque white corneal scar in the right eye. Click to enlarge	Figure 2. Cornea was clear in the left eye. Click to enlarge
Figure 3. Corneal topography revealed an irregular anterior corneal surface caused by the central corneal scar in the right eye. Reliable keratometry readings could not be measured due to distorted mires. Click to enlarge	Figure 4. In contrast to the right eye, corneal topography of the left eye revealed no irregularities. Keratometry readings left eye were 43.9/42.8@005. Click to enlarge

The patient was diagnosed with decreased vision in the right eye due to central corneal opacity associated with history of infectious corneal ulcer from P. aeruginosa and prior contact lens over wear as well as myopia in both eyes. The patient was extensively counseled on the increased risk of complication associated with contact lens over wear. Based on the patient’s motivation and successful diagnostic evaluation, contact lenses were ordered.

Art Optical Ampleye Scleral lens in Optimum Extra Material with plasma:

• Right Eye: -5.50 Power / 4200 Sag / 8.04 BC / 16.5 OAD / 150 micron toric haptic / clear
• Left Eye: -5.50 Power / 4000 Sag / 8.44 BC / 16.5 OAD / 150 micron toric haptic / clear

Follow-up #1

The patient presented for contact lens dispensing as well as insertion and removal training for new scleral lenses. She reported no changes in ocular or medical history since the last examination. Entering acuities with her current glasses were 20/80 in right eye and 20/20 in the left. Pinhole offered no improvement in the right eye. Pupils, extraocular motilities and confrontation visual fields was unchanged. Slit lamp examination revealed stable findings in both eyes with a large central corneal scar in the right eye and clear cornea in the left. Both corneas were free of sodium fluorescein staining.

Best corrected visual acuities with scleral lenses were 20/30 (right) and 20/20 (left). Lens evaluation revealed well centered, complete corneal vaulting with no limbal conjunctival compression and no conjunctival vessel impingement in both right eye (Figures 5 and 7) and left eye (Figures 6 and 8). Patient was trained on proper insertion and removal techniques as well as proper handling and disinfection systems. The patient successfully performed insertion and removal of the contact lenses in office. The patient was instructed on overnight cleaning and disinfection of lenses using a hydrogen peroxide-based solution. The lenses were dispensed, and the patient was advised to return to clinic for a 1-week follow up.

Figure 5. Diagnostic contact lens evaluation with a scleral lens was performed with a trial lens reveals no conjunctival compression and no conjunctival vessel impingement in the inferior quadrant. Over-refraction of -2.50 sphere in the right eye resulted in best corrected visual acuity of 20/300. Click to enlarge	Figure 6. Diagnostic contact lens evaluation with a scleral lens was performed with a trial lens reveals no conjunctival compression and no conjunctival vessel impingement in the superior quadrant. Over-refraction of -2.50 sphere in the left eye resulted in best corrected of visual acuities of 20/20. Click to enlarge
Figure 7. Anterior segment optical coherence tomography measured the diagnostic scleral contact lens with 296 microns of central clearance after approximately 20 minutes of settling in the right eye. Central scarring of the cornea caused thinning and compression of stromal tissue. Click to enlarge	Figure 8. Anterior segment optical coherence tomography measured the diagnostic scleral contact lens with 236 microns of central clearance after approximately 20 minutes of settling in the left eye. Click to enlarge

Follow-up #2

The patient presented for a 1-week contact lens follow-up. Patient reported good comfort and vision with lenses dispensed at the last visit. She reported proper use of contact lens care product since the last visit. She reported no other changes in ocular or medical history and denied any symptoms of ocular redness, pain or discharge. Visual acuities with contact lenses were stable at 20/30 (right) and 20/20 (left). Contact lens evaluation revealed well-fitting lenses. Slit lamp examination revealed a stable, central corneal scar in the right eye and was unremarkable in the left. No changes were made to the contact lenses. The patient was again advised on the increased risk of complication associated with contact lens over wear as well as proper wearing and handling techniques.

Follow-up #3

The patient presented for a 6-month contact lens follow-up. She reported good comfort, vision and compliance to wearing and handling schedule. She reported no changes in ocular or medical history since the last examination. She was applying to the Navy and requested a letter of support. Best-corrected visual acuities with scleral lenses remained stable at 20/30 (right) and 20/20 (left). Contact lens evaluation revealed well-fitting lenses for both eyes. Slit lamp examination revealed a stable central corneal scar in the right eye and was unremarkable for the left. The patient was again advised on the increased risk of complication associated with contact lens over wear as well as the importance of continued care and compliance to a wearing, handling and replacement schedule. The patient was advised to return to clinic in 6 months for an annual comprehensive eye examination, dilated fundus examination, contact lens evaluation and new lenses.

Education Guidelines

Learning Objectives

At the end of the case discussion, participants should be able to:

1. Recognize the hallmark diagnostic signs of aeruginosa keratitis.
2. Discuss the visual consequences of central corneal scars.
3. Recognize the benefits of scleral gas permeable contact lenses for irregular corneas.
4. List the risk factors associated with microbial keratitis due to contact lens wear.
5. Differentiate between aeruginosa the other organisms that can cause microbial keratitis.

Key Concepts

1. Identifying signs and symptoms of aeruginosa keratitis.
2. Differential diagnoses for microbial keratitis associated with contact lens overwear.
3. Scleral gas permeable fitting and evaluation.

Discussion points

Knowledge, understanding and facts regarding this case presentation

1. Describe the hallmark diagnostic signs and treatment of aeruginosa.
2. List the risk factors associated with microbial keratitis from contact lens overwear.

Differential diagnosis

1. List various causative organisms of microbial keratitis associated with contact lens overwear.
2. Describe the characteristic signs of each possible cause of microbial keratitis.

Patient management

1. Detail the appropriate treatment for aeruginosa.
2. Describe ideal fitting of scleral gas permeable contact lenses for irregular corneas.
3. List discussion points for patient education to prevent contact lens complications.

Critical-thinking

1. When a contact lens patient presents with a painful red eye, can you identify the most likely causative organism?
2. When fitting a patient with an irregular cornea with scleral lenses, can you describe an ideal fit?

Teaching methodology

The purpose of this teaching case report is to discuss the benefits of scleral lenses for irregular corneas. This case presentation could be added to a specialty contact lens lecture or course. Additionally, this case presentation identifies the findings associated with P. aeruginosa keratitis. Management of microbial keratitis should be understood by optometric students, residents and clinicians. This case report can be utilized in a grand rounds lecture or small group journal review to discuss the differentials and treatment for microbial keratitis.

Assessment

1. Assessing in a classroom or small group setting with comprehension style test questions to identify the hallmark sign of aeruginosa and other microbial keratitis.
2. Demonstrate application of knowledge by actively discussing the benefits of scleral contact lenses and describing an appropriate scleral lens fitting for irregular corneas.
3. Advanced grand round style presentation and discussion to identify and manage microbial keratitis associated with contact lens over wear.

Discussion

Microbial Keratitis is a relatively uncommon but potentially devastating consequence of contact lens over wear. Patients typically report symptoms of acute ocular pain, redness, light sensitivity and reduced vision. One out of five hospitalized cases ultimately lead to corneal transplantation.⁷ Even with advances in contact lens technology such as higher oxygen permeability materials and more frequent replacement modalities, the incidence of MK has remained consistent over the last few decades.⁸ Overnight wear continues to be the greatest risk factor for MK. Extended wear soft contact lenses (CLs) have been shown to increase the risk of MK by four to seven times compared to daily wear soft CLs.³ Contact lens-induced corneal hypoxia is the main contributing risk factor for microbial keratitis with overnight wear. Other risk factors include poor storage hygiene, infrequent case replacement, smoking, male gender, socioeconomic status, absence of hand washing, misuse of disinfection system, exposure to water and over wear of contact lenses.⁸

P. aeruginosa is the most common cause of contact lens related ulcers (CLRU), found in over 60% of cases.³ P. aeruginosa is a gram-negative rod-shaped bacterium with flagella that adhere and invade corneal epithelium.³ Cytotoxic protease and elastase activity also contribute to the pathogenesis and severity of the keratitis. P. aeruginosa keratitis is typically described as a MK with a ring abscess, or an accumulation of polymorphonuclear leukocytes in a ring shape surrounding a central corneal lesion.⁵ Satellite lesions and hypopyon are also commonly found in P. aeruginosa keratitis.³

Other potential causes of MK in contact lens wearers are Staphylococcus aureus, Fusarium and Acanthamoeba.

Staphylococcus aureus, a gram-positive cocci, is a leading cause of keratitis in non-contact lens wearers.¹³ It has become a public health concern due to the development of resistance to antibiotic therapy.¹³ Methicillin resistant S. aureus (MRSA) ocular infections can result in corneal perforations , cellulitis and endophthalmitis.¹³ Fortified vancomycin is regarded as the standard in treatment of MRSA keratitis.¹³

Fusarium is a filamentous-septated fungi, which is the most common cause of fungal keratitis associated with contact lens wear.¹⁰ Fungal keratitis can be difficult to diagnose and treat. The hallmark of a fungal keratitis is a corneal ulcer with a dull gray infiltrate and satellite lesions.¹⁰ The infiltrate associated with fungal keratitis typically presents with feathery, branching borders.¹⁰ But advanced cases can look similar to bacterial keratitis. The incidence of fungal keratitis in contact lens wearers has decreased in the recent years due to a recall of certain multipurpose solutions.⁹

Acanthamoeba, a ubiquitous amoeba, is an uncommon but extremely painful and challenging form of keratitis to treat.⁹ Corneal ulcers from Acanthamoeba typically appear as ring shaped with perineural infiltrates.¹¹ However, Acanthameoba infections have actually risen. The main risk factor for developing Acanthamoeba keratitis with contact lens wearers is improper lens care, specifically using tap water to clean or store lenses.¹¹

Most cases of MK are managed and resolve without culturing. Culturing is optional in cases of small, peripheral corneal ulcers without stromal involvement. However, culture and smears are indicated in cases of a large, central corneal infiltrate or ulcer, especially if it extends into the deep stroma. Culturing is also helpful in cases of suspected fungal or acanthamoeba keratitis. For example, cases of trauma with vegetable matter or history of storing contact lenses in tap water should be cultured. ¹⁴

Visual correction after any type of MK is challenging if the patient has an irregular cornea and visually significant corneal scarring. Scleral gas permeable contact lenses are becoming a widely used treatment for irregular corneas. Scleral gas permeable contact lenses mask corneal irregularity and reduce higher order aberrations by creating a tear layer between the lens and the cornea.¹⁵

The ideal scleral contact lens should be vault the cornea limbus to limbus and land on the bulbar conjunctiva.¹⁶ Central clearance upon on initial insertion should range between 200-300 microns.¹⁶ The ideal central clearance after 4-6 hours of settling should measure 150-250 microns, however 50-100 microns may still be acceptable.¹⁶ Limbus clearance should measure between 50-100 microns in all four quadrants.¹⁶ The edge of the scleral lens should lay tangent on the conjunctiva without any compression or vessel impingement in all four quadrants.¹⁶ Large diameter gas permeable lenses with toric haptics can improve lens stability, comfort and wearing time.^{16, 17, 18,} Anterior segment ocular coherence tomography may be utilized to quantify central and limbal clearance as well as image the scleral lens edge profile.¹⁶

Corneal scarring, whether secondary to infectious or non-infectious causes, may be managed using medical or surgical approaches. Superficial keratectomy and phototherapeutic keratectomy (PTK) are appropriate for the management of superficial stromal haze and opacities.¹⁹ Lamellar or penetrating keratoplasty was discussed in consultation with a corneal specialist. Due to the patient’s young age, however, corneal transplantation was not considered first-line therapy. Penetrating keratoplasty typically demonstrates graft survival of 15-20 years, while lamellar techniques may achieve greater longevity.¹⁹ As the patient was in their teenage years, a repeat graft would likely be required during their lifetime. Consequently, specialty contact lens intervention was considered the preferred initial management.

Conclusion

Patients who develop a central corneal ulcer from P. aeruginosa associated with contact lens over wear often must discontinue contact lenses indefinitely. Many patients may need penetrating keratoplasty if they have a visually significant corneal scarring. However, many patients may still request contact lenses as a visual correction for sports and other activities when penetrating keratoplasty is not recommended. This case demonstrates that scleral gas permeable lenses can be prescribed when other forms of contact lenses may not be ideal. Scleral lenses may improve vision beyond glasses or soft contact lenses when the cornea is irregular. In this case, the patient can maintain and enjoy an active healthy lifestyle by wearing scleral gas permeable contact lenses.

The Optometry Admission Test (OAT) has long been a foundation of the admissions process, but its efficacy in predicting student success is increasingly debated. In an era where the value of standardized testing is under scrutiny across educational disciplines, the optometry community finds itself at a crossroads—to maintain the OAT as an admissions tool or to eliminate it. This paper examines whether the OAT truly serves as a reliable predictor of performance in optometry school.

Common objections to standardized tests in the health professions include: bias against lower economic status students, racially underrepresented students and women, creating unnecessary barriers that limit diversification of the professions; limited predictive value for student success restricted to first- and second-year GPA; and failure to measure non-cognitive factors—such as grit and motivation—that also influence performance in professional school.^1–4 It has also been argued that test scores are becoming weaker predictors of success.^2,5

Consequently, there have been growing calls to eliminate or reevaluate standardized tests—including the OAT—as admissions requirements.^2,3,5,6 In response, many institutions, including some in the health professions, have adopted test-optional admissions policies.⁵ While the concerns raised against standardized tests are valid, the central question is whether the tests should be abolished entirely or instead reframed and used more judiciously. Notably, some schools that previously removed test requirements are now reinstituting them due to their predictive power, further underscoring the importance of this discussion.^7,8

Standardized tests are decision-making tools that provide consistent evidence for stakeholders to select, sort and support candidates. As with any tool, it is important to define their ultimate purpose to determine if the tools are measuring what they are supposed to measure and if decision makers apply the results appropriately. The purpose of the OAT, for instance, is to measure general academic ability, knowledge and comprehension of scientific information, as well as preparedness of students for a rigorous professional education.^9,10 Beyond preparedness, some argue that standardized tests offer a fair and objective criterion when selecting candidates in an environment in which the number of qualified candidates exceed the number of available seats.¹¹

Schwartz states that Optometry, as a licensed profession intended to treat and diagnose disease, should be compared to other professions that assign its professionals equal rights and privileges, such as medicine.¹² Various studies in the field of medical education have confirmed the validity of standardized tests in predicting academic performance, licensing examination performance and persistence.^1,13

Jakirlic et al. pointed out the paucity of studies on the effectiveness of the OAT in predicting performance in optometry school.² However, the American Dental Association (ADA), which  is responsible for administering  the OAT, periodically issues an OAT validity study describing the relationship between the OAT and 7 subject areas in optometric education (optics, biomedical science, vision science, ocular health science, clinical science, clinic, other) for 15 optometry schools.¹⁴ This validity study, which supports the findings from similar OAT validity studies, concludes that the OAT and undergraduate GPA, taken individually, are reliable predictors of academic success, and that combined, their predictive power increases.^13–15 Consequently, the study recommends that colleges of Optometry should consider both GPA and standardized test results when making admissions decisions.

The purpose of this study is to add updated information to the discussion about the power of the OAT to predict academic achievement in optometry school and to address some objections directed at standardized tests. Questions explored by this study include:

• How well do admissions metrics including OAT, Undergraduate GPA and Institutional Rating assess entering students for optometry school readiness and uninterrupted progress?
• How well do admissions metrics assess entering students for NBEO Part 1 readiness?
• How well do admissions metrics assess entering students for Clinical readiness?

Method

Participants

Data from enrolled students at a state school of optometry from the Class of 2016 to the Class of 2024 were included in this study. Admissions metrics were obtained from their admissions files and academic and clinical performance for all 4 years was provided by the registrar’s office. Transfer and advanced standings students were excluded from the analysis.

Sample: In total, 848 students from the classes of 2016 up to the class of 2024 were part of this analysis. The Class of 2016 included 84 new students (9.91%), 2017 had 90 (10.61%), 2018 had 91 (10.73%), 2019 and 2020 each had 99 (11.67%), 2021 had 96 (11.32%), 2022 had 101 (11.91%), 2023 had 98 (11.56%), and 2024 had 90 students (10.61%).

Gender: Females represented 73.1% (620) of the overall sample and males 26.9% (228).

Race and Ethnicity: White students represented 42.7% (362) of the sample, followed by Asian students (41.5%, 352), International students (5.2%, 44), Hispanic students (4.6%, 39), Black/African American students (2.9%, 25), students who identified as two or more races (2.4%, 20), and unknown (0.7%, 6).

Measures and Variables: 

• Total ugGPA. Mean grade-point average (GPA) for all undergraduate courses taken by students.
• BCP ugGPA. Mean GPA for all Biology, Chemistry and Physics undergraduate courses.
• Didactic GPA. Mean GPA for all didactic courses completed during Years 1-3, excluding clinical courses and Pass/Fail courses (e.g., Integrative Seminar).
• Overall OD GPA. Mean GPA for every graded course completed in the program, excluding all Pass/Fail courses.
• Clinical GPA. Mean GPA for all clinical courses taken in Years 3 and 4. Students who were dismissed from the program before reaching Year 3 do not have a clinical GPA and were not computed in the Clinical GPA analysis.
• Undergraduate Institutional Rating (UIR). To determine if undergraduate GPA differed by the type of institution attended, students were assigned an Undergraduate Institutional Rating (UIR) score. The UIR score was created based on Barron’s Best University ranking of undergraduate institutions following a 5-point scale, from non-competitive (open admissions) to most competitive. Because international schools are not rated by Barron’s, international students were excluded from the analysis.
• NBEO Part I Scores. Overall composite score for first attempt of the NBEO Part I exam. Scores range from 100 to 900, and a score of 300 or higher indicates passing the exam. Students who were dismissed prior to attempting NBEO Part I, as well as those who voluntarily opted not to take the examination (given that it is not a graduation requirement), were excluded from this analysis.

Normality Testing of Variables: All dependent and independent variables used in the predictive models, including undergraduate GPA, Overall OD GPA, First-Year OD GPA, OAT scores, UIRs and Overall NBEO Part 1 scores were tested for normality using skewness and kurtosis statistics. Skewness and kurtosis values between -1 and +1 were considered acceptable indicators of approximate normality. All measures fell within this range except for Clinical GPA, which showed acceptable skewness but high kurtosis, indicating a non-normal distribution.

Statistical Analysis: This study used various statistical methods to answer the proposed research questions, including descriptive statistics, Pearson correlation coefficients to assess linear relationships between variables, ANOVA to test differences in means, chi-square to test difference between expected and observed frequencies between groups, and regression analysis to determine the linear relationship between independent and dependent variables. Statistical significance was set at p < .05. Because clinical GPA was not normally distributed, an ordinal regression was used. Data analysis was conducted using SPSS.

The study was reviewed and deemed Exempt by the Institutional Review Board (IRB NET ID 2159150-2, approval date June 6, 2024).

Results

Entering Admissions Metrics

OAT. The total mean Academic Average OAT for the sample was 343 ± 21.2, with a range of 280 to 400, and the mean Total Science OAT was 347 ± 27, ranging from 290 to 400.

Undergraduate GPA.  The mean Biology, Chemistry and Physics Undergraduate GPA (BCP ugGPA) was 3.42 ± .31 (range 2.44-4.0) and the mean Total ugGPA was 3.54 ± .25 (range 2.74-4.0).

Institutional Ranking. The average institutional rank for all students is 4.3, on a 1-6 scale. Twenty one percent of students are from institutions rated 5 or above, 20% from institutions rated 4-4.9, 19.4% from institutions rated 3-3.99, and 6% from institutions rated below 3.

Performance in the Professional Program

Table 1. Mean of OD GPA by Class Graduating Year. Click to enlarge.

The GPAs for each class can be found on Table 1. The mean Didactic OD GPA—calculated from all didactic courses taken in Years 1-3—is 2.98 ± .56, the mean Overall OD GPA is 3.12 ± .47, the mean Clinical OD GPA is 3.40 ± .42, and the mean First Semester OD GPA is 3.04 ± .63.

OAT and OD GPAs

Table 2. Pearson’s Correlation Between OAT (TS and AA) and Various Measures of Performance in the Program. Click to enlarge.

Pearson correlation coefficients were computed to assess the linear relationship between the OAT and various GPAs in the professional OD program. As shown in Table 2, Total Science (TS) and Academic Average (AA) OAT scores correlate positively and significantly with all measures of GPA, except for Clinical OD GPA. The AA OAT had a stronger correlation with all measures of GPA compared to TS. Specifically, AA OAT had the strongest correlation with first-year GPA (r = .47).

Admissions Metrics (OAT, ugGPA, Institutional Rating) as Predictors of Overall OD GPA

A regression analysis was conducted to test the linear relationship between admissions metrics and OD GPA. As seen in Table 3, OAT AA alone explained 14% of the variance in Overall OD GPA, and Total ugGPA explained 11% of the variance.

Table 3. Prediction of Overall OD GPA Based on OAT AA and ugGPA. Click to enlarge

Similar patterns emerged when predicting first semester OD GPA (Table 4). OAT AA alone explained 25% of the variance in first semester OD GPA, and Total ugGPA explained 12% of the variance.

Table 4. Prediction of First Semester OD GPA Based on OAT AA and ugGPA. Click to enlarge

Undergraduate Institutional Ranking

Pearson coefficient correlations were computed to assess the linear relationship between UIR and Admissions Metrics and various GPAs in the professional program. As seen in Table 5, there was a positive correlation between UIR and OAT scores, and all OD GPAs, except for Clinical OD GPA. There was a negative correlation between UIR and ugGPA, both BCP and Total. This is not surprising as more competitive schools are known for being more stringent on grading.

Table 5. Pearsons’ Correlation between Institutional Rank, Admissions Metrics and OD GPAs. Click to enlarge

Relationship Between Overall OD GPA and All Admissions Metrics Combined

Multiple regression analysis was performed to predict Overall OD GPA using three admissions metrics: AA OAT, Total ugGPA and UIR.

Table 6. Regression of Institutional Ranking and Admissions Metrics as predictors of Overall OD GPA. Click to enlarge

As Table 6 shows, AA OAT and Total ugGPA together explained 22% of the variance in Overall OD GPA (R² = .22, F(2, 773) = 106.82, p <.001). AA OAT (standardized β = .31, p <.001) was a stronger predictor than Total ugGPA (β = .28, p <.001).

Upon adding UIR to the regression, there was a 2% increase in the predictive power of the model (Model 2 on Table 6) (R² = .24, F(3, 772) = 79.71, p <.001). In the new model, it was found that all measures, Total ugGPA (standardized β = .33, p <.001), AA OAT (β =.27, p <.001), and UIR (β =.15, p <.001) significantly contributed to the prediction of Overall OD GPA. The addition of UIR to the model led to an increased predictive power of Total ugGPA compared to AA OAT, suggesting that when controlled for UIR, Total ugGPA’s predictive power increases.

First-Year OD GPA

Multiple regression analysis was used to predict First-Year OD GPA using three admissions metrics—AA OAT, Total ugGPA and UIR. The results showed that AA OAT and Total ugGPA together accounted for  29% of the variance (R²=.29, F(2, 773)=156.68, p <.001), with AA OAT (standardized β = .41, p <.001) being the stronger predictor compared to Total ugGPA (standardized β =.27, p <.001).

Table 7. Regression – Institutional Rank and Admissions Metrics as Predictors of First Year OD GPA. Click to enlarge

When UIR was included in the multiple regression, the model’s predictive power increased by 1% (Model 2 on Table 7) (R² = .30, F(1, 722) = 17.56, p <.001). In the new model, all measures, Total ugGPA (β = .31, p <.001), AA OAT (β = .37, p <.001), and UIR (β = .13, p <.001) significantly contributed to predicting first-year GPA. Although UIR increases the standardized beta coefficient for Total ugGPA, unlike with the Overall OD GPA, AA OAT remained the stronger predictor of First-Year OD GPA.

It has been argued that test scores are becoming weaker predictors of success.^2,5 This argument was tested using First-Year OD GPA in the professional OD program as a proxy for success. Pearson’s correlational analysis was conducted to examine the relationships between AA OAT and ugGPA to First-Year OD GPA for each entering class. As shown in Figure 1, the correlations between AA OAT and First-Year OD GPA ranged from .40 to .56, while ugGPA ranged from .26 to .49. Correlation for both measures fluctuated year by year. Only in 1 out of 9 years ugGPA showed a stronger correlation with First-Year OD GPA than the OAT. In the last 2 years of the analysis, AA OAT had a stronger correlation coefficient with First-Year OD GPA.

Figure 1. Pearson’s Correlation of ugGPA and AA OAT. Click to enlarge

Clinical Performance

Table 8. Pearson’s Correlation Between Clinical OD GPA and AA OAT, Subsections of the OAT, UG Total and BCP. Click to enlarge

As determined earlier, Clinical OD GPA correlates poorly with admissions metrics and does not have a linear relationship with OAT scores. The three admissions metrics that have linear relationships with Clinical GPA are the Reading Comprehension section of the OAT (r = .12, p = .01), and Total ugGPA, and BCP ugGPA (r = .19, and .14, p = .01, respectively) are shown in Table 8.

Clinical GPA and Admissions Metrics

Figure 2 shows that although the relationship between AA OAT is not linear, students at the high end of the OAT range also command higher clinical GPA. This distribution suggests that, although AA OAT scores may not directly predict Clinical GPA performance, higher OAT scores might be an indicator of potential academic success in the clinical setting.  However, students at the lower end of the OAT scale, perform relatively well in the clinical component of the program.

Figure 2. Relationship between Clinical OD GPA (Binned) and AA OAT (Binned). Click to enlarge

An ordinal logistic regression was conducted to examine the relationship between OAT score groupings (≤320, 330–340, ≥350) and Clinical GPA quartiles. The model significantly improved prediction over the intercept-only model, χ²(2) = 6.261, p = .044, although it explained little variance (Nagelkerke R² = .008). Goodness-of-fit tests indicated adequate model fit (Pearson χ²(4) = 5.802, p = .214; Deviance χ²(4) = 5.941, p = .204). Compared to students with OAT scores ≥350, students in the ≤320 group had significantly lower odds of achieving higher Clinical GPA quartiles (estimate = -0.366, p = .039), as did students in the 330–340 group (estimate = -0.309, p = .036). Although the associations reached statistical significance, the effect sizes were small.

Relationship Between OAT Scores and Academic Progress: Repetition and Dismissal

This section analyzes demographics and admissions metrics of students who were either dismissed from the program or repeated at least one academic year. Of the total number of students, 7.4% (63) repeated or were dismissed.

Table 9. AA OAT by Repeats and Dismissals. Click to enlarge

Table 9 shows the percentage of students who repeated a year or were dismissed from the program by AA OAT band. Among the total sample, students in the <=310 AA OAT range represented 9% (76), and 17% (13) of them repeated or were dismissed. For students in the 320-330 band, which represented  29.5% (249) of the sample, 9.2% (23) repeated or were dismissed. Students in the 340-350, which represented 33.5% (283) of the sample, 6.4% (18) were dismissed or repeated. Finally, students in the >=360 band represented 28% (237) of the sample, and 3.4% (8) repeated or were dismissed.

OAT Scores and NBEO Part I Performance

In examining the relationship between students’ first-time NBEO Part I performance and OAT scores, Pearson coefficient correlations were computed to assess the linear relationship between the OAT and its subsections with NBEO Part I board scores. As seen in Table 10, all OAT scores correlate positively and significantly with overall board scores. AA OAT had the strongest correlation with board scores.

Table 10. Pearson’s Correlations Between OAT scores and NBEO Part I Scores. Click to enlarge

Overall Boards Scores and Admissions Metrics

Multiple regression analysis was employed to predict NBEO Part I scores using three admissions metrics—AA OAT, Total ugGPA and UIR—along with Didactic GPA. Using an enter method, the AA OAT score explained 19% of the variance in Board scores, while Total ugGPA and institutional rank increased predictive power by 3% (Models 1 and 2 on Table 11). Combined, the admissions metrics alone accounted for 22% of the variability in Overall Boards Score (R² = .22, F(2,724) = 14.9, p <.001). AA OAT (β = .37, p <.001), Total ugGPA (β = .18, p <.001) and UIR (β = .09, p < .00) contributed significantly to the prediction.

When Didactic GPA was added to the model, the predictive power increased by 30% percentage points, with all variables together accounting for 52% of the variance in NBEO Part I scores. In the final model (Model 3) the only significant predictors were AA OAT and Didactic GPA.

Table 11. Multiple Regression – Admissions Metrics (AA OAT, Total ugGPA, and Institutional Rank) as predictors of Boards. Click to enlarge

Figure 3. Relationship Between Boards Passing and AA OAT Scores (Binned). Click to enlarge

Pass/Fail. Since the NBEO Part I is a pass/fail threshold exam, this section explores the relationship between students’ OAT scores and their likelihood of passing the NBEO Part I on the first attempt.  Figure 3 shows that 29.9% (20) of students in the <=310 AA OAT band did not pass NBEO Part I in the first attempt, compared to 22.2% (51) in the 320-340 bin, 13.1% (35) in the 340-350 band, and 4.9% (11) in the  >=360 band. The difference was statistically significant, c² (1, 788) = 39.7, p <.00).

Discussion

Given the ongoing debate regarding the use of the OAT as an admissions tool, this study examined whether the OAT serves as a reliable predictor of performance in optometry school.

The OAT was positively associated with various markers of academic success, including first-year GPA, overall GPA, NBEO Part 1 scores and pass rate, and uninterrupted progress in the optometry program.

Some argue that the OAT is becoming a weaker predictor of success, and that the term ‘success’ is subjective and may have different meanings.⁵ Although we agree that success can be defined in many ways, based on the markers defined by this analysis, the OAT is a valid and reliable predictor of academic achievement in optometry school. Moreover, this study does not support the claim that the predictive power of the OAT is diminishing. In fact, based on data from the Association of Schools and Colleges of Optometry (ASCO), the average ugGPA for all schools of optometry has increased over the past 5 years. This could be an indication that schools are becoming more selective or that ugGPAs are inflated, making standardized tests ever more relevant in the admissions equation.¹⁶

It is a commonly held view that the OAT is not an infallible predictor of success, a sentiment often expressed anecdotally by faculty and administrators evidenced by statements such as ‘there are students who do well on the OAT but who also have academic difficulties.’ However, this perspective overlooks the fact that it is unrealistic to expect any single test to serve as a perfect and exclusive predictor of success in any aspect of human endeavor. The OAT is a tool for predicting success, but like with any tool, it has limitations. The OAT explains up to 22% of a student’s first-year GPA. While this could be the difference between passing or not, there is still 78% of the variance of a student’s grade that is explained by other factors. When ugGPA and institutional rating is added to the model, the combined explanatory power increases to 33%. There is still 67% of the variance in grades that remains unexplained by these variables. Although not ideal, the explanatory power of these variables is consistently valid and reliable.

Furthermore, this study shows that ugGPA alone explained 13% and that the addition of OAT to the model more than doubled the predictive power of first-year GPA. Any tool with the ability to increase predictive power by this much should not be dismissed or excluded from a holistic admissions process.¹⁵

This study shows that for all measures of GPA in the professional program, the predictive power of ugGPA increases when accounting for institutional ranking, lending support to the familiar adage that “not all GPAs are created equal.” Students in schools with higher institutional rankings tend to have lower ugGPAs. Thus, by eliminating the OAT, schools would have to rely on fewer objective markers of success, ugGPA and quality of undergraduate education probably becoming the main focal points, potentially disadvantaging students from lower ranked institutions. The OAT allows for students from lower ranking institutions with reasonable OAT scores to demonstrate to the admissions committee that they have the requisites necessary to succeed.

The relationship between OAT scores and clinical performance has not been widely examined in the optometric literature, although prior studies have established the relationship between standardized tests and clerkship performance in medical school.¹  In this study, students with lower OAT scores had significantly lower odds of achieving higher clinical GPA quartiles, though the effect sizes were small.

This study supports previous findings¹⁷ indicating that NBEO Part I performance is primarily predicted by Didactic GPA within the professional program. The addition of OAT to the model further increased its predictive power. In contrast, when admissions metrics and Didactic GPA variables were included together, Total ugGPA did not contribute significantly to the model. In addition, students with lower AA OAT are significantly more likely to not pass Part 1 on the first attempt.

This study shows the potential for academic and clinical excellence among students in lower OAT bands.  Conversely, this study also shows that students in lower bands of the OAT have higher chances of struggling academically and on Part I of the NBEO exam. Therefore, students in lower OAT bands may require access to adequate, accessible support services in their academic journeys. Schools considering changes to OAT-related policies must be transparent about their ability to invest the necessary human and financial resources to provide remedial academic support to the students who may require it.¹⁸

There are calls for barriers to be removed, the OAT being one of them, from admissions processes to expand access to underrepresented groups who have faced systemic discrimination.⁶ Evidence suggests that test-optional policies have not yielded the anticipated increases in representation of underrepresented students on college campuses.^18–20 In fact, studies indicate that these policies may be “insufficient” in achieving meaningful transformation and may instead enhance the selectivity and prestige of the institutions that adopt them.¹⁹ By removing a valid measure of success, we risk unintended consequences and unanticipated changes. Research indicates that without standardized tests, admissions committees may be compelled to emphasize criteria that could disproportionately benefit White, Asian and affluent students, such as extracurricular activities, personal statements, advanced coursework and school rankings.¹⁹

Medical and optometry schools have successfully increased the enrollment of racially underrepresented students without eliminating standardized tests.²¹ To genuinely support and advocate for underrepresented students, it is crucial to maintain a balanced approach that incorporates valid assessments while implementing targeted strategies to enhance diversity and inclusion in the admissions process. Strategies such as culturally responsive recruitment, intentional outreach, holistic admissions processes and broadening acceptable score ranges have proven effective in diversifying the profession.^19–21 In addition, they can expand opportunities for applicants to meet these standards—for example, by creating pathway programs that offer academic and financial support tailored to the OAT and nurture students’ community cultural wealth.²¹

Students accepted without a standardized measure of knowledge and academic achievement may lack the requisite knowledge, study strategies and academic habits required to perform in rigorous health professions programs, potentially leading to academic failure and dismissal. This study supports the notion that students at lower ranges in the OATs tend to be more prone to academic difficulty, including dismissal. The cost of failure in optometry school should not been taken lightly. Struggling students often present with high levels of anxiety, depression and shame, an emotion strongly associated with mental health challenges such as addiction and post-traumatic stress disorder.²² In addition to the psychological toll, failing to complete the OD program or obtain licensure can result in significant financial burdens that may take years to overcome.

Limitations of this Study

Restriction of range is a common weakness of studies in health care programs attempting to study the relationship between standardized tests and academic and clinical performance. This weakness is applicable to this study, as students analyzed here had AA OAT scores at the higher end of the OAT range.  Based on the performance and persistence by AA OAT bands presented here, it is a logical conclusion that students in lower ranges would likely have higher rates of underperformance and failure. This is not to say that they could not perform well in the program, but that they are considerably more likely to struggle. This study is also the snapshot of one school of optometry. Similar analysis should be made including a larger group of schools. In addition, future research is needed to determine whether students with lower OAT scores are more likely to fail the NBEO Part I multiple times, and whether higher scorers are more likely to be accepted into residency programs.

Conclusion

The OAT is a high stakes examination used by admissions committees across the country to make admissions decisions. As with any admission metric, the OAT may present a barrier to potentially qualified students. As such, the validity of the OAT as a tool for admissions committees needs to be confirmed. This study adds to the body of research providing empirical evidence of the validity of the OAT in predicting various forms of academic performance, including first-year and overall GPA, retention and successfully passing Part 1 of the NBEO licensing examination. This study supports the use of the OAT as one component of a holistic admissions process for the OD program, but not as the sole basis for rejecting applicants. The finding that lower OAT scores are associated with higher rates of academic struggle and dismissal suggests that standardized tests serve as valuable, though imperfect, early indicators of academic risk. As discussed in prior research, drastic changes in admissions testing policies can lead to both intended and unintended consequences, including psychosocial, emotional and financial impacts on students and institutions. Admissions committees have to successfully balance the need to increase access to a diverse class, while at the same time enroll those who are most likely to succeed, avoiding the costly consequences of failure. While this is no easy feat, there are options that can be further explored.

Syphilis is a sexually transmitted infection (STI) caused by the spirochete, Treponema pallidum. Although thought to be a rare infection, syphilis cases have been on the rise over the last 20 years in the US and globally. Per the Centers for Disease Control and Prevention (CDC), there were over 200,000 cases of syphilis in 2022, which was the greatest number of cases since 1950, with an increase of 17% since 2021.¹ The World Health Organization (WHO) estimates globally, that 11 million new cases of syphilis occur in adults 15 to 49 years of age.² This is considered to be due to an increase in HIV preventive medications, an increase in unprotected sex, especially in young men who have sex with men, and decreased public health initiatives. Although there has been an increase in documented cases of primary and secondary syphilis, neurosyphilis (including ocular syphilis) numbers have not been well documented.³

There are four categories of syphilis defined by the CDC, which are based on the stage of the infection and the tissues/organs affected: primary, secondary, latent and tertiary. The primary stage of syphilis occurs when the infection enters the body, presenting as a sore(s) or chancre(s) at the inoculation site. These sores most often affect the penis, vagina, anus, rectum, mouth and can last 3-6 weeks. These chancres are typically firm, red and painless, which may lead to them going unnoticed by patients and therefore remaining untreated. Untreated syphilis will progress to the secondary stage. Although the knowledge of pathogenesis in humans is unclear, animal models show the infection spreads from the inoculation site to the lymph nodes, spreading throughout the body in its early stages.³ In the secondary stage, a non-itchy rash will typically arise at the sore location or on the palms of the hands or bottom of the feet. Flu-like symptoms can also occur in this stage, as well as weight loss and hair loss. The infection can be fought off partially from the body’s adaptive immune response, but if left untreated, T. pallidum can persist for years by impacting immune-privileged sites, such as the eye, and the infection will enter the latent stage or tertiary stage.³ In the latent stage, the infection becomes asymptomatic and can persist in a patient’s body for years. Individuals in the latent stage remain contagious and will test positive in serological tests; increasing the spread of syphilis if not treated. The infection enters the tertiary stage years after being latent or can be a result of progression from the secondary stage. Although uncommon, the tertiary stage of untreated syphilis will start to affect major organs, such as the heart, blood vessels, brain and nervous system. When syphilis affects the neurological system, including the eye, it is termed neurosyphilis. Neurosyphilis can occur in any stage of syphilis but is most likely to occur in the secondary stage. Optometrists play a key role in the detection of syphilis risks as it may manifest in the eye, including the posterior segment. Therefore, it is essential for eyecare providers to recognize the signs and symptoms of ocular syphilis, understand appropriate diagnostic approaches, and be familiar with current treatment strategies to support optimal visual outcomes and overall patient health.

This teaching case report is valuable for third- and fourth-year optometry students and residents, as it underscores the diverse posterior segment manifestations of ocular syphilis and highlights the importance of prompt recognition, evaluation and treatment to preserve visual potential and prevent further systemic complications. Additionally, an overview of ocular syphilis is presented, covering its epidemiology, pathophysiology, potential ocular differential diagnoses, testing modalities and treatment options.

Case Description

A 71-year-old African-American male presented with complaints of pain in the left eye and on the left frontal side of the head that started 3 days prior. He also noticed an increase in flashes and floaters in the left eye and a “black blob” in the center of his vision with only mild improvement since the initial occurrence. His ocular history was positive for primary open angle glaucoma and posterior vitreous detachments in both eyes. The patient had a history of insulin-dependent type 2 diabetes, hypertension and hyperlipidemia. He stated his last hemoglobin A1C to be around 7% and his last blood sugar reading earlier that morning to be 97mg/dL. His current medications were ezetimibe, Lantus, lisinopril, 81mg aspirin, preservative free artificial tears, and latanoprostene bunod 0.025% (Vyzulta 0.025%). He reported good compliance with all systemic and ocular medications.

The entering best-corrected visual acuity in the right eye was 20/20, whereas the left eye demonstrated a reduction to 20/600 with no improvement upon pinhole testing, compared with a documented acuity of 20/20 at his glaucoma follow-up examination 1 month earlier. Confrontational visual fields, extraocular motility and pupils were unremarkable in both eyes. His slit lamp findings were remarkable for grade 1 nuclear cataract in both eyes with no evidence of anterior chamber cell or flare in either eye. His intraocular pressure (IOP) was stable at 12 mmHg in both right and left eyes, measured by Goldmann Applanation Tonometry. A dilated fundus exam was performed on both eyes. Glaucomatous cupping of .8/.8 in the right eye was noted with a stable posterior vitreous detachment (PVD) but was otherwise unremarkable. A dilated fundus examination of the left eye was limited by significant vitreous haze and the presence of pigmented vitreous cells versus vitreous hemorrhage (Figure 1).

Figure 1. Presenting wide field imaging of the poster segment clinical findings day one. Blue arrow: Posterior vitreous detachment. Red Arrow: Pre-retinal hemorrhage. Yellow Arrow: Vitreous hemorrhage/cells obscuring views to underlying retina and the optic nerve, which appears edematous and pale. Click to enlarge

Figure 2. Magnified imaging of Figure 1 (day 1) demonstrating retinal periarteritis plaques (black Arrows) and preretinal hemorrhage (red arrow). Click to enlarge

The optic nerve was also obscured but appeared to have disc edema and pallor (Figure 2). The patient declined symptoms of scalp tenderness, jaw claudication, fever, malaise or muscle pain or weakness. As mentioned in above entrance testing, no APD was present declaring that the optic nerve head edema was mild and optic nerve function still preserved.  The superior temporal mid-peripheral retina showed retinal hemorrhages, sclerotic vessels and vessel plaques with hazy views (Figures 1 and 2).

Figure 3. B-scan ultrasound obtained on day 1 confirming large vitreous debris (vitreous hemorrhage vs vitreal cells). Click to enlarge

As views were limited, a B-scan ultrasound was ordered and confirmed no retinal detachment. However, a large vitreous body (vitritis vs vitreous hemorrhage) was visualized (Figure 3). A spectral domain optical coherence tomography (SD-OCT) macular scan of the left eye was ordered due to decreased vision, poor views upon dilation, as well as retinal and vascular findings that could point to macular edema. The macular SD-OCT showed a loss of foveal contour with internal limiting membrane (ILM) traction, retinal pigment epithelium (RPE) disruption, and a loss of the ellipsoid zone (EZ) nasal to the fovea (Figure 4).

Figure 4. Day 1 Cirrus SD-OCT 5-line raster scan. 4A: Vitreal cells/heme are noted on the infra-red scan as a pre-retinal black shadow (red arrow). 4B: OCT of the macula revealing nasal disruption to the ellipsoid zone (light blue arrow). Click to enlarge

Differential Diagnoses at this time were:

Anterior ischemic optic neuropathy⁴

Non-atretic anterior ischemic optic neuropathy (NAAION): This condition occurs due to hypoperfusion of the short posterior ciliary arteries supplying the optic nerve that leads to acute ischemia, resulting in axonal swelling. This leads to compression of the optic nerve circulation, increasing optic nerve swelling and ischemia.

1. 1. Symptoms/Signs: Acute, monocular, painless loss of vision with diffuse or segmental optic disc edema with peripapillary flame hemorrhages.
   2. Etiologies: Vasculopathic diseases (diabetes, smoking, hypertension and hypercholesterolemia), use of phophodiesterase-5 inhibitors (i.e. sildenafil), small cup to disc ratio (aka “disc at risk”), or ocular surgeries (due to the rise of perioperative IOP leading to a decrease in optic nerve perfusion).
   3. This diagnosis was excluded based on the pallor of the affected optic nerve, the absence of flame hemorrhages and the vitreous presentation. Furthermore, comparison with the fellow eye revealed no evidence of a “disc at risk” appearance.

Arteritic anterior ischemic optic neuropathy (AAION): This results from endothelial cell inflammation secondary to giant cells, leading to thrombosis and occlusion in the posterior ciliary artery of the optic nerve head, leading to optic nerve head swelling.

1. 1. Symptoms/Signs: Acute vision loss with or without headache, scalp tenderness, jaw claudication, fever, malaise or muscle pain or weakness (symptoms related to giant cell arteritis (GCA)). Pale optic nerve edema typically without disc hemorrhages.
   2. Etiologies: GCA or systemic or ocular vasculitis caused by polyarteritis nodosa, systemic lupus erythematosus or herpes zoster.
   3. AAION was ruled out based on the presence of vitreal signs and lack of associated symptoms.

Optic Neuritis⁵

Definition: Inflammatory infiltration of the optic nerve head causing swelling of the optic nerve.

1. 1. Signs/Symptoms: Typical optic neuritis, often associated with demyelinating disease, presents as an acute, unilateral and painful loss of vision. In contrast, atypical optic neuritis—typically related to infectious or autoimmune etiologies—is less commonly associated with ocular pain.
   2. Etiologies: Infection (i.e., tuberculosis, syphilis, sarcoidosis, cat-scratch disease, herpes zoster), demyelination disorders (i.e. multiple sclerosis), or auto-immune conditions (i.e., lupus or Sjogren’s).
   3. This condition could not be excluded at this stage given the appearance of the patient’s optic nerve, and further evaluation and diagnostic testing were warranted.

Vitreous hemorrhage⁶

Definition: Blood in the vitreous due retinal vascular blood leakage.

1. 1. Symptoms/signs: Increase in floaters, hazy vision, shadowing of vision or cobwebs in vision. Blood or pigmented fibers floating in the vitreous, occluding retinal views.
   2. Etiologies (Limited to the likely differentials associated with the case presented): Proliferative vascular retinopathies (caused by diabetes), vein occlusions, vasculitis from infections such as HIV, CMV, syphilis, etc., sickle-cell, idiopathic polypoidal choroidal vasculopathy, trauma, retinal arterial macroaneurysm, posterior vitreous detachment, blood disorders (leukemia, anemia, thrombocytopenia or hemophilia), or Valsalva retinopathy.
   3. This differential could not be excluded based on the retinal presentation, the patient’s symptoms or systemic conditions such as diabetes and hypertension.

Posterior uveitis

Definition: A type of uveitis defined by Standardization of Uveitis Nomenclature (SUN) primarily affecting the choroid and the retina causing chorioretinal inflammatory lesions. This condition includes choroiditis, retinochoroiditis, retinitis or neuroretinitis.⁷ There are two classes in posterior uveitis; infectious and non-infectious, where non-infectious primarily affects the choroid.⁸

1. 1. Symptoms/signs:⁹ Sudden onset of floaters, blurred vision, loss of vision or distorted vision. Retinitis will appear as poorly defined, superficial white patches, while choroiditis lesions are yellow with regular borders, deeper to the retinal vessels.
   2. Etiologies:⁹ (Limited to the likely differentials associated with the case presented):
      • Infectious: cytomegalovirus (CMV), toxoplasmosis, herpes, tuberculosis (TB), syphilis, fungal infections or histoplasmosis.
      • Non-infectious with systemic association: sarcoidosis or Behcet’s disease.
      • Non-infectious without systemic association: Multifocal chorioretinitis/panuveitis, multiple evanescent white dot syndrome/placoid retinitis.
   3. This differential couldn’t be excluded due to ocular findings, patient’s symptoms and need for further imaging and blood work.

Vitritis (intermediate uveitis)¹⁰

Definition: Inflammatory material (white blood cells) found in the vitreous from an infectious or inflammatory condition.

1. 1. Symptoms/signs: Unilateral or bilateral blurry vision with or without floaters. Will observe cells floating in the vitreous. Collections of inflammatory material seen at the inferior vitreous base, known as snowballs or if located at the pars plana or anterior retina, are referred to as snowbanks.
   2. Etiologies (Limited to those most risk associated with the case presented): Caused by conditions such as toxoplasmosis, cytomegalovirus, herpetic disease, syphilis, tuberculosis or Behcet disease.² Other causes for vitreous cells include lymphoma, melanoma, rhegmatogenous retinal detachment, leukemia or amyloidosis.¹¹
   3. This is a differential that can’t be excluded due to the patient’s posterior pole findings, symptoms and need for a further blood workup.

Figure 5. Spectralis OCT of the left optic nerve on day 2, with the retinal specialist. Optic nerve edema is appreciated based on indistinct disc margins on the infrared (IR) scan (green arrow) as well as the retinal nerve fiber layer scan, especially in the inferior quadrant (blue line). Click to enlarge

Based on the patient’s posterior segment findings and vitreous involvement, he was diagnosed with presumed posterior and intermediate uveitis of unknown etiology. Additional case history was obtained to assess new systemic conditions, recent changes in routine blood work (performed every 3 months), and symptoms such as fatigue, flu-like illness, chest pain, increased cough, dyspnea or features suggestive of GCA. He denied any of these changes or symptoms. Unfortunately, at this time, sexual history questions were not inquired about. He was referred immediately for a retinal consultation for further evaluation.

A retinal specialist saw the patient the next day (day 2) noting stable and unremarkable findings in the right eye with BCVA at 20/20. The left eye BCVA had improved to 20/200. Entrance testing was unremarkable, including pupils. Anterior segment examination via slit lamp remained stable with no changes or new findings. A grade 1+ vitreous hemorrhage was noted with vitreous cells indicating the likelihood of inflammatory driven vasculitis resulting in retinal ischemia and secondary retinal neovascularization. The optic nerve was visible and confirmed optic nerve head edema nasally with general congestion and hyperemia without hemorrhages (Figures 1, 5 and 6). A Spectralis SD-OCT of the optic nerve was performed as well to confirm the optic nerve swelling (Figures 5 and 6).

Figure 6. Spectralis OCT of the optic nerve at the 2 week follow-up visit. 6A: Infra-red (IR) scan showing obvious and worsening optic nerve head edema (red arrow) compared to the patients 2-day visit (Figure 5). 6B: Retinal nerve fiber layer scan showing worsening edema as compared to the initial scan (Figure 5). Click to enlarge

Sclerotic vessels and retinal periarteritis plaques consistent with retinal vasculitis (Figure 2), as well as pre-retinal hemorrhages in the left eye (Figure 1) were also evident. Because of these findings, the retinal specialist ordered an intravenous fluorescein angiogram, which demonstrated severe perfusion delay in the left eye with poor filling of the superior-temporal artery with noted plaques indicating retinal ischemia. Preauricular nodes (PAN) were palpated, and the left PAN was palpable, indicating a possible viral infection. He denied feelings of malaise, flu-like symptoms, dental issues, ear infections or cancer.  He denied family or personal past history of sickle cell anemia. He also confirmed negative giant cell arteritis symptoms (scalp tenderness, fever, chills and jaw claudication).

Further questioning of the patient’s sexual history was asked at this visit and the patient disclosed he was sexually active with other men. Based on the posterior segment findings of optic nerve papillitis, retinal vasculitis, vitritis, and the patient’s history, posterior/intermediate uveitis of unknown inflammatory or infectious origin was suspected. To rule out infectious or inflammatory conditions, the patient was referred for comprehensive blood work including a CBC with differentials and a uveitis work up including rheumatoid factor, syphilis testing including Rapid Plasma Reagin (RPR) non-treponemal testing and Treponema pallidum particle agglutination-treponemal (TP-PA) testing, chest radiography, serum ACE and lysozyme, Lyme serology, QuantiFERON Gold for tuberculosis, ELISA Bartonella serology, viral polymerase chain reaction for herpes simplex, zoster, HIV and cytomegalovirus, and antibody titers for toxoplasmosis and toxocariasis. A magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), magnetic resonance venography (MRV), computed tomography (CT) and computed tomography angiography (CTA) of the brain and orbits without contrast were ordered to rule out malignant or benign lesions, vascular abnormalities (i.e. aneurysms), as well as demyelinating diseases. Due to the lack of patient’s symptoms and presence of vitritis, GCA blood work including ESR and CRP was not ordered. Although ESR and CRP are commonly ordered in cases of uveitis, it was determined that these tests would not contribute meaningfully to the diagnosis, as they indicate only the presence of systemic inflammation and are not specific to any particular underlying etiology. Therefore, in this case, more specific testing was ordered to determine it was infectious.

The patient’s syphilis testing revealed a reactive Rapid Plasma Reagin (RPR) indicating the need for Treponema pallidum Particle Agglutination (TP-PA) treponemal testing, which concluded a reactive result, confirming the diagnosis of syphilis. The MRI of the brain and orbits without contrast confirmed active left optic nerve enhancement as well. All other test results and imaging were unremarkable. The patient was diagnosed with neurosyphilis based on ocular involvement (posterior uveitis), optic nerve involvement per the MRI and ocular exam findings and serological testing. Neurosyphilis (likely tertiary or late latent stage syphilis) was diagnosed based on the optic nerve and retinal findings, as well as no other primary or secondary stage findings of rash, chancres or anterior uveitis. He was immediately referred and admitted to the emergency department for IV antibiotics (penicillin G) to treat his neurosyphilis. At this time, he confirmed he was engaged in high-risk sexual behavior and educated to notify all sexual partners regarding his confirmed syphilis diagnosis.

The patient’s non-treponemal titers improved after a 14-day treatment of intravenous penicillin G. The patient followed up multiple times with a retinal specialist over the next 2 years with no signs of retinal necrosis, neurological manifestations or vision loss. The patient continued to follow up with an infectious disease specialist and presently his syphilis is non-detectable per his serological non-treponemal titers. The patient continues to show no further systemic manifestations related to syphilis. On his last visit, his visual acuity improved to 20/30 in the left eye. Current ocular findings of the posterior pole can be seen in Figure 7 showing optic nerve pallor with vitreal traction, retinal periarteritis plaques within the vessels, as well as sclerotic vessels and residual retinal hemorrhages. The patient continues to be seen by the retinal specialist every year. His glaucoma care is managed every 3 to 6 months by his optometrist. He continues to see his infectious disease specialist annually.

Figure 7. Optos wide field imaging 8 months after initial onset. Vision at this time was 20/30. Blue arrow: Traction and vitreal scarring from nerve to macula. The optic nerve appears pale due to the resolution of the initial optic nerve edema. Light green arrows: Sclerosed vessels from resolution of vasculitis. Red arrow: Residual intra retinal hemorrhages. Click to enlarge

Educational Guide

This educational guide can be utilized in a multitude of ways to teach students and/or residents’ knowledge about posterior segment findings that can be associated with syphilis. The learning objectives, key concepts and discussion questions provided below can be helpful for an educator to use the case to further expand student knowledge and understanding of ocular syphilis presentations in the posterior segment.

The case could be presented to students/residents in a grand rounds format after a PowerPoint lecture presentation using this case report’s findings as an example for posterior segment findings of syphilis. Followed by a multiple-choice test focusing on the discussion questions below. The case can also be presented in a clinical setting or a systemic/ocular disease course with one student/resident or a group of students/residents.

For example, instructors may present the specific case findings and prompt students to develop differential diagnoses, identify appropriate additional testing, determine necessary referrals and systemic evaluations, and formulate the final diagnosis. Subsequent discussion of treatment strategies and management considerations would further illustrate how this case and the accompanying educational guide can be effectively utilized.

Assessment of students’/residents’ analytical skills may be accomplished through case-based discussion lectures, guided verbal analysis of clinical decision-making or written case reports following the format outlined above.

Learning Objectives

1. 1. Recognize the importance of case history questioning and using specific questionnaires to identify the risks for syphilis with specific posterior segment presentations arise.
   2. Recognize posterior segment presentations caused by ocular syphilis.
   3. Identify appropriate ophthalmic testing, laboratory testing and neuroimaging required when suspecting ocular syphilis.
   4. Identify other professionals needed to collaborate with when managing a patient with ocular syphilis.

Key Concepts

1. 1. Understand/correlate the stages of syphilis and when posterior segment manifestations of ocular syphilis are likely observed.
   2. Development of appropriate case history questions for those suspected of ocular syphilis.
   3. Use of specific ocular and laboratory investigations to aid in diagnosing ocular syphilis.
   4. Treatment and management of ocular syphilis in the posterior segment.

Discussion Questions

1. 1. What is the epidemiology of ocular syphilis and why is there a growing concern?
   2. What is the pathophysiology of syphilis and ocular syphilis?
   3. What are the stages of syphilis and in what stage(s) do posterior segment manifestations occur?
   4. What are the signs and symptoms of ocular syphilis in the posterior pole?
      • What signs and symptoms did the patient demonstrate in this case?
   5. What are the most likely differential diagnoses for posterior segment involvement of ocular syphilis based off chief complaints, systemic findings, personal medical and social history and ocular signs and symptoms?
   6. What are important ocular examination tests and systemic testing that need to be considered to make a prompt diagnosis of ocular syphilis?
      • What tests were used to help diagnose the patient in this case?
      • Were there other tests that should have been considered and why?
   7. What are the recommended treatment and management strategies for systemic neurosyphilis and ocular syphilis?
   8. What other healthcare providers should optometrists co-manage with when managing patients with ocular syphilis?
      • What healthcare providers did the patient in this case obtain care from?
      • Are there other healthcare providers that should have been involved in this case?

Discussion

Epidemiology and growing concern of ocular syphilis

Consequently, the resurgence of syphilis has been accompanied by an apparent increase in cases of ocular syphilis. However, because ocular involvement is often underreported, the true magnitude of this increase remains difficult to quantify. The CDC reported in 2016 that it received over 200 cases of ocular syphilis from 20 states over the years of 2014 to 2016.¹² Multiple studies from US, Canada and China have shown that 0.50% to up to 2.6% of those diagnosed with syphilis had ocular syphilis.¹³ The incidence in ocular syphilis and its increase can also vary due to exam coding variability and cases without hospitalizations.¹² Most of the incidences of ocular syphilis manifest in the form of uveitis. A study using the codes of “syphilis and uveitis” extracted from the National Inpatient Sample data records for hospitalized patients in the US from 1998 to 2009 reported the annual incidence 4 per million persons.^2,7 A study in Baltimore reported that from 2013 to 2017 there were 5 cases of ocular syphilis reported per year versus 1.7 per year from 1984 to 2014 in academic and community clinical settings.^13,14

Neurosyphilis, ocular syphilis and otic syphilis, also known as NOO syphilis, is not available as a single national rate, but a CDC report found that 1.5% of all syphilis cases in California and Chicago in 2023 were NOO syphilis.¹⁵ In that same 2023 Chicago report, 60% of those NOO cases were ocular syphilis cases.¹⁵

Pathophysiology

The only vector for the spread of syphilis is humans via sexual contact. The bacteria,Treponema palladium (T. pallidum), infects the human immune system quite easily due to the unrecognizable cell membrane of the bacteria making it difficult for the immune cells to identify and ward off quickly.¹⁶ The immune response is therefore slow and will allow the bacteria to incubate in the body for up to 3 months.¹⁶ This infection leads to chancre formation. Syphilis is spread through chancres, a primary or secondary stage of infection, found on the external genitals, vagina, anus/rectum and mouth. These chancres are often missed or are asymptomatic, and individuals go undiagnosed for years, leading to more transmission since individuals don’t seek care or treatment. Once the painless chancre blisters are exposed, the bacteria can spread via contact with another via mucosal exchange. This leads to lymphadenopathy, causing it to spread to other organs such as the eyes or brain where it can cross the blood-retinal and blood-brain barriers. The inflammation from the immune response created by T. pallidum over the years leads to further ocular findings. T. pallidum also is known to localize to immune-privileged sites, such as the eye, taking on a minimally metabolically active latent form allowing it to persist in the human body for years.^13,17

Stages

The main stages of syphilis are primary, secondary, latent and tertiary. Syphilis most often spreads during the primary and secondary stages of the disease via sexual contact orally, vaginally or through the anus. Infectivity is high with an estimated per partner transmission up to 60% especially with men who have unprotected sex with other men.^13,18 Ocular involvement can occur at any stage of syphilis, but commonly is found during the secondary stage of the infection presenting as anterior uveitis, however ocular syphilis involving the posterior segment is often associated with the tertiary or late latent stages of the infection.

The primary stage of the disease has an incubation period of 25 days, after which a chancre forms.^13,19 The chancre tends to be painless, but ulcerated, with non-purulent discharge that spontaneously resolves even without treatment.²⁰ Again, the chancre will occur at the inoculation site (vagina, penis, anus or mouth) as well regional lymphadenopathy.

The secondary stage occurs 1-2 months after the primary stage due to T. pallidum’s dissemination.²⁰ In this stage the individual can appear to have a maculopapular rash, most commonly found on the palms of the hand or feet, fever and generalized lymphadenopathy that often will spontaneously resolve.²¹

If the secondary stage is left untreated, the patient can enter latent syphilis, an asymptomatic phase. Latent syphilis can recur within 1 year after exposure (early latent stage) or more (late latent stage), remaining infectious and still detectable on serological testing, allowing for further transmission.²² In the late latent stage, about 70% of patients maintain lifetime latency and 30% progress to the tertiary stage.²³

The tertiary stage occurs 2-50 years after infection and has the most long-term complications including cardiovascular syphilis, ocular syphilis, otic syphilis, gummatous disease and late neurosyphilis.²⁰ Late neurosyphilis occurs 5-12 years after the initial infection and can cause general paresis as well as damage to the meninges of the nervous system, which can eventually lead to death.^20,24,25

Posterior Segment Presentations of Ocular Syphilis

Intermediate Uveitis²⁵

• Vitritis: Vitreal cells appear in ocular syphilis to be have a round, white-like appearance and are multiple in numbers.¹⁶ The patient’s vitreal appearance in this case report presented differently with more diffuse haziness and a large coalescing of vitreous cells as seen in Figures 1 and 2. The difference in appearance may be attributable to a combination of inflammatory cells and vitreous hemorrhage secondary to the underlying vasculitis.

Posterior Segment findings (Often presenting as posterior uveitis)

Figure 8. Spectralis OCT macula scan 1 week after initial presentation showing acute posterior placoid chorioretinopathy (purple arrows), often a distinguishing feature of ocular syphilis. Click to enlarge

• Posterior scleritis (rare): Global inflammation to the globe of the outer tunic of the eye affecting superficial and deep capillary networks.²⁶
• Posterior Uveitis:
  • Chorioretinitis/Acute posterior placoid chorioretinopathy (ASPPC) (a distinguishing feature of ocular syphilis): This finding appears as yellowish, poorly defined placoid lesion(s) that is often located in the mid-periphery or posterior pole of the fundus.^20,27 These lesions are characterized by a faded center surrounded with hyperpigmentation of the retinal pigment epithelium (RPE).²⁰ In this case, the patient’s foveal SD-OCT in Figure 8, shows early placoid chorioretinopathy within the posterior pole confirming chorioretinitis is present and the likelihood of a syphilis infection.
  • Focal retinitis/syphilitic punctate inner retinitis (migrating superficial retinal precipitates): Multiple, small, white inflammatory pre-retinal or inner-retinal deposits that form in areas of active retinitis. They are associated with retinal vasculitis leading to retinal pigment epithelium damage. OCT findings will show hyper-reflective dots in the inner retina.²⁸ These inflammatory precipitates were observed in this case report as seen in Figure 9.
    

    Figure 9. Spectralis OCT macula scan 1 week after initial presentation showing syphilitic punctate inner retinitis (blue arrow). Click to enlarge

  • Retinal vasculitis (common): Inflammation of the retinal vessels (arteries, veins and/or capillary networks). This leads to sheathing, perivascular cuffing, perivascular exudation and vascular occlusions leading to pre-retinal hemorrhages, vitreous hemorrhage and neo-vascularization.^{28, 29} Retinal vasculitis findings of pre-retinal and vitreous hemorrhages , as well as vessel sheathing were observed in our patient as seen in Figures 1, 2 and 7.
  • Necrotizing retinitis/syphilis retinal necrosis (SRN): Presents after severe inflammation of the retina that causes death of the retinal tissue leading to irreversible vision loss. It appears as coalescing multifocal lesions that start from the posterior pole and have a layer of exudative membrane obscuring the underlying retina, appearing more mottled.^{16, 28} Fortunately, in the case presented the patient never developed retinal necrosis.
• Exudative retinal detachment: Occurs when fluid leaks into the sub-retinal space due to disruption of the blood-retinal-barrier (BRB) from inflammation, which causes ischemia to the BRB cells.³⁰ Fortunately, the patient in the case report didn’t experience a retinal detachment of any kind.
• Optic disc edema: The optic disc can be affected in one or both eyes. This can present as anterior or retrobulbar optic neuritis.¹⁶ Disc edema was a finding presented in this case as seen in Figure 1, as well as confirmed via the patient’s MRI.

Neurological findings²⁵

• Argyl Roberston pupils: Bilateral, asymptomatic, mitotic, pupils, with anisocoria. Pupils don’t constrict in bright light but constrict with convergence/accommodation (light-near dissociation) and with poor dilation caused by tertiary syphilis.

Differentials for posterior ocular syphilis (Most common of the “Great Masquerader/Mimicker”)^{16, 31}

• Diabetic retinopathy
• Retinal detachment
• White dot syndromes including but not limited to multiple evanescent white dot syndrome (MEWDS)
• Other infectious retinitis (i.e. toxoplasmosis, CMV, HSV)
• Other vasculitis causes (i.e. TB)
• Acute retinal necrosis (ARN)/Progressive outer retinal necrosis (PORN)
• Central serous chorioretinopathy
• Anterior/retrobulbar neuritis due to demyelinating diseases
• Ischemic optic neuropathies

Table 1.^51,52  Testing to be considered when attempting to differentiate syphilis from other underlying conditions that cause similar posterior segment findings. (GCA: Giant Cell Arteritis, TB: Tuberculosis, CMV: Cytomegalovirus, MS: Multiple Sclerosis, NMO: Neuromyelitis Optica, MOGAD: Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease). Click to enlarge

As with the presenting case, many of the patient’s ocular signs and symptoms could point to any of the above differentials. However, there were presenting and evolving findings pointing to the possibility of syphilis. For example, diabetic retinopathy could have been high on the differential list in this case, especially with the appearance of the vitreous hemorrhage. The unilateral appearance and sudden onset of his symptoms as well as his well-controlled blood sugars made this differential unlikely. Upon reviewing the b-scan (Figure 2), although a large vitreous opacity is observed, the retina itself was intact, therefore the likelihood of a retinal detachment was low. White dot syndromes can be ruled out in this patient due to the patient age and sex. While white dot syndromes present with symptoms of photopsia, blurred vision and involve the optic nerve, they also tend to affect young, healthy females. Per the OCT testing of the optic nerves and fovea (Figures 4-9) and fundus photos (Figures 1, 2 and 7), retinitis, vasculitis and optic nerve conditions associated with inflammatory or infectious conditions were highly suspected differentials, as well as optic neuritis and neuropathies. Therefore, proper blood tests, imaging and further case history questioning helped in differentiating likely diagnoses and confirming syphilis. Suggested testing can be found in Table 1.

Diagnosing Ocular Syphilis

Due to the diverse ocular presentations of syphilis, it can be difficult to diagnose. There are limited distinct clinical presentations, therefore it should always be included in the list of differential diagnoses when patients present with any of the following:

1. 1. Sexual activity and previous STI diagnosis: It is important to ask in the case history the patient’s sexual preference and past/recent sexual partners. Previous STI diagnoses can help determine the risk factor for syphilis, especially patients that have HIV/AIDs and/or a previous diagnosis and treatment for syphilis.
   2. Illicit drug use history: A case history inquiring about illicit drug use is pertinent, especially intravenous drug use which can help in determining risks for other infectious disease, such as HIV.
   3. Uveitis (anterior, intermediate and/or posterior): It is the most common manifestation of ocular syphilis.
   4. Patients undergoing treatment for other ocular infections or inflammatory conditions without resolution.

Further case history questioning can be a great way to help rule out other conditions mascaraed as syphilis. This case highlights the omission of pertinent sexual history, including sexual orientation and activity, during the initial case history. Inclusion of this information may have elevated syphilis as a primary diagnostic consideration earlier in the evaluation. Inquiring as mentioned above about IV drug use, sexual history/orientation and previous or current STIs is a great start, but further questioning regarding family history to rule out conditions like sickle cell, TB, diabetes, lung issues or neurological issues should be addressed. Obtaining a thorough environmental history is also essential, including inquiry about prior residence outside the country, exposure to animals (such as birds, cats or dogs), and consumption of raw or unpasteurized foods or beverages. Additionally, it is important to elicit any history of previous inflammatory or infectious conditions, such as lupus, sarcoidosis, Crohn’s disease, ulcerative colitis, Lyme disease, herpes zoster or herpes simplex. General systemic review is also warranted, including questions regarding recent overall health status and the presence of symptoms such as fever, unexplained weight loss, malaise, headache, recurrent infections, cough or dyspnea.

To further expand on case history questions to determine proper referrals or testing, it can be helpful to use a questionnaire, such as the Massachusetts Eye Research and Surgery Institution’s Ocular Inflammatory Disease Review of Systems Questionnaire that can be administered in the office. This questionnaire would have been a great tool for the optometrist in this teaching case to use in developing a proper diagnosis for the patient. 

Appropriate ophthalmic exam testing when ocular syphilis is suspected (none of these tests are diagnostic for syphilis)

1. 1. Color fundus photography or ultra-wide field retinal imaging for general observation of the optic nerve, retinal vasculature, macula and retina (posterior pole to the periphery). In the case presented, syphilis related posterior segment findings can be seen in Figures 1, 2 and 7.
   2. Fundus autofluorescence photos (FAF), best with ultra-wide field cameras, shows greater extent of retinal involvement, specifically the RPE. Unfortunately, FAF was not performed in the presenting case. It would have likely outlined ASPPC, highlighting hyperautofluorescence with placoid lesions and RPE disruption.³²
   3. Spectral domain optical coherence tomography (SD-OCT) is a diagnostic tool to observe disorders of the optic nerve, vitreous, retinal layers and the choroid. Specifically, allowing observation of the ellipsoid layer, RPE and the choroid when evaluating for syphilis involvement as seen in Figures 4-6, 8-9.
   4. Fluorescein angiography (FA) is utilized to evaluate retinal and choroidal circulation, with particular attention to vascular integrity and the function of the blood–retina barrier. In ocular syphilis, retinal vasculitis typically manifests as vascular leakage; optic neuritis presents with optic disc leakage; and chorioretinitis is characterized by early hypofluorescence followed by late hyperfluorescence.³³ The patient’s FA presented in this case, demonstrated severe perfusion delay in the left eye with poor filling of the superior-temporal artery with noted plaques indicating retinal ischemia. An FA would also be used to monitor for the development of retinal necrosis.

Serological Testing

Serological testing remains the gold standard for diagnosing or ruling out syphilis. This testing can be ordered by the patient’s primary care doctor, an ophthalmologist, an infectious disease doctor, neuro-ophthalmologist/neurologist or an emergency medical provider.  If an optometrist has lab privileges, they can order this testing, but positive testing would require a referral to an infectious disease provider for proper management. A biopsy of a lesion is the most definitive way to diagnose early syphilis, using polymerase chain reaction tests with darkfield microscopy.²⁰ However, darkfield microscopy is hardly used due to is lack of availability in most clinical settings and the need for a lab to have the specific microscope and training for this specific test.³⁴ Therefore, serological testing using non-treponemal test and a treponemal test is often done to diagnose syphilis.^20,22,25,35 Both the serological testing and biopsy detect the presence of Treponema pallidum. Non-treponemal tests include Venereal Disease Research Laboratory (VDRL) and RPR. Both tests detect antibodies against the membrane phospholipids and are simple, rapid and inexpensive to obtain.²⁰ Although they are not specific to detecting syphilis, they are good indicators of the disease activity for early syphilis, becoming positive within 1-3 weeks after the appearance of a primary lesion.²⁰ The VDRL test is positive in 99% of patients with secondary syphilis, however in later stages of the disease, its sensitivity decreases and only about 70% of patients with tertiary syphilis test positive.¹⁶ VDRL stereological testing has a higher sensitivity in latent stages and CSF VDRL testing is better in detecting neurosyphilis.³⁶ VDRL and RPR titers will decrease once treatment is administered and is determined successful when titers are non-reactive. However, it is important that only the VDRL or the RPR, not both, be used in diagnosing and monitoring progress of treatment because the quantitative results from the two tests are not directly comparable. In contrast, treponemal testing detects the antibodies that are specific for syphilis and will remain positive for life, confirming the diagnosis but not used to determine responses to treatment.^20,23,25 Therefore, treponemal testing is highly specific for T. Pallidum and includes enzyme immunoassay (EIA), T. Pallidum hemagglutination tests (TP-HA or TP-PA), and the most commonly used fluorescent treponemal antibody absorption test (FTA-ABS). The FTA-ABS test is highly specific for syphilis but can show false positive results in patients with rheumatoid arthritis, biliary cirrhosis, systemic lupus erythematosus, hepatitis, HIV, infectious mononucleosis, rickettsial disease, scarlet fever and in pregnancy.^16,37

Serological testing of both non-treponemal and treponemal tests need to be performed to increase the sensitivity and specificity for the diagnosis of syphilis. The CDC recommends using either one or both of the following algorithms when testing for syphilis depending on the test volume, laboratory resources and patient populations:³⁶

• Traditional screening:³⁶ VDRL/RPR as the initial screening test, followed by treponemal testing, such as the FTA-ABS if the screening test is found positive (Chart 1). The advantage of using this algorithm is that it may be more widely available. Disadvantages in using the traditional screening is it may be less sensitive in finding earlier or late latent syphilis.³⁸

Chart 1. Flow chart of traditional screening algorithm for confirming the diagnosis of syphilis. Click to enlarge

• Reverse-Sequence screening⁽³⁶⁾: A treponemal specific immunoassay, such as the EIA or CIA as initial screening test, followed by a non-treponemal titer VDRL/RPR test if the EIA or CIA is positive. If the VDRL/RPR are non-reactive, then a treponemal test, such as the FTA-ABS is performed for confirmation (Chart 2). The advantage of this algorithm has a quicker turnaround for test results and is more sensitive in detecting early and latent syphilis. The disadvantage is that it could produce more false positives in populations with lower prevalence of syphilis⁽³⁸⁾.

Chart 2. Flow chart of reverse-sequence screening algorithm for confirming the diagnosis of syphilis. Click to enlarge

If a patient is found to be positive for syphilis and has ocular manifestations, cerebral spinal fluid should be analyzed, with VDRL and FTA-ABS testing, for a true diagnosis of neurosyphilis. In the presented case, a lumbar puncture was ordered, but the patient refused to undergo the testing. When this diagnosis is confirmed, it is important for an infectious disease doctor to be incorporated into the patient’s care to initiate a proper treatment protocol. At the time of a syphilis diagnosis, all patients should undergo HIV testing due to the strong association between the two infections. In this case, the patient was appropriately tested for HIV, and the result was negative. Co-infection can also lead to an increased risk of developing neurosyphilis due to its increased association with posterior uveitis due to syphilis.³⁹ There is a higher correlation for co-infection in HIV patients that had CD4 counts greater than 200 cells/mm³ and higher titers RPR/VDRL.³⁹ This is believed to result from syphilis remaining undetected due to the false-negative prozone phenomenon, in which non-treponemal tests yield negative results despite active infection. Consequently, without timely initiation of systemic penicillin therapy, the disease may progress to later or latent stages.³⁹ That is why in cases with co-infection, the reverse screening algorithm can be better at catching false negatives. Although it is unclear why this association exists, it is believed that HIV causes the natural history of treponemal infection to change and therefore is not detectable.³⁹

Treatment

Once the diagnosis of ocular syphilis has been established, the patient is subsequently treated as having neurosyphilis, a subset of syphilis involving neuronal tissue that can present in any stage of syphilis. There are treatment protocols for each stage of the disease per the CDC to decrease the risk of the infection progressing to a higher staging level:

1. 1. Primary and secondary syphilis: Treatment with a single dose of intramuscular (IM) penicillin G benzathine or procaine penicillin (non-generic) and probenecid (a treatment to inhibit renal drug excretion), as well as 1 g of either penicillin orally 4 times/day for 14 days. For those allergic to penicillin, doxycycline 100 mg orally twice a day for 14 days or ceftriaxone 1 to 2 g IM or intravenously (IV) daily for 10-14 days or tetracycline 100 mg orally 4 times/day for 14 days.^16,40
   2. Latent and tertiary syphilis (including neurosyphilis and ocular syphilis): Treatment includes aqueous crystalline penicillin G 3 to 4 million units IV every 4 hours for 10-14 days or benzathine penicillin G 2.4 million units IM weekly for 3 weeks. Ceftriaxone and azithromycin have been used as well.^16,26
   3. For pregnant people, penicillin is the only documented treatment that has established efficacy for treating syphilis. For those that are allergic, they are desensitized first and then treated.¹⁶
   4. Adjunct Treatment with Corticosteroids
      • Jarisch-Herxheimer reaction can occur in the first 24 hours of initial treatment with IV penicillin due to a hypersensitivity reaction to treponemal antigens released as the spirochetes are attacked.^3,23 This reaction may also lead to an increase in severity of ocular manifestations of syphilis.⁴¹ Therefore, it is recommended that IV methylprednisolone be used before initiation of IV penicillin and continued for the next 48 hours.⁴¹
      • Oral corticosteroids would be introduced after antibiotic treatment to reduce intraocular inflammation for the treatment of posterior uveitis, vitritis, scleritis and optic neuritis.⁴¹
      • The use of periocular and intraocular steroid injections has been correlated to treatment failure due to the risk of bacterial or virus growth, activating dormant infections that could lead to CMV retinitis.^3,42-44

Prognosis

The prognosis of ocular syphilis can be good when the disease is diagnosed early and treated promptly. Some studies have shown an over 90% improvement in visual acuity to 20/40 or better, while others have shown a 30-40% visual acuity loss of 20/50 or worse despite treatment.^{3,13,39,41,45-47} Prompt systemic treatment with penicillin within 1 month after the onset of ocular manifestations implies the best chance for favorable visual outcomes, especially in those with concurrent HIV.^3,48,49 Permanent vision loss occurs due to structural damage to the retina, especially the macula and the optic nerve. Quality of life may be decreased based on a diagnosis of ocular syphilis, not only due to the possibility of irreversible vision loss, but other issues, such as time away from a job and family, obligations to receive care and the mental health and social stigma of having a known STI.

Due to the complexity of diagnosing, treating and managing ocular syphilis, it is important to have multiple healthcare providers involved in the patient’s care. Inter-professional communication between them is vital to ensure a proper diagnosis in addition to appropriate and timely treatment and management. The healthcare providers involved in this care often include an optometrist, ophthalmologist, primary care physician, neurologist/neuro-ophthalmologist and an infectious disease specialist. Each provider has an important role in continuing care with the patient during and after treatment to ensure the best systemic and ocular outcome. The ophthalmologist, often a retinal specialist, will monitor the posterior findings, ensuring that inflammation is improving and necrosis doesn’t develop. They would also treat any residual ocular complications not resolved after IV penicillin G treatment. For example, an unresolving vitreous hemorrhage would be treated with an Anti-VEGF injection, or if posterior inflammation was persistent, oral steroids would be started. As mentioned above, intra-ocular injections of steroids for the treatment of persistent macular edema should be cautioned until effective systemic penicillin treatment has been initiated and a response in decreased titers is established.  A neuro-ophthalmologist or neurologist will continue to monitor the optic nerve and to ensure no other neurological conditions and symptoms arise, such as, meningeal/meningovascular involvement, paresis or mood/personality/memory changes.⁵⁰ The infectious disease specialist will provide treatment and monitor titers to ensure that the treatment is working, as well as managing co-existing infections like herpes and HIV that are common with a syphilis diagnosis. Once the infection resolves, it’s important for the PCP to continue appropriate long-term follow-ups to ensure no new symptoms of infection arise by testing regularly and evaluating the skin in high prevalence areas where the infection can arise.

Optometrists can play an important role in identifying patients at risk for syphilis, by identifying rashes on hands, observing or asking about chancres and administering the MERSI questionnaire for patients. Optometrists also are necessary during and after treatment of syphilis, continuing to provide regular comprehensive eye exams and communicating with other co-managing providers about any new ocular changes or increased lifestyle activity (i.e. New sexual partners, IV drug use or exposure to syphilis, or other STI, especially HIV) that could pose an increase in another infection. Also, if visual outcomes are not ideal, they can provide patients with glasses, low vision devices and services in hopes of optimizing the patient’s vision and quality of life.

Conclusion

In conclusion, ocular syphilis, especially with posterior segment involvement, can lead to significant visual impairment if not diagnosed and treated promptly. Optometrists play an important role in diagnosing the risks for syphilis when it presents with posterior uveitis, vitritis, vitreous hemorrhage and/or optic neuritis, which are also seen with many other ocular conditions. This teaching case represents the importance an optometrist can have in identifying the risks for syphilis when patients present with similar ocular findings. In this case, although the optometrist considered appropriate differential diagnoses and made a suitable referral, a more comprehensive case history, specifically related to sexual activity and orientation, as well as the application of the MERSI questionnaire might have facilitated a more accurate and quicker diagnosis. Ultimately, serological testing is paramount to confirm syphilis, this case demonstrated the importance of other appropriate testing to rule out other mimicking conditions.  Once syphilis is confirmed, interdisciplinary collaboration is vital to ensure timely treatment is initiated in hopes of achieving ideal patient outcomes.

Scleritis is a rare but critical ocular condition that consists of painful inflammation of the sclera.¹ The condition often presents as a painful red eye that may be unilateral or bilateral in nature.² Scleritis is a significant condition because it can be vision threatening;^1,3,4 therefore, proper diagnosis and management are crucial. Scleritis may be caused by underlying inflammatory systemic disease or an infectious etiology and thus a proper workup to determine the underlying cause of the condition is critical for successful disease management. Scleritis management is often complex and involves a team of healthcare providers. Optometrists can play a key role in the healthcare team managing a case of scleritis, particularly as they may be the first providers to see and identify the condition. The following clinical case discussion is directed toward third- and fourth-year optometry students, optometry residents and practicing doctors.

Case Description

Optometry, Initial Presentation, Visit 1

A 43-year-old White male presented to the optometry department for a problem specific eye exam. His chief concern was a bilateral red eye with a deep pain in and around both eyes for 4-6 weeks. Signs and symptoms were greater in the left eye than the right eye. He rated the pain a 10 out of 10 with 10 being the worst pain imaginable in both eyes. He was mildly light sensitive but denied double vision, discharge or other associated symptoms. The patient reported that he was previously seen at another eye clinic about 4 weeks prior and again 2 weeks ago but had not experienced any relief of his symptoms despite those visits and compliance with recommended treatment. The medical records from the external eye clinic were requested, received and reviewed during the exam.

The patient’s ocular history was significant for myopia, corrected with spectacles and soft contact lenses. The external records indicated that he had a “significant history of soft contact lens overwear and contact lens associated red eye (CLARE),” for which he had been treated with antibiotic-steroid combination eye drops on multiple occasions in the past and was a known steroid responder when using such drops. He also had a history of chronic mild dry eye for which he used artificial tears twice a day in both eyes and stable lattice retinal degeneration in both eyes. The notes indicated that the patient was last seen 2 weeks ago at the external clinic for a follow up visit as he had been diagnosed with CLARE in both eyes and was to discontinue soft contact lens wear until the condition resolved. When the discontinued use of soft contact lenses did not provide relief, he presented to our eye clinic.

The patient’s medical history was significant for hypertension, lower back pain and joint pain which he attributed to a prior work injury. He had no history of concussion or traumatic brain injury (TBI). The patient’s hypertension was managed with lisinopril, and he took 200 mg of ibuprofen as needed for the lower back and joint pain. The patient’s father also had hypertension, but the family medical and ocular history were otherwise unremarkable. The patient was a former smoker and reported drinking alcohol socially with no recreational drug use.

At presentation, his visual acuities with habitual spectacle correction were 20/20 right, left, and both eyes at distance and near. Pupils and confrontation fields were unremarkable in both eyes. Extraocular muscle movements were smooth, accurate, full and extensive. However, the patient reported a “deep pain” in downgaze of both eyes, which was caused by the congestion and inflammation of the scleral shell where the extraocular muscles insert.

Anterior segment evaluation revealed mild capped Meibomian glands of both eyes. The conjunctiva, episclera and sclera presented a diffuse deep red injection worse in the left eye than the right eye. The left eye also had a mild conjunctival chemosis (Figures 1A and 1B). There were no visible nodules, areas of scleral whitening or capillary non-perfusion in either eye. The cornea had a few small scattered round scars in the periphery of both eyes, presumed to be old scarred subepithelial infiltrates (SEI) from past episodes of CLARE. There was mild pannus around the limbus in both eyes. There was no active dendrite or corneal ulcer in either eye. The anterior chamber was deep and quiet in the right eye, but had a mild cell and flare reaction in the left eye. The iris was flat and clear and the Van Herick angle estimation was 1:1 in both eyes. Intraocular pressures (IOP) by Goldmann Applanation Tonometry (GAT) were 15 mmHg in the right eye and 17 mmHg in left eye. The patient was dilated with 2 drops of tropicamide 1% in each eye. Of note, phenylephrine 2.5% was not available in the clinic on the day of presentation.

Figure 1A. Anterior segment photography of the right eye displaying conjunctival, episcleral and scleral injection. Click to enlarge

Figure 1B. Anterior segment photography of the eft eye (B) displaying conjunctival, episcleral and scleral injection. Click to enlarge

The dilated ocular health exam revealed a clear media without vitritis, vasculitis or retinitis. The macula was flat and clear in both eyes. The optic nerve head appeared healthy, well perfused and had a cup to disc ratio of 0.35/0.35 H/V in both eyes. There was lattice retinal degeneration inferiorly in both eyes, with no other significant peripheral retinal findings in either eye.

Figure 2. ASOCT images of (A) a normal conjunctiva, episclera and sclera and of our patient’s scleritis in the right eye (B) and left eye (C). The circular hypopigmented spaces with an underlying shadow are blood vessels. The horizontal lines of hypopigmented spaces between or within layers are edema. The deep delamination and edema is highly suggestive of scleritis in both eyes. Click to enlarge

Ancillary testing was performed the same day including anterior segment photography (Canon USA Inc.)^a and anterior segment optical coherence tomography (ASOCT) (Heidelberg Engineering)^b. The anterior segment photos showed diffuse moderate injection of both eyes (Figures 1A and 1B). The ASOCT line scans through the conjunctiva, episclera and sclera showed blood vessel dilation and edema of all layers (Figure 2).

The patient was diagnosed with presumed diffuse anterior non-necrotizing scleritis of both eyes and mild anterior uveitis of the left eye believed to be associated with the scleritis. The patient was extensively educated on the condition and was started on 400 mg of ibuprofen orally 4 times per day. A table with all prescribed medications over the course of the patient’s treatment can be found in Table 1. Ophthalmology was consulted to assist in management and determining the causative etiology of the suspected scleritis and the patient was scheduled with the uveitis clinic 2 days later. Assessments were also made to acknowledge the patient’s history of dry eye, CLARE with associated corneal remnant findings, prior steroid response, lattice retinal degeneration and refractive error. The patient was instructed to maintain discontinuation of soft contact lenses until the suspected scleritis was under control.

Table 1. Medications prescribed for the patient during the course of his treatment. Click to enlarge

Ophthalmology, Uveitis Clinic, Visit 2

At the ophthalmology consultation 2 days later, the patient’s presenting symptoms, visual acuity and entrance test findings remained unchanged from the prior visit. The anterior segment assessment was also unchanged with the exception of a mild anterior chamber reaction now noted in the right eye in addition to the left eye. IOP by GAT was 17 mmHg in each eye. The patient was dilated with 2 drops of tropicamide 1% in each eye. The dilated posterior segment exam was also unchanged from the previous visit.

Table 2. Blood work, labs and imaging that are often or may be ordered in the presence of scleritis to rule out systemic etiology.12 *Reference ranges were provided by the laboratory with the blood work results. Reference ranges may vary slightly between laboratories. **The only positive findings that our patient had from ordered labs was CCP Ab IgG, which was >250 units compared to the reference ranges listed above. Click to enlarge

The ophthalmology clinic supported the presumed diagnosis of scleritis in both eyes and changed the oral nonsteroidal anti-inflammatory (NSAID) from ibuprofen 400 mg 4 times per day to indomethacin 75 mg orally 2 times per day. The patient was also started on Pred Forte® (prednisolone acetate 1% ophthalmic suspension) 4 times per day in both eyes in addition to cyclopentolate 3 times per day in both eyes for the anterior chamber reaction. Prophylactically, brimonidine tartrate ophthalmic solution 0.2% 2 times per day in both eyes was prescribed due to the patient’s history of being a steroid responder.

Blood work was ordered including rapid plasma reagin (RPR), fluorescent treponemal antibody-absorption (FTA-ABS), Lyme titers, rheumatoid factor (RF), cyclic citrullinated antibody (CCP Ab IgG), human leukocyte antigen B27 (HLA-B27), antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), basic metabolic panel (BMP), thyroid-stimulating hormone (TSH), complete blood count (CBC), angiotensin converting enzyme (ACE) and a chest x-ray (CXR). See Table 2 and discussion below for additional information on recommended blood work. The patient was referred to both rheumatology and dermatology for comprehensive evaluation and was directed to follow up with the ophthalmology clinic in 1 week.

Ophthalmology, Uveitis Clinic, Visit 3

At the 1 week follow-up visit to ophthalmology, the patient’s condition was essentially unchanged from the previous assessment. The patient experienced gastrointestinal (GI) upset due to the high dose oral NSAIDs prescribed, and thus was switched to oral steroids in order to treat the scleritis but avoid the GI symptoms. The labs and blood work were completed and all were negative or within normal ranges with the exception of CCP Ab IgG which came back at >250 units. The reference ranges for CCP Ab IgG were: <20-50 units is normal, and >59 units is considered a strong positive for rheumatoid arthritis (RA). Interestingly, the RF blood work came back negative.

Given the lack of improvement in the condition and GI symptoms, indomethacin was discontinued and oral prednisone 20 mg 2 times per day was initiated. In addition, the patient was switched from Pred Forte® 4 times per day, both eyes to Durezol® three times per day, both eyes. The patient was to continue cyclopentolate 3 times per day both eyes and brimonidine 2 times per day both eyes. The patient was directed to return to the ophthalmology clinic in 1-2 weeks for follow-up.

Rheumatology Consultation, Visit 4

About 2 weeks after the initial ophthalmology consultation the patient had their comprehensive rheumatology examination and was diagnosed with RA given their history of back and joint pain and the strong positive CCP Ab IgG lab results. The patient was instructed to begin subcutaneous methotrexate injections 20 mg weekly with folic acid supplement. The patient was instructed to return to rheumatology in 4 weeks for follow-up and continue with ophthalmology as directed. The dermatology consultation was canceled.

Ophthalmology, Uveitis Clinic, Visit 5

Two weeks after the rheumatology consultation, the patient returned to the ophthalmology clinic for follow-up. The patient’s signs and symptoms were improved, and he reported decreased eye pain, headaches and redness. At this visit, the patient was taking oral prednisone 20 mg orally 2 times per day, Durezol 3 times per day both eyes, brimonidine 2 times per day both eyes and subcutaneous methotrexate injections 20 mg weekly. He had self-discontinued the cyclopentolate eye drops at some point in the week prior as he did not like the blurred vision and light sensitivity.

The patient’s examination findings were consistent with moderate improvement in the left eye greater than the right eye; however, his IOP had increased to 26 mmHg in each eye, about 10 mmHg higher than his usual IOP. Because of the increased IOP, the brimonidine dosing was increased to 3 times per day in both eyes, and Cosopt® (dorzolamide/timolol) 2 times per day in both eyes was initiated. A slow taper of the oral and topical steroids was started due to the improvement seen in the scleritis and anterior uveitis at this visit. The patient was instructed to return to ophthalmology in about 2 weeks for a pressure check and follow-up.

Optometry, Visit 6

About 2 months after the initial optometry presentation, and 4 weeks after his last ophthalmology examination, the patient returned to our optometry clinic. The patient had missed his most recently scheduled ophthalmology follow-up appointment 2 weeks prior. He reported that his symptoms had significantly improved and that he no longer experienced headaches or eye pain in either eye. He was using Durezol® which was currently being tapered at 2 times per day in the right eye and 1 time per day in the left eye for 1 more week, oral prednisone which was being tapered as well and was down to 20 mg daily for 2 more weeks, brimonidine 3 times per day both eyes and Cosopt® 2 times per day, both eyes. In addition, the patient was using subcutaneous injections of methotrexate with a folic acid supplement to manage the RA. He was due to repeat all blood work in 2 weeks.

Upon examination, his visual acuities were 20/20 in each eye with correction, and extraocular muscle movements, pupils and confrontation field were unremarkable; there was no pain on eye movement. Anterior ocular health evaluation revealed mild injection of the temporal conjunctiva of the right eye, otherwise both eyes were white and quiet. The scarred corneal SEI’s and pannus were stable in both eyes. There was no anterior chamber reaction of either eye. IOP measurements were 17 mmHg in each eye. Dilated posterior ocular health assessment was stable to prior assessments.

Examination findings were communicated with ophthalmology and rheumatology and the patient was scheduled to return to ophthalmology in just over 2 weeks so that the results of his next blood work would be available for that evaluation. The patient was directed to continue the tapering plan as outlined by ophthalmology for both the oral and topical steroids, and to continue the other medications as prescribed. He planned to continue care with ophthalmology and rheumatology and follow up with the optometry clinic for comprehensive care or sooner as directed by the tertiary providers. The patient was educated that he may resume soft contact lens wear, but not to instill ophthalmic eye drops while wearing the lenses. Contact lens infection precautions were reviewed. A timeline of the visits outlined above is available in Figure 3.

Figure 3. Timeline of visits with the healthcare team who worked together to manage the patient’s condition. *Acronyms: AT = artificial tears, CLARE = contact lens associated red eye, CCP IgG = cyclic citrullinated peptide immunoglobulin G, D/c = discontinue, IOP = intraocular pressure, NSAID = nonsteroidal anti-inflammatory, OD = oculus dexter (right eye), OS = oculus sinister (left eye), OU = oculus uterque (both eyes), RA = rheumatoid arthritis, SCL = soft contact lens. Click to enlarge

Educator’s Guide

Key Concepts

1. Ocular manifestations of systemic vasculitides
2. Ocular and systemic ancillary testing, imaging and lab work
3. Management of ocular disease with high criticality
4. Interprofessional care

Learning Objectives

1. Describe the characteristic signs and symptoms of scleritis
2. Differentiate scleritis from episcleritis or other similar conditions
3. Describe the classifications of scleritis and key features of each classification
4. Identify systemic conditions associated with scleritis and other potential causes of the condition
5. Identify which tests should be performed to confirm or rule out scleritis
6. Outline a (co-)management plan for a patient with scleritis and develop a referral letter for interprofessional care

Discussion Questions

Knowledge, understanding and facts about the clinical case and condition presentation

1. What is the pathophysiology of scleritis?
2. Describe the typical signs and symptoms of scleritis.
3. What differentiates non-necrotizing scleritis and necrotizing scleritis?
4. Name systemic conditions associated with scleritis.

Differential diagnosis

1. What other conditions are on your list of differential diagnoses?
2. How can scleritis be differentiated from episcleritis?
3. What examination techniques or tests can you utilize to help confirm or rule out a diagnosis of scleritis?

Patient management and role of the optometrist

1. What is the typical prognosis of scleritis?
2. How would you treat anterior non-necrotizing diffuse scleritis? How would your treatment plan change if the condition was necrotizing?
3. How would you communicate your case to other healthcare professionals who may become involved in case management?

Critical-thinking concepts

1. If the scleritis is not responding well to the initial treatment, what other tests should be considered? What other therapies should be considered or changed to manage the condition?

Assessment of Learning Objectives

This case may be used in both the didactic classroom or clinical education setting. In the classroom, this case can be presented as part of a lecture on scleritis in an ocular disease course for third- or fourth-year optometry students. Live quiz features during the presentation such as PowerPoint® Polling (PointSolutions, Turning Tech Intermediary, Inc.^c) or Zoom Polling (Zoom Video Communications, Inc.^d) may assess understanding of key concepts in real time. Knowledge can also be assessed through traditional examination techniques such as multiple choice, “one best answer” or fill in the blank questions based on general knowledge of the condition or through short case-based questions.

In the clinical education setting, this case may be used as part of a journal club presentation or grand rounds discussion. The questions outlined above can be used to facilitate small group discussions about the case and condition.

The recommended approach for this case would be to first review the key concepts, learning objectives and read the discussion questions. Then, read the case presentation and discussion. Finally, answer the discussion questions to satisfy the learning objectives.

Discussion

Epidemiology and Pathophysiology

Scleritis is a rare condition that consists of a painful inflammation of the sclera and potentially other surrounding tissues.¹ The sclera itself is the protective shell of the eye comprised of an extracellular matrix. It is innervated by the ciliary nerves, and the extraocular muscles have points of insertion along the scleral shell.⁵ Anteriorly, the sclera meets with the cornea at the limbus and posteriorly it is continuous with the exception of where it is pierced by the optic nerve. The sclera itself is avascular, but the deep episcleral vascular plexus sits just atop the scleral shell anteriorly while the vortex veins drain posteriorly to the ophthalmic vein. Vasculitis of this deep vascular plexus causes the inflammation and classic deep red appearance associated with scleritis.¹ It is thought that the cause of this vasculitis is often due to autoimmune mechanisms including immune complex mediated inflammation.⁶ Pain on eye movements associated with scleritis is due to the extraocular muscle insertion into the scleral shell which, if inflamed, will cause pain with contraction of the muscles.

Scleritis can be classified by location, diffuse or nodule nature and presence or absence of necrotization. Scleritis can occur anterior to the insertion of the recti muscles (anterior scleritis), posterior to their insertion (posterior scleritis) or both simultaneously. In addition, scleritis can be identified as occurring in a diffuse or nodular form, determined by the presence or absence of an associated nodule. Arguably most important is the ability to classify the scleritis as necrotizing or non-necrotizing as necrotizing scleritis poses an immediate threat to vision and is a true ocular emergency.⁷ Necrotizing scleritis can occur with inflammation or without inflammation; the form without inflammation is also referred to as scleromalacia perforans. Necrosis in scleritis will appear as a whitening of the conjunctival and scleral tissues associated with capillary non-perfusion and absence or death of the vasculature. Necrotizing scleritis without inflammation is an exception to the typical painful presentation of scleritis because it is a chronic wasting of tissue heavily associated with chronic RA and is often asymptomatic.⁸ The scleral tissue slowly wastes away over time and the purple uveal tissue will show through. It is often seen coincidentally on an eye examination due to the asymptomatic nature and gradual chronic progression. Scleritis can occur in one eye or both eyes simultaneously. Bilateral scleritis is thought to be more often associated with systemic disease than unilateral presentations.^2,9,10

While the cause of scleritis can be due to idiopathic inflammation, up to 40 to 50% of cases are associated with systemic conditions or infection.^10-12 As mentioned, it is thought that the vasculitis is immune mediated and possibly caused by immune complex deposition or the upregulation of proinflammatory cytokines. Given this autoimmune pathophysiology, common conditions associated with scleritis include RA, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), reactive arthritis, polychondritis, juvenile chronic arthritis and seronegative polyarthritis to name a few.^12,13 Granulomatous conditions have also been associated with scleritis including Wegener’s granulomatosis and sarcoidosis. Infections are a less common cause of scleritis than systemic disease, but still must be considered, especially postoperatively. The herpes virus is the most common cause of infectious scleritis.¹⁴ Scleritis can occur due to a spillover of an infectious keratitis or can occur due to infection from a retained foreign body or postoperative complications.

Historically, studies have shown that scleritis tends to occur in women more than men and it is thought that this may be due to the higher prevalence of autoimmune conditions in women.¹⁵ However, some recent studies in Asia have shown a slight male preponderance.² Scleritis most often presents in the fourth to sixth decade of life.¹⁵

Clinical Presentation and Prognosis

The classic presentation of scleritis is a very painful, red eye with scleral edema. Due to the depth of the vessels involved and the significant vascular dilation, the red appearance is often a deep red to purple color, sometimes called a violaceous hue.^5,16 The scleral edema associated with anterior scleritis can be observed in natural light, on careful slit lamp examination and with ASOCT.^17-19 If ischemia or necrosis are present, areas of the sclera may appear as a stark white due to the loss of the vasculature in that area. While the deep red appearance is classic with anterior scleritis, posterior scleritis alone (not in conjunction with anterior scleritis) can be harder to discern since the anterior scleral vasculature may not be as obviously inflamed. A careful dilated examination and additional ocular imaging are warranted in cases of suspected posterior scleritis as discussed below.¹²

Patients with scleritis are often in a significant amount of acute or subacute pain due to the degree of vascular dilation and scleral edema. The pain is often described as a deep boring pain that can be felt in the orbit and surrounding tissues.¹ The pain is often worse on eye movements because of the recti muscle insertions into the sclera.

Due to the inflammatory nature of the condition, scleritis may present with associated inflamed ocular tissues including the cornea, ciliary body and trabecular meshwork resulting in keratitis, anterior uveitis and increased intraocular pressure, respectively.¹ Anterior uveitis may present in up to 42% of cases of scleritis.¹⁰  Posterior scleritis may present with other posterior segment findings including exudative retinal detachment, serous retinal detachment, cystoid macular edema, choroidal effusion syndrome, swollen optic discs, choroidal folds, and retinal vascular occlusion, and therefore a careful dilated fundus examination is warranted.^20-22  The vision may be reduced due to these potential findings accompanying the scleritis.

Scleritis is potentially sight threatening and thus must be managed accordingly.^1,3,4,23 The type and severity of the condition determines the likelihood of vision loss with moderate to severe and necrotizing disease being more at risk. Scleritis with necrosis has a high risk for globe perforation highlighting the importance of determining the presence or absence of necrosis on ocular examination. It is imperative to determine the underlying cause to accurately treat the condition and reduce the risk of complications and poor visual outcome.

Ancillary Testing and Differential Diagnosis

When scleritis is suspected, certain ocular testing should be performed including: a thorough case history, a review of systems (ROS) to identify potential systemic disease associations, visual acuity, extraocular muscle movements, a thorough slit lamp examination, intraocular pressure measurement and dilated fundus exam.¹² Anterior segment photography and ASOCT may be helpful to follow and confirm or rule out a diagnosis of scleritis. ASOCT allows the examiner to observe all layers of the conjunctiva, episclera and sclera and determine the depth and extent of the inflammation.¹⁷ If posterior scleritis is suspected, then a B-scan ultrasound should be performed looking for posterior scleral thickening which creates a “T” shape between the sclera and optic nerve known as the “T-sign”.²⁴ OCT with enhanced depth imaging (EDI-OCT) may also be considered for posterior scleritis imaging as posterior segment and choroidal thickness can be assessed.²⁵

In addition to the ocular examination, a complete physical examination should be performed including blood work. Blood work is used to confirm or rule out the presence of causative systemic conditions such as RF and CCP Ab IgG for RA, ANA for SLE, ANCA for Wegener’s granulomatosis and polyarteritis nodosa (PAN), ESR and CRP for giant cell arteritis (GCA), uric acid for gout, CBC for general systemic health and infectious etiology, RPR and FTA-ABS for syphilis, and ACE for sarcoid.^12,14 See Table 2 for a more thorough outline of recommended blood work in a scleritis workup and reference ranges. Additional tests may be considered if suspicion for other etiologies exists including purified protein derivative (PPD) for tuberculosis (TB), CXR for TB and sarcoid, Lyme titers for Lyme disease, magnetic resonance imaging (MRI) and computed tomography (CT) to rule out a neoplasm.¹² As noted above, systemic disease is a common cause of scleritis and thus blood work is paramount for determining the underlying cause of the condition at presentation.

The differential diagnosis for scleritis should include severe cases of conjunctivitis or episcleritis, and keratitis with spillover to the sclera. One exam technique that allows the examiner to differentiate scleritis from severe cases of conjunctivitis or episcleritis is the use of phenylephrine 2.5% ophthalmic eye drops to induce blanching or whitening of the conjunctival and episcleral vessels. Deeper vessels will not blanch as seen in cases of scleritis and thus the presence of blanching after phenylephrine instillation is consistent with conjunctivitis or episcleritis.²⁶

A careful slit lamp examination can determine the presence of keratitis and associated corneal findings such as ulceration. Scleritis can occur as a result of an infectious keratitis, and infection must be considered if there are corneal findings when a scleritis is present.²⁷ Culturing the ocular tissue would be helpful for this determination. Additionally, corneal findings such as peripheral ulcerative keratitis (PUK) may accompany scleritis more commonly in causative systemic conditions such as Wegener’s granulomatosis; Wegener’s should be considered any time corneal findings present simultaneously with scleritis.²⁸

Less common differentials for scleritis may include infectious orbital disease such as orbital cellulitis and endophthalmitis.^29,30 Thorough case history and careful ocular examination can assist in this differentiation, as well as close monitoring of response to treatment. There are also case reports of ocular tumors masquerading as scleritis, highlighting the importance of considering additional imaging.^31,32  Ocular tumors must be considered if scleritis is not responding to initial treatment.

Treatment and Management

Treatment for scleritis depends on the causative agent. For diffuse and nodular anterior non-necrotizing and non-infectious disease, high dose oral NSAIDs and oral steroids are considered in first line treatment.^32-34 Oral NSAIDs are often tried in sequential order including ibuprofen 400 to 600 mg by mouth 4 times per day, naproxen 250 to 500 mg by mouth twice a day, and indomethacin 25 mg by mouth three times a day, respectively.¹² Of note, if prescribing high dose oral NSAIDs, a histamine type 2 receptor blocker or proton pump inhibitor is advised to reduce the likelihood of GI upset. Oral steroid prescribing may include prednisone 60 to 100 mg by mouth daily for 1 week, tapering to 20 mg daily, very slowly over a 2-6 week period, followed by an even slower taper after that. If both oral NSAID and oral steroid therapy are unsuccessful, immunosuppressive agents such as methotrexate, cyclophosphamide, azathioprine and anti-tumor necrosis factor alpha are considered.¹² Failure of NSAID and steroid therapy is also indicative of an undetermined underlying cause and additional testing and imaging should be considered if not already performed.

If the scleritis is necrotizing in nature or non-necrotizing but severe, oral NSAIDs are often skipped and oral steroids alone or in combination with immunosuppressive agents are used in the same prescribing dosages as outlined above.¹² Necrotizing disease has an increased risk of perforation and thus perforation precautions should be considered including polycarbonate lens protection, a fox shield during sleeping hours and scleral patch grafting depending upon the extent of the scleral thinning.¹² Necrotizing disease warrants an urgent/immediate assessment with ophthalmology due to its vision threatening nature.

Due to the high likelihood of associated systemic disease and complex nature of scleritis, the condition is often co-managed by a team of healthcare providers.³⁵ The team may include but is not limited to optometrists, ophthalmologists, primary care providers, rheumatologists, dermatologists and infectious disease experts. Excellent communication and interprofessional care is often required to successfully manage cases of scleritis caused by systemic or infectious disease. The follow-up plan for scleritis depends on the cause and severity of the disease. Close follow-up is recommended until positive clinical response to therapy is seen including reduction of pain and inflammation.¹²

Because other ocular tissues may be involved in cases of scleritis, the associated findings should be treated accordingly. For example, an associated anterior uveitis may be managed with topical ophthalmic steroids and cycloplegic agents as seen in the clinical case outlined above.¹² Of course caution should be exercised if the scleritis is necrotizing in nature and then oral steroids with cycloplegia may be considered instead of topical steroids which have been thought to promote further necrotization. Adverse events from treatment should also be addressed including GI upset from high dose oral NSAIDs, or an increase in IOP from steroid therapy also known as a steroid response. GI upset can be managed with oral histamine type 2 receptor blocker or proton pump inhibitors, while increase in IOP can be managed with IOP lowering agents which are chosen and tailored to the patient at hand.^36,37 Considering all aspects of therapeutic treatment including side effects of the drugs prescribed will lead to better overall case management.

Conclusions

Scleritis is a rare ocular condition that is potentially sight threatening and therefore must be identified and managed accordingly. Patients with anterior scleritis typically present with a red eye and high degree of pain. A thorough history, review of systems and ocular and physical examination are required to assess the condition. Examination techniques such as blanching the ocular blood vessels with topical ophthalmic phenylephrine or image acquisition with ASOCT can help differentiate scleritis from other conditions such as severe episcleritis. Differentiating necrotizing and non-necrotizing scleritis is critical because of the fast acting and devastating nature of necrotizing disease. Due to the common association of scleritis with systemic disease, determining the underlying cause for the condition is paramount as it will direct proper treatment. Blood work and additional imaging are often ordered and needed to determine the underlying cause.

Scleritis cases are managed with therapeutics including oral NSAIDs, oral steroids and immunosuppressive agents that are selected based upon the presentation and nature of the case at hand. Close follow-up is warranted until a positive clinical response to therapy is observed. Management of scleritis is often complex with disease co-management and excellent interprofessional communication being key to proper case management.

This case outlined a bilateral anterior non-necrotizing diffuse scleritis due to an underlying systemic disease, rheumatoid arthritis. ASOCT was helpful in confirming the suspected condition, and blood work was key to determining the underlying cause. The usual course of scleritis management was exercised in this case by first using high dose oral NSAIDs, followed by oral steroids and finally, immunosuppressive therapy with methotrexate as indicated by the RA diagnosis. This case also demonstrated the importance of managing side effects of treatment including GI upset from high dose oral NSAIDs and IOP reduction due to topical steroid response. Co-management and communication with ophthalmology and rheumatology were crucial to the successful diagnosis and management of this case.

Granular corneal dystrophy (GCD) is an autosomal dominant inherited corneal epithelial stromal dystrophy that results in the deposition of discrete and irregular white-grey deposits at the level of the corneal epithelium and anterior stroma.^1,2 Different genetic mutations in the TGFBI (transforming growth factor beta induced) gene, specifically at the 5q31 locus, result in either of two subtypes of GCD, type 1 (GCD1) or type 2 (GCD2).³ Regardless of subtype, both conditions can potentially cause significant visual symptoms including loss of vision and photophobia secondary to progression and coalescing of deposits over time.⁴ The conditions can be diagnosed with careful slit lamp examination, in-vivo imaging, and a thorough history indicating potential involvement of other family members. However, definitive diagnosis is made through genetic testing, as at times the subtypes are indistinguishable.^4,5 While no cure exists for either subtype, non-surgical and surgical treatments are available to patients.^6,7 This case series presents two brothers who were ultimately diagnosed with GCD1. The pathophysiology, differential diagnoses, adjunct testing results and potential treatment options are discussed.

Patient 1 Case Report

A 23-year-old Hispanic male presented for an ocular health examination. He reported being diagnosed at age 16 with an unknown corneal dystrophy and was informed at that visit that no treatment was available. The patient reported no specific ocular complaints but wanted to learn more about his condition and any potential treatment options. His last eye exam was reported to be about 3 years ago at another office at which time a new prescription for glasses was given. However, the unknown corneal dystrophy was not further investigated. The patient denied any history of ocular surgeries or trauma. The patient’s medical history was unremarkable. He also denied any current or past medication use or any allergies. His family’s medical history was unremarkable; however, their ocular history was significant for an unknown corneal dystrophy for his mother, younger brother, maternal uncle, maternal grandmother and maternal cousin.

Figure 1: Anterior segment photos of the right (A) and left (B) eye of patient 1 showing white bread crumb like deposits that are concentrated more centrally and separated by clear corneal spaces. Click to enlarge

Best corrected visual acuities were 20/25 in the right eye and 20/30 in the left eye. Confrontation visual fields, pupils, and extra ocular motility testing were unremarkable. Biomicroscopic examination of the anterior segment revealed diffuse central breadcrumb-like deposits in the anterior stromal layers of both eyes. The deposits were irregular in shape with rough edges (Figure 1). The density and central location of the deposits likely accounted for the mildly reduced acuities. All other anterior segment structures were unremarkable. Intraocular pressures were 16mmHg in both eyes with Goldmann applanation tonometry. Dilated fundus examination was unremarkable in each eye. An anterior segment optical coherence tomography (OCT) (Zeiss, Dublin CA) scan of each eye was obtained. The OCT for each eye revealed hyper-reflective deposits in the anterior stroma of the cornea with clear intervening areas. Posterior shadowing was also seen in the stroma, correlating with hyper-reflective deposits seen anteriorly (Figure 2).  Genetic testing was ordered (Avagen, Menlo Park, CA); results were positive for a heterozygous mutation in TGFBI, c.1663C>T, p.R555W., a mutation known to cause GCD1. The patient was informed of his diagnosis and was advised to contact the genetic counselor made available to him through the initial genetic testing to discuss the autosomal dominant inheritance pattern of the mutation. As his family history suggested that other family members likely have GCD1, he was advised to encourage these family members to present for examination as well. Unfortunately, all other family members were out-of-state, with the exception of a younger brother, who presented for examination (Case 2).

Figure 2: Anterior segment OCT of the right eye (A) and left eye (B) of patient 1 showing hyper reflective deposits at the level of anterior stroma (blue arrows). Posterior shadowing of the cornea secondary to the deposits is also visible (orange arrow). Click to enlarge

As the patient was asymptomatic, had no history of any prior instances of corneal erosion, and with the natural progression of the condition known, annual monitoring of the condition with repeat imaging was suggested to monitor for and document any objective evidence of progression. The patient was also informed that corneal surgery was not needed at this time based on the relatively stable and good visual acuities. The patient, however, requested a consultation for possible removal of the deposits. A referral was made per his request to a corneal specialist. The corneal specialist agreed with the initial recommendations and also advised annual monitoring.

Patient 2 Case Report

A 20-year-old Hispanic male presented with suspected GCD1 based on confirmation of GCD1 in his older brother. The patient reported constant blurry vision at distance and near in both eyes. No other ocular complaints were stated. The patient’s last eye exam was unknown and was described to be many years ago at a different location. He was given glasses at the visit but was not compliant in wearing them. The patient denied any history of ocular surgeries or trauma. The patient’s medical history was unremarkable. He also denied any current or past medication use or any allergies. His family’s medical history was unremarkable. Family ocular history was positive for confirmed GCD1 for his older brother and likely/but not confirmed GCD1 for his mother, maternal uncle, maternal grandmother and maternal cousin.

Figure 3: Anterior segment photos of the right (A) and left (B) eye of patient two showing white bread crumb like deposits that are concentrated more centrally and separated by clear corneal spaces. Click to enlarge

Best corrected visual acuity was 20/25 in the right and left eye. Confrontation visual fields, pupils and extra ocular motility testing were unremarkable. Intraocular pressures were 11mmHg in the right eye and 9mmHg in the left eye with Goldmann applanation tonometry. Examination of the anterior segment revealed diffuse central breadcrumb like deposits in the anterior stromal layers of both eyes. The deposits were irregular in shape with rough edges (Figure 3). The precipitates appeared irregular with rough edges and clear spaces between them. The density of the deposits centrally likely accounted for the mildly reduced acuity in each eye. All other anterior segment structures were unremarkable. Dilated fundus examination was also unremarkable in each eye. Anterior segment OCT showed similar findings to those of the patient’s older brother: hyper-reflective deposits in the anterior stroma of the cornea with corresponding posterior shadowing (Figure 4). Genetic testing was also ordered for the patient, with the results showing a heterozygous mutation similar to that of the older brother, TGFBI, c.1663C>T, p.R555W. As the patient was asymptomatic and had no history of any prior instances of corneal erosion, annual monitoring of the condition with repeat imaging was suggested. The patient was also informed that corneal surgery was not needed at this time based on the relative stability and good visual acuities.

Figure 4: Anterior segment OCT of the right eye (A) and left eye (B) of patient two showing hyper reflective deposits at the level of anterior stroma (blue arrows). Posterior shadowing of the cornea secondary to the deposits is also visible (orange arrow). Click to enlarge

Educator’s Guide

Key Concepts

• The pathophysiology and specific genetics of GCD1 and GCD2
• The value of ancillary testing in GCD1 and GCD2
• Available treatment options for patients with GCD1 or GCD2

Learning Objectives

• Define and identify phenotypic variations in GCD1 and GCD2
• Compare and contrast other corneal epithelial stromal dystrophies as differential diagnoses for GCD1 and GCD2
• Understand and interpret in vivo imaging to assist in the diagnosis and management of GCD1 and GCD2
• Review existing non-surgical and surgical treatment options GCD1 and GCD2 and their outcomes

Discussion Questions

1. Knowledge, understanding and facts about the clinical case and condition presentation

• Define the characteristic appearance of GCD1
• Define the characteristic appearance of GCD2
• Compare and contrast the genetics of these two conditions

2. Differential diagnosis

• What other corneal dystrophies present with a phenotype similar to GCD1 and/or GCD2?
• How would a clinician distinguish between these conditions based on the patient’s phenotype, history (personal and family) and multimodal imaging results?

3. Patient management and role of the optometrist

• What supplementary testing should be considered for patients and their family members who possibly have GCD1 or GCD 2?
• What surgical and non-surgical options are available and when are they indicated?
• How would you educate them on the prognosis of both conditions?

4. Critical-thinking concepts

• Understand the many different presentations of TGFBI mutations and their role in corneal epithelial stromal dystrophies.
• How might reduced visual acuities and increased glare affect activities of daily living?

Assessment of Learning Objectives

GCD1 and GCD2 are corneal epithelial stromal dystrophies with many differential diagnoses because different mutations in a single gene, TGFBI, result in different disorders. Since a basic understanding of corneal anatomy, physiology, genetics and familiarity with multimodal imaging is needed for diagnosis and treatment, these cases are suitable for optometry students in their second year and beyond. The cases can also be utilized by residents and academic and non-academic providers. Assessments can include, but are not limited to, the following:

• Presenting the cases in a small or large group setting. Large group settings can include formal lectures on corneal dystrophies, in a student’s anterior segment/cornea class. These cases could comprise a part or section of the overall lecture(s) on corneal dystrophies or could be presented as a stand-alone lecture. Understanding and comprehension of the material could be achieved through answering the discussion questions in class or as an individual assignment to be completed and submitted at a later date. Immediate comprehension could be assessed through open-ended questions by the lecturer or through the use of testing technologies such as Turning Point. Formal understanding could be achieved through traditional means such as midterm and final examinations consisting of questions of the examiner’s choice (fill in the blank, multiple choice, essay, etc).
• A small group format could also be utilized, implemented in student labs for anterior segment and cornea, in which this format would be more feasible. Students could be presented initially with the case history and presentation. From there, students could discuss the case as a group and formulate an appropriate diagnosis with a corresponding treatment and management plan.
• A small group setting could also be used by residents in which the cases are discussed. Cited articles could also be used for further review.
• Lastly, independent reading of the article could be utilized by practicing and non-practicing clinicians who could answer the discussion questions while referencing the article.

Discussion

Corneal dystrophies represent a rare group of genetic conditions arising from mutations in various genes. These mutations result in corneal deposits with varying ages of onset, inheritance patterns (dominant, recessive or X-Linked), and clinical courses. At times, the dystrophies resemble each other making the diagnosis difficult and uncertain. In general, corneal dystrophies are classified based on the location of the deposits in the cornea. However, the most recent classification, referred to as the IC3D Classification of Corneal Dystrophies, considers traditional definitions together with the results of genetic testing and histology. Specifically, the dystrophies are classified as being either epithelial and subepithelial, epithelial-stromal TGFBI, stromal, or endothelial.¹

GCD is an autosomal-dominant, inherited corneal condition characterized by the bilateral accumulation of distinct whitish deposits in the corneal stroma and epithelium not due to inflammation, trauma or systemic disease.^1-5 Granular corneal dystrophy is considered an epithelial stromal dystrophy based on this classification and is further differentiated into two subtypes: GCD1 and GCD2.^1,6

GCD1 occurs from mutations in the TGFBI gene which encodes for a keratoepithelin. This protein is thought to be responsible for corneal cell adhesion, movement and expansion.⁷ Mutations and impairments in this gene lead to the expression and production of abnormal hyaline deposits. The specific mutation seen is pArg555Trp, resulting in a phenotype that presents with multiple and small distinct whitish/gray granules that deposit in the anterior stroma.⁸ The phenotype can vary, as the deposition has also been observed as drops, crumbs or rings.⁹ Initially, clear areas of cornea can be visualized between the deposits with the condition being isolated to the central cornea. Patients at this early stage can be asymptomatic or can present with mild reductions in vision with accompanying glare. Visual acuity is not expected to improve with pinhole testing, as the reduction stems from stromal opacities rather than uncorrected refractive error or higher-order aberrations. As the condition progresses, the clear area between the granular deposits diminishes and the number of granules also increases, leading to further vision loss, glare and the potential for the development of recurrent corneal erosions (RCE).^3,8,10 Corneal dystrophies, such as GCD, but namely epithelial basement membrane dystrophy, have been widely implicated in the development of RCEs. The mechanism is damage to the corneal hemi-desmosomes caused by the stromal deposits. These hemi-desmosomes play an important part in providing a link or anchor between the corneal epithelium, its basement membrane and deeper layers (Bowman’s layer and stroma).¹¹  Homozygote cases tend to have more apparent and aggressive signs and symptoms compared to those experienced by heterozygotes.^1,4,12 Both of our patients had heterozygous mutations which correlate with their relatively good acuity and lack of other signs and symptoms. Interestingly both GCD1 and GCD2 can show a phenomenon referred to as granular drop out. This phenomenon can occur after a RCE and subsequent corneal healing resulting in stromal clearing. However, new deposits can then fill in this gap over time.¹

GCD2, originally called Avellino corneal dystrophy based on a region of Italy from where two affected families originated, is also an autosomal dominant corneal dystrophy.⁸ The condition also occurs due to a mutation in the TGFBI gene; however, the mutation in this case is isolated to pArg124His.^8,13 This mutation causes the condition initially to have a clinical presentation like GCD1: grey, white granules in the anterior stroma. However, fewer deposits are seen when contrasted with GCD1. The condition tends to be present in early adulthood compared to the first decade of life as seen in GCD1 patients. As GCD2 progresses, the condition tends to differentiate itself from GCD1 as lattice-like amyloid lesions develop.⁸  These lesions tend to be deeper in the corneal stroma when compared to the granular lesions.⁷ The lattice presentation is likely owing to a similar genetic etiology for lattice corneal dystrophy and GCD2, mutations in TGFBI. Progression of GCD2 also leads to reduced vision, increased glare and RCE’s like GCD1, although the frequency of RCE is much less compared to RCE frequency in GCD1.¹⁴ Similar to GCD1, homozygote patients tend to have a more severe presentation and rapid progression when compared to that experienced by heterozygotes.⁷

In terms of epidemiology, GCD1 and GCD2 are both rarely encountered; therefore, accurate statistics are not available for the prevalence of the conditions worldwide. However, observations have been made in certain populations. GCD2 has been observed more commonly in Korea and Japan.^12,13,15 Specifically, PArg124HIs mutations, which result in GCD2, according to one study were frequently observed in the Japanese population and were responsible for 73% of all corneal dystrophies.¹⁶ The second most observed dystrophy in this same population was lattice corneal dystrophy. One large study of affected patients in South Korea, estimated the prevalence of GCD2 to be 11.5 patients per 10,000.¹³ However, a more recent study estimates the prevalence to be 2 to 3 times higher than the previously mentioned study.¹⁵ In contrast, GCD1 is more common in Europe, with statistics not being available.¹² Regardless, both conditions are still considered extremely rare. One study did note that GCD was more common among women. However, the study did not classify GCD into subtypes.¹⁷ Further studies and analysis are needed to see if gender predilections exist.

Although clinical slit lamp examination (biomicroscopy) is often sufficient to make a diagnosis, at times the clinical signs can be subtle, atypical or overlapping with those of other corneal dystrophies. Therefore, ancillary testing can help clinicians diagnose GCD1 and GCD2 with more accuracy and efficiency. Traditionally, corneal dystrophies were studied using histopathological techniques. However, histological evaluation is not clinically practical. Therefore, in vivo imaging with anterior segment OCT and/or confocal microscopy provides clinicians with a quick, non-invasive and easily accessible way of characterizing corneal dystrophies.

Anterior segment OCT scans and images the corneal layers, in a way similar to a histology section, allowing for the localization of the corneal dystrophy deposits.¹⁸ Also noteworthy is that OCT can guide physicians in the surgical management of patients with corneal dystrophies, as the surgeons can determine the depth of the deposits, allowing for the selection of advanced treatments, whether superficial laser treatment or surgery.^10,19 Typical OCT findings for GCD1 and GCD2 include delineated hyper reflective lesions that deposit in the anterior two thirds of the stroma, as well as the epithelium and Bowman layers to a lesser extent.^10,18,20 This pattern was observed for both patients. Rarely, deposits can extend into the posterior stroma.²¹ Similar to OCT, confocal microscopy allows for in vivo analysis of the cornea, with images that are comparable to ex vivo histology section.²² Results of confocal imaging in GCD1 and GCD2 are similar to AS OCT, revealing irregular and highly reflective deposits, with clear cornea between them, isolated to the epithelium, Bowmans, and mainly the anterior stroma.^21,22 Unfortunately, we did not have access to this technology; however, OCT and genetic testing were adequate to make a diagnosis.

Although the above imaging techniques can help clinicians arrive at a diagnosis, definitive diagnosis can be made with genetic testing, especially in atypical cases. With the introduction of commercially available genetic testing, clinicians now have a method of confirming suspected corneal dystrophies without solely relying on clinical findings, histopathological sections and/or multimodal imaging. Genetic testing is simple to perform as tests today only require a buccal or saliva sample before being sent for analysis. Testing can confirm a tentative diagnosis while also providing information to clinicians and patients on the genetics and inheritance patterns of a suspected condition.²³ Ideally, when a corneal dystrophy is confirmed through genetic testing, genetic counselling should be provided to the patient and their family members.^24,25 Unfortunately, genetic testing for corneal conditions can be cost prohibitive, as compared to genetic testing for retinal conditions for which testing can be free of charge.²⁶

Differentials

The main differential for GCD1 is GCD2 and vice versa. The types can be differentiated based on their clinical appearance and the results of genetic testing, as mentioned earlier. However other epithelial-stromal corneal dystrophies can present with similar clinical signs and symptoms due to similar mutations in the TGFBI gene.^7,8,14

• Lattice corneal dystrophy (LCD): An epithelial stromal corneal dystrophy like GCD1 and GCD2, lattice corneal dystrophy presents with linear and lattice-like amyloid deposits. LCD is also inherited autosomal dominantly and is also due to mutations in the TGFBI gene. However, the mutations in the gene are different when compared to GCD1 and GCD2. In LCD the mutation is in 5q31 locus of the TGFHBI gene, specifically at Arg124Cys.⁷ Two types of LCD (with various subtypes, respectively) exist. The previously mentioned mutation would be LCD Type 1 while LCD Type 2 is due to mutations in the gelosin gene.^7,14 Our patients did not present with lattice or linear corneal signs. Note that the lattice like lines that appear with GCD2 are more dash like than linear, whiter in color than refractile and rarely cross each other when compared to LCD.⁸ Genetic testing also confirmed the lack of the mutation; therefore, LCD 1 and 2 were ruled out.
• Thiel-Behnke corneal dystrophy (TBCD): Also referred to as honeycomb corneal dystrophy, this condition is linked to Arg555Gln mutations in the TGFBI gene resulting in irregular-shaped deposits that eventually evolve into a honeycomb like appearance.^7,14 This pattern was not evident with our two patients and genetic testing excluded this condition.
• Reis Buckler corneal dystrophy: Mutations in the TGFB1 gene at Arg124Leu, which are inherited in an autosomal dominant pattern, result in irregular geographic like deposits that early on can resemble TBCD. A honeycomb or reticular pattern was not seen in our patients with genetic testing also excluding this condition.^19,27

Non TGFBI dystrophies can also present similar to GCD1 and GCD2. Although genetic testing is definitive in excluding them, exclusion can also be accomplished with a detailed clinical examination.

• Schnyder’s corneal dystrophy (SCD): SCD is an autosomal dominant stromal corneal dystrophy. However, SCD is not considered a TGFBI corneal dystrophy because its mutation occurs in the UBAID1 gene. This mutation results in the buildup of and deposition of cholesterols and phospholipids in the corneal stroma that can resemble granular deposits. These patients may also present with corneal arcus at an early age owing to elevated serum levels of cholesterol. The cholesterol elevation is also due to UBAID1 gene mutations, as the gene is responsible for cholesterol transport and metabolism. Our patients did not have any cholesterol issues or corneal arcus. Genetic testing also ruled out SCD for both patients.^28-30
• Macular corneal dystrophy (MCD): an autosomal recessive stromal dystrophy that manifests secondary to mutations in the CHST6 gene. These mutations results in gray-white central stromal opacities (glycosaminoglycan), that resemble deposits seen in GCD 1 and 2.^1,14 With multiple family members in different generations being involved in our cases, this diagnosis was less likely in our patients. Genetic testing ruled out MCD for both patients.

Treatment

Non-Surgical

Glare and reduced visual acuities can result in impairment of activities of daily living for patients if severe enough. Clinicians should consider appropriate correction of refractive error, photochromatic or polarized lenses to minimize glare and a possible referral to low vision providers if surgical intervention is not indicated or preferred by patients.

Non-surgical treatment options also are available, mainly to treat RCE caused by GCD1 and GCD2. The mechanism by which RCE’s occur relates to the position of the granular deposits. Stromal deposits disrupt the hemidesmosomes in corneal basal epithelial cells. These hemidesmosomes are part of an extracellular adhesion complex (along with collagens, metalloproteinases and laminins) that secures the corneal epithelium to the underlying stroma. When this complex is disrupted, the epithelium has a weaker attachment to its basement membrane and is at risk of sloughing off or eroding.³¹ The epithelium is most vulnerable upon awakening due to the strong adhesive force between the eyelid and cornea from overnight corneal desiccation.¹¹

Treatment of RCE is aimed at reducing friction caused by blinking, promoting epithelial attachment/adhesion, preventing infection and reducing pain. First line therapy for an acute episode is conservative in nature and consists of frequent lubrication using preservative-free artificial tears, nighttime lubricating ointment and antibiotic drops.¹¹ If a patient is in significant pain, a topical cycloplegic drop or bandage contact lens (BCL) can be used. BCL’s offer a twofold benefit in the treatment of RCE: BCLs improve the patient’s symptoms and protect the delicate epithelium and its basement membrane adhesion complex from the overlying eyelid.^11,31,32 A prophylactic antibiotic must be used in conjunction with a BCL to prevent secondary infection. Amniotic membranes offer similar advantages to a BCL and can be considered as an alternative, though their cost is significantly greater.¹¹

Once an epithelial erosion has healed, prophylactic treatment to prevent recurrence should be considered. Topical hypertonic sodium chloride ointments or drops promote adhesion of the epithelium and may decrease recurrence by decreasing corneal edema in the intracellular space. Low dose oral doxycycline and topical corticosteroids both prevent breakdown of the corneal extracellular adhesion complex and, therefore, provide stability to the epithelium. Both should be considered in patients unresponsive to first line therapy and/or to prevent recurrence after an acute erosion.³³ If an erosion does not heal with traditional therapy, or if recurrent erosions develop within the visual axis, phototherapeutic keratectomy (PTK) can be used and is discussed in more detail below.

Surgical

Corneal laser or surgery are both treatment options when visual acuity is significantly affected or with recurrent corneal erosions that are affecting quality of life in patients with GCD.³⁴ PTK is the least invasive treatment option and can be used when granular deposits are anterior in the stroma. Ablation depth varies with PTK but ranges from 50 to 200 µm, with incomplete deposition clearance occurring more frequently with more shallow ablation depths.²⁷ Hyperopic refractive error, corneal haze and irregular astigmatism due to epithelial hyperplasia are potential complications of PTK.^27,35 PTK can be safely repeated and re-treatment is often necessary since recurrence of GCD after PTK is common.³⁵

When PTK is unsuccessful or GCD deposits lie deeper than the anterior stroma, more invasive surgical options are chosen. Anterior lamellar keratoplasty (ALK), deep anterior lamellar keratoplasty (DALK), and penetrating keratoplasty (PK) are all viable treatment options to improve vision.²⁷ ALK can be used to remove mid-stromal deposits. Even deeper deposits, or deposits that form at the graft-host interface after ALK, can be treated with DALK or PK.^27,35

Visual recovery time after PTK is quicker than for both lamellar keratoplasties and PK, given its less invasive protocol. In a large, single center study comparing treatment outcomes between PTK, ALK, DALK and PK, patients undergoing PTK achieved their best corrected visual acuity significantly faster, just 1.8 months after the procedure, compared to 5.3 months after PK and 8.4 months after DALK. All patients, no matter the surgical intervention, achieved postoperative final visual acuities between 20/25 and 20/30. These results demonstrate that all surgical options provide favorable outcomes, but visual recovery is quickest with PTK.³⁵ Other published literature supports this finding, with many patients experiencing visual recovery within several weeks after PTK.^27,34,36

Recurrence of GCD is well-reported and can occur after any surgical intervention. Recurrence occurs centrally and anteriorly in the cornea.³⁵ While PTK offers quick visual recovery, patients experience recurrence sooner than with deeper surgical interventions.³⁵ In the previously mentioned study by Lewis et al, the median length of time until significant recurrence after PTK was 2.7 years, as compared to the median time to significant recurrence after PK of 13.7 years. Both lamellar keratoplasties had similar lengths until significant recurrence at 3.7 years (ALK) and 3.2 years (DALK).³⁵ Genetic status has been proposed as playing a role in rates of recurrence, with homozygous patients experiencing recurrence sooner than heterozygotes.^27,35 This proposal aligns with the previously described clinical course of homozygotes having a more severe clinical presentation. Note that PTK and lamellar keratoplasty (LK) can both be performed safely on graft tissue after a PK, if recurrence is noted.^34,37,38 LK is often preferred to PTK in these instances, as consecutive PTK’s flatten and thin the graft tissue, leading to a higher risk of hyperopia and ectasia development.³⁸ Furthermore, data suggests that subsequent PTK retreatments on PK grafts are performed at shorter intervals, indicating that recurrence may occur more rapidly after each consecutive treatment.³⁷

Penetrating keratoplasty (PK) was the only form of surgical treatment for many years and may offer a longer interval until recurrence, but PK is a more invasive procedure compared to LK and PTK, requiring full host tissue removal. Lamellar keratoplasty is less invasive and offers an advantage over PTK in removing deeper deposits, but patients may still require repeat procedures and take longer to visually recover compared to treatment with PTK alone.³⁵ Selection of a surgical treatment must weigh the rate of visual recovery against the potential for recurrence and need for retreatment. The genetic composition of a patient’s GCD and the depth of their granular deposits also play a role in surgical selection.

Genetic Treatment Options

Because the cornea is easily accessed and imaged, the tissue is a viable target of genetic research. In addition, the cornea is immune-privileged which allows for easy gene transfer.²³ However, as promising as gene therapy is, especially for retinal conditions in which surgery is not option, surgical success for corneal conditions is likely limiting the introduction and production of possible gene therapies for corneal dystrophies. Surgical options in the past have included the excising and replacement of the entire cornea (PK). With advents in technology, specific layers of the cornea can be removed, with the potential for good visual outcomes within weeks of surgery.²⁷ However, granular deposits may recur as mentioned earlier; thus, surgery exists as a treatment option and not a cure.^8,39 Further studies are needed at this time. Therefore, the viability of future genetic treatment options, including gene editing with newer technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR), will be vital going forward.⁴⁰

Conclusion

GCD 1 and GCD2 are rare autosomal dominantly inherited corneal epithelial stromal dystrophies. Early in the disease process the conditions may appear similar; therefore, clinicians should be cognizant of differentiating the individual disease processes as the two conditions progress. In addition, many other corneal dystrophies can mimic GCD 1 and/or 2. In vivo imaging can aid clinicians in arriving at a faster diagnosis, and genetic testing is the ultimate confirmatory tool. Although no cure exists, sequala such as reduced visual acuity and corneal erosions can be managed through non-surgical and surgical means.

The purpose of this case study is to report the effectiveness of topical prednisolone acetate 1% for treating IGS, with a focus on its ability to improve visual acuity and central macular thickness. This case underscores the importance of distinguishing the causes of reduced vision following cataract extraction. It highlights a patient in whom IGS developed after uncomplicated cataract extraction. Optometric management plays an essential role in evaluating and addressing postoperative complications, thereby ensuring optimal visual outcomes and ocular health for patients. Specifically, third- and fourth-year optometry students and residents should demonstrate proficiency in identifying common causes of postoperative reduced vision following cataract extraction.

Case History

A 73-year-old female with moderate-stage primary angle closure glaucoma in both eyes presented to the State University of New York (SUNY) Optometry University Eye Center for a scheduled follow-up. Despite excellent uncorrected vision immediately following cataract extraction, she reported progressively declining vision in her left eye over several months after the surgery.

Her pertinent ocular history included laser peripheral iridotomy (LPI) of the right eye in 2011 prior to cataract extraction of the right eye in 2012. LPI was performed in the right eye due to the appearance of peripheral anterior synechiae (PAS) observed inferiorly and nasally on 4-mirror gonioscopy. The left eye did not undergo LPI, presumably because there was no evidence of PAS and IOP had been adequately controlled with topical IOP-lowering therapy. Cataract extraction was performed on the left eye in late 2021. She was subsequently inherited for care following cataract extraction of the left eye.

Prior to cataract extraction, maximum recorded intraocular pressures (IOP) were 56 mmHg and 40 mmHg in the right and left eyes, respectively. At presentation, she was using latanoprost 0.005% once daily in both eyes, dorzolamide–timolol ophthalmic solution (22.2 mg/mL – 6.8 mg/mL; Cosopt ®) twice daily in both eyes, and brimonidine 0.2% twice daily in both eyes, with excellent reported adherence.

Her medical history included medical management of rheumatoid arthritis, diagnosed in 2002, overseen by an outside rheumatologist who prescribed abatacept (Orencia ®). She also had a reported positive family history of glaucoma on her father’s side, which was relevant to her own diagnosis and management considerations.  

Case Description

Visit One

Visual acuities at presentation were 20/20 -2 in the right eye and 20/40 -2 in the left without correction. The left eye pinhole acuity was 20/25 +1. Pupils were round, reactive and responsive to light. There was no relative afferent pupillary defect (RAPD) in either eye. Confrontation visual fields were grossly full to finger counting in each eye. Extraocular motilities were full in each eye. Best-corrected visual acuities following manifest refraction were 20/20 in the right eye and 20/25 in the left.

Slit lamp biomicroscopy of the anterior segments revealed no pathology of the adnexa, eyelids, sclera and conjunctiva. Both corneas had temporal cataract excision scars, with a well-demarcated stromal opacification. Angles were determined to be “open” on Van Herrick technique using slit lamp biomicroscopy. A patent peripheral iridotomy at 11:00 was present in the iris of the right eye, but otherwise, it was unremarkable. The iris of the left eye was unremarkable. In both eyes, the anterior chamber was deep and quiet, with no cells noted. Posterior chamber intraocular lenses (PCIOLs) were present in both eyes, with acceptable positioning and posterior capsules were clear.

IOP in each eye was 16 mmHg on Goldmann applanation tonometry. Tropicamide 1% and phenylephrine 2.5% were used to dilate the patient’s pupils. Indirect ophthalmoscopy with a 90D fundus lens revealed posterior vitreous detachments in both eyes. The right eye had a cup-to-disc ratio of 0.70, with inferior rim thinning, but otherwise a distinct border and a well-perfused appearance. The left eye had a cup-to-disc ratio of 0.60 with distinct borders and a well-perfused appearance. The macula of the right eye was flat with an evident foveal reflex. The macula of the left eye was elevated with an absent foveal reflex. Indirect ophthalmoscopy with a 20D lens was performed for peripheral evaluation. No evidence of accompanying retinopathy, such as hemorrhages or exudates, was noted on examination. Both eyes had normal vessel contour and caliber, and the retina was flat and intact 360 degrees.

Figure 1: Baseline SD-OCT imaging at Visit One. Scan quality of the right eye was 8; scan quality of the left eye was 9; these were considered acceptable. Baseline imaging of the left eye macula revealed central subfield thickness of 358 microns. The left eye demonstrated intraretinal cystic changes and subretinal fluid on the B-scan, consistent with active central macular edema. The right eye macular scan showed a central thickness of 239 microns with an apparent mildly thin inferior quadrant. The right eye showed normal retinal architecture and no signs of fluid or structural abnormality. Click to enlarge

A macular cube 512 x 218 scan was acquired using Zeiss Cirrus 5000 spectral-domain optical coherence tomography (SD-OCT) to determine central macular thickness. The right eye demonstrated normal foveal contour without subretinal or intraretinal fluid on the B-scan. However, the inferior quadrant demonstrated relative thinning on the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid, falling just below the average range for age-matched controls. There was no evidence of edema, subretinal fluid or structural disruption. The central subfield thickness of the right eye was 239 microns – stable and within normal age-adjusted limits. The left eye demonstrated a central subfield thickness of 358 microns which was “Above Normal” relative to normative data for age, consistent with macular thickening. There was evident loss of foveal contour with cystoid intraretinal spaces and subretinal fluid on the B-scan, shown to be predominantly in the central and temporal macula on the ETDRS grid. (Figure 1).

The presence of cystoid macular edema in the context of recent cataract extraction suggested IGS. To treat the condition, ketorolac 0.5% was initiated 4 times daily in the left. The patient was instructed to discontinue the use of latanoprost 0.005% in both eyes and continue with dorzolamide–timolol and brimonidine 0.2% twice daily in both eyes. A follow-up was scheduled in 4 weeks to assess the progress, and the patient was released with return precautions, such as acute onset pain, blurred vision or distorted vision. She was instructed to return immediately to the clinic in the event any changes in vision were noted.

Visit Two

The patient returned for a doctor-directed follow-up 4 weeks later. She had self-discontinued ketorolac 0.5% 2 weeks prior due to ocular surface irritation. She had continued use of latanoprost 0.005% since the last clinic visit. She reported adherence to brimonidine tartrate 0.2% and dorzolamide–timolol twice daily in both eyes. No new visual symptoms were reported during case history. Entering visual acuities were 20/25 -1 in the right eye and 20/80 -1 in the left eye without correction. Assessment of pupillary testing, extraocular motilities and confrontation visual fields were within normal limits and stable compared to previous examinations.

Anterior segment evaluation revealed no cells or flare of either eye. IOP were 16 mmHg in the right eye and 14 mmHg in the left on Goldmann applanation tonometry. Tropicamide 1% and phenylephrine 2.5% were used to dilate the patient’s pupils. Posterior pole findings observed with indirect ophthalmoscopy using a 20D and 90D lens on biomicroscopy were stable compared to the previous visit. No vitreous cells were noted on direct ophthalmoscopy using a slit lamp.

Figure 2: SD-OCT imaging at Visit Two. Scan quality of the right eye was 9; scan quality of the left eye was 7; these were considered acceptable. At the follow-up visit, SD-OCT of the LE showed progression of the macular edema, with central subfield thickness increasing to 458 microns. There was worsening of cystoid spaces and expansion of subretinal fluid, leading to increased foveal disruption in the left eye. These findings prompted initiation of corticosteroid therapy. The right eye central macular thickness remained stable at 239 microns. The retinal contour of the right eye was unchanged with no structural changes. Click to enlarge

A macular cube 512 x 218 scan was acquired using Carl Zeiss Cirrus 5000 SD-OCT to assess the response to ketorolac 0.5%. The scan demonstrated stable central subfield thickness of the right eye with no structural abnormalities or fluid present on the B-scan. The central subfield thickness remained stable at 239 microns – stable and within normal age-adjusted limits. The mild inferior parafoveal thinning remained unchanged on the ETDRS grid. The central subfield of the left eye increased from 358 to 458 microns, representing increasing central macular edema. On the ETDRS grid, more inner and outer subfields shifted into the “Above Normal” zone, particularly in the temporal and superior parafoveal regions, deviating further from age-based norms. The B-scan showed progression of the cystoid changes and increased subretinal fluid, resulting in greater foveal disruption (Figure 2).

Given the presence of increased intraretinal thickness in the left eye, the patient was started on prednisolone acetate 1% every 2 hours while awake. The patient was again advised to discontinue latanoprost 0.005%. A follow-up was scheduled in 1 week to assess progress and the patient was released with clear instructions for follow-up if symptoms worsened.

Visit Three

The patient returned for a doctor-directed follow-up 1 week later. She reported excellent adherence to prednisolone acetate 1% every 2 hours while awake in the left eye. She had discontinued using latanoprost 0.005% as instructed and reported adherence to brimonidine tartrate 0.2% and dorzolamide–timolol twice daily in both eyes. No new visual symptoms were reported. Entering visual acuities were 20/25 -1 in the right eye and 20/60 +2 in the left, without correction. Pinhole acuity of the left eye demonstrated no improvement. Assessment of pupillary testing, extraocular motilities and confrontation visual fields were within normal limits and stable compared to previous examinations.

Anterior segment evaluation revealed no cells or flare of either eye. IOP were 16 mmHg in the right eye and 13 mmHg in the left on Goldmann applanation tonometry. Due to the lack of visual improvement in the left eye, a dilated fundus exam was recommended to evaluate for the progression of macular pathology. However, the patient deferred dilation due to a time constraint. In lieu of dilation, indirect ophthalmoscopy using a 90D lens was performed, allowing for a limited yet sufficient evaluation of the posterior pole. Findings were stable compared to the previous visit. SD-OCT imaging of the macula was not repeated at this visit given the deferred dilation and the absence of new visual symptoms.

Given the clinical stability and absence of acute signs of inflammation, a steroid taper was initiated to minimize the risk of steroid-induced side effects while maintaining control of any residual inflammatory activity. The patient was instructed to taper prednisolone acetate 1% to 4 times daily for 1 week, then twice daily for 1 week, and once daily for 1 week in the left eye. A follow-up was scheduled in 1 week to assess progress and the patient was reeducated on return precautions.

Visit Four

The patient returned for a doctor-directed follow-up 1 week later. She reported using the prednisolone acetate 1% 4 times daily in the left, which was twice the daily frequency that had been prescribed. She had discontinued using latanoprost 0.005% as instructed and reported adherence to brimonidine tartrate 0.2% and dorzolamide–timolol twice daily, in both eyes. Improved vision of the left eye was reported. Entering visual acuities were 20/25 -1 in the right eye and 20/80 in the left, without correction. Pinhole acuity of the left eye was 20/40. Assessment of pupillary testing, extraocular motilities and confrontation visual fields were within normal limits and stable compared to previous examinations.

Anterior segment evaluation revealed no cells or flare of the left eye. IOP were 18 mmHg in the right eye and 15 mmHg in the left on Goldmann applanation tonometry. Tropicamide 1% and phenylephrine 2.5% were used to dilate the patient’s pupils. Posterior pole findings observed with indirect ophthalmoscopy using a 20D and 90D lens on biomicroscopy were stable compared to the previous visit. No vitreous cells were noted on direct ophthalmoscopy using a slit lamp.

Figure 3: SD-OCT imaging at Visit Four. Scan quality of the right eye was 9; scan quality of the left eye was 10; these were considered acceptable. Follow-up SD-OCT imaging demonstrated stable central subfield thickness in the right eye (238 microns) with no structural abnormalities. The left eye showed marked improvement in central subfield thickness from 458 to 273 microns, with near complete resolution of subretinal fluid and intraretinal cystic changes. The right eye macular thickness and contour remained stable with a central subfield thickness of 238 microns. The retinal contour of the right eye was unchanged with no structural changes. Click to enlarge

A macular cube 512 x 218 scan was acquired using Carl Zeiss Cirrus 5000 SD-OCT to determine central macular thickness. SD-OCT of the right eye demonstrated stable central subfield thickness at 238 microns. No structural changes were noted. SD-OCT of the left eye showed improvement in central subfield thickness from 458 to 273 microns, with near complete resolution of subretinal fluid and intraretinal cystic changes. These findings support a positive anatomical response to corticosteroid therapy, consistent with improved control of macular edema (Figure 3).

Given substantial resolution of subretinal fluid and intraretinal cystic spaces, the patient was instructed to taper the prednisolone acetate 1% to 3 times daily for 1 week, then twice daily for 1 week in the left eye. She was instructed to not restart the latanoprost 0.005% at this time. The patient was reminded to continue with brimonidine tartrate 0.2% and dorzolamide–timolol twice daily, in both eyes. A follow-up was scheduled in 1 week to assess progress and the patient was released with clear instructions to return sooner if symptoms worsened.

Visit Five

The patient returned for a doctor-directed follow-up 1 week later. She reported using the prednisolone acetate 1% 2 times daily in the left eye, as instructed. She reported adherence to brimonidine tartrate 0.2% and dorzolamide–timolol twice daily, in both eyes. No new symptoms were reported. Entering visual acuities were 20/25 -2 in the right eye and 20/25 in the left, without correction. Assessment of pupillary testing, extraocular motilities and confrontation visual fields were within normal limits and stable compared to previous examinations. Anterior segment evaluation revealed no cells or flare of the left eye.

IOP were 16 mmHg and 14 mmHg in the right and left eyes, respectively, on Goldmann applanation tonometry. Tropicamide 1% and phenylephrine 2.5% were used to dilate the patient’s pupils. Posterior pole findings observed with indirect ophthalmoscopy using a 20D and 90D lens on biomicroscopy were stable compared to the previous visit. No vitreous cells were noted on direct ophthalmoscopy using a slit lamp.

Figure 4: SD-OCT imaging at Visit Five. Scan quality of the right eye was 9; scan quality of the left eye was 8; these were considered acceptable. At the follow-up visit SD-OCT of the left eye demonstrated marked improvement, with central subfield thickness reduced to 245 microns and complete resolution of prior intraretinal and subretinal fluid. The right eye demonstrated central subfield thickness of 235 microns. The retinal contour of the right eye was unchanged with no structural changes. Click to enlarge

A macular cube 512 x 218 scan was acquired using Carl Zeiss Cirrus 5000 SD-OCT to determine central macular thickness (Figure 4). SD-OCT macula for the right eye demonstrated structural stability with a central subfield thickness of 235 microns, consistent with prior measurements. The left eye showed substantial improvement, with central subfield thickness decreasing from a peak of 458 microns (Figure 2) to 245 microns, nearing the normal range. B-scan imaging confirming resolution of both subretinal fluid and intraretinal cystic spaces, indicating effective response to the prednisolone acetate 1% therapy. The retinal architecture in both eyes was preserved, with no ongoing edema or distortion of the macular layers.

Given the complete resolution of the intraretinal and subretinal fluid, the patient was instructed to taper the prednisolone acetate 1% once daily for 1 week in the left eye. She was instructed to not restart the latanoprost 0.005% at this time. The patient was reminded to continue with brimonidine tartrate 0.2% and dorzolamide–timolol twice daily, in both eyes. A follow-up was scheduled in 1 week to assess progress and the patient was released with clear instructions for follow-up if symptoms worsened.

Visit Six

The patient returned for a doctor-directed follow-up 1 week later. No new symptoms were reported. She reported using the prednisolone acetate 1% once daily in the left eye, as instructed. She reported adherence to brimonidine tartrate 0.2% and dorzolamide–timolol twice daily, in both eyes. Assessment of pupillary testing, extraocular motilities and confrontation visual fields were within normal limits and stable compared to previous examinations. Entering visual acuities were 20/25 -1 in the right eye and 20/20 -1 in the left, without correction. Anterior segment evaluation revealed no cells or flare of the left eyeon direct ophthalmoscopy with slit lamp.

IOP were 18 mmHg in the right eye and 17 mmHg in the left on Goldmann applanation tonometry. Indirect ophthalmoscopy using a 90D lens was performed, allowing for a limited yet sufficient evaluation of the posterior pole. Findings were stable compared to the previous visit. Given the excellent visual outcome, along with absence of patient symptoms, the patient was instructed to discontinue prednisolone acetate 1%. The patient was placed on a maintenance dose of ketorolac tromethamin 0.5% (Acular ®) 1 time daily in the left eye. No changes were noted at the final visit scheduled for the management of this condition. A follow-up was scheduled in 3 weeks to assess progress and the patient was released with clear instructions for follow-up if symptoms worsened.

Education Guidelines

In a didactic setting, third- and fourth-year optometry students and residents can be presented with this case and associated SD-OCT images in slideshow format or imaging forums to develop a primary diagnosis, differential diagnosis and management plan specific to IGS. Subsequently, structured discussion questions can then guide exploration of the case history, characteristic SD-OCT features and treatment considerations in the context of postoperative inflammation. In a clinical setting, students and residents should be encouraged to review postoperative SD-OCT scans and identify early signs of IGS, such as parafoveal cystic changes, retinal thickening and changes to subfoveal contour. During follow-up visits, students and residents can be tasked with explaining the inflammatory pathophysiology of IGS including surgical trauma, cytokine-mediated endothelial changes and blood-retinal barrier disruption and discussing treatment strategies in patients with comorbidities such as glaucoma. Learners should also participate in decision-making strategies regarding when to escalate therapy or discontinue specific drops (e.g., prostaglandin analogs). Finally, these concepts can be reinforced by tracking the resolution of IGS across visits, emphasizing the importance of serial SD-OCT imaging in monitoring treatment response and preventing chronic visual loss.

Learning Objectives

1. 1. Identify common causes of reduced vision following cataract extraction.
   2. Outline the pathophysiology, related mediators and timeline of intraocular inflammation following cataract extraction.
   3. Recognize the presentation of macular edema on SD-OCT and describe how serial imaging can be implemented to track treatment response.
   4. Compare appropriate treatment modalities for IGS, including topical therapy, intraocular injections and laser therapy.
   5. Determine indications for escalating treatment for refractory cases of IGS.

Key Concepts

1. 1. Complications that can arise from iatrogenic postoperative inflammation that can contribute to the development of IGS.
   2. The timeline, risks factors and key differential diagnoses associated with IGS following cataract extraction.
   3. The value of SD-OCT in characterizing the disease course and in guiding the evaluation, treatment and management of IGS.
   4. Appropriate therapeutic and management strategies to improve visual outcomes in IGS.

Discussion Questions

1. 1. What disease processes result in reduced vision following cataract surgery?
   2. What are the components of intraocular inflammation?
   3. What complications can arise from chronic intraretinal fluid that lead to reduced vision?
   4. What are common vasculopathic disorders that can also present with macular edema?
   5. How do you classify presentations of macular edema?
   6. What proposed role does intraocular inflammation play in Irvine-Gass Syndrome?
   7. What treatment modalities exist to reduce intraocular inflammation?
   8. What is the mechanism of action of steroidal and non-steroidal agents in reducing intraocular inflammation?
   9. When would you refer a patient with Irvine-Gass syndrome to an external provider for further treatment?

Learning Assessment

In a case-based discussion, learners should be able to explain the underlying pathophysiology of IGS, including the role of postoperative inflammation and disruption of the blood-retina barrier. Participants will review clinic snapshots involving reduced vision following cataract extraction to identify likely causes and differentiate them from unrelated conditions. Group discussion and guided questioning will be used to assess comprehension of etiology and mechanisms of intraocular inflammation, as well as the underlying pathophysiology of IGS. Sequences of SD-OCT imaging can be presented to emphasize the role of serial analysis at follow-up visits to guide the treatment timeline. Furthermore, SD-OCT imaging can play a role in emphasizing intra- and sub-retinal anatomical landmarks. Learners should be able to identify mediators involved in the inflammatory process and how treatment targets specific mediators. Finally, awareness of referral criteria will be gauged by having participants outline the decision-making process for escalating care to a specialist when complications arise. This multifaceted approach ensures that learners do not rely on factual information recall but rather apply it to realistic clinical scenarios.

In evaluating the etiology of macular edema, learners should be encouraged to begin with the more common causes and then systemically work toward the less frequent ones, guided by the accompanying clinical context. This process should consider both the patient’s medical and ocular histories, as well as adjunctive clinical signs. For example, diabetic macular edema typically develops without associated anterior segment inflammation, postoperative inflammatory changes following cataract surgery may point more directly to IGS. Emphasizing this structured, context-driven approach helps students prioritize their differential diagnosis logically and tailor management more effectively.

Discussion

Irvine-Gass syndrome (IGS) is the most common complication of cataract surgery.¹ The mechanism of pathogenesis was first thought to be incarceration of the vitreous in the anterior segment with resulting vitromacular traction; however, it is now widely recognized as an inflammatory-mediated process.^2–4 The occurrence of IGS in modern cataract extraction has an estimated incidence of 2–12%.⁵ Peak incidence of IGS following cataract extraction is around 4 to 6 weeks postoperatively.⁶ Risk factors for IGS include diabetes, capsule rupture, pre-existing epiretinal membrane, uveitis, retinal vein occlusion and retinal detachment repair.⁷ Furthermore, higher incidences are noted with rupture of the posterior capsule, intracapsular cataract extraction and iris fixed intraocular lenses.⁸ Diabetes mellitus, regardless of the presence of diabetic retinopathy, is an independent risk factor for the development of postoperative IGS in cataract surgery patients.⁹ Although most cases are self-limiting, persistent or visually significant IGS requires timely treatment to prevent chronic visual impairment.¹⁰

Pathophysiology and Complications of IGS

IGS is characterized by fluid accumulation in the macula following uncomplicated cataract extraction, which leads to reduced visual acuity, distorted vision and visual disturbances.⁴ Postoperative inflammation is considered the primary catalyst for IGS following cataract surgery.⁴ During cataract extraction, manipulation of the anterior chamber releases arachidonic acid from uveal tissue, initiating the release of inflammatory mediators such as leukotrienes and prostaglandins.^11–12 These mediators diffuse throughout the vitreous cavity and toward the retina, where they disrupt the blood–retinal barrier by increasing perifoveal capillary permeability.¹³ Despite their diffuse distribution, fluid accumulates preferentially at the fovea due to its high metabolic activity and lack of vascular supply within the foveal avascular zone.⁸ As a result, leakage of intravascular contents from dilated perifoveal capillaries accumulates in the outer plexiform and inner nuclear layers, forming cystic spaces that can coalesce into larger pockets of intraretinal fluid.⁸ When vascular permeability exceeds the drainage capacity of the retinal pigment epithelium, microcysts develop in the outer plexiform and inner nuclear layers, eventually merging into larger intraretinal cysts.⁸ If left unresolved, prolonged edema can progress to structural complications. Chronic fluid accumulation may lead to lamellar macular holes, persistent subretinal fluid, foveal atrophy, epiretinal membrane, macular ischemia and macular fibrosis.^8,14 Because of these risks, rapid recognition and treatment of IGS is essential to prevent photoreceptor dropout and irreversible central retinal damage.¹⁵

Prognosis is guided by SD-OCT biomarkers. These include disorganization of the inner retinal layers, presence of intraretinal cystoid spaces, photoreceptor outer segment length and integrity of the external limiting membrane and ellipsoid zone.¹⁴ Disorganization of the inner retinal layers involving more than 50% of the central 1 mm foveal zone is associated with poor visual prognosis.¹⁶ Larger intraretinal cysts are often linked to macular ischemia, with giant cysts disrupting the outer nuclear layer and ellipsoid zone and resulting in worse visual prognosis.¹⁴

Differential Diagnosis of IGS

Differential diagnoses for macular edema should include several key conditions that must be distinguished from IGS. Differential diagnoses for the patient’s IGS included diabetic macular edema (DME), retinal vein occlusion (RVO), uveitic macular edema and central serous chorioretinopathy (CSCR). Each condition has distinct clinical presentations, patient demographics and SD-OCT characteristics that aid in accurate diagnosis and appropriate treatment selection.

Macular edema is the primary cause of vision loss in patients with diabetic retinopathy.¹⁷ In diabetic retinopathy, cell-cell junctions between endothelial cells are damaged, resulting in the increased leakage of plasma, lipid and red blood cells; clinically, this is noted as edema, hard exudates and intraretinal hemorrhages.^18-19 Retinal hypoxia causes capillary hyperpermeability through vascular autoregulation dysfunction, primarily due to hypoxia-induced vascular endothelial growth factor (VEGF) upregulation.²⁰  Expression of VEGF leads to increased permeability, obstruction and damage of retinal capillaries, resulting in serous blood components leaking.²¹ Since the patient did not report having diabetes mellitus and no other signs of diabetic retinopathy were observed, DME was ruled out as a potential differential. Given the unilateral presentation of macular edema in this case, along with the patient’s history of recent cataract extraction, IGS became a more likely diagnosis.

Macular edema can occur as a complication of RVO. The pathogenesis of RVO is believed to involve vascular endothelial damage and compression of the retinal vein, ultimately leading to thrombus formation.²²  Hypoxic retinal cells release VEGF, which promotes vascular permeability and vascular proliferation by binding to endothelial cell receptors.²² Vascular endothelial injury increases retinal capillary pressure, promoting fluid translocation into the extracellular space and development of macular edema.²³ The patient presented with no history of vasculopathy. Fundoscopic examination revealed no accompanying retinopathy, including hemorrhages or exudates. The normal fundus appearance and absence of vasculopathic disease ruled out RVO as the cause of macular edema.

Uveitic macular edema involves a breakdown of the blood-retinal barrier due to release of inflammatory mediators such as VEGF, which results in leakage of fluid into retinal tissue and formation of cystic spaces in the outer plexiform layer.²⁴ Defective RPE can also lead to accumulation of fluid underneath the neurosensory retina.²⁴ Changes to the choroid, which influences fluid homeostasis across the outer blood-retinal barrier, can affect the process of retinal fluid reabsorption across RPE cells.²⁴ Corticosteroids are the mainstay of controlling inflammation in noninfectious uveitis complicated by macular edema; topical corticosteroids may be effective in milder cases of uveitic macular edema.²⁵ Topical non-steroid anti-inflammatory drugs (NSAIDs) can be used in milder cases or as adjunctive treatment with steroids.²⁵ Periocular corticosteroids are usually effective in controlling uveitic macular edema, though repeat injections may be required during the course of the disease.²⁵ Uveitic macular edema was excluded given the lack of anterior chamber inflammation on slit-lamp examination and the rarity of uveitis in rheumatoid arthritis patients.²⁶

Central serous chorioretinopathy (CSCR) should be considered as a differential due to the presence of subretinal fluid noted on SD-OCT. CSCR is a retinal disorder characterized by localized serous detachment of the macula.²⁷ During the disease process, choroidal vessels become hyperpermeable, leading to increased tissue pressure and disruption of the anatomic integrity of the retinal pigment epithelium (RPE); this results in choroidal fluid detaching the neurosensory retina.²⁷ Treatment of CSCR consists of restoring choroidal vasculature and restoring RPE and photoreceptor function.²⁸ The temporal association with recent ocular surgery made the diagnosis of CSCR less likely, along with preceding intraretinal fluid accumulation.

Treatment Options for IGS

Universal first-line treatment for IGS appears to be topical NSAIDs, either as monotherapy or in combination with corticosteroids.⁴ NSAIDs reduce inflammation by inhibiting cyclo-oxygenase (COX) enzymes, thereby decreasing prostaglandin production.^29-30 Topical NSAIDs have demonstrated efficacy in reducing acute or chronic postoperative IGS after cataract extraction.³¹  They offer advantages such as stable IOP during application, a lower risk of infection and analgesic effects.³¹ Transient stinging and irritation are common adverse effects from topical NSAIDs.³² The patient was initially managed with NSAID monotherapy as first-line treatment, but developed ocular surface irritation that limited tolerability. The decision was made to discontinue the NSAID and proceed with corticosteroid monotherapy to maintain anti-inflammatory coverage while avoiding further surface discomfort.

Corticosteroids act higher in the inflammatory cascade by inhibiting phospholipase-A2 and preventing the formation of arachidonic acid, while also inhibiting COX enzymes.³³ However, they are associated with risks such as elevated IOP, delayed wound healing and increased susceptibility to secondary bacterial infection.³⁴ Furthermore, cataract formation is a well-known side effect of steroid treatment that leads to reversible vision impairment.³⁵ Despite their well-established anti-inflammatory and VEGF-inhibiting properties, and the potential risk associated with their use, the relative benefits of corticosteroids compared with NSAIDs for postoperative inflammation remain unclear.³⁶ Given this uncertainty and the patient’s intolerance to NSAIDs, initiating corticosteroid monotherapy was deemed the most appropriate strategy to ensure adequate anti-inflammatory control while minimizing discomfort, with appropriate monitoring for IOP and ocular surface health.

Periocular steroids, including intravitreal and sub-tenon administration, have been shown to improve vision and promote resolution of IGS, particularly in cases refractory to topical therapy.⁴ Sub-tenon injections are considered a cost-effective alternative and avoid the risk of intraocular inflammation associated with intravitreal administration.¹⁰ Ozurdex, a biodegradable intravitreal drug delivery system that maintains continuous delivery of preservative free dexamethasone, effectively treats refractory cases and may decrease the need for retreatment.³⁷ In this patient, these periocular and intravitreal options were not considered necessary, as topical prednisolone acetate 1% provided adequate anti-inflammatory effect while minimizing procedural risk. This highlights the principle of therapeutic escalation: invasive approaches should be reserved for cases where simpler, lower-risk strategies have failed to provide sufficient response.

Corticosteroid Response in Glaucoma Patients

Steroid-induced glaucoma is a form of secondary glaucoma that occurs when elevated IOP leads to optic neuropathy.³⁸ The underlying mechanism involves increased resistance to aqueous outflow at the level of the trabecular meshwork.³⁸ Trabecular meshwork cells, which contain glucocorticoid receptors, are directly affected by corticosteroids, leading to alterations in cell migration and phagocystosis.³⁹ In addition, corticosteroids promote extracellular matrix deposition, particularly collagen and fibronectin,  in the juxtacanalicular region, further contributing to increased outflow resistance.³⁹

Individuals who demonstrate elevated IOP after steroid use are termed “steroid responders,” defined as IOP of 21–24 mmHg or an increase of 5–10 mmHg from baseline.⁴⁰ Among commonly used agents, prednisolone is generally associated with a lower risk of significant IOP elevation than dexamethasone, though both can cause clinically meaningful IOP spikes.⁴¹ Approximately one third of the population are steroid responders after 2 or more weeks or topical glucocorticoid use, with the prevalence exceeding 90% in patients with pre-existing POAG.^42–44 Steroid-induced IOP increase occurs 3-6 weeks following topical corticosteroid use and often normalizes within 2 weeks of cessation.³⁸  Sustained IOP rises secondary to steroid use can cause vision loss, usually through glaucomatous damage to the optic nerve.⁴⁵ From a management standpoint, this means that timing and duration of therapy matter as clinicians cannot assume that short-term use is entirely risk-free. In practice, even modest IOP spikes can matter in a glaucomatous eye already near its threshold of optic nerve tolerance.

Notably, our patient with a history of PACG was treated with cataract extraction, which has been shown to significantly reduce IOP and glaucoma drug requirements.⁴⁶ Although pseudophakia deepens the anterior chamber, patients with a history of PACG remain susceptible to steroid-induced elevation, as trabecular outflow compromise persists and these eyes continue to show IOP fluctuations and glaucomatous progression after lens extraction.^47–48 In our patient with known PACG, these risks were carefully considered. While corticosteroid therapy was necessary for postoperative inflammation control, we closely monitored IOP for abnormal spikes, recognizing both the heightened risk of steroid response and potential for glaucomatous progression.

SD-OCT imaging was critical for tracking the temporal response to prednisolone acetate 1%. Its non-invasive nature and superior morphologic resolution compared with color photography and angiography make it well-suited for detecting subtle macular changes, particularly in IGS, where defective RPE function and choroidal alterations can allow intraretinal fluid to accumulate subretinally where the RPE is unable to efficiently clear it.^24,49 SD-OCT also provides a normative database with a color-based scale for measurement comparison, though thinner-than-average macular thickness in the RE maye reflect physiologic interocular variation.⁵⁰ Importantly, SD-OCT normative databases may misrepresent certain “normal” demographic profiles, exaggerating apparent thinning of central retinal thickness, and age-related thinning of retinal layers, particularly photoreceptors, is a well-documented trend.⁵⁰ Subacute autoimmune retinopathy may be considered in the differential diagnosis, as retinal atrophy and reduced central macular thickness on SD-OCT are characteristic findings, although discussion of this possibility is beyond the scope of this report.⁵¹ In this case, the absence of fluid or structural abnormalities on imaging, coupled with a lack of visual symptoms, supported a benign explanation for asymmetry.

For glaucoma patients with IGS, a tailored management strategy is required. Corticosteroid therapy carries the risk of steroid-induced IOP elevation, making close surveillance of IOP mandatory. Adjustments to glaucoma therapy or discontinuation of steroids may be necessary if acute spikes occur. In our patient with PACG, SD-OCT imaging in combination with vigilant IOP monitoring helped guide the use of corticosteroid monotherapy. While this case did not incorporate an Amsler grid, such tools can provide additional value by allowing patients to self-monitor central vision changes at home. Ultimately, coordination of diagnostic imaging, IOP monitoring and clinical examination allows for effective use of corticosteroids in this high-risk population.

Conclusion

Prednisolone acetate 1% monotherapy can be effective for IGS, even in patients with established glaucoma. In such cases, however, the risk of corticosteroid-induced IOP elevation must be carefully balanced against the anti-inflammatory benefit. Frequent monitoring is essential to ensure treatment does not inadvertently accelerate glaucomatous damage. Prompt initiation of therapy increases the likelihood of full visual recovery while reducing the risk of chronic macular changes.

Management should remain flexible and individualized. Patients with glaucoma may require closer follow-up or adjustments in their IOP-lowering medications. A stepwise approach can be useful, for example beginning with topical monotherapy but remaining prepared to escalate therapy if clinic response is incomplete or if side effects arise.

Equally important is patient education. Setting expectations regarding the need for regular visits, the possibility of treatment adjustments and the importance of adherence helps optimize outcomes. With timely diagnosis, thoughtful therapeutic selection and close monitoring, favorable long-term visual outcomes can be achieved in IGS.

Polypoidal choroidal vasculopathy (PCV) is believed to be a subtype of exudative age-related macular degeneration associated with an abnormal branching network of vessels with aneurysmal dilations referred to as polyps.¹ Typically, it presents with orange nodules in the macular area or with a large (greater than 4-disc diameters) subretinal hemorrhage.² Although less common, it may also occur in the peripapillary or extramacular areas. While PCV is a variation of choroidal neovascularization, it has a different pathophysiology compared to choroidal neovascularization related to exudative age-related macular degeneration.³

PCV has an estimated prevalence of 10-20% in a Caucasian population and as high as 22-62% in an Asian population.⁴ PCV occurs more often in males and bilaterally in a Caucasian population. In contrast, PCV occurs more often in females and unilaterally in an Asian population.⁵ It is most commonly diagnosed between the ages of 50-65 years old.⁶ Risk factors for PCV that have been identified include smoking, cardiovascular disease, hyperlipidemia and high body mass index.^7-10

PCV is often misdiagnosed as central serous chorioretinopathy or exudative age-related macular degeneration. Multimodal imaging can help distinguish between these conditions. This teaching case report discusses a patient with PCV who was previously misdiagnosed with central serous chorioretinopathy. This case report presents the pathophysiology and evidence-based management guidelines for PCV. The target audience is third- and fourth-year optometry students, optometry residents and practicing optometrists.

Case Discussion

A 58-year-old Caucasian male presented to the eye clinic with a chief complaint of blurry vision in the left eye for the last 2 months. He further described it as constant darkness and waviness to his vision. He was last evaluated at the eye clinic 6 months prior. His systemic history was positive for hypertension, gastroesophageal reflux and sleep apnea, for which he was taking amlodipine besylate 10mg, losartan 50mg, aspirin 81mg and melatonin 3mg. A CPAP machine was used to manage his sleep apnea. No known medical allergies were reported. His ocular history was positive for dry eye syndrome, cataracts and simple hyperopia with presbyopia in both eyes. He was previously diagnosed with central serous chorioretinopathy in the left eye 7 years prior. The diagnosis was confirmed by a retina specialist. However, the patient elected to monitor without intervention. His ocular surgical history was negative and his family ocular history was negative.

At his current visit, his visual acuity in the right eye was stable at 20/25^– and the left eye was reduced to 20/100 with no improvement upon refraction or pinhole compared to 20/30 6 months prior. Pupils were equal, round and reactive to light, motilities were full, and confrontation facial fields were full in each eye. His anterior segment in each eye was unremarkable. His intraocular pressure (IOP) by Goldmann Applanation Tonometry was 18mmHg in each eye at 2:05 PM. On posterior segment assessment, both eyes had 1⁺ nuclear sclerotic cataracts and vitreous syneresis, and both optic nerves had 0.25 round cupping. The macula in the right eye was within normal limits, while the left eye had a 1.5-disc diameter central area of hemorrhaging noted. The artery-to-vein ratio for both eyes were 2/3, and the periphery was within normal limits.

Figure 1A: Right eye macula OCT showing a normal foveal contour, inner/outer segment junction and RPE layer intact. Click to enlarge

Figure 1B: . Left eye macula OCT showing a central macular hemorrhage (green arrow), double-layer sign (red arrow), and a thickened choroid (yellow arrow). Click to enlarge

Spectral-domain optical coherence tomography (SD-OCT) of the macula was performed without enhanced depth imaging. The right eye (Figure 1A) showed a normal contour with the inner segment/outer segment junction and retinal pigment epithelium layer intact. Comparatively, the left eye (Figure 1B) showed a subretinal hemorrhage, subretinal fluid, double-layer sign and a thickened choroid. Optos imaging was also obtained, showing no retinal pathologies in the right eye (Figure 2A) compared to a central macular hemorrhage in the left (Figure 2B).

Figure 2A: . Optos imaging in the right eye showing no retinal pathology. Click to enlarge

Figure 2B: . Optos imaging in the left eye showing a central macular hemorrhage. Click to enlarge

His diagnosis was changed from central serous chorioretinopathy to polypoidal choroidal vasculopathy in the left eye based on his clinical exam findings, including dilated fundus exam and OCT. He was referred to a retina specialist within a couple of weeks for further evaluation and management. The retina specialist confirmed the diagnosis and began treating the patient with anti-VEGF therapy.

Teaching Instructions

This teaching case report is most appropriate for third- and fourth-year students as well as residents. Appropriate assessments include presenting the case at a journal club at an optometry school, optometric rotation or residency site. Students and/or residents may work independently or in groups to answer the discussion questions.

Learning objectives

• Understand the signs and symptoms of PCV
• Understand the pathophysiology of PCV
• Understand the differential diagnoses of PCV
• Describe appropriate diagnostic testing for PCV
• Understand the treatment and management of PCV
• Understand the prognosis for PCV

Key concepts

• Identify the demographics and epidemiology of PCV
• Identify the clinical presentation of PCV
• Understand the different diagnoses of PCV
• Appropriate diagnostic testing for PCV
• Appropriate referrals, treatment and management for PCV

Discussion questions

Knowledge and understanding of the case and condition presentation

• What are the expected patient signs and symptoms in a case of PCV?
• What are the risk factors associated with PCV?

Differentials diagnoses

• What other conditions present in a similar clinical manner to PCV?
• How does a clinician differentiate between these similar conditions based on patient presentation and ancillary testing results?

Diagnostic testing

• Describe critical clinical testing for aiding the diagnosis of PCV and expected findings.
• What are the typical features of PCV noted on OCT, FA and ICGA?

Treatment and management

• What specialty referral would you consider making if you suspect PCV?
• What is the prognosis for PCV?

Discussion

Signs and Symptoms of PCV

Patients often report blurry vision and a central scotoma/metamorphopsia. On dilated fundus exam, a small, medium or large orange-red elevated central macular lesion may be noted. Polypoidal lesions are commonly noted in the macula in 69.5% of cases and peripapillary involvement in 4.5% of cases.¹¹ PCV lesions can be isolated and single or multiple and widespread.¹²

Pathophysiology of PCV

PCV has been categorized as part of the pachychoroid spectrum of retinal conditions. This group of conditions also includes central serous chorioretinopathy, pachychoroid pigment epitheliopathy and pachychoroid neovasculopathy.¹³ “Pachychoroid” refers to thickening of the choroid with pathognomonic dilation of blood vessels in Haller’s layer. These vessels are referred to as “pachyvessels” and are associated with an abnormal increase in choroidal permeability.¹⁴ Pachyvessels are also accompanied by thinning of the choriocapillaris and middle choroid layer vessels that overlie them. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and increases vascular permeability. Elevated levels of VEGF have been found in the aqueous of eyes with PCV, though in lower levels compared to neovascular age-related macular degeneration.¹⁵

Spontaneous subretinal hemorrhages may occur due to the rupture of the thin-walled choroidal vessels. Therefore, PCV lesions can be classified clinically as quiescent, hemorrhagic or exudative. Quiescent refers to the presence of polyps but lack of subretinal or intraretinal fluid or hemorrhage. Hemorrhagic refers to any subretinal or sub-retinal pigment epithelium (RPE) hemorrhaging with or without other exudative changes. Lastly, exudative PCV is characterized by the absence of hemorrhaging but the presence of exudative changes such as neurosensory detachments, sensory retinal thickening, pigment epithelium detachment (PED) and subretinal lipid exudation.⁶

There is also an association between increased levels of C-reactive protein, a nonspecific inflammatory protein and PCV.^16,17 Other pro-inflammatory and pro-angiogenesis factors have been implicated in the pathogenesis of PCV, including VEGF, IL-23 (interleukin-23), MCP-1 (monocyte chemoattractant protein-1), and tumor necrosis factor-a.¹⁸ MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes and macrophages at the site of inflammation. MCP-1 induces angiogenesis via upregulation of hypoxia-inducible factor 1 alpha gene expression, and VEGF, in turn, stimulates MCP-1, suggestive of a positive regulatory feedback loop.¹⁹ Studies have found higher levels of MCP-1 in PCV eyes, indicating that MCP-1 is a significant biomarker and a potential therapeutic target.²⁰ Tumor necrosis factor-a is another pro-inflammatory cytokine that can increase vascular leakage, ultimately contributing to choroidal neovascularization.²¹ IL-23 has a particularly strong association with PCV. IL-23 is a pro-angiogenic cytokine that increases the inflammatory response, such as the upregulation of matrix metalloproteinase MMP9.²² Matrix metalloproteases (MMP) degrade extracellular matrix (ECM) proteins. In those with PCV, MMP2 and MMP9 have been found to be elevated, implying that MMPs may serve as a biomarker of ECM metabolism for patients with PCV.²³ Elevated serum levels of MMPs may indicate that PCV may be a type of systemic vascular disease, such as atherosclerosis.²⁴ IL-17 (interleukin-17) is also a pro-inflammatory cytokine.²⁴ It promotes angiogenesis by enhancing choroidal endothelial cell migration and tube formation, ultimately promoting the abnormal vessel growth associated with PCV.²⁵

Genetic variants within complement factor H have been identified that increase the risk of developing both age-related macular degeneration and PCV.^26,27 Both I62V, a specific coding variant, and the ARMS2 gene have been found to be strongly associated with PCV.^28,29

What are the differential diagnoses of PCV?

• Macular Degeneration: Also causes blurry vision and/or metamorphopsia in those ages 60 and up. This is commonly noted bilaterally, drusen will be present, and a thinner choroid on OCT will be noted.
• Central serous chorioretinopathy: Causes unilateral blurry vision and/or metamorphopsia in those ages 20-50. This is a sensory retinal detachment that self-resolves over months, unlike PCV.
• Pachychoroid Neovasculopathy: Both pachychoroid neovasculopathy and polypoidal chorioretinopathy will demonstrate a thicker choroid and dilated choroidal vessels (pachyvessels); however, PCV will have polypoidal lesions present. ICGA can help further distinguish the two.
• Pathological myopia: Clinical features that are present include atrophic lesions in the macula, lacquer cracks and Fuch’s spots.
• Choroidal tumors or metastases: PCV is generally slow growing with recurrent hemorrhages, while a choroidal tumor demonstrates rapid growth and vision loss. ICGA can help distinguish these two by showing the polypoidal lesions in PCV, compared with distinct vascular patterns and a large, solid mass in a choroidal tumor/metastasis.

What ancillary testing is used to diagnose PCV?

Optical Coherence Tomography (OCT) can reveal hallmark signs indicative of PCV.  A sharply peaked PED or notched “thumbprint” PED, thickened choroid and subretinal fluid are some examples. A sharply peaked PED denotes a polyp, and a thickened choroid helps exclude the diagnosis of macular degeneration, as a thinner choroid is more typical.³⁰ The dual reflective layer, known as the “double layer sign,” is seen in 59% of eyes with PCV.³¹ This is seen as two highly reflective lines, one in the RPE layer and the other in Bruch’s membrane, indicating the location of the choroidal vascular network.²⁹ PCV lesions also appear as chronic, multiple “serosanguineous” detachments of the RPE and/or neurosensory retina.³² According to the Asia-Pacific Ocular Imaging Society PCV Workgroup, a combination of the following three specific OCT findings supports the diagnosis of PCV: sub-RPE “ring-like” lesions, en face complexes of RPE elevations and sharply-peaked PEDS. Utilizing these three findings as diagnostic criteria led to an accuracy rate above 80%.³³

Enhanced depth imaging OCT (EDI-OCT) can help identify features to distinguish PCV from exudative age-related macular degeneration. EDI-OCT will show increased choroidal thickness in eyes with PCV, whereas it is thinner in eyes with age-related macular degeneration. OCT angiography (OCT-A) can also aid in confirming the diagnosis of PCV. OCT-A can identify the polypoidal lesions and branching vascular network, which is not noted in exudative-age related macular degeneration.³⁴

Fluorescein angiography (FA) favors the diagnosis and classification of macular degeneration over PCV due to the inability of the fluorescein to visualize RPE subtypes, such as polyps.³⁵ Exudative lesions display uniform hypofluorescence in the early phase with pooling in the late phase. Hemorrhagic lesions are hypofluorescent secondary to blockage of dye due to blood, causing macular PCV to often be misdiagnosed as age-related macular degeneration based solely on fluorescein angiography findings.³⁸ Similarly, PCV may appear similar to central serous chorioretinopathy on FA, as both ocular disorders will display a thickened choroid and RPE leakage.³⁹

Indocyanine green angiography (ICGA) remains the gold standard for diagnosing PCV. This is because indocyanine green dye absorbs and emits near-infrared light that penetrates the RPE, allowing better imaging of the choroidal structures. Compared to fluorescein dye, indocyanine green dye does not leak from the choriocapillaris, allowing choroidal lesions to be more discernible. ICGA should be considered when a dilated fundus exam reveals orange subretinal nodules, notches, or hemorrhagic or serous PED, spontaneous, massive subretinal hemorrhage, or a lack of response to anti-VEGF therapy. During the early phase of ICGA, an abnormal choroidal branching vascular network filling is noted. The polyps in terminal vessels will become hyperfluorescent. During the mid-phase, leakage from the polyps is noted along with choroidal hyperfluorescence of the lesion. During the late phase, the reversal pattern of the dye is seen with the center of the lesion becoming hypofluorescent and the surrounding area becoming hyperfluorescent. Lastly, during the very late phase, a non-leaking PCV lesion will become “washed-out” whereas a leaking PCV lesion remains hyperfluorescent.³⁸

According to evidence-based guidelines by Tan et al, diagnosis of PCV is defined as single or multiple focal nodular areas of hyperfluorescence from choroidal circulation within 6 minutes after injection of indocyanine green dye with one or more of the following features:

• nodular appearance of the polyps on stereoscopic examination
• hyperfluorescent halo surrounding the nodule(s)
• association with branching vascular network on ICGA
• pulsation of the polyps on dynamic ICGA
• orange, subretinal nodules on color fundus photography
• massive (> 4-disc diameters) submacular hemorrhage¹⁴

What is the treatment and management of PCV?

Treatment of PCV is based on the location of the lesion, active leakage and whether it is affecting visual acuity. Approximately 50% of lesions are self-limiting and are not visually significant.³⁹ Consider co-management with a retina specialist when the etiology is uncertain to ensure optimal visual outcome. PCV is considered to be active if any of the following findings are present: OCT and/or angiographic findings characteristic of PCV contributing to a decline in vision of at least 5 letters (EDTRS), subretinal fluid with or without intraretinal fluid, PED or subretinal hemorrhage, or angiographic evidence of leakage.⁶ Focal laser was used as monotherapy to ablate extrafoveal polyps; however, due to scarring and recurrence, this therapy is not used as often anymore.⁴⁰ Photodynamic therapy (PDT) was also used to treat PCV; however, complications of this therapy include subretinal hemorrhage, choroidal infarction and RPE tear.⁴¹ Extrafoveal lesions tend to have complete resolution after being treated with laser photocoagulation; however, subfoveal and juxtafoveal PCV lesions are considered sight-threatening, and treatment is based on guidelines established by the EVEREST, EVEREST II and PLANET studies.⁴²

The EVEREST study was a multicenter, double-masked, prospective study analyzing symptomatic PCV patients treated with verteporfin PDT combined with ranibizumab (Lucentis) vs. PDT alone vs. ranibizumab monotherapy. At 6 months, 71.8% treated with verteporfin PDT monotherapy had complete regression with BCVA improvement of 7.5 letters, compared to 77.8% had complete regression with PDT verteporfin combined with ranibizumab, with a BCVA improvement of 10.9 letters. Those receiving ranibizumab monotherapy achieved a complete regression rate of 28.6% and BCVA improvement of 9.2 letters. Based on these results, subfoveal and juxtafoveal PCV should be treated with either ICGA-guided verteporfin PDT or a combination of verteporfin PDT and three 0.5-mg ranibizumab intravitreal injections at monthly intervals.³⁹ The authors recommended that combination therapy should be considered in cases of large amounts of subretinal fluid or exudation associated with PED, leakage from branch vascular network and polyps, ICGA features that are unclear between PCV and choroidal neovascularization, and/or if the lesions are a combination of PCV and choroidal neovascularization. It is recommended to monitor the subfoveal of juxtafoveal PCV 3 months after initial treatment, and if leakage is still noted on OCT/FA but lacks complete regression on ICGA, retreatment with ranibizumab is recommended. If there is incomplete regression of polyps, retreatment with verteporfin PDT monotherapy or combined with ranibizumab is recommended.⁶

The follow-up study, EVERST II, a multicenter, double-masked randomized trial, investigated the efficacy and safety of ranibizumab monotherapy vs combination therapy with ranibizumab and PDT in treating PCV. Participants were randomized to either ranibizumab plus PDT or ranibizumab with sham PDT and monitored over 24 months. In the combination therapy group, the average BCVA improved to 9.6 letters, and 56.6% of polyp lesions had complete regression compared to 5.5 letters in the monotherapy group, and 26.7% of polyp lesions had complete regression (consistent with the findings in the EVEREST trial). These results suggested that ranibizumab with PDT remained a superior option compared to ranibizumab monotherapy.⁴³

The PLANET study, a randomized double-masked trial, compared intravitreal aflibercept (Eylea) monotherapy to aflibercept and rescue photodynamic therapy. All participants received treatment with intravitreal aflibercept for the first 3 months, then were randomized into either an aflibercept monotherapy group or a PDT “rescue” group, which was subdivided into a sham PDT group and a rescue PDT group. After 52 weeks, the mean BCVA improvement for the aflibercept monotherapy group was 10.7 letters and 33.1% of polyp lesions had complete regression. Comparatively, the mean BCVA improvement was 9.1 letters in the aflibercept plus PDT rescue group and 29.1% had polyp regression. This study concluded that aflibercept monotherapy was just as effective for PCV patients as combination therapy, and additional treatment with rescue PDT did not offer any significant benefit.⁴⁴

What is the prognosis of PCV?

Generally, small lesions less than one disc diameter have a good visual prognosis. Factors that lead to poor prognosis/vision loss include large lesions, PED, cluster polyps, lesion recurrence and Caucasian race.^45,46 Larger polyps or polyps near the macula may lead to complications such as a serous or hemorrhagic PED, subretinal hemorrhaging or exudative retinal detachment.^47,48 Long-term follow-up is recommended for eyes with PCV, even in eyes with inactive lesions, as they can worsen in the future, even if stable for years. Severe vision loss can be found in about one-third of eyes with PCV due to choroidal ischemia, inflammation, RPE damage and breaks in Bruch’s membrane.^49,50 Understanding the prognosis of PCV may prompt a referral for low vision rehabilitation services if the condition becomes visually significant to enhance the patient’s quality of life.

Conclusion

Polypoidal choroidal vasculopathy is an infrequent, distinct retinal disorder that is commonly misdiagnosed. Utilizing multimodal imaging can aid in appropriate diagnosis. Proper diagnosis allows patients the best opportunity for successful treatment and outcome. It is important for optometrists to understand the pathophysiology and progression of PCV to properly diagnose the condition, provide appropriate co-management and counsel patients on its prognosis.

Keshia S. Elder, OD, MS, MS, FAAO

I am pleased to announce that Optometric Education has appointed two new Associate Editors to join the editorial team, Dr. Marc Taub and Dr. Parres Wright.

Dr. Taub is a Professor of Optometry at Southern College of Optometry. The 2001 Pennsylvania College of Optometry graduate serves as the Residency Supervisor for the Vision Therapy and Rehabilitation Residency and the Residency Co-Supervisor for the Residency in Pediatrics and Vision Therapy.

Dr. Wright, a 2007 graduate of Nova Southeastern University College of Optometry, is an Associate Professor at Midwestern University-Chicago College of Optometry. She serves as the Clinic Care Lead for the Low Vision and Advanced Care Departments.

The Optometric Education team is excited to have filled these positions. We know our new Associate Editors will be help lead the Journal into our next 50 years!

Drs. Taub and Wright will share their priorities and vision for the journal below.

Marc B. Taub, OD, MS, EdD, FAAO, FOVDR, FNAP, Dipl AAO

I picked up the writing bug in optometry school when I teamed up with a classmate to write a paper with my mentor, Andy Gurwood. When I saw the article in print and the feedback was positive, my endorphins started pumping. I was immediately hooked. After 20-plus years, that feeling still has not worn off. I still love writing. This love transferred to editing when I realized that I could help others develop their work and find their voices. There is nothing more satisfying than helping a fellow author.

I love being an educator. For me, this does not end in the classroom, lab, or clinic. Writing and editing are an extension of teaching. One of the reasons I completed an educational doctorate was to learn more about teaching and to understand how I could improve my teaching. The articles in Optometric Education offer readers the same opportunity and cannot be found in any other journal. The research centers around the pedagogy and andragogy of optometry. The case reports are not simply case presentations; they are steeped in teaching and include educational guidelines. The Journal’s uniqueness is a treasure for the entire field of optometry, and I am thrilled to be part of its storied journey.

Parres M. Wright, OD, FAAO

I’ve always been a proponent of innovative educational approaches and varied teaching strategies. As Associate Editor of Optometric Education, I hope to help the Journal offer educators actionable insights that meaningfully enhance optometry’s curriculum design and clinical reasoning.

The Journal is an invaluable resource for the next era of optometric education. As an editorial team, we are committed to supporting innovative pedagogical models that prepare faculty for the evolving demands of the field. I plan to focus on bridging theory and practice to help ensure the Journal serves as both a trusted resource and a catalyst for innovation.

I look forward to continuing the mission of the journal as it stands as a reflection of our field’s progress and looks forward as we imagine what comes next. We have a great opportunity to facilitate the cultivation of a scholarly community where educators, clinicians and researchers can engage in meaningful dialogue and shape the future of optometric training.

Please join us in welcoming Dr. Taub and Dr. Wright to the Optometric Education team!