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Kansas Kansas EyeCon EyeCon

April 8 & 9, 2016 The Venue 4800 W 135th St., Ste. 108 Leawood, KS 66209

Sponsored by the University of Kansas Department of Ophthalmology and the Lemoine Alumni Society

DEPARTMENT OF OPHTHALMOLOGY SCHOOL OF MEDICINE CLINICAL FACULTY

7400 State Line Rd 3901 Rainbow Blvd., Ste. 1011 Miller Prairie Village, KS 66208 Kansas City, KS 66160 Appointments : 913 - 588 - 6600 Appointments: 913-588-6688

kumed.com/kueye

C. Scott Atkinson, MD Miranda Bishara, MD Dirck DeKeyser, OD William Godfrey, MD Pediatric Ophthalmology Cornea/Refractive/Cataracts Optometrist Uveitis

Shree Kurup, MD Paul Munden, MD Ajay Singh, MD Jason Sokol, MD Retina and Vitreous Glaucoma & Anterior Segment Retina and Vitreous Oculofacial Plastic & Orbital Surg.

John Sutphin, MD, Chair Matthew Twardowski, O.D. W. Abraham White, MD Thomas J. Whittaker, JD, MD Cornea & Anterior Segment Optometrist Comprehensive Neuro-Ophthalmology DEPARTMENT OF OPHTHALMOLOGY SCHOOL OF MEDICINE RESIDENTS 2015 – 2016

Third-Year Residents

Anna Berry, MD Michelle Boyce, MD Lillian Yang, MD Pager: 0369 Pager: 0418 Pager: 1488

Second-Year Residents

Derek Horkey, MD Anjulie Quick, MD Robert Null, MD Pager: 4935 Pager: 0404 Pager: 0732

First-Year Residents

Luke Dolezal, MD Joshua Jones, MD Reid Mollman, MD Pager: 2016 Pager: 1487 Pager: 0447 EDUCATING TOMORROW’S GENERATION ~ CARING FOR TODAY’S Kansas EyeCon 2016 We wish to acknowledge and sincerely thank these organizations for exhibiting at this conference:

Platinum Sponsors:

Alcon Laboratories, Inc. Ellex Enhanced Medical Services Heidelberg Engineering Regeneron Pharmaceuticals, Inc. Shire Medical Affairs

Silver Sponsors:

Allergan, Inc. Bio‐Tissue Carl Zeiss Meditec, Inc. Bronze Sponsor: KU Audio‐Reader Network Kansas EyeCon 2016 The Venue 4800 W 135th St., Ste. 108 Overland Park, KS April 8 & 9, 2016

Program Overview ‐ This conference is intended to provide ophthalmologists with an educational forum to learn about new developments in the profession and their application to patient care. Covering a cross‐section of all sub‐specialties, physicians can expect to walk away having heard evidence‐based presentations.

Target Audience ‐ This program is designed to meet the needs of practicing ophthalmologists.

Learning Objectives ‐ Upon completion of the educational activity, participants should be able to: Orbital Session 1. Provide an overview of the indications, history, symptoms, biopsy results and outcomes of patients with suspected giant cell arteritis; 2. Evaluate the efficacy and utility of temporal artery biopsies performed at the University of Kansas Hospital; 3. Describe the clinical presentation of orbital myeloid sarcoma; 4. Describe the natural history of the disease, as well as the available treatments; 5. Recognize the most common periorbital skin malignancy associated with immunosuppressive therapy; 6. Determine if periorbital skin malignancies while on immunosuppressive therapy result in a higher incidence of exenteration; 7. Outline the most common reasons for eye destructive procedures in a tertiary care center; 8. Recognize the most common neoplasms requiring eye destructive procedures; 9. List two major potential benefits of virtual reality technology in vision science; 10. Explain the outcomes of some virtual reality‐based interventions to improve visual scanning capabilities of patients with low vision. Cataract and Pediatric Session 11. Understand the role of microtropia in the spectrum of diplopia, strabismus and peripheral fusion; 12. Diagnose microtropia using the Bruckner red reflex test, Bagolini lens test, tbase ou prism test and stereo testing; 13. Recognize Cataract surgery difficulties and solve these problems, or at least better manage them when they occur; 14. Identify several ways the ophthalmologist will learn over time to improve the quality of eye care for the patients served by embracing personal education through reading, personal observation and experience; 15. Learn new insights to enhance surgical outcome with cataract surgery. Anterior Segment and Refractive Session 16. List two advantages to the use of femtosecond laser for use in posterior polar cataract extraction; 17. Implement essential surgical steps to reduce complications in removal of posterior polar cataract; 18. Describe the three stages of the Dysfunctional Lens Syndrome; 19. List the advantages of Refractive Lens Exchange surgery; 20. Understand the timing and approaches to surgery in complex uveitis; 21. Diagnose uveitis patients who benefit with vitreoretinal surgery; 22. Describe risk factors for intraocular pressure elevation after dexamethasone intravitreal injection; 23. Discuss treatment interventions for increased intraocular pressure after dexamethasone intravitreal injection; 24. Provide a differential diagnosis for posterior uveitis; 25. Describe the pros and cons of treatment options for chronic posterior uveitis; 26. Describe what functional visual changes occur in diabetic retinopathy prior to development of visible vascular lesions; 27. State which cell types in the retina are involved in early diabetic retinopathy; 28. Discuss the effects of diabetes on the ocular surface and patient reported dry eye symptoms; 29. Discuss the correlation in diabetic patients of ocular surface disease, severity of diabetic retinopathy and a history ofr retinal lase treatment; 30. Analyze results of clinical trials in diabetic macular edema and apply them to clinical practice; 31. Manage patients with anti‐VEGF and steroid‐based therapies through the preferred dosing practices; 32. Recognize the protective effect of fenofibrate on progression of diabetic retinopathy; 33. Describe what driving forces generate the excess of vascular endothelial growth factor in advanced stages of diabetic retinopathy; 34. Summarize the interpretation of visual fields obtained by static perimetry and describe how static automated perimetry can be used over time to monitor for glaucomatous changes in a clinical setting; 35. Describe the artifacts introduced with simulated afferent pupillary defects during automated perimetry field testing; 36. Generate and interpret Humphrey Field Analyzer GPA reports; 37. Use the event and trend analysis GPA functions to determine the likelihood of progressive visual field loss in glaucoma patients.

Method of Participation Statements of credit will be awarded based on the participant's attendance and submission of the activity evaluation form. A statement of credit will be available upon completion of an activity evaluation/claimed credit form that should be turned it at the end of the meeting. If you have questions about this CME activity, please contact AKH Inc. at [email protected]. CME Credit Provided by AKH Inc., Advancing Knowledge in Healthcare Physicians

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AKH Inc., Advancing Knowledge in Healthcare and the University of Kansas, Department of Ophthalmology and The Lemoine Alumni Society. AKH Inc., Advancing Knowledge in Healthcare is accredited by the ACCME to provide continuing medical education for physicians.

AKH Inc., Advancing Knowledge in Healthcare designates this live activity for a maximum of 7.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

FACULTY DISCLOSURES Name Relationship Commercial Interest Abiodun E. Akinwuntan, PhD, MPH, MBA N/A Nothing to Disclose Michelle Boyce, MD N/A Nothing to Disclose Gerhard Cibis, MD N/A Nothing to Disclose Luke Dolezal, MD N/A Nothing to Disclose Luther Fry, MD N/A Nothing to Disclose Derek Horkey, MD N/A Nothing to Disclose John Hunkeler, MD N/A Nothing to Disclose Joshua Jones, MD N/A Nothing to Disclose Shree Kurup, MD N/A Nothing to Disclose Reid Mollman, MD N/A Nothing to Disclose Paul Munden, MD N/A Nothing to Disclose Robert Null, MD N/A Nothing to Disclose Anjulie Quick, MD N/A Nothing to Disclose Rithwick Rajagopal, MD N/A Nothing to Disclose Chetan Soni, MD N/A Nothing to Disclose Jason Stahl, MD N/A Nothing to Disclose Natalia Villate, MD N/A Nothing to Disclose Lillian Yang, MD N/A Nothing to Disclose PLANNER DISCLOSURES KUMC/KSEPS Staff and Planners N/A Nothing to Disclose AKH Staff and Planners N/A Nothing to Disclose

Commercial Support There is no commercial support for this activity.

Disclosures It is the policy of AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities. The author must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identified conflicts of interest are resolved by AKH prior to accreditation of the activity and may include any of or combination of the following: attestation to non‐commercial content; notification of independent and certified CME/CE expectations; referral to National Author Initiative training; restriction of topic area or content; restriction to discussion of science only; amendment of content to eliminate discussion of device or technique; use of other author for discussion of recommendations; independent review against criteria ensuring evidence support recommendation; moderator review; and peer review.

Disclosure of Unlabeled Use and Investigational Product This educational activity may include discussion of uses of agents that are investigational and/or unapproved by the FDA. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer This course is designed solely to provide the healthcare professional with information to assist in his/her practice and professional development and is not to be considered a diagnostic tool to replace professional advice or treatment. The course serves as a general guide to the healthcare professional, and therefore, cannot be considered as giving legal, nursing, medical, or other professional advice in specific cases. AKH Inc. specifically disclaim responsibility for any adverse consequences resulting directly or indirectly from information in the course, for undetected error, or through participant's misunderstanding of the content. LEMOINE DISTINGUISHED ALUMNI LECTURERS

LECTURER TITLE DATE

Timothy W. Olsen, MD Rock Chalk Retina Talk: 100 year KU 5/9/2014 KU SOM MD ‘89

Luther L. Fry, MD Standard Cataract Surgery: Tips & Tricks 5/8/2015 KU SOM MD ‘67 Learned after 40,000+ Cases

John D. Hunkeler, MD Continuous Education 4/8/2016 KU SOM MD ‘67 KU Eye Residency ‘73 Alumni Speakers

Luther L. Fry, MD MD: 1967

John D. Hunkeler, MD MD: 1967; Residency: 1973

Natalia Villate, MD Residency: 2008

AGENDA

Kansas EyeCon April 8 - 9, 2016 The Venue 4800 W 135th St., Ste. 108 Leawood, KS 66209

Friday, April 8, 2016

12:00 p.m. Registration and lunch with exhibitors

1:00 p.m. Welcome: Miranda Bishara, MD Orbital Session

1:05 p.m. Lillian Yang, MD, Temporal Artery Biopsy Outcomes in Patients with Suspected Giant Cell Arteritis

1:15 p.m. Reid Mollman, MD, Bilateral Orbital Myeloid Sarcoma in an Adult with Recurrent AML

1:25 p.m. Joshua Jones, MD, Recurrent Squamous Cell Carcinoma with Orbital Invasion (some requiring exenteration) in the Setting of Immunosuppression Following Organ Transplants – Case Series

1:35 pm Derek Horkey, MD, Retrospective Review of Indications of Evisceration, Enucleation or Exenteration at one Academic Institution

1:45 p.m. Abiodun Akinwuntan, MD, Virtual Reality Technology and Vision Cataract and Pediatric Session 2:35 p.m. Gerhard Cibis, MD, Microtropia (Lang); Monofixation(Parks): Prevalence, Significance, Evolution, Diagnosis with the Bruckner Red Reflex Test

3:00 p.m. Break

3:30 p.m. Luther Fry, MD, Common Cataract Surgery Difficulties: How to Avoid or Manage Them

3:55 p.m. Introduction of Dr. Hunkeler: Luther L. Fry, MD

4:00 p.m. John Hunkeler, MD, Lemoine Distinguished Alumnus Lecturer, Continuous Education

5:00 p.m. Session Adjourns

Onsite reception immediately following

University of Kansas Department of Ophthalmology and The Lemoine Alumni Society Kansas EyeCon April 8 – 9, 2016

Saturday, April 9, 2016

7:30 a.m. Breakfast with exhibitors

7:30 a.m. Michael Ellis, MS4, A Rapid Cycle Quality Improvement Project: Implementation of Diabetic Retinopathy Screening in a Primary Care Setting Using Tele-Ophthalmology

8:00 a.m. Welcome – Miranda Bishara, MD

Anterior Segment and Refractive Session 8:05 a.m. Chetan Soni, MD, Femtosecond Laser Assisted Cataract Extraction of Posterior Polar Cataracts

8:25 a.m. Jason Stahl MD, Refractive Lens Exchange

8:50 a.m. Shree Kurup, MD, Macular Surgery in Posterior Uveitis

9:15 a.m. Anjulie Quick, MD, Risk Factors for Intraocular Pressure Elevation After the Dexamethasone Intravitreal Injection

9:25 am Luke Dolezal, MD, Pattern Dystrophy: Case Series

9:35 a.m. Rithwick Rajagopal, MD, A Neurologic Perspective on Diabetic Retinopathy

10:00 a.m. Break

10: 25 a.m. Michelle Boyce, MD, Tear Osmolarity in Diabetic Patients

10:35 a.m. Natalia Villate, MD, Update on Diabetic Retinopathy and DME Management

11:00 a.m. Rithwick Rajagopal, MD, The Microvascular Pathology of Diabetic Retinopathy

11:25 am. Robert Null, MD, Effects of Simulated Afferent Pupillary Defect on Automated Perimetry

11:35 a.m. Paul Munden, MD, Detecting Functional Change in Progressing Glaucoma; Visual Field Guided Progression Analysis (GPA)

12:00 p.m. John Sutphin, MD, Luther and Ardis Fry Professor and Chairman, Closing Remarks: Future of KU Eye

12:15 p.m. Session Adjourns

University of Kansas Department of Ophthalmology and The Lemoine Alumni Society

ABSTRACTS

Temporal Artery Biopsy Outcomes in Patients with Suspected Giant Cell Arteritis

Lillian Yang, MD, Resident, Class of 2016 Primary Supervisor: Jason Sokol, MD

Giant cell arteritis (GCA) is a systemic disease that can have devastating ophthalmic consequences.

The diagnosis is based on clinical characteristics and established by the presence of inflammatory

markers. However, the only specific diagnostic test is a temporal artery biopsy (TAB). Although

uncommon, complications related to TAB, such as postoperative hematoma, scalp necrosis, wound

infection, damage to facial nerve, and drooping of eyebrow, can occur. Additionally, TAB as a

diagnostic tool for GCA is not perfectly sensitive, with reported rates of 70–90%. This presentation

is intended to review results from temporal artery biopsies performed at the University of Kansas

Hospital and to determine their utility in diagnosing GCA. Bilateral Orbital Myeloid Sarcoma in an Adult Patient with Recurrent Acute Myeloid Leukemia (AML)

Reid Mollman, MD, Resident Class of 2018 Primary Supervisor: Jason Sokol, MD

Objective:

Here, we discuss a single case of Myeloid Sarcoma, also previously referred to as chloroma or granulocytic sarcoma, which manifested as bilateral orbital masses in an adult with recurrent AML.

Method:

Presentation of a single case of bilateral orbital Myeloid Sarcoma in an adult with recurrent AML.

Results:

The patient in this case presented with substantial proptosis and ophthalmoplegia secondary to large bilateral Myeloid Sarcoma orbital masses in the setting of recurrent AML. Six weeks after treatment with intrathecal chemotherapy, as well as radiation, the patient had virtually complete resolution of the orbital masses.

Conclusion:

This is an interesting and rare case, where an adult patient presented with bilateral orbital Myeloid Sarcoma. It is very rare for myeloid sarcoma to present in the orbit, and, making this case even rarer, is the presentation in an adult. Upon literature review, it appears that only approximately 20 cases of this nature have been described in the past two decades. Recurrent Squamous Cell Carcinoma with Orbital Invasion (some requiring exenteration) in the Setting of Immunosuppression Following Organ Transplants – Case Series

Joshua Jones, MD, Resident Class of 2018 Primary Supervisor: Jason Sokol, MD

Purpose: Review current literature on anti‐graft medication pharmacology and discuss the increased risk of squamous cell carcinoma in transplant patients, along with retrospectively reviewing cases in which transplant patients were treated by an interdisciplinary team, including Oculoplastics and Otolaryngology for squamous cell carcinoma with orbital involvement.

Design: Charts were analyzed from four patients who underwent surgical resection, some radical, for treatment of squamous cell carcinoma following immunosuppressive therapy for transplants between 2011 and 2016, recording the association with the type of immunosuppressive medication and blood levels, extent of invasion of the tumors and type of procedure required for effective treatment.

Setting: Ophthalmology Department at a university‐hospital setting

Patients: Among the 4 patients included, average age was 62 years old; 2 were male and 2 were female. One patient was deceased at the time of retrospective review, due to metastatic disease. Each patient had a different type of transplant, such as heart, liver, kidney or bone marrow. The average time at initial diagnosis of squamous cell carcinoma was 6.3 years following initiation of anti‐graft medication.

Conclusions: Squamous cell carcinoma is a significant cause of morbidity and mortality for patients on long term immunosuppression following otherwise successful transplants. In our series of 4 patients, 50% required lifesaving radical surgical resection, including exenteration. Even with a successful surgery, the rate of mortality is high, given the extent of invasion. Our findings confirm what other studies have shown: that these patients need to be monitored closely for signs of peri‐orbital malignancy and treatment should not be delayed, given the high rates of recurrence and tissue invasion.

Retrospective Review of Indications of Evisceration, Enucleation or Exenteration at one Academic Institution

Derek Horkey, MD, Resident Class of 2017 Primary Supervisor: Jason Sokol, MD

Purpose: At times in ophthalmology, instead of vision‐enhancing or vision‐preserving procedures, it is necessary to perform eye destructive procedures, including evisceration, enucleation, and exenteration. The purpose of this study was to analyze, over a five year period, the number of eye destructive procedures and investigate the most common indication for said procedures.

Methods: After obtaining IRB approval, all medical records from August of 2010‐February of 2015 from patients having eye destructive procedures performed by one surgeon at one academic tertiary care facility were reviewed, investigating clinical indication for the procedure.

Results: There were 103 eye destructive procedures performed on 101 patients at one institution over the roughly 5 year period. Of these 103, 69% of the procedures were enucleations, 27% were exenterations and 4% were eviscerations. The two most common indications for procedure were trauma (40%) and malignancy (34%). The other noted indications were blind painful eye (15%), infection (10%) and ruptured cornea (1%).

Discussion: As one might imagine, more complicated cases were very common indications for eye destructive procedures at a tertiary care center. The hospital is a level I trauma center, which would account for a high volume of trauma cases. Also, given that there is a large cancer center, the high incidence of malignancy is accounted for as well. There were also five exenterations performed because of invasive mucormycosis. In these five patients, four had known malignancies and one had immunodeficiency, secondary to unknown reason, which was being worked up at the patient’s time of death. These numbers suggest that often complicated orbital trauma and malignancies are transferred or referred to tertiary care centers for definitive management and treatment. Our institution has a large cancer center, which contributes to our significant number of procedures secondary to those malignancy, as well as malignancy related infections.

References:

1. Hansen, Anja Bech, et al. "Review of 1028 bulbar eviscerations and enucleations, Changes in aetiology and frequency over a 20‐year period." Acta Ophthalmologica Scandinavica 77.3 (1999): 331‐335. 2. Rasmussen, Marie Louise Roed, et al. "Review of 345 eye amputations carried out in the period 1996–2003, at Rigshospitalet, Denmark." Acta ophthalmologica 88.2 (2010): 218‐ 221. 3. Zheng, Chengjie, and Albert Y. Wu. "Enucleation versus evisceration in ocular trauma: a retrospective review and study of current literature." Orbit 32.6 (2013): 356‐361. 4. Vemuganti, Geeta K., et al. "Enucleation in a tertiary eye care centre in India: prevalence, current indications and clinico‐pathological correlation." Eye 15.6 (2001): 760‐765.

Virtual Reality Technology and Vision

by Abiodun E. Akinwuntan, PhD, MPH, MBA NFB Blind Driver Challenge Video ‐ YouTube Dean and Professor School of Health Professions The University of Kansas Medical Center

Introduction Vision

• Driving is an IADL that is very crucial in the US • Some visual conditions/diseases that impact driving ability

• Vision is a critical component of driving – Macular degeneration ‐ Stroke

– Retinitis pigmentosa ‐ Multiple sclerosis • It contribute > 90% of sensory input to driving – Glaucoma ‐ Alzheimer’s disease • Vision disorders at the or at the elevate risk to driver safety – Diabetic retinopathy ‐ Parkinson’s disease

– Cataracts ‐ Head trauma • Further complicated by aging (baby boomers) of the population – Post‐surgery ‐ Sleep disorders

Vision Assessments for driving

• Common visual problems that impact driving ability • Typical ‐ Visual acuity and Perimetry (state driving laws)

– Static and dynamic visual acuity ‐ Depth perception • Driving‐related – Visual field (central & peripheral) ‐ Color perception – Perception (color & depth) – Speed of visual processing ‐ Contrast sensitivity – Sensitivity (contrast & glare) – Attention (divided, selective, sustained) ‐ Glare sensitivity – Useful Field of View (UFOV) – Anopia ‐ Diplopia – Cognitive (memory, search, spatial)

– Driving (simulator and on‐road) The Useful Field of View apparatus Dynavision apparatus First study

• 7 Patients with age‐related macular degeneration plus • Investigate the effect of training on driving performance

• Rehabilitation consisted of 10 hours of static versus dynamic vision training

Driving Simulator Result

Lane positioning Brake reaction time Overtaking

Road sign recognition Hazard perception Anticipation

Akinwuntan et al, Arch Phys Med Rehabil, 2014

Visual exploration and cognitive workload during a Objectives visual search task in individuals with PD

To investigate differences in visual search performances between patients with cognitive workload Parkinson’s disease, with or without cognitive impairment and control volunteers = degree of mental effort needed to execute a task

To explore cognitive workload during an efficient visual search

Pupillometry electroencephalogram

Maud Ranchet, John Morgan, Abiodun E. Akinwuntan, Hannes Devos Methods Visual search task

Pre‐identified 10 controls target 17 individuals with Parkinson’s disease ‐ 9 paents with a MOCA score ˃ 26 –Patients with no cognitive impairment (NCI) ‐ 8 patients with a MOCA score ≤ 26 –Patients with mild cognitive impairment (MCI) (Age controls: 65.1± 8.4 patients‐NCI: 65.0 ± 9.1, patients‐MCI: 71.3 ± 7.6, p>0.05)

PRESENT ABSENT 42 trials 21 trials with target present Eye tracking 60 Hz FOVIO Eye tracker 15 s per trial Fixation duration cognitive workload measures changes in pupil dilation = reliable estimate of mental effort (Marshall et al., 2000). Left Right Values range from 0 to 1 eye eye

Results

Controls Patients - NCI Patients- MCI Mean SD Mean SD Mean SD p-value (2-tailed) Number of correct responses 36.5 3.5 36.6 4.1 31 5.8 0.049 Number of errors 4.6 3.2 3.4 4.1 5.3 2.7 0.21 Number of omissions 0.9 1.5 1.5 1.9 5.6 6.1 0.12 Correct Response times 7.3 1.4 8.1 1.4 9.4 1.7 0.01

* 12 * ** 40 10 30 8 6 20 Outcomes: 4

10 Response(s) times 2 Correct responsesCorrect n = 44), (max score 0 0 Correct responses; Errors; Omissions; Correct response times Controls Patients - Patients - Controls Patients - Patients - NCI MCI NCI MCI Fixation duration; Cognitive workload (0‐1) No significant differences between the 3 groups for fixation duration and cognitive workload for the whole task (p > 0.05)

Results Discussion

- Average cognitive workload of both eyes Larger sample sizes - Data normalized (0% -100%)

1 controls 0.8 0.6 0.4 CONTROLS PATIENTS WITH NO APPARENT COGNITIVE IMPAIRMENT

cognitive workload cognitive workload 0.2

0 The cognitive workload  good marker of early cognitive decline in individuals with 0% 20% 40% 60% 80% 100% % of response times Moment of stimulus onset moment of response Parkinson’s disease with no cognitive impairment apparent = press the “present” button 9 controls, 5 patients-NCI, 7 patients-MCI Methods

Driving simulator desktop

4 scenarios => Test the visual field performance with a visual field of 100 degrees Performance-Based Visual Field Main task: while focusing on the white square or the Testing in Drivers with Glaucoma lead vehicle, hit the trigger button as soon as a red square appears 100°

Eye tracker Control the eye movement of participants Measure the impact of cognitive workload on visual field outcomes FOVIO ‐ Eyetracker

19 20

First scenario: C1

Aim: To investigate the effect of visual field performance

Task: Focus on the white square and press the button as soon as a red square appears

21 22

Second scenario: C2 Aim: To investigate the effect of dynamic condition (visual flow)

Task: White central fixation point has been replaced by lead vehicle Automatic pilot at 45 mph Focus on the lead vehicle and press the button for each red symbol

23 24 Third scenario: C3 Aim: To investigate the effect of driving activity on the visual field performance

Task: The participant has follow a lead vehicle driving 45 mph Speed warnings if the driver is above 50 or below 40 mph Random wind gusts to keep driver attentive Press the button for each red target symbol

25 26

Fourth scenario: C4

Aim: To investigate the effect of driving context on the visual field performance

Task: Drive while obeying all traffic rules Press the button for each red target symbol

27 28

Expected results Visual Field (VF) and Driving

‐ Poorer performances of visual field tests in ‐ 36 states in the US have binocular horizontal VF requirements (15 = 1400; 18 = 1050‐1300; 1 = 1500) glaucoma patients compared to controls ‐ Kansas and Arkansas further specified the horizontal VF ‐ The C4 scenario will be a better predictor of requirement for drivers with only one useful eye (550‐1050) driving performances for glaucoma patients ‐ 16 states: None except fails a visual acuity test or using special telescopic lenses and has been referred for further testing by an ‐ The cognitive workload will be associated to ophthalmologist or optometrist visual field performances ‐ Only 1 state has vertical VF requirement

‐ In 2 states, no driver’s license for a person with homonymous hemianopia 29 30 Visual Field (VF) and Driving Visual Field (VF) and Driving

‐ Healthy drivers ‐ 10 visual field deficits

‐ Interpupillary distance and facial anatomy

31 32

Thank you and questions Gerhard W. Cibis MD

Clinical Prof. Ophth. KU Eye Emeritus Chief CMH • 40% of treated esotopes (surgery or glasses) end up microtropic Microtropia (Lang) Mono fixation (Parks) • Traditional tests for microtropia are impossible in children Prevalence,Significance • Bruckner red reflex helps identify Evolution,Diagnosis with the microtropes Brueckner red reflex test

Pupil Red Reflex "Brueckner Test" Indicates Fixation

Strabismus • Refractive Error

• Superior Crescent from Hyperopia Aligned by • Hyperopic Superior Crescent Hirschberg Disappears with glasses correction OD Hyperopic crescent +5 Cherry Red OS +1.5 minimal crescent Inferior Myopic Crescent OU Orthotropic 3/3 Lang Stereo

Not Accommodating Aligned

• OD ET Accommodating

Alternating Mic ET

OD Mic ET

OS Mic ET • Not Accommodating no Crossing

Residual R Mic with 18 BO prism

• OD ET OS Fixing no diplopia 17year old modest myope acute onset diplopia alternating esotropia • Still Microtropic with 18 BO Prism

L Mic ET

• 17 year old female with myopia. Microtropia never recognized. Sudden onset ET with Lenses sees two lights and streaks OS fix diplopia

• Tumor workup and consternation as to what is going on

18 BO Prisms over Bagolini lenses sees one light • Broken Down microtrope streaks form an X gap in left streak confirms L suppression scotoma • May need surgery L mic. • Microtropia (Lang) aka Monofixation (Parks) • Suppression scotoma in the deviated eye allows for the following characteristics • Deviation of no more than 8-10 prism diopters • Fusion of Worth 4 dot lights at near where they • Usually ET but XT mic. exists fall outside of the suppression scotoma but not at distance where a light falls within the scotoma • Central suppression scotoma in the deviated eye allows for “peripheral fusion” without diplopia • Steroacuity between 3000-60 seconds arc on Titmus but zero on Lang or other Random Dot Stereograms

• Cibis-Tongue A., Cibis GW: Brückner Test. Ophthalmology; 88:1041-1044, • 4 diopter base out prism displaces the image 1981.

within the suppression scotoma when held in front • Cibis GW, Tongue AC, Stass-Isern M: Decision Making in Pediatric of the microtropic eye therefore no fixation shift Ophthalmology, C.V. Mosby Co.(St Louis), 1993. • Cibis GW: Strabismus. Lang J., Slack Pub., translation from German into English, 1983. • Held in front of the fixing eye both eyes shifts to • Cibis GW: Video vision development assessment (VVDA): Combining the refixate the target but the microtropic eye fails to Brückner test with eccentric photorefraction for dynamic identification of reconvert amblyogenic factors in infants and children. Tr Am Ophth Soc; XCII:644-685, 1994 . • These observations are very hard in practice • Cibis GW: Video Vision Development Assessment In Diagnosis and Documentation of Microtropia. Binocular Vision Strabismus Quarterly; #20: impossible on squirmy young children compared to 151-158. red reflex observations

• Cibis GW: Microtropia letter to the editor Binocular Vision & Strabismus Quarterly, #21 (2): 77, 2006.

• Cibis GW (2011). Chapter 5: Binocular Vision. In Lippincott, Williams and Wilkins (Eds.) Duane’s Ophthalmology 2011.

• The Decompensated Monofixation Syndrome:R. Michael Siatkowski MD Trans Am Ophthalmic Soc 109:2232 -250, 2011

• Parks MM. The monofixation syndrome. Trans Am Ophthalmol Soc 1969;67:609- 657.

• Lang J. Die Bedeutung des primären Mikrostrabismus für die Entstehung des Schielens. Klin Monatsbl Augenheilkd

• 1967;151:352-361.

• Lang J. Microtropia. Int Ophthalmol 1983;6:33-36.

Common Cataract Surgery Difficulties: How to Avoid or Manage Them (video presentation)

Luther Fry, MD Volunteer Faculty, KU Eye

Effect of ocular hypotensive drops given immediately after cataract surgery on 3‐ and 24‐hour post‐op IOP.

Summary of our multiple studies; 8 studies, approximately 1000 patients, scattered over the past 3 years.

Cosopt BEST, Combigan, Simbrinza and Timolol 0.5% next, Trusopt and Alphagan next.

Pilocarpine 2%, Betoptic‐S and Lumigan NO BETTER than control (artificial tears).

Systemic carbonic anhydrase inhibitors NO BETTER than topical.

Generics as good as brand name.

So, we now use: generic Cosopt for non‐asthmatics; Simbrinza for asthmatics and NO systemic CAIs.

Notes: Albert N. Lemoine Jr. Continuous Education • Professor and Chairman

• Department of Ophthalmology John D. Hunkeler, MD

• University of Kansas School of Medicine April 8, 2016

• 1950‐1980

Personal Interaction Al Lemoine

• Medical School= Dr. Lemoine • Family Man

• Residency= “Chief” • Clinician

• Volunteer Faculty= “Al” • Educator

• Leader

Clinician Educator

• Premier cataract surgeon • Medical students and residents

• Excellent diagnostician • Massachusetts Eye and Ear Infirmary Lancaster Course Leadership Notable Faculty

• KU Chairman • James T. Robison‐ retina

• Recruited volunteer faculty, his practice • Earl Padfield‐ glaucoma included • Sam Jones‐ peds and pathology

• L.L. “Fred” Hyde‐ cornea/cataract

Returning Fellows as Faculty Personal Post Graduate Mentor

• Jerry Wurster • Private practice with Fred Hyde

• Bill Godfrey • Micro surgery pioneer

• Penetrating Keratoplasty triple procedure

• Planned extracapsular cataract extraction

International Mentors • Bob Sinskey

• Charles Kelman • Steve Shearing

• Harold Ridley • Tom Mazzocco

• Daniele Aron‐ Rosa • Manus Kraff

• Dick Kratz Cataract Surgical Technique Incision= stainless steel blade

• Intracapsular Cataract Extraction • Paracentesis‐ tapered

• Planned Extrcapsular Cataract Extraction • Two‐ step primary incision (2.7 mm internally)

• Phacoemulsification • Visco‐ elastic

• Femto Laser Assisted Cataract Surgery

Phacoemulsification Capsulorhexis/Hydrodissection

• Disposable bent 21 gauge needle • Posterior polar exploration (Howard Gimbel) • Disposable B.S.S cannula • Divide and conquer technique (spatula assist)

Cortex Irrigation and Aspiration Lens Implant Insertion

• Sub‐incisional cortex removal‐ bi‐manual • Enlarge incision to 3mm

• Aspiration via paracentesis 180 degrees from • Implantation into capsule bag primary incision • Rotate trailing haptic to vertical • Irrigation via primary incision Complete Procedure Post‐ op Examination

• Remove visco elastic • Portable slit lamp exam

• I & A visco‐ elastic behind lens implant • Instill Simbrinza (thanks, Luther) • Hydrate Incision • Speak with patient and family

Lens Implant Exchange Intracapsular Cataract Extraction

• Intolerable unwanted optical image

Conclusion

• Thanks for your attention

• Thanks for the honor to remember Dr. Lemoine 3/24/2016

Femtosecond laser assisted cataract FL in posterior‐polar cataract surgery extraction of posterior polar

cataracts • Surgical consideration in posterior polar cataract extractions

• Counseling (high risk of PCR, vitreous loss, dropped nucleus, retinal detachment, Nd:YAG capsulotomy)

• Surgical approach: Anterior

• Incision Chetan Soni, MD, FACS. • Viscoelastic ‐ cohesive • Capsularrhexis ‐ optimum size between 4‐5 mm. Large capsularrhexis may not support sulcus fixated IOL, small may lead to difficulty in prolapsing nucleus if need be.

1

FL in posterior‐polar cataract surgery FL in posterior‐polar cataract surgery

• Surgical consideration in posterior polar cataract extractions • Surgical consideration in posterior polar cataract extractions • Surgical approach: Anterior • Surgical approach: Anterior

• Hydrodissection: best avoided • Rotation: best avoided

• Hydrodelineation: several authors recommend • Division and fragment removal hydrodelineation as a good method to separate nucleus • Epinucleus removal (Ref) • Pseudohole • Inside‐out delineation: • Cortex removal

• Posterior capsular polishing

FL in posterior‐polar cataract surgery FL in posterior‐polar cataract surgery

• Surgical consideration in posterior polar cataract extractions • Surgical consideration in posterior polar cataract extractions

• Surgical approach: Posterior • Surgical approach: Posterior

• plana lensectomy and vitrectomy • plana lensectomy and vitrectomy

• interventional case series of 11 eyes of 8 patients. • interventional case series of 11 eyes of 8 patients.

• During a mean follow‐up of 13 months, 3 of 11 eyes • During a mean follow‐up of 13 months, 3 of 11 eyes developed posterior segment complications. developed posterior segment complications.

1 3/24/2016

Femtodelineation

Technique first described by Dr. A. R. Vasavda (ref) Surgical videos Outcome of our 11 case series

Thank you.

2 Financial Disclosure

Refractive Lens Exchange • None

Jason Stahl, MD Durrie Vision Overland Park, KS

Refractive Lens Exchange Baby Boomers

• Active lifestyle • 4 in 1 procedure • Invest to improve quality of life • Distance Vision • Near Vision • Do not want to wait for “cataract” surgery like parents did • Eliminates future cataract surgery • Refractive surgery patient • Stable Vision • Enjoyed good uncorrected vision following vision correction surgery • Expect good uncorrected vision following RLE • Distance and near

Patient Education Dysfunctional Lens Syndrome • Why lens based surgery best option • Dysfunctional Lens Syndrome • Effect on visual quality • IOL options • Presbyopia-correcting • Blended vision (modified monovision) • Ocular health • Patient lifestyle/visual needs • Appropriate expectations

Nuclear Sclerosis Vision Correction

1. Change the corneal curvature

2. Exchange the lens

Dysfunctional Lens Syndrome DLS Stage 1 Surgical Options

• LASIK/PRK: Blended Vision/Monovision  Stage 1 (mid 40’s – early 50’s) • Lens stiffens • Corneal Inlays – Kamra • Loss of ‘zoom’ • Refractive Lens Exchange for higher hyperopia

Dysfunctional Lens Syndrome DLS Stage 2 Surgical Options

• Stage 2 (50’s-60’s) • LASIK/PRK: Blended Vision/Monovision • Lens optics degrading • Educate patients • Increasing lens haze • Refractive Lens Exchange • Yellow discoloration • Scatter of light Dysfunctional Lens Syndrome DLS Stage 3 Surgical Options

• Stage 3 (60’s – 80’s) •IOL Surgery • Opacity of lens • Functional decline

The Dysfunctional Lens Stage 1 DLS: HD Analyzer Results

• Mid-normal OSI, MTF, and PSF.

• Good predicted VA

23 year old lens 48 year old lens 55 year old lens Stage 1 DLS Stage 2 DLS

Stage 1 DLS: Densitometry Stage 1 DLS: Slit Lamp Exam

• Mildly increased nuclear density • Very mild “back scatter” Stage 1 DLS Stage 2

• Typically over 50 y/o • Loss of accommodation • Loss of visual quality

• Moderate OSI, PSF, and MTF • Good predicted VA • Recommend RLE

Stage 2 DLS: HD Analyzer Results Stage 2 DLS: Densitometry

• Moderate OSI, PSF, • Moderately increased nuclear density and MTF • Good predicted VA

Stage 2 DLS: Slit Lamp Exam Stage 2 DLS

• Moderately increased “back scatter” • Increasing yellow discoloration Stage 3 DLS Stage 3 DLS: HD Analyzer Results

• Typically >65 but any age possible • Poor PSF • Loss of accommodation and visual quality • Poor MTF • Loss of visual acuity • Poor predicted VA • (BCVA and or glare testing<20/40) • Moderate to poor OSI • Poor OSI, MTF and predicted VA

• Recommend refractive cataract

Stage 3 DLS Stage 3 DLS: Densitometry

• Greatly increased nuclear density

Stage 3 DLS: Slit Lamp Exam Stage 3 OD and Stage 2 OS

• Greatly increased “back scatter.” • Yellow to brunescent discoloration • Cloudy appearance Dysfunctional Lens Index Before and After Lens Surgery

Ocular Health Patient lifestyle and visual needs

• Ocular issues to consider: • Patient Questionnaire • • Dry Eyes – moderate/severe Spend time talking to patient! • • Map-dot-fingerprint Occupation • • S/P RK – corneal aberrations Hobbies • S/P LASIK/PRK/CK – corneal aberrations • Fuch’s Dystrophy • Significant corneal scaring • PXE • Macular pathology (ARMD, ERM, DR)

Patient Expectations IOL Options

• Presbyopia-correcting IOLs • No guarantee that will be 100% spectacle free at • Multifocal all distances • Diffractive • Depends on IOL(s) used (combine IOLs) • Central apodized optic: 2.5 D, 3 D and 4 D add (ReSTOR) • Under-promise to exceed expectations • Full optic, non-apodized: 2.75 D, 3.25 D and 4 D add (Tecnis MTF) • FDA clinical trials: 80% spectacle-free • Accomodative • Quality of vision/Halos • Crystalens (toric available) • Combine (Mix and Match) to increase range of vision • Adaptation over time • Functional near vision • Pseudophakic monovision (blended vision) • Monofocal and Toric IOLs • “You will not have vision of a 20 year old” Binocular UCVA-Distance Binocular UCVA-Near (16 inches)

% %

Defocus Curve - Monocular Defocus Curve - Binocular

Intermediate Intermediate

Distance P<0.05 Distance

Near Near

My (Simple) Approach: My (Simple) Approach: Quality > Range Quality > Range

• Dominant Eye • Non-Dominant Eye (2 options) • Tecnis One/Toric • 1. Blended Vision • Target distance • Tecnis One/Toric • Best image quality and quantity • Target: -1.00 to -1.50 D (based on pupil size) • 80-90% spectacle free • Occasional +1.00 D OTC readers and/or night driving glasses • Candidates • Previous corneal refractive surgery • Corneal aberrations • Small pupils • Increase depth of focus • Concerned about visual quality My (Simple) Approach: Quality > Range

• Non-Dominant Eye (2 options) • 2. Multifocal Extended Depth of Focus IOLs • Tecnis Multifocal • +2.75D, +3.25D or +4.0 D add • 90% spectacle free • Occasional +1.00 to +1.50 D for intermediate tasks • Candidates • Typically younger patient • Concerns about blended vision • Less concerns about visual quality

Depth of Focus Comparison Optical Modeling, 3.0 mm Pupil CE Marked IC-8™ IOL Design (Acufocus) IC-8™Small Aperture IOL Extended Depth of Focus (TC -0.75D) 20/50 • IOL Material 20/40 20/30 • Single-piece hydrophobic acrylic 20/20 20/10

• Mask 0.0 D -0.5 D -1.0 D -1.5 D -2.0 D -2.5 D Standard Mono-focal • PVDF & nano-particles of carbon 20/50 • 1.36 mm aperture 20/40 20/30 • 3.23 mm total diameter 20/20 20/10

• 3200 microperforations 0.0 D -0.5 D -1.0 D -1.5 D -2.0 D -2.5 D Diffractive Bi-focal • 6 microns thick 20/50 20/40 20/30 20/20 20/10

0.0 D -0.5 D -1.0 D -1.5 D -2.0 D -2.5 D (66 cm) (50 cm) (40 cm) 46

Tolerance to Uncorrected Astigmatism IC-8™ IOL Extends Depth of Focus (IC-8™ Eyes vs. Monofocal Eyes)

• Defocus curve results from IC-8 IOL patients demonstrate broad • Cylinder defocus was done in 0.5 D steps, starting from manifest refraction. range of vision across near, intermediate and far distances versus a • Change in distance visual acuity compared to the visual acuity corrected at monofocal IOL manifest refraction at each cylinder defocus step was plotted against cylinder defocus steps • Mean post-op MRSE at their last follow-up was -0.14 D +/- 0.52 Cylinder Defocus Curves

Far Near IC-8 vs Monofocal -0.20 -0.10 0.00 0 0.10 20/25 0.20 0.05 One line of loss 0.30 20/40 0.40 0.50 0.1 0.60 Acuity (LogMAR) Acuity 0.70 0.15 IC-8 0.80 0.90 Monofocal 0.2 1.00 1.10

Change in Visual Acuity (logMAR) Acuity Visual in Change 0.25

N=10 Defocus Lens Power 0.3 Simulated Monofocal IOL Ang 6M (n=8) 0 -0.5 -1 -1.5 -2 -2.5 -3 Cylinder Defocus Data courtesy of Robert Ang, MD AMO Symfony AMO Symfony

• CE Mark • Currently in FDA Clinical trials Tecnis Monofocal

Tecnis Multifocal

Tecnis Symfony

AMO Symfony Hit the Target

• Refractive outcome optimized for best performance • IOL calculations • Intraoperative aberrometry • Astigmatism correction – LRI vs Toric • Ocular surface • Correcting residual refractive error • LASIK, PRK, LRIs • Yag capsulotomy

Conclusion

• Dysfunctional Lens Syndrome • Diagnostics help educate patients on need for lens- based refractive surgery Thank You • Refractive Lens Exchange • 4 in 1 procedure • Patient education key – postop expectations • Future IOL options will improve visual range/quality • Hit the Target • Refractive lens surgeon: you need to have all the tools • Refractive surgery patient expectations Surgery in Uveitis Macular Surgery in Uveitis . Fraught with risks . Timing is of essence . Generally in “good prognosis” patients Sara Branson BS . Avoid in active disease Claudia Hooten, MD . No macular surgery in general Shree Kurup, MD . Lets discuss some real problems KU EyeCon 2016

TAKE HOME MESSAGE Case 1 HPI • 24 year‐old Caucasian female presents with bilateral . There is value in surgery even in advanced panuveitis severe uveitis • Hx of poor vision OU, recurrent red eyes and light sensitivity . Selection is key past 3 years • Hx IVDU on suboxone . Younger tend to be better • Hx of oral ulcers and skin “blisters” on legs . Macular edema still challenging . If possible, get it inactive • VA 20/200 OD and CF 4ft OS • 2+Vitreous cell OD, +hypopyon OS with 3+vitreous cell

Fundus FA FA OCT

Course

. Started oral prednisone 10mg PO daily, Valtrex 1g TID, Levaquin 500mg PO BID, PF 1 gtts QID and atropine daily

. Immune focused investigations were done, negative except HLA B51

. Diagnosed with Behcets disease Japanese criteria “GOOSE”

. She was ultimately treated with Cellcept, cyclosporine and low dose prednisone and she remained quiet after 1 year . VA 20/200 OD and 20/40 OS

Question? Idiopathic Macular hole . Would you consider vitrectomy and macular . Prevalence ranges from 0.2‐3.3 per 1000 hole repair in the right eye? . Bilateral MH incidence ranges from 5‐16%

. Risk factors include age >65years and female gender

. Pathogenesis: vitreomacular traction, contraction of premacular vitreous cortex, formation of foveal cyst Macular hole stages Secondary Macular Hole . Orbital trauma . High myopia . Uveitis (Behcets, Cat scratch, Fungal endophthalmitis, Syphilis, VKH) . Retinitis Pigmentosa . Stargardt disease . Alport syndrome . Best macular dystrophy . X linked Juvenile retinoschisis . Retinal arterial macroaneurysm . Laser induced maculopathy

Macular hole closure Behcets . Idiopathic macular hole closure rate is 85% or more . Uveitis in Behcets is most frequently with use of PPV/ILM peel and gas or silicone panuveitis tamponade

. Spontaneous closure is less common . Macular edema is common and can get irreversible ischemia . Secondary hole closure rate has lower rate . Due to larger hole size . Full thickness macular holes are uncommon . Decreased retinal extensibility after retinal and reported at 3.4% inflammation

Pars plana vitrectomy with internal limiting membrane removal for a macular hole associated with Behçet's disease Macular Hole in Behcets Disease T‐T Wu and M‐C Hong Hassan Al‐Dibhi et al Sept 2011

. Retrospective study of Behcets patients with MH from Jan 1998‐ Nov 2008

. Of 159 patients, 21 eyes of 17 patients had MH . . 6 patients underwent PPV (2 had MH related RRD) only 1 hole closed

. Surgical intervention did not result in significant visual improvement as compared to non‐ operated eyes

. EXCEPT for 1 patient who did not have macular ischemia Back to our patient OCT POM#1 and #2 . Patient underwent PPV/membrane peel/C3F8 13% gas 6.12.15

Question? 20/80 OCT at POM#1

. Now her vision is 20/100 OD

. How would you manage this patient now?

. Observe vs re-operate?

. She underwent second PPV/membrane peel/C3F8 13% gas 10.21.15

Case 2: Sarcoidosis 20/100 from 1 yr ago 20/60 20/40 2 year prior Watch? Compare

Post Op

MFC with intractable CME . On TNF‐I Cellcept and CSA plus periodic Ozurdex: risk of CNV but persistent CME would destroy central macula. BEFORE &AFTER SI OIL

References . Gass JD. Idiopathic senile macular hole: Its early stages and pathogenesis. Arch Ophthalmol 1988;106:629‐ 39. . Johnson RN, Gass JD. Idiopathic macular holes. Observations, stages of formation, and implications for surgical intervention. Ophthalmology 1988;95:917‐24. . Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol 1995;119:752‐9. . Spaide RF: Measurement of the posterior precortical vitreous pocket in fellow eyes with posterior vitreous detachment and macular holes. Retina. 23:481‐485 2003 . Privat E, Tadayoni R, Gaucher D, et al.: Residual defect in the foveal photoreceptor layer detected by optical coherence tomography in eyes with spontaneously closed macular holes. Am J Ophthalmol. 143:814‐819 2007 . Criteria for diagnosis of Behçet′ sdisease. International Study Group for Behçet's Disease. Lancet. 1990;335:1078–80 . Angioi‐Duprez K, Maalouf T, Gérin M, George JL. A full thickness macular hole as an uncommon complication of Behçet disease. J Fr Ophtalmol. 2001;24:172–4. . Sheu SJ1, Yang CA. Kaohsiung J Med Sci. 2004 Nov;20(11):558‐62. Macular hole in Behcet's disease. Risk Factors for Intraocular Pressure Elevation After Dexamethasone Intravitreal Implant

Julie Quick, MD, Resident Class of 2017 Primary Supervisor: Paul Munden, MD

Purpose: Intravitreal steroids are a recognized cause of increased intraocular pressure (IOP). The goal of this study was to analyze what risk factors are associated with the dexamethasone intravitreal implant 0.7 mg (DEX implant) and what medical and surgical interventions were necessary to control the IOP.

Methods: A retrospective, descriptive, chart review was performed after IRB approval. All patients who received a DEX implant by a single retinal surgeon in our department between 2014 and 2016 were identified. In each case, gender and age of the patients, diagnosis, number of re‐ interventions and laterality were registered.

Results: Out of 48 patients (60 eyes) who received the DEX implant, 13 eyes (22%) had an IOP elevation > 5mmHg from baseline. On average, peak IOP was 6 weeks after injection. Eight eyes (62%) with IOP elevation were adequately controlled with an average of two IOP lowering drops; 4 eyes (30%) required filtering surgery and 1 eye (8%) did not require intervention, as the IOP was < 21mmHg. The most common diagnosis associated with elevated IOP was posterior uveitis (30%) followed by DME (27%), BRVO (18.8%) and CRVO (12.5%). Nine patients had a history of primary open angle glaucoma (POAG). Of these patients, 3 had an IOP elevation > 5mmHg. Two of these patients were not taking IOP lowering medications at the time of their injection. The 6 patients who did not have an IOP elevation were already on either an IOP lowering drop or had a history of glaucoma surgery. All 4 patients with a known history of increased IOP after topical steroids had an IOP elevation after DEX implant.

Conclusions: The majority of patients who had an elevated IOP after DEX implant were controlled with IOP lowering medications. A history of glaucoma that is untreated, posterior uveitis, DME, and history of steroid response are potential risk factors for IOP elevation and should be monitored closely.

Pattern Dystrophy: Case Series

Luke Dolezal, MD, Resident, Class of 2018 Primary Supervisor: Ajay Singh, MD

Pattern dystrophies are a group of macular diseases characterized by various patterns of pigment

deposition and lipofuscin accumulation within the macula due to RPE dysfunction. Patterns may

fluctuate in individual patients over time and may differ between eyes. Disease onset is typically in the 5th‐6th decade. They have a relatively good visual prognosis, although slow progressive central

vision loss may occur, including severe vision loss in up to 50% of patients after age 70, due to

chorioretinal atrophy and/or CNV. Patients diagnosed at an older age may be misdiagnosed as

having age related macular degeneration, due to a similar fundus appearance. Accurate diagnosis

is important to avoid unnecessary treatment and patient anxiety.

This presentation will review cases of Pattern Dystrophy seen at KU Eye Clinic. We will discuss

clinical features and multimodal imaging used in the diagnosis and monitoring of these patients.

Clinical features of diabetic retinopathy

• Mild to severe • Progressive (requires passage through intermediate stages) A Neural Perspective • Exclusively vascular features on Diabetic Retinopathy Early events in diabetic retinopathy Rithwick Rajagopal, M.D., Ph.D. Assistant Professor Department of Ophthalmology and Visual Sciences • Histologic and electron micrographic findings Washington University School of Medicine

April 9, 2016 No financial disclosures

A Current View of DR Progression Clinical evidence for neuro-retinal dysfunction in diabetes • Electroretinography in patients with no evidence of retinopathy DM • Aggregate data suggest inner retinal pathology Microaneurysms • Amplitude and kinetics of b-waves, oscillatory potentials Hemorrhages Macular Edema Ischemia Other assays of visual function Elevated Proliferation glucose • Multi-focal ERG Microvascular Damage; • Measures of contrast sensitivity Inflammation; • Perimetry Loss of Endothelial Integrity VEGF Prospective clinical trials

An Alternative Model for DR Progression Development of a relevant animal model

DM • High-fat diet induces obesity and diabetes in mice (as in humans) • Progressive weight gain, adiposity and insulin resistance Visible • Initial hyperinsulinemia, followed by relative hypoinsulinemia Dysregulated insulin Neuroretinal Damage Microvascular signaling; Defects Elevated glucose Neuro- inflammation;

Loss of Neurovascular Coupling Classic Retinopathy Detection of retinopathy in rodents Rodent electroretinography

• Trypsin-digest analysis of retinal microvasculature • Full-field studies under anesthesia • Capillary leakage assays • Analysis of a-waves and b-waves • Detection of retinal inflammatory mediators • Oscillatory potentials • Association with disease severity

Metabolic stress induces neuro-inflammation Stages of Diabetic Retinopathy in the Type 2 Diabetes Mouse • Hijacking a system designed for defense against bacteria • Neuro-inflammatory • Robust retinal inflammation occurs early in disease • Neuro-retinal • May be more prominent in the inner retina • Microvascular • A potential early therapeutic target • Disease progresses slowly through these stages, allowing for controlled studies

Retinopathy Progression in the HFD Mouse: Future Directions Lessons Learned • Analysis of amacrine cells, bipolar cells and ganglion cells. • Screening for changes in gene expression, metabolites and lipids 1. Metabolic disease is relatively mild, and retinopathy • Manipulation of signaling pathways in the retina takes time to manifest!

2. Disease occurs in stages, and inner retinal dysfunction occurs early

3. This pattern is consistent with human disease Acknowledgements

Clay Semenkovich, MD Sheng Zhang Li Yin Xiaochao Wei, PhD Larry Spears, PhD

Peter Lukasiewicz, PhD Greg Bligard Funding WUSTL DOVS Core Labs Horncrest Foundation Anne Hennig, PhD K08-EY-025269 Belinda Dana P30-EY-002687 Guanyi Ling Research to Prevent Blindness

Contact: [email protected] // Referrals: 314-362-EYES Tear Osmolarity in Diabetic Patients

Michelle Boyce, MD, Resident, Class of 2016 Primary Supervisor: Ajay Singh, MD

Diabetes Mellitus is a prevalent condition in the United States with many associated ophthalmic complications, including diabetic retinopathy and ocular surface disease. Studies have shown ocular surface disease is more common in the diabetic population than the general population.1,2 Diabetic patients have been shown to have a multitude of ocular surface irregularities that lead to the morbidity associated with ocular surface disease. Studies of diabetic patients have demonstrated changes in tear osmolarity,3 tear film instability,2,4 decreased reflex tearing,5 decreased corneal sensation,6,7 and loss of goblet cells.4,5 Deceased corneal sensation and the resultant decrease in sensory input to the autonomic nerves of the lacrimal gland may lead to reduced basal and reflex tear secretion.8-10 Additionally, studies have shown that panretinal photocoagulation (PRP) used in the treatment of proliferative diabetic retinopathy may alter the corneal subbasal nerve plexus11,12 and corneal sensitivity.6,13,14 Prior studies have shown variable results when assessing if diabetes disease severity markers can be correlated to the presence and severity of ocular surface disease.3,15,16

Common clinical testing for diagnosis and management of ocular surface disease includes tear break-up time (TBUT), Schirmer testing for tear production, staining of the cornea and conjunctiva, and tear osmolarity. Tear osmolarity is regarded as a hallmark of dry eye and has been shown to be the single best marker for diagnosis and classification of dry eye.17,18

Our study objectives were to determine if tear osmolarity in diabetic patients could be correlated to markers of diabetes severity, such as duration of disease, severity of diabetic retinopathy, history of requiring treatment by PRP, and history of nephropathy or neuropathy. Additionally, we examined the effects that PRP had on symptoms of ocular surface disease and tear osmolarity. Results of the research provides insight into the course of ocular surface disease in diabetics, particularly those patients with proliferative diabetic retinopathy requiring PRP, and allows us to better treat the morbidity associated with these conditions.

References: 1. Kaiserman I, Kaiserman N, Nakar S, Vinker S. Dry eye in diabetic patients. American Journal of Ophthalmology. Mar 2005;139(3):498-503. 2. Inoue K, Kato S, Ohara C, Numaga J, Amano S, Oshika T. Ocular and systemic factors relevant to diabetic keratoepitheliopathy. Cornea. Nov 2001;20(8):798-801. 3. Sagdik HM, Ugurbas SH, Can M, et al. Tear film osmolarity in patients with diabetes mellitus. Ophthalmic Research. 2013;50(1):1-5. 4. Dogru M, Katakami C, Inoue M. Tear function and ocular surface changes in noninsulin-dependent diabetes mellitus. Ophthalmology. Mar 200:108(3):586-592. 5. Goebbels M. Tear secretion and tear film function in insulin dependent diabetics. The British Journal of Ophthalmology. Jan 2000;84(1):19-21. Tear Osmolarity in Diabetic Patients, continued:

6. Rogell GD. Corneal hypesthesia and retinopathy in diabetes mellitus. Ophthalmology. Mar 1980;87(3);229-233. 7. Rosenberg ME, Tervo TM, Immonen IJ, Muller LJ, Gronhagen-Riska C, Vesaluoma MH. Corneal structure and sensitivity in type I diabetes mellitus. Investigative Ophthalmology & Visual Science. Sep 2000;41(10):2915-2921. 8. Parra A, Madrid R, Echevarria D, et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nature Medicine. Dec 2010;16(12):1396-1399. 9. Acosta MC, Peral A, Luna C, Pintor J, Belmonte C, Gallar J. Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerves. Investigative Ophthalmology & Visual Science. Jul 2004;45(7):2333-2336. 10. Cousen P, Cackett P, Bennett H, Swa K, Dhillon B. Tear production and corneal sensitivity in diabetes. Journal of Diabetes and its Complications. Nov-Dec 2007;21(6):371-373. 11. De Cilla S, Ranno S, Carini E, et al. Corneal subbasal nerve changes in patients with diabetic retinopathy: an in vivo confocal study. Investigative Ophthalmology & Visual Science. Nov 2009;50(11):5155-5158. 12. Misra S, Ahn HN, Craig JP, Pradhan M, Patel DV, McGhee CN. Effect of panretinal photocoagulation on corneal sensation and the corneal subbasal nerve plexus in diabetes mellitus. Investigative Ophthalmology & Visual Science. Jul 2013;54(7):4485-4490. 13. Schiodte SN, Effects on choroidal nerves after panretinal xenon arc and argon laser photocoagulation. Acta Ophthalmol. Apr 1984;62(2):244-255. 14. Ruben ST. Corneal sensation in insulin dependent and non-insulin dependent diabetics with proliferative retinopathy. Acta Ophthalmol. Oct 1994:72(5):576-580. 15. Fuerst N, Langelier N, Massaro-Giordano M, et al. Tear osmolarity and dry eye symptoms in diabetics. Clinical ophthalmology. 2014;8:507-515. 16. Najafi L, Malek M, Valojerdi AE, et al. Dry eye and its correlation to diabetes microvascular complications in people with type 2 diabetes mellitus. Journal of diabetes and its complications. Sep-Oct 2013;27(5):459-462. 17. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). The Ocular Surface. Apr 2007;5(2):108- 152. 18. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. American Journal of Ophthalmology. May 2011;151(5):792-798 e791. UPDATE ON DIABETIC ALDOSE REDUCTASE OSMOTIC RETINOPATHY AND DME GLUCOSE SORBITOL Lens changes DAMAGE

MANAGEMENT NADPH NADP Kansas Eye Con 2016 APOPTOSIS RETINOPATHY ENDOTHELIAL DIABETIC April 8 & 9, 2016 CELL DYSFUNCTION PERICYTE Natalia Villate, M.D. HYPERGLYCEMIA DAMAGE INFLAMMATION AGE  RAGE

NEURO DEGENERATION

DISCLOSURE ROLE OF VEGF IN EYE DISEASE

• Dr Villate has no conflict of interest regarding this • Elevated intraocular VEGF levels are a presentation major driver of neovascularization, • Fort Lauderdale Eye Institute is currently enrolling leakage, and macular edema—all of patients in Industry-sponsored clinical trials and is which can result in vision loss2-5 also a participating center for the DRCR network. Dr

Villate is co-investigator in all current trials at FLEI. • In the eye, overexpression of VEGF is • Genentech and Regeneron provided original slides of associated with DME, wAMD, and clinical trial results used in this presentation macular edema following RVO1-3

References: 1. Funatsu H, et al. Graefes Arch Clin Exp Ophthalmol. 2005;243:3-8. 2. Ma W, et al. Invest Ophthalmol Vis Sci. 2007;48:1355-1361. 3. Chung AS, Ferarra N. Annu Rev Cell Dev Biol. 2011;27:563-584. 4. Zhang W, et al. Immunotherapy. 2011;3:609-628. 5. Aiello LP, Wong JS. Kidney Int. 2000;58(suppl 77):S113-S119.

11

MAYOR CHANGES IN LAST DECADE DIABETES PREVALENCE IN THE US

2009 Estimates of the Percentage of Adults • In 2010, 25.6 million people ≥20 Years Old With Diagnosed Diabetes3 • 1. OCT ≥20 years old in the US had diabetes1 • 11.3% of the population1 • By 2020, prevalence is • 2.AntiVEGF drugs for AMD expected to rise to 15% of • The use of anti VEGF therapy for CNV and 2 adults in the US (39 million) Age-adjusted percent wet macular degeneration has helped reduce the 0 - 6.3 6.4 - 7.5 7.6 - 8.8 vision loss by 41% and blindness by 46%. 1. Centers for Disease Control and Prevention Website. National Diabetes Fact Sheet, 2011. 8.9 - 10.5 http://www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed May 18, 2012. > 10.6 2. UnitedHealth® Center for Health Reform and Modernization. Working Paper 5, 2010. (JAMA Ophthalmol, 2014;132(4):456-463. http://www.unitedhealthgroup.com/hrm/UNH_WorkingPaper5.pdf. Accessed June 23, 2012. 3. Centers for Disease Control and Prevention Website. Diabetes Data & Trends. 2009. http://apps.nccd.cdc.gov/DDT_STRS2/NationalDiabetesPrevalenceEstimates.aspx. Accessed May 18, 2012. MICRO- AND MACROVASCULAR COMORBIDITIES IN ETDRS PATIENTS WITH DIABETES1-5 • ETDRS – how often was there improvement? 28.5% Diabetic retinopathy (DR) in patients 40 years of age or older • Only 3% had > 3 lines of improvement Patients can reduce 13.6% Diabetic macular edema (DME) • Only 17% had any improvement in vision after 5 years the risk and severity in patients with DR 9.1% Stroke • Vision improvement depends where you start of DME by controlling in patients 35 years of age or older 6,7 • Only 114 treated eyes had vision ≤ 20/40 their ABCs : 21.9% Coronary heart disease* in patients 35 years of age or older • 640 treated eyes (85%) had vision better than 20/40 •A 1c 29.9% Diabetic nephropathy •Blood pressure in diabetes patients • Of those that could gain three lines (start with baseline vision of 20/40 or ≈60% to 70% Diabetic neuropathy worse) how many gained three or more lines in the ETDRS? •Cholesterol in diabetes patients • About 40% References: 1. Diabetes statistics. American Diabetes Association website. http://www.diabetes.org/diabetes-basics/diabetes-statistics/?loc=DropDownDB-stats. Published January 26, 2011. Accessed June 21, 2012. 2. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Centers for Disease Control and Prevention website. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed October 22, 2013. 3. Varma R, et al. Poster presented at: 2012 Joint Meeting of the American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology; November 10-13, 2012; Chicago, IL. Poster PO252. 4. Diabetes data & trends. Centers for Disease Control and Prevention website. • About how much treatment to expect? http://www.cdc.gov/diabetes/statistics/cvd/fig2.htm. Updated November 6, 2012. Accessed October 22, 2013. 5. United States Renal Data System. http://www.usrds.org/atlas.aspx. Accessed February 7, 2013. 6. National EyeReferences: Institute, National 1. Xu L, Instituteset al. Invest of Health.Ophthalmol NIH VisPublication Sci. 2013;54:1616-1624 No. 2642. 7. Ciulla. 2. TA,Chakravarthy et al. Diabetes U, et Care al; IVAN. 2003;26:2653-2664. Study Investigators. Ophthalmology. 2012;119:1399-1411. - Quarterly visits. Three to five lasers over one to two years

MAJORITY REMAIN UNDIAGNOSED OR UNTREATED

American Academy of Ophthalmology: Recommended Eye Examination Schedule (Including Dilated Eye Exam) for Diabetic Patients

Recommended Time Recommended Diabetes Type for First Examination Follow-up Type 1 3–5 years after diagnosis Yearly Type 2 At time of diagnosis Yearly SO WHAT IS NEW Modified, with permission, from the American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern® Guidelines, Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2008. Available at www.aao.org/ppp • 40%–50% of diabetic patients do not receive recommended eye care1 • Joslin study of patient self-awareness of DR2 • At their first study visit, 83% of patients with DR and 78% with vision-threatening DR were unaware that they had the disease • 50% with vision-threatening DR did not have timely follow-up eye exams

1. Healthcare Effectiveness Data and Information Set Report (HEDIS) 2011. http://www.sanfordhealthplan.org/ClassLibrary/Page/Images/files/HEDIS_Report_2011.pdf. Accessed May 30, 2012. 2. Soliman et al. ARVO, 2011 abstract.

ETDRS

• Overall, decreased moderate visual loss by ~ 50% • Add anti VEGF to laser or possibly replace laser.

• Treated group 13% • Control group 22% • Use Steroids to treat inflammatory component of retinopathy

• Medical management matters more than many Moderate visual loss of us realize.

ETDRS Report #1 Arch Ophthalmol 103:1796-806, 1985 RIDE/RISE

MACULAR AND PANRETINAL LASER TREATMENT THROUGH MONTH 24

Pooled RIDE and RISE HOW DOES ANTI VEGF MEDICATIONS AFFECT DIABETIC RETINOPATHY? Sham LUCENTIS Outcome Measure (n=257) 0.3 mg (n=250)

Received macular lasera 72.0% 37.6%

Mean no. of treatmentsb 1.7 0.7

Received panretinal laser 11.7% 0.8%

aExploratory endpoint. Adjusted difference vs sham was: -34.4% for the 0.3-mg group; P<0.0001 for LUCENTIS groups vs sham (Cochran-Mantel-Haenzel chi-squared test [stratified]). bP<0.0001 for all LUCENTIS groups vs sham (Wilcoxon test [stratified]). Beginning at month 3, patients were evaluated monthly for the need for rescue macular laser according to protocol-specific criteria: OCT CFT ≥250 μm with <50-μm change from prior month, no laser in prior 3 months, and evaluating physician deems laser therapy to be beneficial. LUCENTIS FDA Briefing Book.

RIDE/RISE RIDE/RISE RIDE AND RISE - STUDY DESIGN KEY FINDINGS Objective: Evaluate efficacy and safety of intravitreal RANIBIZUMAB compared with sham injections in patients with center-involved DME • Aprox. 40% % gained ≥3 lines with monthly Ranibizumab 0.3 mg vs

DME 15.2% in the sham group

Screening: BCVA 20/40 to 20/320, OCT CST ≥275 μm • Rapid and sustained improvement in both vision and retinal anatomy as early as day 7 1:1:1 Randomization (one eye per subject) • Delayed treatment with Ranibizumab (after month 24) in patients Sham Injection RANIBIZUMAB 0.3 mg RANIBIZUMAB 0.5 mg originally randomized to sham did not result in the same extent of (n=257)a (n=250)a,b (n=252)a improvement seen in patients treated with Ranibizumab from the 24-Month Controlled Treatment Period (monthly intravitreal/sham injections; macular laser, if eligible, beginning month 3) outset Month 24 Primary • Majority of Ranibizumab-treated patients did not receive any Monthly Endpoint Monthly Monthly RANIBIZUMAB 0.3 RANIBIZUMAB 0.5 protocol-specified laser treatment, while almost half of sham patients RANIBIZUMAB 0.5 mg mgb mg Month 36 received 2 or more laser treatments

Long-term Open-label Extension With 0.5 mg LUCENTIS • Patients treated with Ranibizumab showed improvement in the aPooled RIDE and RISE enrollment. RANIBIZUMAB is approved for a 0.3-mg dose in DME severity of retinopathy Nguyen et al. Ophthalmology. 2012;119:789.

RIDE/RISE ≥15 ETDRS LETTERS FROM BASELINE AT MONTH 24 VIVID and VISTA:Study Design (PRIMARY ENDPOINT)

Pooled RIDE and RISE Randomized, multicenter, double-masked trials in patients with clinically significant DME with central involvement and ETDRS BCVA 20/40 to 20/320 N=406 (VIVID) N=466 (VISTA)

Percentages of patients who lost Patients randomized  = 24.0 (P<0.0001)a ≥15 letters from baseline at 1:1:1 month 24 (secondary endpoint) LUCENTIS 0.3 mg: 2.0% IVT Aflibercept IVT Aflibercept Laser Sham: 9.3% 2 mg q4 wks 2 mg q8 wks* Photocoagulation Percent of subjects of Percent

Primary endpoint: Primary Endpoint: Key Secondary endpoints Mean change in BCVA Week 52 Change in OCT Sham 0.3 mg Change in Diabetic (n=257) (n=250) Retinopathy Severity Scale (DRSS)

aCochran-Mantel-Haenszel chi-squared test (stratified). Continued treatment through Year 3 The LOCF imputation method was used. Vertical bars are 95% confidence intervals. Reported percentages and differences vs sham are unadjusted, test and P

value are adjusted for baseline VA (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior treatment for DME (yes, no). LUCENTIS FDA Briefing Book. *After 5 initial monthly doses Proportion of Patients Gaining ≥10 and ≥15 Letters at Week 100 KEY FINDINGS PRIMARY ENDPOINT

VISTA • Aflibercept was as effective as Ramibizumab at improving vision in 100% VIVID Laser IAI 2q4 aprox 40% of treated patients IAI 2q8 80%

63.6% • Treatement every 8 weeks was almost as effective as monthly 58.1% 59.6% 60% The proportion of patients 49.6% treatements ( after dose loading period) loosing >15 letters was aprox 38.2% 38.3% 40% 33.1% 11% (9.7% and 12.9%) in the 31.1% • 27.9% Anatomic response was significantly better in patients treated with 25.0% laser group and less than 3% in Proportion of patients of Proportion Aflibercept than in laser patients 20% 12.1% 13.0% the aflibercept treated groups (2.2% and 3.2% in IAI 2q4 and 0% 1.5% and 0.7% in IAI 2q8) • Independent of the treatement interval,approximately 1/3 of ≥15 letters ≥15 letters ≥10 letters ≥10 letters Aflibercept treated patients showed improvement in the severity of the retinopathy Compared with baseline; last observation carried forward. VIVID FAS: Laser: n=132; IAI 2q4: n=136; IAI 2q8: n=135; VISTA FAS: Laser: n=154; IAI 2q4: n=154; IAI 2q8: n=151.

Mean Change in Central Retinal Thickness Through Week 100 DRCR NETWORK COMPLETED PROTOCOLS SECONDARY ENDPOINT Protocol # of Subjects Week 0 4 8 12162024283236404448525660646872768084889296100 I: Laser-Ranibizumab-Triamcinolone Study for DME 691 0

-50 -66 J: Laser-Ranibizumab-Triamcinolone Study for DME + PRP 333

-100 VIVID -86 Laser K: The Course of Response to Focal Photocoagulation for DME 128 -150

-200 -196 IAI 2q8 L: Autorefraction and E-ETDRS Measurements in DME 490 - -212 IAI 2q4 -250 195* N: Intravitreal Ranibizumab for Vitreous Hemorrhage from PDR Study 261 -

µm *P<0.0001 192* vs laser O: Comparison of Time Domain OCT & Spectral Domain OCT in DME 1183 0

-50 -73 P: Pilot Study of Individuals with DME Undergoing Cataract Surgery 68 -84 Laser -100 VISTA Q: Individuals with Diabetes without DME Undergoing Cataract Surgery 317 -150 -191* IAI 2q4 -200 - -191* IAI 2q8 R: NSAIDs in Eyes with Non Central Involved DME 125 186* -250 - S: Prompt PRP vs. Ranibizumab + Deferred PRP for DPR* 305 Central subfield; SD-OCT. 183* VIVID FAS: Laser: n=132; IAI 2q4: n=136; IAI 2q8: n=135. VISTA FAS: Laser: n=154; IAI 2q4: n=154; IAI 2q8: n=151. T: Anti-VEGF comparison* 66023

Proportion of Patients With ≥ 2 Step Improvement in DRSS at Week 100 SECONDARY ENDPOINT DRCR NETWORK ONGOING PROTOCOLS

100% VIVID VISTA

# of 80% Protocol Subjects Laser M: Diabetes Education Study* 1875 60% IAI 2q4 IAI 2q8 U: Phase II Persistent DME Study** 37.0% 37.1% 40% 32.6% 29.3% V: Very Good Visual Acuity** 39

Proportion of patients of Proportion 20% 15.6% 8.2% Genetics Ancillary Study: Genes in Diabetic Retinopathy** 855 85 82 86 154 154 151 0% DRCR Network Participant Total Since 2003 8807 P=0.0004 2q4 vs laser P<0.0001 2q4 vs laser P<0.0001 2q8 vs laser P<0.0001 2q8 vs laser * Enrollment done/in active follow-up; **Recruiting

In VISTA, analyses were performed using the FAS. In VIVID, analyses included only evaluable patients defined as those with a gradable baseline DRSS and a post-baseline DRSS score. Compared with baseline; last observation carried forward DRSS, Diabetic Retinopathy Severity Score MEAN CHANGE IN VISUAL ACUITY AT FOLLOW-UP THE DIABETIC RETINOPATHY VISITS AMONG EYES THAT WERE CLINICAL RESEARCH NETWORK PSEUDOPHAKIC AT BASELINE* 5-Year Follow-up of a Randomized Trial Evaluating Ranibizumab Plus Prompt versus Deferred Laser for Diabetic Macular Edema PROTOCOL I

Visit Week 28 * Values that were ±30 letters were assigned a value of 30

STEP CHANGES OF IMPROVEMENT/WORSENING IN PROTOCOL I MAIN OUTCOMES DIABETIC RETINOPATHY BY BASELINE SEVERITY • Number of visits at 5 years: Sham Ranibizumab Triamcinolone • 38 in the ranibizumab + Prompt Laser (13-8-7-5-4) +Prompt +Prompt +Prompt • 40 in the Ranibizumab + deferred laser (13-10-8-6-5) Change from baseline to 1-year Laser Laser or Laser visit* Deferred Laser Baseline Severity: Moderately Median of Injections at 5 years N = 150 N = 182 N = 80 Severe NPDR or Better • 13 in the ranibizumab + Prompt Laser (8-2-1-0-0) Improved by ≥2 levels 4% 25% 25% • 17 in the Ranibizumab + deferred laser (9-3-2-1-0) Worsened by ≥2 levels 7% 3% 3% P value for comparison with P = 0.08 P =0.17 Additional Laser treatements needed at 5 years Sham Baseline Severity: Severe NPDR or • All received laser in the ranibizumab + Prompt Laser N = 83 N = 121 N = 70 worse • Less than 50% needed laser in the Ranibizumab + deferred laser Improved by ≥2 levels 19% 28% 13% Percentage of patients with vision improvement > 15 ETDRS letters at 5 yeasr Worsened by ≥2 levels 8% 1% 3% P value for comparison with P = 0.03 P = 0.17 • 27% in the ranibizumab + Prompt Laser Sham 29 *Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab • 38% in the Ranibizumab + deferred laser groups, and 33 eyes in the triamcinolone+prompt laser group

CHANGE IN VA OVER 5 YEARS STRATIFIED BY BASELINE VA PROTOCOL I KEY FINDINGS • VA gain at 1 year was maintained to 5 years concomitant with diminishing need for treatment over time • Adding laser at initiation of ranibizumab was no better than deferring laser at least 24 weeks • Deferring laser may be associated with more VA gain through 5 years, especially in eyes with worse VA at baseline • Eyes assigned to prompt laser needed fewer injections over 5 years • Few eyes in either group had substantial VA loss • About 1/3 still thickened  more work to be done

27 • Test for interaction at 5 Year time point: P = 0.001 • Consider IVTA for subjects pseudophakic at baseline • Test for interaction from longitudinal model: P = 0.004 30 RESTORE

WHAT ABOUT RBZ RANIBIZUMAB ALONE? RBZ + Laser

Ophthalmology. 2010;117:2146-51. Epub 2010 Sep 19. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Laser alone

--The Restore Study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular Edema Ophthalmology 2011;118:615–25.

READ 2 THREE YEAR OUTCOMES

Mean number of injections

2.3 +2.0 letters 24 μm p=0.08 5.4 HOW ABOUT AVASTIN? PACORES and BOLT -1.6 letters -36μm

3.3 p=.11

Ophthalmology. 2010;117:2146-51. Epub 2010 Sep 19. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.

PACORES

READ-2 CONFIRMED -- THE RESTORE STUDY Mitchell P, Bandello, F, Schmidt-Erfurth U, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615–25. J. F. Arevalo, J. G. Sanchez, L. Wu et al., “Primary intravitreal bevacizumab for diffuse diabetic macular edema. The Pan-American Collaborative Retina Study Group at 24 months,” Ophthalmology, vol. 116, no. 8, pp. 1488–1497.e1, 2009.

Real-World Results With Bevacizumab for DME Doesn't Match Trial Results Arevalo et al. Br J Ophthalmol 2016. DME TREATMENT: ANTI-VEGF BOLT (COMPLETERS OF THE GIVEN VISIT ONLY)

Global • • 80 eyes randomized to laser Aflibercept Bevacizumab Ranibizumab‡ A prospective randomized P-Value trial of intravitreal vs. bevacizumab. bevacizumab or laser # of Injections: Median (25th, 75th percentile) therapy in the management • The bevacizumab group of diabetic macular edema Year 1 9 (8, 11) 10 (8, 12) 10 (8, 11) 0.045† (BOLT study) 12-month data: gained a median of 8 ETDRS report 2. letters, whereas the laser Year 2 5 (2, 7) 6 (2, 9) 6 (2, 9) 0.32 group lost a median of 0.5 • Michaelides, et al, Ophthalmology. 2010 Jun;117:1078-1086.e2. ETDRS letters (P = 0.0002). Over 2 Years 15 (11, 17) 16 (12, 20) 15 (11, 19) 0.08

NOTE: 98% of protocol required re-injections were given over 2 years † Pairwise comparisons (adjusted for multiple comparisons): A-B: P = 0.045, A-R: P = 0.19, B-R: P = 0.22. 40 Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. ‡Seven study eyes received 1 injection and 2 eyes received 2 injections of 0.5-mg of ranibizumab prior to the FDA approving a 0.3–mg dosage of ranibizumab for DME treatment and protocol revision to use 0.3-mg dose Goyal, et. al., Graefes Arch Clin Exp Ophthalmol. 2011;249:15-27.

DME TREATMENT: LASER (COMPLETERS OF THE GIVEN VISIT ONLY)

Global Aflibercept Bevacizumab Ranibizumab P- Value HOW DO ANTI VEGF AGENTS COMPARE? At least one focal/grid laser <0.001 Year 1 37% 56% 46% *

Year 2 20% 31% 27% 0.046‡

Over 2 Years 41% 64% 52% <0.001†

*Pairwise comparisons (adjusted for multiple comparisons): A-B: P<0.001, A-R: P=0.06, B-R: P=0.06 41 ‡ Pairwise comparisons (adjusted for multiple comparisons): A-B: P=0.046, A-R: P=0.12, B-R: P=0.37. †Pairwise comparisons (adjusted for multiple comparisons): A-B: P<0.001, A-R: P=0.04, B-R: P=0.01.

DIABETIC RETINOPATHY CLINICAL SUBGROUP ANALYSIS RESEARCH NETWORK 1 YEAR RESULS

Aflibercept, Bevacizumab, or 20/32-20/40 20/50 or worse 20 Ranibizumab for DME: Two-year Results +19 15 +14 PROTOCOL T 10 ~+8 +12 Supported through a cooperative agreement from the

National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Letter Score 5 Department of Health and Human Services EY14231, EY14229, EY018817 0 Mean Change is Visual Acuity 0 8 16 24 32 40 48 0 8 16 24 32 40 48 Visit Week Visit Week

Aflibercept Bevacizumab Ranibizumab ≥15 LETTER IMPROVEMENT AT 2 YEARS

20/32 – 20/40 20/50 or wose WHAT ABOUT PRP? Observed Data Observed Data

*P 0.75 PROTOCOL S *P 0.89 Prompt PRP 58% 52% 55% vs. Percent

Percent Ranibizumab + Deferred PRP for PDR Study 20% 17% 19%

* P-values adjusted for baseline visual acuity and multiple comparisons

POST HOC ANALYSIS OF APTC ADVERSE EVENTS STRATIFIED BY PRIOR MI/STROKE PRIMARY QUESTION

% of pts with at Aflibercept Bevacizumab Ranibizumab • Is visual acuity using ranibizumab for PDR not worse than least one event No Prior treatment with PRP at 2 years? N = 203 N = 193 N = 193 MI/Stroke . Non-inferiority margin of 5 letter Non-fatal MI 3% 2% 2% Non-fatal stroke <1% 3% 3% SECONDARY QUESTION Vascular death <1% 2% 4% Any APTC Event 5% 6% 9% • Are there potential benefits of ranibizumab on: Prior MI/Stroke N = 21 N = 25 N = 25 . Vision throughout follow-up (area under the curve) Non-fatal MI 5% 0 8% . Peripheral vision Non-fatal stroke 0 4% 20% Vascular death 5% 16% 8% . Macular edema 44 Any APTC Event 10% 20% 36% Global P-value adjusting prior myocardial infarction, prior stroke: P = 0.06. . Incidence of vitrectomy

KEY FINDINGS PROTOCOL T MEAN CHANGE IN VISUAL ACUITY 2 YEAR RESULTS AREA UNDER THE CURVE ANALYSIS 15  VA gains in all three drugs at 2 years, with reduced number of Adjusted Mean Difference over 2 years (AUC): +4.2 P-value<0.001 injections and lasers in year 2 10 95% Confidence Interval: (+3.0, +5.4)  With MILD initial VA loss  little difference in visual acuity. 5  At worse levels of initial visual acuity aflibercept more effective at + 4.5

improving visual acuity versus bevacizumab, but not ranibizumab. (Letter Score) 0 -0.3  Pre-defined systemic APTC rates were higher in the Mean VisualAcuity Change Mean -5 ranibizumab group, not seen in previous clinical trials (outlier) 0 1632526884104 N = 191 Visit Week N = 160 N = 203 N = 168 45 Ranibizumab Group PRP Group 48

Area under the curve (AUC) analysis: Pre-planned secondary outcome Mean Change in Visual Acuity KEY FINDINGS PROTOCOL S Stratified by Baseline DME PRP remains effective for PDR in 21st century With “Baseline DME” Without “Baseline Ranibizumab for PDR is a as good as PRP for VA at 2 years 14 DME” 12 . Ranibizumab is an alternative to PRP for PDR 10 +7.9 8 . No substantial safety concerns for at least 2 years 6 4 +2 +1.8 . May be the preferred initial treatment for some patients 2 0  PDR and DME but cost, follow-up compliance, and

(Letter Score) (Letter Score) -2 -0.5 -4 patient preference need to be considered 0 1632526884104 0 1632526884104 Mean Visual Acuity ChangeAcuity Visual Mean N = 42 Visit Week N = 33 N = 147 Visit Week N = 126 • Longer follow-up needed to determine if effect is sustained N = 46 N = 37 N = 155 N = 130 49 through 5 years 52 Ranibizumab Group PRP Group *Outlying values were truncated to 3 SD from the mean

PERIPHERAL VISUAL FIELD OUTCOMES 2-YEAR VISIT Humphrey Visual Field 30-2 + 60-4 Ranibizumab PRP Group Group (N = 58) (N = 57) WHAT ABOUT STEROIDS? Cumulative Point Score Change from Baseline Mean -23 -422

Difference (P-Value) 372 dB (P<0.001)

Mean Deviation Change from Baseline

Mean -0.08 -2.50

50 Difference (P-Value) 2.2 (P< 0.001)

PROPORTION OF EYES DEVELOPING CENTER INVOLVED DME WITH VISION IMPAIRMENT STEROIDS FOR DME: AVAILABLE MOLECULES (EYES WITHOUT BASELINE DME AND VISION IMPAIRMENT) Triamcinolone acetonide (FDA approved for GCA,SO,Uveitis) 2-Year Adjusted Difference: 19% • Triescence: Off label for DME 95% Confidence Interval: (10% to 28%) P-value < 0.001 Dexamethasone Implant Ozurdex™ Fluocinolone acetonide Ivuvien™, Safety concerns N = 155 cataract

N = 147 Glaucoma 51 Other 66 yo ♂, phakic. NIDDM diagnosed in May 2014. Metformin/Glipizide/Lisinopril STEROIDS FOR DME: CLINICAL TRIALS Initial eye exam Severe NPDR with DME A1C 9%

10/24/2014 10/24/2014 • MEAD: (n=148) Treatement-naïve patients with DME, BCVA of 20/50 OD 20/100 s/p Avastin x 3 OS 20/100 s/p Avastin x 3 to 20/200 and CRT of ≥300 (OZURDEX) vs sham. 3 year results: • 19.5% gained ≥3-lines vs 10.7% overall 637µ • Pseudophakic patients: 20% vs 11% 560µ • Cataract formation 65% vs 20.4% in sham group • Increases in IOP usually controlled with medication or no therapy; • 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.

Ophthalmology. 2014 Oct;121(10):1904-14. doi: 10.1016/j.ophtha.2014.04.024. Epub 2014 Jun 4. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, HashadY, Whitcup SM; Ozurdex MEAD Study Group

STEROIDS FOR DME: CLINICAL TRIALS 67 yo ♂, phakic. 1 year later (11/04/2015) A1C 6.9% OS: 20/60 (3 line gain) OD: 20/60 (3 line gain) 170 µ decrease CFT 163 µ decrease CFT s/p 12 Injections (7L 5 E) • FAME: (n=956) persistent DME despite treatment with s/p 11 Injections (6L 5 E) s/p 1 Focal laser available therapies. Primary endpoint=VA gain≥15 letters at 24 s/p 1 Focal laser months. • 3-year results: ~30% improved ≥ 3 lines from baseline (17% in control group) • 75% had 1 ILUVIEN implant over 3 years • ≥30 mmHg IOP rise in 18.4% • 5% rate of incisional glaucoma surgery (4.8-8.%) • 81.7% developed cataract at month 36 (80% had CE)

67 yo ♂, phakic. 5 months later (3/09/2016) A1C 6.8% STEROIDS: RATIONALE FOR CLINICAL USE OD: 20/50 (4 line gain) OS: 20/50 (4 line gain) 59µ decrease CFT (Total 222µ) 154µ decrease CFT (Total324 µ) • Aprox 1/3 of patients do not respond or have an incomplete response to s/p IVT and Ozurdex (1/20/16) s/p IVT and Ozurdex (2/20/16) Total 13 injections Total 14 injections Anti VEGF therapy regardless of agent • Predominantly VEGF-mediated disease • benefit form AntiVEGF agents • Non-predominantly VEGF-mediated disease • partial or no benefit from AntiVEGF combination therapy • Side effect profile • Phakic vs pseudophakic status may lead us to switch earlier of later in the treatment process FIBRATES AND STATINS: FIELD STUDY

PRIMARY OUTCOME FIELD (OPHTHALMOLOGY SUB STUDY) • Fenofibrate Intervention and Event Lowering • ETDRS photos performed on 1012 BUT, THERE MAY BE in Diabetes (FIELD) study designed to assess subjects the effect of fenofibrate on cardiovascular INCREASED COSTS … events (N~10,000). • Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. Economic considerations of macular edema therapies. SECONDARY OUTCOME Smiddy WE.Ophthalmology. 2011 Sep;118:1827-33. • 30% reduction (p=0.003) in need for a first laser therapy with fenofibrate compared to placebo.

Lancet 2005; 366: 1849–61 • Lancet, 2007: 370, 1687-1697.

ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES DO NOT FORGET LASER ACCORD TRIAL • Studied effects of intensive glucose DRCR Prospective study of 122 eyes with center-involved control on cardiovascular endpoints Hgb A1C diabetic macular edema. in type 2 diabetes. At 16 weeks, about 50% had a decrease in CST by > or =10% compared with baseline • Similar to DCCT in type 1 diabetes. 23% to 63% continue to improve without additional treatment. • ~10,000 subjects Laser effect slow and steady, might eventually allow fewer visits - ~3,000 participated in the eye and injections. substudy.

the use of intensive therapy to target The course of response to focal/grid photocoagulation for diabetic macular edema. normal glycated hemoglobin levels for 3.5 years increased mortality. Diabetic Retinopathy Clinical Research Network. Retina. 2009;29:1436-43. Supplement to: The ACCORD Study Group and ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44. DOI: 10.1056/NEJMoa1001288.

ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES ACCORD TRIAL

• Triglycerides reduced • Effect on retinopathy progression

WHAT ABOUT SYSTEMIC DIABETES CONTROL?

Supplement to: The ACCORD Study Group and ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44. DOI: 10.1056/NEJMoa1001288. WHAT ABOUT EDUCATION?

Effect of Diabetes Education During Retinal Ophthalmology Visits on Diabetes Control (Protocol M)

Thank You Worldwide Rates of Diabetic Retinopathy

1. Increasing in the United States, although visual impairment rates The microvascular pathology of are on decline diabetic retinopathy 2. Rapid (and disproportionate) global increases in this disease

Rithwick Rajagopal, M.D., Ph.D. 3. Many populations will not have resources to treat vision loss, as it Assistant Professor is treated in wealthier nations Department of Ophthalmology and Visual Sciences Washington University School of Medicine

April 9, 2016 No financial disclosures

Current treatments for microvascular disease due to The Transformative Effect of VEGF Antagonism diabetes

1. Glucose control (with glycated hemoglobin being the endpoint). 1. Review of relevant clinical trials

2. VEGF antagonism 2. Comparative efficacy

3. Laser 3. Safety concerns

4. Corticosteroids

The role of VEGF in maintenance of healthy retina The “Glucose-Centric” Diabetic Retinopathy Hypothesis

DM 1. Overview of expression of VEGF and its receptors in the retina Microaneurysms Hemorrhages 2. Concerns for chronic antagonism Macular Edema Ischemia Elevated Proliferation glucose Microvascular Damage; Inflammation; Loss of Endothelial Integrity VEGF Is Glucose Really the Primary Culprit Causing Diabetic Microvasculopathy?

1. Use caution when interpreting data from clinical trials (DCCT, EDIC, UKPDS) 1. Can we intervene at earlier stages of disease?

2. Lessons from previous glucose metabolism pathway-targeted therapy (PKC-DRS, Sorbinil trials) 2. Can we do so in a more cost-effective manner?

Two Undersold Studies in Ophthalmology What are the Obstacles to Using Fenofibrate for Diabetic Retinopathy? 1. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) • Multicenter study based in Australia 1. Adverse effects • Does use of fenofibrate reduce retinopathy? 2. Questions about its mechanism of action 2. Action to Control Cardiovascular Risk in Diabetes (ACCORD) • U.S.-based multicenter trial • Also assessed effect of fenofibrate on microvascular disease

How Does Fenofibrate Protect the Retina in Diabetes? What Molecules are Altered in the Retina with Fenofibrate Therapy?

1. What are the effects (or lack of) on serum lipids? 1. Screening for candidates 2. Direct actions in the retina through transcriptional regulation 2. Validation of putative targets

3. Modification of retinal lipid environment

4. Anti-inflammatory actions Acknowledgements

Clay Semenkovich, MD Sheng Zhang Li Yin Xiaochao Wei, PhD Larry Spears, PhD

Washington University Retina Service P. Kumar Rao, MD Rajendra Apte, MD, PhD Stanford Taylor, MD Funding Horncrest Foundation DOVS Core Labs K08-EY-025269 Anne Hennig, PhD P30-EY-002687 Belinda Dana Research to Prevent Blindness Guanyi Ling

Contact: [email protected] // Referrals: 314-362-EYES

Effects of Simulated Afferent Pupillary Defect on Automated Perimetry

Robert Null, MD, Resident, Class of 2017 Primary Supervisor: Paul Munden, MD

Glaucoma is a progressive optic neuropathy characterized by known patterns of vision loss. Functional

testing of visual fields through automated perimetry allows the clinician to monitor for glaucoma

progression. Predictive threshold models, most notably the Swedish Interactive Thresholding Algorithm

(SITA) have been developed to speed testing time, and judicious statistical analysis of field data can provide insights into rate of disease progression and efficacy of treatment. However, it is less well understood how these statistical models behave when other etiologies of vision loss are introduced. To further investigate

the behavior of these models, otherwise healthy subjects participated in at 24-2 SITA fast automated visual

field in the dominant eye. Fields were tested with and without the presence of 0.9 neutral density (ND)

filter to simulate a non-specific, quantifiable, generalized visual depression. Statistical parameters commonly utilized to assess glaucoma severity and progression, including mean deviation, pattern deviation, and visual field index (VFI), were compared between filtered and non-filtered fields, with significant trends reported in detail in the accompanying presentation. Vision loss from glaucoma does not occur in a clinical vacuum and better understanding of commonly used statistical metrics under non-ideal conditions will aid the clinician in the assessment and management of this complex disease.

Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA)

Paul Munden, MD Associate Professor, KU Eye

Glaucoma – A characteristic optic neuropathy associated with multiple conditions and usually associated with a higher than normal intraocular pressure.

Diagnosis based on characteristic changes in optic nerve: Structure Clinical examination Concentric enlargement of ON cup Increased vertical C/D ratio Focal notching and thinning at superior/inferior poles ISNT Disc hemorrhages Excavation NFL defects Zone beta peripapillary atrophy

ON and NFL OCT Loss of peripapillary NFL thickness ISNT Function Automated Visual Fields Characteristic NFL associated loss

Initiate Treatment - Consider IOP goal Medical Laser Surgical

Verify IOP at goal

Monitor for progression

CPM if stable

Alter or increase therapy if IOP above goal or progression noted

Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA), continued:

Glaucoma Diagnosis

Set IOP Goal

Initiate and Optimize Therapy

Monitor IOP Disc Photos ON OCT Automated VF

Stable Progression

Confirm Progression

Add or Alter Reset GPA Therapy Baseline Fields

Glaucoma progresses treated or untreated!

Can lead to visual disability and blindness

Important to be able to detect progression and modify IOP goal and therapy

How do we detect progressive glaucoma?

Structural changes from baseline Serial Disc photographs In OHT majority of patients converted to glaucoma on the basis of ON changes Progressive glaucoma

Serial Optic Nerve OCT Patients with progressive NFL thinning had progressive visual field loss by three different VF progression criteria

Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA), continued:

Functional changes from baseline Serial automated visual fields

Difficult to assess actual functional progression examining serial automated visual fields

We compare the most recent field to the one before or maybe the first field

Interpretation can be challenging! Long term and short term fluctuation

OHTS 86% of initial abnormal VF had subsequent normal field 66% of those with two abnormal fields had subsequent normal field 12% of those with three abnormal fields had subsequent normal field

CNTG as many as 4 to 6 abnormal fields necessary to confirm progression

Test-retest variability of perimetry results depend on many factors Frequency of seeing curve Scotoma depth and location Overall visual field status Less variability with very good or very bad fields Test strategy used Full Threshold, SITA Standard, SITA Fast Patient Experience Learning effect External factors Inexperienced technicians Room temperature Chair comfort Patient physical limitations “Bad Hair” day

Is there a tool to help us discern actual functional progression from artifact?

Guided (Glaucoma) Progression Analysis

Software package for Humphrey Field Analyzer Designed to identify and quantify statistically significant visual field loss progression for glaucoma patients Two tests designated as baseline. Up to 14 follow-up tests may be compared to the averaged baseline examinations Identifies progression when testing results fall outside the expected range of test-retest variability

GPA Normative database 363 subjects 9 sites world-wide Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA), continued:

Mild to severe glaucoma First time test takers excluded 4 clinic visits in 1 month, 3 fields per visit Full Threshold, SITA Standard, SITA Fast

Event Analysis An event that is a statistically significant (“real”) change from baseline

Evaluating each individual point in central field for test-retest variability in pattern deviation value Filters out changes in overall height of hill of vision Differentiates between localized glaucoma damage and effect of cataract or pupil size

EMGT event criteria: 3 consecutive visual fields with contain three or more identical points that have changed at a statistically significant level from baseline

Trend Analysis Rate of change of Visual Field Index (VFI) over time Regression analysis of slope of line Statistical analysis to determine slope is “real” vs fluctuation within expected limits Rate of Progression and visual trend of progression pattern plotted graphically.

Using GPA Software activation Set up Print Out options Choosing Baseline Fields Two oldest automatically chosen unless Learning effect False Positives of 15% or more

Choose new Baseline fields after change in therapy or identification of learning effect

Compares subsequent fields with baseline fields with statistical analysis Statistical evaluation of effectiveness of therapy in slowing or stopping progression

Baseline – Follow-up Configurations SITA Standard F/U Exam must have SITA Standard of Full Threshold Baseline Exams SITA Fast F/U Exam must have SITA Fast or Full Threshold Baseline Exams May have 30-2 and 24-2 Exams in the same analysis Does not support FastPac or Central 10-2 for Baseline or F/U

GPA Reports

GPA Summary Report Baseline fields with grayscale and key indices at top VFI plot and VFI bar in center

Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA), continued:

Current visual field with grayscale and indices at bottom Progression Analysis Probability Plot and GPA alert at bottom

Single Field Analysis with GPA Standard Single Field Analysis with grayscale and usual indices Separate box for GPA info and Progression Analysis Probability plot No VFI plot or linear regression analysis

Full GPA report The whole ball of wax Baseline page with grayscale and indices including VFI plot All follow-up exams (up to 14) with Progression Probability Analysis and GPA alert

GPA Last 3 Follow-up Full GPA lite Baseline page and three most recent follow-up exams

Interpreting GPA Reports

Deviation from Baseline Plot Compares pattern deviation of follow-up test to average of pattern deviation of baseline tests

Progression Analysis Probability Plot Denotes statistical significance of the dB changes shown in deviation plot Evaluates point by point Weighted toward center points

Single dot – point not changing by statistically significant amount

Open triangle- at least 5% greater deterioration from expected Average of 2-3 points (out of 76) by chance alone Not uncommon in glaucoma patients

Half-filled triangle – statistically significant deterioration at that point in 2 consecutive tests

Solid triangle - statistically significant deterioration at that point in 3 consecutive tests

X – data out of range for analysis. GPA cannot determine if deviation at that point statistically significant Usually in areas where defect already very deep or absolute

GPA Alert Alerts to deterioration in consecutive tests Applies to the whole field, not individual points

Detecting Functional Change in Progressing Glaucoma: Visual Field Guided Progression Analysis (GPA), continued:

No Progression Detected

Possible Progression – statistically significant deterioration in 3 or more points on two consecutive tests

Likely Progression – statistically significant deterioration in 3 or more points on three consecutive tests

VFI Plot Graphs VFI values of included exams as a function of patient’s age

Linear regression analysis of VFI over time At least 5 exams over 2 years Not drawn when slope positive (learning effect) Not drawn when 95% confidence level on slope is greater than 5%

VFI Bar – histogram indicates current VFI value and will graphically indicate the 2 to 5 year projection of the linear progression line.

Clinical Interpretation

GPA Software is a statistical analysis software not a replacement for clinical observation and physician interpretation

Aid in analysis of data - does not make clinical judgment

How does it compare to the “experts” when calling progression?

“Level of agreement between majority expert consensus of subjective determination of visual field progression and GPA is “fair.” In cases of disagreement with GPA, the expert consensus was usually progression. Access to GPA results after initial classification changed expert consensus in 11 of 100 cases.” Tanna, Budenz, et al, Ophthalmology. 2012 March; 119(3):468-473

Garbage in – Garbage Out

Inspect the printout Assess the triangles Check the defect depth, location, contiguous, anatomic (RNFL) pattern Possible Progression Likely Progression

Correlate with other examination findings!

If progression, check progression fields for reliability

Reset Baseline fields following intervention for progression KU MD and Residency Alumni

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Alan Hromas MD Charles E. Graham MD Andrew J. Jefferson MD Residency Class: 2014 Residency Class: 1993 Residency Class: 1986 Houston, TX Las Vegas, NV Leawood, KS Ana G. Huaman MD R. Bruce Grene MD MD Class: 1984 Faisal Jehan MD MD Class: 1978 Residency Class: 1996 MD Class: 1998 Wichita, KS Albuquerque, NM Residency Class: 2003 Fontana, CA Hasan Hakim MD Quentin C. Huerter MD Residency Class: 1997 MD Class: 1959 Cindi Kalin Johnson MD Dearborn, MI Residency Class: 1969 Residency Class: 1994 Leawood, KS Leavenworth, KS James R. Hardin MD Residency Class: 1997 Denise A. Hug MD Josh Jones MD Salisbury, NC MD Class: 1996 Residency Class: 2018 Kansas City, MO Prairie Village, KS Wilmer Harms MD MD Class: 1956 John D. Hunkeler MD Raymond E. Kandt MD North Newton, KS MD Class: 1967 Residency Class: 1967 Residency Class: 1973 Prairie Village, KS Toby Hartong MD Overland Park, KS Residency Class: 1982 Neda Karimi MD Leawood, KS Joel Hunter MD MD Class: 2001 Fellow: 2010 Residency Class: 2005 James D. Haug MD Orlando, FL Santa Monica, CA MD Class: 1981 Residency Class: 1985 Richard L. Irwin MD Rickey D. Kellerman MD Atchinson, KS MD Class: 1975 MD Class: 1978 Residency Class: 1980 Wichita, KS K. Dwight Hendricks MD Putnam, CT Residency Class: 1983 Daniel M. King MD Kansas City, KS Srinivas Iyengar MD MD Class: 1974 Residency Class: 2008 Residency Class: 1982 James A. Hiatt MD Littleton, CO Red Bluff, CA MD Class: 1999 Residency Class: 2003 Randolph Jackson MD David A. Kingrey MD Mesa, AZ Residency Class: 2004 MD Class: 1994 Kansas City, KS Wichita, KS KU MD and Residency Alumni

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Wilber McElroy MD Ernest Kovarik MD Rebecca Linquist MD MD Class: 1961 Residency Class: 1969 Residency Class: 2013 Topeka, KS Shawnee Mission, KS Rapid City, SD Frank E. McKee MD Randall J. Kresie MD Robert A. Lowenthal MD MD Class: 1970 MD Class: 1984 Residency Class: 1994 Overland Park, KS Residency Class: 1988 Springfield, IL Topeka, KS Peter Mitrev MD Barry C. Malloy MD Residency Class: 1998 Kartik Kumar MD Residency Class: 1989 Chesapeake, VA Residency Class: 2011 Wyomissing, PA Houston, TX Reid Mollman MD Babak Marefat MD Residency Class: 2018 Leila Kump MD MD Class: 1999 Prairie Village, KS Residency Class: 2010 Topeka, KS Gaithersburg, MD Louis Monaco DO John Marsh MD DO Class: 1982 Bradley R. Kwapiszeski MD MD Class: 1992 Clinton, MO MD Class: 1991 Residency Class: 1996 Shawnee Mission, KS Topeka, KS Susan K. Mosier MD MD Class: 1995 Brian A. LaGreca MD Federico Mattioli MD Lawrence, KS Residency Class: 1992 Residency Class: 2000 Everett C. Moulton MD Billings, MT Houston, TX Residency Class: 1979

Ft. Smith, AR Dale Laird MD Donald Maxwell MD MD Class: 1968 Residency Class: 1986 Andrew Moyes MD Residency Class: 1974 Oklahoma City, OK MD Class: 1989 Belton, MO Kansas City, MO Mark Mazow MD Ryan Larscheid MD Residency Class: 1990 Brian C. Mulrooney MD Residency Class: 1974 Dallas, TX Residency Class: 1999 Fountain Valley, CA Huntsville, AL Thomas L. McDonald MD Diana Lind DO MD Class: 1984 Forrest P. Murphy MD Residency Class: 1997 Residency Class: 1988 MD Class: 1978 Kearney, NE Hays, KS Residency Class: 1985 La Jolla, CA KU MD and Residency Alumni

Todd Nickel DO Cindy Penzler MD Robert Reinecke MD DO Class: 2000 MD Class: 1985 MD Class: 1959 Residency Class: 2004 Residency Class: 1989 Philadelpha, PA Tyler, TX Topeka, KS Martin Reinke MD Robert Null MD Ryan Pine MD Residency Class: 1995 Residency Class: 2017 Residency Class: 2012 Southlake, TX Prairie Village, KS Charleston, IL Donald A. Relihan MD Bruce B. Ochsner MD Kenneth C. Place MD MD Class: 1954 MD Class: 1965 MD Class: 1973 Residency Class: 1957 Wichita, KS Prairie Village, KS Wichita, KS

Sara O'Connell MD John Pokorny MD Garrick Rettele MD MD Class: 1994 MD Class: 1989 MD Class: 1991 Overland Park, KS Hays, KS Coffeyville, KS

Timothy Olsen MD Patrick (Frank) Price MD Michael G. Reynolds MD MD Class: 1989 MD Class: 1975 MD Class: 1988 Atlanta, GA Blue Springs, MO Emporia, KS

Lynn W. O'Neal MD Bradford S. Prokop MD Geoffrey L. Rice MD MD Class: 1977 Residency Class: 1961 Residency Class: 1985 Lawrence, KS Ft. Myers, FL Ukiah, CA

Richard A. Orchard MD Gary V. Puro MD James R. Rinne MD MD Class: 1965 Residency Class: 1975 MD Class; 1984 Lawrence, KS Santa Fe, NM Residency Class: 1988 Campbellsville, KY Charles F. Palmer MD Anjulie Quick MD David S. Rothberg MD Residency Class: 2000 Residency Class: 2017 Residency Class: 1983 Cheyenne, WY Prairie Village, KS Palm Harbor, FL

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