· Over 30 years of history of putting your patients first! EYE SPECIALISTS OF INDIANA Indiana’s Optometry-Based Co-Management Referral Center offering: More than three decades

JULY 15, 2020 | CARMEL, IN

Indiana Optometric Association

Hot Topics in Optometry

Over 30 years of history of putting your patients first!

EYE SPECIALISTS OF INDIANA Indiana’s Optometry-Based

Co-Management Referral Center offering:

More than three decades ofOptometric education and support

Experience with more than100,000 laser and cataractprocedures

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7:30 – 9 am Continental Breakfast and Registration8 – 9 am Optional Bonus Hour of CE -- Laser Therapy: An Update and How to Implement Nathan Lighthizer, OD, Tahlequah, OKAnterior segment laser procedures, including YAG caps, SLTs and LPIs, are being done by optometrists in multiple states currently. This interactive lecture will discuss the indications of when to perform these procedures, proper patient selection, procedural techniques, how to implement into your practice and the most recent evidence that discusses and specifically recommends that “SLT should be offered as first line therapy.” 1 Hour IOB and Legend Drug (Laser Procedures)9 – 11 am Optometric Surgical Procedures for Every Optometrist Nathan Lighthizer, OD, Tahlequah, OKOptometric surgical procedures, including lump and bump removal, chalazion treatment, punctal occlusion, suture correction for entropion and various anterior segment laser procedures, among others, are essential procedures for optometrists to be familiar with. Optometrists in many states are now performing these procedures on a routine basis. This interactive presentation will review and update these optometric surgical procedures including indications, contraindications, risks, complications, treatment protocols and pre- and post-op management. 2 Hours IOB & Legend Drug (Surgery Procedures - Optometric)11 am – 12 pm Diabetes New Testing and Treatment for Retinopathy Nathan Lighthizer, OD, Tahlequah, OKThis course will provide an update and thorough understanding of the flash flicker electroretinogram (ffERG), proper indications and protocols and how to interpret the results. Diabetic retinopathy has historically been evaluated and followed with structural tests DFEs, OCTs and fundus photos. This lecture will explore functional testing ERG that helps in the evaluation of diabetic patients and will also discuss the newest literature regarding supplementation of diabetic retinopathy patients. 1 Hour IOB & Legend Drug (Trt/Mngmnt Posterior Segment)12 – 1 pm Lunch (included in registration fee)1 – 3 pm The Neuro-Ophthalmology of Concussion: The Evaluation Management of Vision and Visual-Motor Abnormalities Valerie Kattouf, OD, Chicago, ILThe CDC estimates that there are approximately four million sports-related concussions in the US per year. Research has shown that vision and visual-motor abnormalities are frequently associated with concussion and serve as validated biomarkers for initial diagnosis and long-term management. This course provides an overview of pathophysiology of concussion. We will review the clinical picture of concussion and the significant effect on the visual system. Additional focus will be on the optometric examination sequence and the role the optometrist plays in the decision for the concussion patient to return to their previous level of activity. 2 Hours IOB (Neuro-Optometry) 3 – 4 pm iStrain: What Effect Do Today’s Tablets and Media Devices Have on Vision? Valerie Kattouf, OD, Chicago, ILToday’s world and technology options present a variety of challenges with vision usage. You will learn the effect of today’s exponential use of digital media and its effect on children’s vision and academics. Common visual symptoms and the diagnosis and treatment of the accommodative and binocular vision issues that cause them will be reviewed. The information shared will aim at allowing practitioners to give the proper treatment to patients and the proper advice to parents who ask about the effect of the digital age on vision development. 1 Hour IOB (Functional Vision/Pediatrics or General Optometry)4 – 5 pm Update on Retinal Diagnostics, Therapy and Surgery Tom Ciulla, MD, Indianapolis, INThis course will provide an update on aspects of eyecare related to retinal diagnostics, therapeutics and surgery. Commonly available diagnostic interpretation will be reviewed for OCT, photos and Bscan. Case examples, including AMD masquerade syndromes, will be presented. New retinal medications, delivery methods and gene therapy will be discussed. Diagnosis, referral indications and surgical highlights will be reviewed for common surgical retinal diseases, including persistently symptomatic vitreous membranes and strands, macular holes and macular pucker. 1 Hour IOB & Legend Drug (Trt/Mngmnt Posterior Segment)

HOT TOPICS IN OPTOMETRY SCHEDULE July 15, 2020

COVID-19 InformationAn inherent risk of exposure to COVID-19 exists in any public place where people are present. The IOA is following guidance from the Indiana State Department of Health and the Centers for Disease Control and Prevention (CDC) regarding large gatherings, including CDC recommendations on preventing the spread of COVID-19. While attending the seminar, please keep in mind these recommendations on how to keep yourself and others healthy:If you have tested posititve for COVID-19, have had close contact with someone who has symptoms of COVID-19 within the past 14 days, are sick or feel you are getting sick, we ask that you please stay home. We will process a refund of your registration fee at your request. Attendees 65 and older and those with known high-risk medical conditions should adhere to social distancing guidelinesPlease wear a face covering or mask. They are strongly recommended.

Please visit and thank the exhibitors and sponsors who have generously supported the Indiana Optometric Association this year! Exhibitors today include Alcon, Allergan, Bosma Enterprises, CooperVision, Interstate Lab Group, Maculogix, Novartis and Price Vision Group.

Nathan Lighthizer, OD Tahlequah, OKBorn and raised in Bismarck, North Dakota, Dr. Nate Lighthizer, O.D., F.A.A.O., is a graduate of Pacific University College of Optometry. Upon graduation, he completed a residency in Family Practice Optometry with an emphasis in Ocular Disease through Northeastern State University Oklahoma College of Optometry. Dr. Lighthizer has since joined the faculty at the Oklahoma College of Optometry and serves as the Chief of Specialty Care Clinics and the Chief of Electrodiagnostics Clinic. In 2014, he founded and now heads the Dry Eye Clinic at the College of Optometry. Also in 2014, he was named the Director of Continuing Education as well as the Assistant Dean for Clinical Care Services at the Oklahoma College of Optometry. He is a founding member, and currently serves as Vice President, of the Intrepid Eye Society which is a group of emerging thought leaders in optometry. He was named a member of PCON 250 – a list of the top 250 optometrists in the country who practice progressively, provide innovative patient care, conduct optometric research or excel in academia and share what they have learned with other optometrists to advance the profession. Dr. Lighthizer lectures nationally on numerous topics, most notably advanced ophthalmic procedures, electrodiagnostics and ocular disease.

Valerie Kattouf, OD Chicago, ILDr. Valerie M. Kattouf is an Associate Professor at the Illinois College of Optometry where she teaches in the classroom and clinic, works with residents, and conducts clinical research. Upon graduation from the Illinois College of Optometry, Dr. Kattouf completed a residency in Pediatrics and Binocular Vision at the State University of New York Optometric Center. Dr. Kattouf has years of clinical experience in the areas of infant and toddler vision care, strabismus and amblyopia, concussion and adult binocular vision disorders. Dr. Kattouf is currently Chief of the Lewenson Pediatrics and Binocular Vision Center at the Illinois Eye Institute. Dr. Kattouf is a fellow of the American Academy of Optometry and the College of Optometrists in Visual Development who lectures nationally and internationally.

Tom Ciulla, MD Indianapolis, INDr. Ciulla is a volunteer clinical professor at Indiana University and board member at Midwest Eye Institute. He also currently serves as Chief Medical Officer and Chief Development Officer at Clearside Biomedical and previously served a VP role at Spark Therapeutics, where he led medical strategy to support development and commercialization of Luxturna, the first FDA-approved gene therapy for a genetic disease. He has served a variety of roles in over 100 national clinical trials, presented at over 200 conferences, and co-authored over 200 publications. Dr. Ciulla graduated from Harvard College and UCSF Med School, followed by an internship and residency at Harvard Med School, fellowship at Tufts Med School, and an MBA from Indiana University’s Kelley School of Business, specializing in the business of medicine.

THANK YOU OPTOMETRY’S PAC CONTRIBUTORS 2020

Nicole R. Albright, O.D.Chris Ambrose, ODNilah Nicole Bonham, O.D.E. Cy Burkhart, O.D.Matthew R. Clark, O.D.David L. Cripe, O.D.Damon Dierker, OD, FAAOD. Barry Downing, O.D.Craig A. Fenimore, O.D.Jeremy S. Gard, O.D.Courtney Gonzales, O.D.Juliana Grove, O.D.Daniel J. Harmon, O.D.Andrew D. Hoffman, O.D.Sarah A. Huseman, O.D.William H. Jones Jr., O.D.Kristina R. Jordan, O.D.Jeffrey E. Kirchner, O.D.Robert E. Kline, O.D.Marjorie J. Knotts, O.D.Elli Kollbaum, O.D.Kenneth E. Lawrence, O.D.Angela Leonhard, O.D.Jerry W. Logan, O.D.Lance E. Malott, O.D.Andrew F. Mansueto. O.D.Ronald T. McDaniel, O.D.Teresa K. McGuire, O.D.Gregory D. Norman, O.D.John J. Offerle, O.D.Kristina L. Offerle, O.D.Jeffrey D. Perotti, O.D.Judy (Smith) Risch, O.D.Joseph N. Sisley, O.D.Thomas E. Smith, O.D.Mark A. Snyder, O.D.Don A. Steward, O.D.James S. Stickel, O.D.Christa L. Walling, O.D.David J. Weigel, O.D.Eric D. Weigel, O.D.Mark A. Williams, O.D.Laura K. Windsor, O.D.Richard L. Windsor, O.D.

Thank you for your PAC donations which help extend Optometry’s influence at the Indiana Statehouse! For more information on Optometry’s PAC, contact PAC Chair Polly Hendricks, OD, [email protected]. The Optometry’s PAC drawing for a $1000 vacation travel voucher is held every year at the Winter Seminar. Optometrists receive an entry or entries in the drawing each year determined by their contribution that year. A $250 contribution to the PAC provides one entry; $500 receives three entries; $750, five entries; and $1000, seven entries.

Levels of Giving$100 - 499 Falcon $500 - 999 Hawk $1000+ Eagle

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Partnering with Indiana Optometristsfor Generations

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Christopher Knight, MD • David Ryser, MDAnn Wiarda, MD • Matthew Ralstin, MD • Allison Pernic, MD

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Locations in: Warsaw • Mishawaka • Elkhart • Plymouth

• Cataract surgery• Diabetic retinopathy treatments• Macular degeneration treatments• LASIK laser vision correction & refractive surgery• Glaucoma care & surgery• Pediatric eye care

IOA BOARD OF TRUSTEES - APRIL 2020 - APRIL 2021

Dr. Damon Dierker Indianapolis

Dr. Jeffrey KirchnerWest Lafayette

Dr. Piper Groppel Indianapolis

Dr. Gregory NormanDelphi

Dr. Jamie Stickel Goshen

Dr. Michael ZirkleMarion

Dr. Nicholas Garn Zionsville

Dr. Jeremy Gard Muncie

Dr. Jennifer KohnMerrillville

Dr. Polly Hendricks Borden

Dr. Kyle KingEvansville

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VARILUXSHAMIRCRIZALEYEZENSIGNATUREICON ARTRANSITIONSTURN AROUNDSERVICEPOLARIZEDDEFINITYEXPERIENCEINTELLIGENCEMIRRORSKIDS PACKTECHNOLOGY

2/17/20

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Nate Lighthizer, O.D., F.A.A.O.

¨ Why we use lasers

¨ YAG capsulotomy¨ Laser Peripheral Iridotomy (LPI or PI)¨ Argon Laser Peripheral Iridoplasty (ALPI)¨ Argon Laser Trabeculoplasty (ALT)¨ Selective Laser Trabeculoplasty (SLT)¨ Other Laser Trabeculoplasty

¨ Vision is decreased from PCO following cataract surgery

¨ Narrow angles/angle closure¨ Glaucoma is progressing in a pt on max meds

¡ Something else needs to be done¡ Surgery not wanted yet

¨ Compliance issues¨ Cost issues¨ Convenience issues¨ Doctor preference

¨ Lens capsular bag has an anterior and posterior surface¡ Anterior surface usually removed w/ capsulorhexis

¨ PCO is the formation of a cloudy membrane on the posterior surface of the capsular bag following ECCE¡ AKA: Secondary cataract

¨ Incidence:¡ Most common complication of post ECCE¡ 10-80% of eyes following cataract surgery¡ Can form anywhere from a few days to years post surgery¡ Younger patients higher risk of PCO¡ IOL’s

ú Silicone > acrylic

¨ Prevention:¡ Capsulotomy during surgery¡ Posterior capsular polishing

¨ Nd: YAG laser¡ Neodymium: Yttrium aluminum garnet laser

¨ Tissue interaction: Photodisruptive laser¡ High light energy levels cause the tissues to be

reduced to plasma, disintegrating the tissue¡ A large amount of energy is delivered into very small

focal spots in a very brief duration of timeú 4 nsec

¡ No thermal reaction/No coagulation when bv’s are hit¡ Pigment independent*

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¨ Visual acuity, glare testing, PAM/Heine lambda¡ Vision 20/30 or worse

¨ Slit Lamp Exam¨ IOP’s¨ Dilate – will be able to visualize

the PCO much better¨ Posterior segment exam

¡ Macula¡ Periphery

¨ Educate Pt¨ Informed Consent Signed

CONTRAINDICATIONS RISKS/COMPLICATIONS

1. Corneal problems2. Intraocular inflammation3. Macular problems4. Patient unable to hold

steady or fixate

1. IOP spike/elevationú Most often transient

2. Inflammationú Pred Forte QID X 1 weekú Use appropriate laser energy

3. Floaters4. IOL Pitting

¡ Silicone IOL most common5. Retinal detachment6. Permanent vision loss

¨ Patient Pre-op Drops¡ dilating drops¡ 1 drop Alphagan or Iopidine 5 minutes prior to laser

¨ Laser Settings¡ Energy 1.3 – 2.5 mJ¡ Spot Size fixed¡ Duration fixed¡ Pulses 1¡ Offset 250 microns

¨ Focus HeNe beams on the PCO¨ Perform the procedure

¡ No pain for patients¡ May feel popping/snap/clap in ears

¨ Usually done in a cruciate pattern¨ Other patterns:

¡ Horseshoe¡ Circular

¨ Post-op Care¡ Remove laser lens¡ Rinse Eye/Clean eye¡ 1 drop of Alphagan or Iopidine post-laser¡ IOP measurement 15-30 minutes post-laser

¨ Post-op drops¡ Pred Forte QID to surgical eye X 1 week¡ Pt ed – S/S of RD

¨ RTC 1 week for f/u

¨ VA’s¨ Anterior segment exam

¡ Check for cell/flare¨ Check IOP¨ Dilate

¡ Check for holes/tears/RD’s

¨ D/C Pred Forte¨ Release back to referring doc

2/17/20

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¨ Reimbursement codes¡ 66821

¨ 90 day global period

¨ Anatomic disorder characterized by peripheral iris & TM apposition

¨ 4 basic forms:¡ Pupillary block¡ Plateau iris¡ Phacomorphic glaucoma¡ Malignant glaucoma





2/17/20

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¨ Primary angle closure¨ Plateau iris syndrome/configuration¨ Secondary pupillary block

¡ Phacomorphic, malignant glaucomas¨ Pigmentary glaucoma¨ Prophylaxis*

¡ Narrow angles on gonioscopy¡ Most often reason why PI is done

¨ How likely is this patient to develop glaucoma?¨ How do we predict whether she will progress?¨ How effective is LPI?¨ What do we do if LPI fails?

1. Anatomically narrow (PACS)– Indentation gonioscopy opens angle–Normal IOP–Heightened suspicion

2. Anterior synechiae and/or elevated IOP (PAC)–Minimal natural history data

3. Closed angles and glaucomatous damage(PACG)

(Fourth category: Acute symptomatic angle closure)

¨ Gonioscopy: iridotrabecular contact in at least 180 degrees

¡ Iridotrabecular contact = failure to see posterior meshwork

¨ AS-OCT: angle opening is less than 5-10 degrees¡ Visante: use lens vault measurement

1. Anatomically narrow (PACS)– Indentation gonioscopy opens angle–Normal IOP–Heightened suspicion

2. Anterior synechiae and/or elevated IOP (PAC)–Minimal natural history data

3. Closed angles and glaucomatous damage(PACG)

(Fourth category: Acute symptomatic angle closure)

¨ Surgical Iridectomy¡ Equal results to laser PI¡ Much more invasive

ú More trauma to irisú Infection

¡ If concurrent surgery not occurring, laser PI is the way to go

2/17/20

5

¨ Visual acuity ¨ Slit Lamp Exam OU

¡ Note lid position¡ Note AC depth

¨ Gonio OU¡ Pigment in the TM?¡ Neovascularization?¡ Peripheral anterior synechiae?

¨ IOP’s OU

¨ Educate Pt¨ Informed Consent Signed

CONTRAINDICATIONS RISKS/COMPLICATIONS

1. Corneal problems2. Intraocular inflammation3. Iris in contact with endo4. Angle closure from NVG

or inflammatory glaucoma5. Patient unable to hold

steady or fixate6. Macular problems?

1. Non-perforation 2. IOP spike/elevation

ú Most often transient


¨ Others: hyphema, synechiae, peaked pupil, floaters, blur, monocular diplopia, RD, permanent vision loss

¨ Patient Pre-op Drops¡ 1 drop Pilocarpine 1% or 2% OU¡ 1 drop Alphagan or Iopidine OU

¨ Laser Settings¡ Depends on which laser you use

ARGON LASER YAG LASER

¨ Less commonly used¨ Advantages:

¡ Less bleeding¡ Less debris

¨ Disadvantages:¡ Less successful compared to

YAG laser in penetrationú Requires more shots

¨ Settings:¡ Spot size = 50 microns¡ Duration = 0.1 sec¡ Power = 300-1200 mW

¨ More commonly used¨ Advantages:

¡ Very good penetration rate¨ Disadvantages:

¡ More likely to bleed¡ Much more debris

¨ Settings:¡ Spot size = fixed¡ Duration = fixed¡ Energy = 2.0 – 5.0 mJ¡ Offset = 0 – 250 microns

¨ Sit patient comfortably¨ Adjust laser for your comfort

¡ Armrest, oculars, controls¨ Instill proparacaine in both eyes¨ Select PI location

¡ Usually superiorly under lid¡ Crypt ¡ 11:00 or 1:00

¨ Place Abraham Iridotomy laser lens on eye with goniosol or celluvisc¡ Orientation of lens matters¡ Button @ 11 or 1 o’clock (for a superior PI)

¨ Focus HeNe beams on the iris¨ Perform the procedure OU

¡ Argon first for pre-treatment¡ YAG to finish PI¡ No pain for patients - usually¡ May feel popping/snap/clap in ears

¡ Takes longer than a YAG Capú Occasional bleedingú Debris/pigment

“pigment plume”

2/17/20

6

¨ It may take 1-2 visits depending on the thickness of the iris to get through (usually only 1 visit)¡ 150-250 mJ maximum energy for me on 1 visit

¨ Goals: ¡ patent PI ≈ 1mm in size¡ Deepening of the AC¡ IOP control

¨ Post-op Care¡ Remove laser lens¡ Rinse Eye/Clean eye¡ 1 drop of Alphagan or Iopidine post-laser¡ IOP measurement 30 minutes post-laser

¨ Post-op drops¡ Pred Forte QID to surgical eye X 1 week

¨ Pt ed

¨ RTC 1 week for f/u

¨ VA’s¨ Anterior segment exam

¡ Check for cell/flare¡ Note AC depth¡ Is the PI patent?

¨ Gonio – did angle deepen?¨ Check IOP

¨ D/C Pred Forte¨ Release back to referring doc

¨ Reimbursement codes¡ 66761

¨ 10 day global period

¨ Glaucoma is progressing in a pt on max meds¡ Something else needs to be done¡ Surgery not wanted yet

¨ Compliance issues¨ Cost issues¨ Convenience/quality of life issues¨ Systemic side effect issues of drops¨ Doctor preference

2/17/20

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¨ Glaucoma is progressing in a pt on max meds¡ Something else needs to be done¡ Surgery not wanted yet

¨ Compliance issues¨ Cost issues¨ Convenience/quality of life issues¨ Systemic side effect issues of drops¨ Doctor preference

¨ Use of laser light to burn areas of the TM to increase aqueous outflow

¨ Two types¡ Argon laser trabeculoplasty (ALT)¡ Selective laser trabeculoplasty (SLT)

¨ Both increase aqueous outflow

¨ Most common laser procedure for OAG¡ ALT in the 90’s and early 2000’s¡ SLT has largely taken over

¨ Usually a Secondary Line of Treatment ¡ After meds fail to control IOP

¨ Some use as Primary Treatment

¨ Universally Accepted

¨ Glaucoma Laser Trial (1990)¡ Compared ALT to topical meds in the control of IOP

and VF and ONH status¡ Results:

ú Pts who underwent ALT as first-line therapy achieved better control of IOP and better VF and ONH status than those treated initially with topical meds

ú 44% proper IOP control in the ALT groupú 30% proper IOP control in the meds groupú Fewer eyes that underwent ALT as first-line therapy

ultimately required 2 or more meds postoperatively to control IOP

¨ POAG¨ Normo-tensive glaucoma¨ Pigmentary dispersion glaucoma¨ Pseudoexfoliative glaucoma

¨ Advanced POAG¨ Narrow Angle Glaucoma¨ Angle Closure (Emergency IOP decrease)¨ Inflammatory Glaucoma¨ Angle Recession Glaucoma¨ Neovascular Glaucoma¨ Congenital Glaucoma¨ Prior LTP that failed¨ Under 40 years of age¨ Hazy media

2/17/20

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¨ Traditional form of laser therapy for patients with glaucoma

¨ Presented as an alternative to filtering surgery for patients whose open angle glaucoma was not controlled by meds

¨ Exact mechanism of effect is unknown but:¡ Mechanical effects from laser burns scarring tissue

and causing contracting of tissue and opening of adjacent areas of the TM

¡ Biologic effects with increased inflammatory cells with “clean up” the TM

¨ ALT complications/risks1. IOP spike/elevationú Most often transientú High risk pt – may consider Diamox


3. Peripheral Anterior Synechie (PAS)ú As the scar tissue forms from the laser PAS can formú May increase IOP long-term

¨ Patient Pre-op Drops¡ 1 drop Alphagan or Iopidine 15-30 minutes prior to¡ 1 drop pilocarpine 1% (optional)

¨ Laser Settings¡ Energy 600 mW¡ Spot Size 50 microns¡ Duration 0.1 sec¡ Pulses 1 (shoots once every time you push the

foot pedal)

¨ Focus on the anterior aspect of the pigmented TM*****¡ Aim is much more critical with ALT than SLT

¨ Adjust Energy as needed¡ Pigment blanching¡ Small bubble formation

¨ Treat inferior 180 degrees first¨ Space burns approximately 2 spot sizes apart

¡ 45-60 burns per 180 degrees

¨ Post-op Care¡ 1 drop of Alphagan or Iopidine¡ Check IOP 15-30 minutes after the procedure¡ Continue all glaucoma meds

¡ Pred Forte QID X 1 week¡ RTC 1-2 weeks for f/u

2/17/20

9

¨ 1-2 week post-op exam:¡ Check IOP¡ Check for A/C reaction

ú Should be minimal to no C&F

¨ 6 week post-op exam:¡ Check IOP¡ Start to consider reducing glaucoma meds if pressure is reduced¡ May consider treating superior 180 degrees

¨ Long term outcome¡ 80% effective at 1 year¡ 50% effective at 5 years¡ 30% effective at 10 years

¨ Retreatments¡ Success rate is much lower¡ More likely to get complications¡ 50% of retreatments require filtering procedure

within 6 months to lower IOP

¨ Newer form of laser therapy for patients with glaucoma

¨ Presented as an alternative to filtering surgery for patients whose open angle glaucoma was not controlled by meds

¨ Exact mechanism of effect is unknown but:¡ Biologic effects with increased inflammatory cells

with “clean up” the TMú Laser energy causes chemical mediators to attracts

macrophages and phagocytes to come and clean up the debris in the TM

Scanning electron microscopy comparison of TM after ALT above and SLT below

¨ Optimal laser is a Q-switched frequency doubled 532 nm Nd:YAG Laser (Lumenis, formerly Coherent, Selecta II Glaucoma Laser System)

¨ Permits selective targeting of pigmented TM cells w/o causing structurally or coagulative damage to the TM

2/17/20

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¨ SLT works on the principle of Thermalysis which involves the Thermal Relaxation Time¡ The time required by melanin granules to convert electromagnetic

energy into thermal energy¡ Melanin has a TRT = 1 microsecond¡ SLT has a pulse duration = 3 nanoseconds

¡ Since pulse duration is so quick, melanin cannot convert the laser electromagnetic energy into thermal energyú No thermal damage (“cold laser”)

¨ SLT Med Study (2012)¡ Dr. Katz @ Wills Eye in Philadelphia

ú J Glaucoma 2012;21:460-468

¡ SLT (100 applications over 360 degrees of TM) vs. prostaglandin analog

¡ Primary outcome -> IOP¡ Secondary outcome -> # of treatment steps

¨ SLT Med Study (2012)Results:1. 29 SLT patients -> IOP reduced from 24.5 to 18.2 (6.3

mmHg reduction)25 prostaglandin patients -> IOP reduced from

24.7 to 17.7 (7.0 mmHg reduction)

2. SLT group -> 11% of eyes required additional SLTProstaglandin group -> 27% of eyes required

additional medication

2/17/20

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¨ IOP decreased by 30% (7.7 mmHg), from 25.5 to 17.9 mmHg over the f/u period

¨ Forty eyes (89%) had a decrease of 5 mmHg or more

“Selective laser trabeculoplasty is effective and safe as a primary treatment for patients with ocular hypertension and open-angle glaucoma.”

Arch Ophthalmol. 2003;121: 957-960

¨

¨¨ SLT complications/risks

1. IOP spike/elevationú 3-5% riskú Most often transient

2. Inflammationú Anti-inflammatoryú Use appropriate laser energy

3. Stromal haze/edemaú Rare – usually responds to a topical steroid

4. Peripheral Anterior Synechie (PAS)ú Less likely due to less/no scar tissue formationú May increase IOP long-term

¨ Patient Pre-op Drops¡ 1 drop Alphagan or Iopidine 15-30 minutes prior to¡ 1 drop pilocarpine 1% (optional)

¨ Laser Settings¡ Energy 0.6 – 1.2 mJ (0.8 – 1.0 mJ most often used)¡ Spot Size 400 microns¡ Duration 3 nsec¡ Pulses 1 (shoots once every time you push the

foot pedal)

¨ Sit patient comfortably¨ Adjust laser for your comfort

¡ Armrest, oculars, controls, safety glasses¨ Instill proparacaine in both eyes¨ Place laser lens on eye with goniosol or

celluvisc¨ Gonio mirror usually at 3:00 or 9:00

¡ Treat 360 degrees in both eyes unless significant pigment in the TM

2/17/20

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The Latina SLT Gonio Laser Lens was designed specifically for Selective Laser Trabeculoplasty. 1 .0x magnification maintains laser spot size and 1 to 1 laser energy delivery. Tilted anterior lens surface corrects astigmatism to maintain circular laser beam profile and give sharp images for examination. Suitable for standard laser trabeculoplasty.

ALT on the left SLT on the right

¨ Large spot size – cover the entire TM¡ Aim is less critical with SLT compared to ALT¡ Easier to do**

¨ Adjust Energy as needed (start around 0.8 mJ)¡ Usually don’t want to see pigment blanching w/

SLT¡ Small bubble formation

¨ Treat 360 degrees in both eyes unless significant pigment in the TM

¨ Space burns right next to each other¡ 45-60 burns per 180 degrees

¨ Post-op Care¡ 1 drop of Alphagan or Iopidine¡ Check IOP 15-30 minutes after the procedure¡ Continue all glaucoma meds¡ Give pt post-op med(s)¡ RTC 1-2 weeks for f/u

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¨ 1-2 week post-op exam:¡ Check IOP¡ Check for A/C reaction

ú Should be minimal to no C&F

¨ 6 week post-op exam:¡ Check IOP¡ Start to consider reducing glaucoma meds if pressure is reduced¡ May consider treating superior 180 degrees???

¨ Long term outcome¡ 80-90% effective at 1 year¡ 40-50% effective at 5 years¡ 10-30% effective at 10 years

¨ Tends to be very effective for 12-48 months¡ Effect perhaps wanes after that

¨ Retreatments¡ Since no mechanical damage -> can we repeat SLT???

¨ SLT Enhancement: Treating previously untreated area (27 eyes)

¨ Repeatability: Re-treating previously treated area (15 eyes)¨ Retrospective analysis of case notes¨ Average SLT Life

¡ After enhancement: 18.26 months¡ After repeat treatment: 17.47 months

¨ SLT enhancement success rate¡ One year: 70.37%¡ Two years: 55.55%¡ Three years: 25.93%

¨ SLT repeat treatment success rate¡ One year: 70.37%¡ Two years: 53.33%

Nagar M, Shah N, Vadav R: AAO Poster , Las Vegas 2006

¨ 52 Eyes with successful IOP reduction for at least one year¡ Pretreatment IOP: 21.1 mmHg¡ Post-treatment IOP at one year: 17.0 mm Hg ¡ IOP reduction of 4.1 mmHg

¨ Retreated with 360° SLT¡ IOP reduction of re-treated eyes: 3.6 mm Hg

Bournias TE, Lai J: AAO Paper, Las Vegas 2006

2/17/20

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¨ Retreatments¡ Since no mechanical damage -> can repeat SLT

¡ How many times do we repeat it?ú Usually twice

¨ Positives¡ Work about 80-95% of the time¡ On average, takes the place of 1 medication

ú ALT & SLT average IOP reduction of 20-35% ALT 20-25% reduction SLT 28-35% reduction as primary therapy SLT 21-25% reduction as secondary therapy

¡ Doesn’t interfere with other treatments or meds

¨ Negatives¡ Effect tends to diminish over time¡ ALT has more side effects and fails more often as time goes by than SLT

¨ Code for ALT & SLT is the same¡ 65855

¨ Global Period is the same as well¡ 10 global period¡ Contrast that to YAG cap & laser PI

ú 90 days

¨ Positives¡ Work about 80-95% of the time¡ On average, takes the place of 1 medication

ú ALT & SLT average IOP reduction of 20-35% ALT 20-25% reduction SLT 28-35% reduction as primary therapy SLT 21-25% reduction as secondary therapy

¡ Doesn’t interfere with other treatments or meds¡ Cost benefit?

¨ Negatives¡ Effect tends to diminish over time¡ ALT has more side effects and fails more often as time goes by than SLT

2/17/20

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Ben Gaddie, O.D., F.A.A.O.Nate Lighthizer, O.D., F.A.A.O.

2/12/20

1

Nate Lighthizer, O.D., F.A.A.O.

¨ Eyelid anatomy review¨ Eyelid lesions

¡ Review¡ Benign vs. Precursors vs. Cancer¡ How it relates to the anatomy

¨ Eyelid surgery clinical tips¨ Lesion removal techniques/terms¨ Radiofrequency surgery (Ellman Unit)

¡ Indications¡ Contraindications¡ Techniques for removal of lesions¡ Videos

¨ Chalazion management

¨ Most eyelid lesions are benign

¨ Benign lesions originate in the skin (epidermis) and grow outward

¨ The skin of the eyelid is ideally suited for office surgery

¨ Very thin (4 – 5 cell layers thick)

¨ Uniform depth¨ Fastest turnover (5 – 7

days)¨ No dermal papilla present

(absent rete ridges & rete pegs)¨ Potential space between

epidermis & dermisaccommodates local anesthetic well

¨ Lid Margin: Stay 2 mm from margin is possible

¨ Eyelid proper: Skin is only 4 – 5 cell layers thick

¨ Inner canthus: Beware lacrimal apparatus, angular vein, etc…

¨ Outer Canthus: Beware moving outer canthus up or down as this significantly changes individuals appearance

¨ Lid Crease: Can be altered ¨ Brow: Stay 2 mm below the

brow if possible.

¨ Benign¡ Hyperkeratoses: eg,

squamous papilloma¡ Pseudoepitheliomas:

eg, seborrheic keratosis¡ Cysts: eg, chalazion¡ Nevi: eg, Clark nevus

¨ The Gray Zone (pre-malignant): eg, actinic keratosis

¨ Malignant: eg, squamous cell carcinoma

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¨ Benign Lid Lesions¡ Chalazion¡ Skin tag/papilloma¡ Verrucae¡ Seborrheic Keratosis¡ Cyst of Moll & Zeiss¡ Sebaceous Cyst¡ Freckle/nevus

¨ Precursors To Cancer¡ Actinic Keratosis¡ Keratoacanthoma

¨ Cancer¡ Basal Cell Carcinoma¡ Squamous Cell Carcinoma¡ Malignant Melanoma¡ Sebaceous Gland

Carcinoma

ü H: loss of hair bearing structures?

q A: asymmetrical?q A: abnormal blood

vessels (telangectasia’s)?q B: boarders irregular?ü B: bleeding reported?q C: multicolored? ü C: change in the size or

color of the lesion?ü D: overall diameter > 5

mm?

¨ Lesion work-up¡ How long has that been there?¡ Is it changing/enlarging?¡ Is it bothersome?¡ Is it bleeding?¡ Personal history of cancer?

¡ Is it ulcerated?¡ Is there hair loss?¡ Is there destruction of tissue?

¨ AKA papilloma or Skin Tag¨ Squamous papillomas are the most common

benign neoplasms of the eyelid and conj**¨ Usually not bothersome to patient other than

cosmetic concerns¨ Often been there for many years¨ More likely seen in overweight people

¨ Signs:¡ Flesh-colored, avascular

pedunculated lesion¡ Often seen at areas of skin rubbing¡ May be one or several

¨ DDx:¡ Verruca vulgaris¡ Seborrheic keratosis¡ Intradermal nevus

¨ Tx:¡ Simple excision at the

base of the lesion

¨ AKA Viral Warts or Common Warts¨ Caused by epidermal infection with the HPV

¡ Spread by direct contact and fomites¡ Contagious***

¨ More common in children and young adults¨ May occur anywhere on the skin

¡ Occasionally on the eyelids

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¨ Signs:¡ Single or multiple elevated flesh-colored lesions with

an irregular, hyperkeratotic papillomatous surface¡ If on lid margin can shed viral particles into the tear

film -> mild viral conjunctivitis

¨ DDx:¡ Skin tags

¨ Treatment:¡ Observation ¡ Simple excision

¨ AKA Basal cell papilloma¨ Common, slow growing benign epithelial

neoplasm most often found on the face, trunk, and extremities of older individuals

¨ Signs:¡ Single or multiple discrete, greasy brown plaque

with a “stuck on” appearance

¨ DDx:¡ Pigmented basal cell

carcinoma¡ Skin nevus¡ Malignant melanoma¡ Verruca vulgaris¡ Skin tag

¨ Tx:¡ Shave excision of flat lesions¡ Excision of pedunculated lesions

Elman unit Seborrheic keratosis removal

¨ Small, non-translucent cyst on the anterior lid margin arising from obstructed sebaceous glands associated with the eyelash follicle

¨ Only problem may be a cosmetic concern for pt¨ Basically is a type of sebaceous cyst¨ Tx:

¡ Surgical excision/drainage¡ Pt ed they may recur¡

¨ Cyst of Moll (AKA apocrine hydrocystoma) = small retention cyst of the lid margin apocrineglands.

¨ Appears as a round, non-tender, translucentfluid-filled lesion on the anterior lid margin.

¨ Only problem may be a cosmetic concern for pt¨ Tx:

¡ Surgical excision/drainage¡ Pt ed they may recur

¨ Benign cyst filled with cheesy sebum from a sebaceous gland in the skin

¨ Caused by a blocked sebaceous gland/follicle¨ May be found on the eyelid or ocular adnexa¨ Only problem may be a cosmetic concern for pt¨ Tx:

¡ Surgical excision/drainage¡ Pt ed they can recur

2/12/20

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¥ 2nd most common benign lesion after the epithlialhyperplasias

¥ develop from epidermal cells trapped within the hair follicle, allowing keratin to accumulate beneath the cutaneous surface

¨ Freckle = brown macule due to increased melanin in the epidermal basal layer, usually in sunlight exposed areas

¨ Nevus = sharply demarcated lesion of the skin¡ AKA birthmarks or moles¡ Benign by definition¡ Correct term is melanocytic nevus for most lesions¡ 4 main types:

ú Junctional nevusú Compound nevusú Intradermal nevusú Dysplastic nevus

¨ Junctional nevus – occurs more often in young individuals. Usually brown macule. Nevus cells are located at the junction of the epidermis and dermis and have low potential for malignant transformation (although higher than the next 2).

¨ Compound nevus – occurs more often in middle aged individuals. Usually light tan-dark brown slightly raised papular lesion. Nevus cells extend from the epidermis into the dermis. It has low malignant potential.

¨ Intradermal nevus – most common nevus. Typically occurs in old age. Usually papillomatous lesion and flesh-colored (not pigmented). Nevus cells are confined to the dermis. No malignancy potential.

¨ Dysplastic nevus – usually a compound nevus with cellular and architectural dysplasia. Can be flat or raised. Typically larger than normal nevi and tend to have irregular borders and coloration. More likely to transform into melanoma.

¨ Signs:¡ Usually pigmented, flat or slightly elevated skin lesion¡ Located anywhere on the body

ú Frequently at the lid margin¨ DDx:

¡ Melanoma¨ Diagnosis:

¡ A¡ B¡ C¡ D¡ E

¨ Tx:¡ Photodocument q3-6 months for any changes¡ Biopsy if suspicious***

¡ If you cut on a melanoma in OK = malpractice***¡ Be darn sure that is not a melanoma***

¨ AKA strawberry hemangioma or nevus¨ One of the most common tumors of infancy

¡ Usually present shortly after birth

¨ Female: male ratio is 3:1¨ May present as a small isolated lesion of

minimal clinical significance or as a large disfiguring mass that can cause visual impairment and systemic complications

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¨ Signs:¡ Unilateral, raised bright red lesion which blanches

with pressureú May appear dark blue or purple if below the skin

¡ Large lesion may cause a mechanical ptosis¡ Large orbital tumors may give rise to proptosis¡ Biggest ocular concern????

¨ Tx:¡ Usually just leave it alone and it will go away

ú 30% of lesions resolve by 3 years of ageú 70% of lesions resolve by 7 years of age

¡ Steroid injections – primary treatment¡ Surgical excision/resection¡ Refer to a PCP for any treatment

¨ Most common acquired vascular lesion to involve the eyelids/conj

¨ Usually occurs after surgery or trauma to area¨ Symptoms:

¡ Asymptomatic¡ Cosmetic concerns

¨ Signs:¡ Fast growing, fleshy,

pinkish red mass¨ Treatment:

¡ Steroid QID X 1-2 weeks¡ Surgical excision

¨ AKA Solar Keratosis¨ Most common pre-cancerous lesion**

¡ 60% of predisposed people over the age of 40 will have one of these in their lifetime

¨ Elderly, fair-skinned individuals with excessive sunlight exposure

¨ Most often seen on the forehead, face, and backs of the hands

¨ Low potential for conversion to SCC***¡ 1 in 1000

¨ Signs:¡ Hyperkeratotic plaque with distinct borders and a

scaly surface¡ Dry, rough area when running your fingers over it¡ Usually minimally elevated

¨ DDx:¡ SCC¡ Seborrheic keratosis

¨ Tx:¡ Precancerous so referral to dermatologist¡ Biopsy & excision¡ Cryotherapy – liquid N2 to freeze of the AK¡ 5-FU – chemotherapy agent which causes the area to

become red and inflamed and the lesion will then fall off

¡ PDT – injecting dye into the bloodstream which makes AK more sensitive to light therapy

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¨ Rare tumor usually occurring in fair skinned individuals

¨ Often a history of chronic sun exposure¨ More likely seen on the face, neck,

hands/forearms¨ Histopathologically, it is regarded as part of

the spectrum of SCC¨ Symptoms:

¡ Lesion that comes about fairly rapidly (within weeks to months)

¨ Signs: (in order)¡ Pink, rapidly growing hyperkeratotic

lesion, often on the lower lid¡ May double or triple in size in weeks¡ Growth ceases for 2-3 months, after

which spontaneous involution occurs¡ During the period of regression, a

keratin-filled crater may develop¡ Resolution may take up to a year and

often leaves a nasty scar

¨ DDx:¡ SCC**

¨ Tx:¡ Derm consult¡ Complete surgical excision/biopsy

ú Removal with RFPú Cryotherapy

¡ Topical or intralesional 5-FU




Carcinoma

¨ Lesion work-up¡ How long has that been there?¡ Is it changing/enlarging?¡ Is it bothersome?¡ Is it bleeding?¡ Personal history of cancer?

¡ Is it ulcerated?¡ Is there hair loss?¡ Is there destruction of tissue?

¨ Slow-growing, locally invasive, non-metastatic tumor

¨ Most common malignant lid tumor***¡ 90% of cases

¨ 90% of cases occur on the head and neck¡ 10% of these are on the eyelid

¨ Risk factors:¡ Fair skin¡ Chronic exposure to UV sunlight¡ Age

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¨ Signs:¡ Most common location is

the lower eyelidú Medial canthus > upper

eyelid > lateral canthus¡ Pearly, raised, rolled edges

of a raised or ulcerated firm lesion¡ Rolled, raised, pearly border/margins***¡ Usually not pigmented¡ Often small dilated feeder

bv’s on its surface

¨ Signs:¡ Nodular BCC – most common – grows slowly and it

may take 1-2 years to reach 0.5 cm in size¡ Noduloulcerative BCC (rodent ulcer) – central

ulceration, pearly raised rolled edges and dilated irregular bv’s over its lateral margins

¡ Sclerosing BCC – less common and harder to diagnose since it infiltrates laterally beneath the epidermis as an indurated plaque

¨ DDx:¡ SCC¡ Melanoma

¨ Tx:¡ Derm/oculoplastics consult¡ Biopsy/excision¡ Chemotherapy

cream (5-FU)¡ PDT

¨ Much less common, but more aggressive tumor than BCC¡ Metastasis to regional lymph nodes in ≈ 20% of cases

¨ 5-10% of eyelid malignancies¨ May arise de novo or from pre-existing actinic

keratosis, keratoacanthoma, or cancinoma in situ

¨ Risk factors:¡ Fair skin¡ Chronic sun exposure¡ Age

¨ Signs:¡ No pathognomonic characteristics¡ Has a predilection for the lower

lid, lid margin, and medial canthus¡ May be indistinguishable from BCC

ú Surface vascularization is usually absent

ú Growth tends to be more rapidú Hyperkeratosis is more often present

¨ Signs:¡ Nodular SCC – hyperkeratotic nodule which may

develop crusting erosions¡ Ulcerating SCC – reddish, sharply defined raised or

ulcerated scaly plaqueú Scalier, reddish, dryer look to it***

¡ Cutaneous horn – rarest form and has underlying SCC beneath it

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¨ DDx:¡ BCC¡ Actinic keratosis¡ Keratoacanthoma

¨ Tx:¡ Derm/oculoplastics consult¡ Biopsy/excision¡ Chemotherapy

cream (5-FU)¡ PDT¡ Much more rare than BCC….

but neglected cases are more likely to metastasize

¨ Malignant tumor of melanocytes¨ Much less common than other skin cancers

¡ But causes 75% of deaths related to skin cancer¨ More often develops in sun-damaged skin

¡ Face, head, neck, hands/forearms in older pts¡ But can develop anywhere

ú Iris, choroid, retina, inside of mouthú Rarely on the eyelids, but is potentially lethal

¨ Pigmentation is a hallmark of malignant melanomas…but¡ ½ of lid melanomas are non-pigmented

¨ Features suggestive of melanoma:¡ Recent onset of pigmented lesion¡ Change in an existing pigmented lesion¡ Irregular margins¡ Asymmetric shape¡ Color change or presence of multiple colors¡ Diameter greater than 6 mm

¨ DDx:¡ Nevus¡ Lentigo maligna¡ Seborrheic keratosis

¨ Tx:¡ Refer for biopsy/wide excision***

ú May include local lymph node removal¡ If you cut on a melanoma that is malpractice***




Carcinoma

¨ A Radiofrequency Surgical Device¡ RF surface ablation¡ Incisions¡ Excisions¡ Hemostasis/cautery¡ RF Epilation¡ RF punctal occlusion¡ Telangiectasias

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¨ History of Electrosurgery¨ What is Radiofrequency (RF) Surgery¨ Advantages of RF surgery¨ Indications¨ Contraindications¨ Equipment¨ Surgical Technique

¡ Specific approaches for various lesions¨ Risks/Complications¨ Post-procedure patient care¨ CPT/Billing Codes

¨ Electro surgery at radiofrequency¨ Why radio surgery?

¨ Radio Surgery vs. Electrocautery vs. Hyfrecation

¨ Origins in electrocautery¨ Albucasis (980BC) used hot iron to stop bleeding¨ Of course, this also caused third degree burns and

poor cosmesis¨ In 1893, Arsenne d’ Arsonval was experimenting

with passing high frequency electrical current through tissues and discovered that electric currents >100KHz do not cause muscle spasm…..this is known as the FARADIC EFFECT

¨ In 1975, Dr Irving Ellman designed, patented, and produced a relatively small, lightweight, solid state radiosurgery instrument which produced a 3.9 MHz frequency signal

¨ In 1978, Manness published a study showing that fully filtered 3.8 MHz waves were optimal for cutting soft tissue

¨ Radiosurgery is the passage of high frequency radiowaves through soft tissue to cut, coagulate, and/or remove the target tissue

¨ Resistance of the tissue to the radiowavescauses water in the cells to heat and the cell vaporizes

¨ Radio-surgical unit consists of¡ Active electrode¡ Antennae (passive electrode)¡ Transformer

¨ Ideal frequency = 3.8 - 4.0 MHz

2/12/20

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¨ Radiosurgery is the passage of high frequency radiowaves through soft tissue to cut, coagulate, and/or remove the target tissue

¨ Resistance of the tissue to the radiowavescauses water in the cells to heat and the cell vaporizes

¨ Radio-surgical unit consists of¡ Active electrode¡ Antennae (passive electrode)¡ Transformer

¨ Ideal frequency = 3.8 - 4.0 MHz

¨ Cuts and coagulates at the same time¨ Nearly bloodless field¨ Minimal biopsy artifact damage*¨ Quick and easy (to do and to learn)

¡ Pressureless & bacteria-free incisions

¨ Minimal lateral heat¨ Minimal Post-op pain¨ Rapid healing¨ Fine control with variety of tips¨ No muscle contractions or nerve stimulation from

radiowaves (Faradic effects)

¨ 90% Cutting¨ 10% Coagulation¨ Cutting current: high

frequency sine wave that is not dampened.

¨ Produces very focused heat buildup that ruptures tissue through either molecular activity or through production of steam microbubbles

¨ Minimal lateral heat¨ Use for biopsy, incisions,

chalazion

Power ≈ 3.0 (old unit) or 20 (newer unit)

2/12/20

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¨ 50% Cutting¨ 50% Coagulation¨ When don’t need

biopsy¨ Helps greatly with

bleeding during procedure

¨ Very useful in vascular regions

¨ Great for excising ¡ Skin tags, verruca

¨ Waveform we use the most

Power ≈ 3.0 (old unit) or 20 (newer unit)¨ 90% Coagulation¨ 10% Cutting¨ Coagulating current: high

frequency but dampened (rectified) sine wave.

¨ Produces oscillation of molecules leading to generation of intracellular heat that ultimately causes tissue dehydration/coagulation (hemostasis)

¨ Epilation, punctal occlusion

Power ≈ 2.5 (old unit) or 20 (newer unit)

¨ Spark gap fulgurating current (hyfrecation) for superficial cautery

¨ Doesn’t penetrate deeply – superficial treatment

¨ Electrodessication (papilloma bed)

¨ Destruction of cyst remnants

¨ Intentional destruction of diseased tissue¡ BCC¡ SCC

Power ≈ 8 (old unit) or 80 (newer unit)





Lateral heat = time x waveform x power x electrode sizefrequency

Factors Affecting Lateral Heat¨ Electrode contact time: slow passage = increased heat¨ Excessive power can lead to sparking (too little power leads to

tissue drag)¨ Larger electrode head sizes lead to greater power/heat generation¨ Different waveforms are associated with different levels of heat:

¡ Fulguration> COAG > CUT/COAG > CUT ¨ Higher frequency associated with less lateral heat





2/12/20

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¨ Excess lateral tissue damage¨ Smoke hazard/unpleasant smells in office¨ Don’t use in presence of flammable fumes/liquids¨ Pacemaker

¡ “Do not work near the heart and place the antenna (or grounding) plate well away from the heart. Use the least power possible. Activate the handpiece intermittently rather than continuously. The cutting mode is the most risky, so avoid it if possible. Use another form of treatment if it is an option. The pacers are purportedly “shielded” and the current in the ESUs should not affect them, but all things are not perfect! Therefore caution is needed. Asystole and tachycardia are potential adverse outcomes.”

¡ Pfenninger and Fowler's Procedures for Primary Care, 3rd Edition. John L. Pfenninger, MD, FAAFP and Grant C. Fowler, MD

¨ ELLMAN¡ http://www.ellman.com/radiosurg ery/medical

¨ COOPER SURGICAL LEEP¡ http://www.coopersurgical.com

¨ Valley Lab Force II ¡ http://www.valleylab.com/main.html

¨ Wallach SurgicalDevices¡ http://www.wallachsurgical.com

¨ Circon (Cryomedics) ¡ http://www.circoncorp.com

2/12/20

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¨ Skin papillomas/skin tags¨ Seborrheic keratoses¨ Verruca¨ Sebaceous cysts¨ Benign Nevi¨ Pyogenic Granulomas¨ Incision into chalazion¨ Trichiasis

¨ Xanthelasma¨ Blepharoplasty incisions¨ Biopsies of suspicious lesions (BCC, SCC, melanoma)

¨ Do NOT perform shave excision on pigmented lesion unless certain is not melanoma!!!

¨ Don’t use in presence of flammable fumes/liquids¨ Pacemaker

¡ “Do not work near the heart and place the antenna (or grounding) plate well away from the heart. Use the least power possible. Activate the handpiece intermittently rather than continuously. The cutting mode is the most risky, so avoid it if possible. Use another form of treatment if it is an option. The pacers are purportedly “shielded” and the current in the ESUs should not affect them, but all things are not perfect! Therefore caution is needed. Asystole and tachycardia are potential adverse outcomes.”

¡ Pfenninger and Fowler's Procedures for Primary Care, 3rd Edition. John L. Pfenninger, MD, FAAFP and Grant C. Fowler, MD

¨ Pre-op (photos, consent, BP and Pulse, VA)¨ Pacemaker? Allergies?¨ Clean area, drape if needed

¡ Betadine needs 3 mins on skin!¨ Anesthetize (infiltrative usually)¨ Turn on Ellman unit: warm up for at least 30 seconds¨ Choose appropriate waveform¨ Choose initial power setting (will often need to adjust

depending on tissue response to energy level chosen)

¨ Have assistant turn on/position vacuum unit –USE vacuum and masks! ¡ Have isolated HPV and HIV in smoke

¨ Place yourself in comfortable/stable position to do procedure

¨ Brace your handpiece wrist on patient for stability

2/12/20

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¨ Electrode tip should be applied perpendicularly to allow even distribution of energy

¨ Press footplate activator when ready to begin procedure

¨ Move in expeditious but controlled fashion: always keep electrode moving when contacting tissue

¨ Keep the tissue around the lesion taut¨ Keep surgical site moist (saline gauze) to avoid

tissue drag¡ Removes debris on surgical field

¨ Also wipe energized tip to remove tissue stuck to it

¨ When feathering down a lesion with a loop, keep perpendicular---remove until healthy tissue seen

¨ Can use forceps closed tips to touch end of area of bleeding, touch electrode to forceps to transfer energy to area to stop bleeding

¨ Clean area of betadine¨ Apply antibiotic ung

¡ Pt ed about moist healing¨ Don’t let patient jump and run as you sit them up!¨ Blood pressure and pulse post-op¨ Write op report in chart along with patient

instructions on wound care and follow-up schedule

¨ Skin papillomas/skin tags¨ Seborrheic keratoses¨ Verruca¨ Sebaceous cysts¨ Benign Nevi¨ Pyogenic Granulomas¨ Incision into chalazion¨ Trichiasis

¨ Xanthelasma¨ Blepharoplasty incisions

¨ Cut offending lashes¨ Anesthetize???¨ Grab lash with forcep¨ Use microinsulated needle ¨ Put needle beside lash shaft

into follicle until cannot go further

¨ Lowest power setting, Coag¨ Touch and let off

immediately of footplate¨ Gently tug lash – if comes

out smooth are done¨ If not treat quickly again

Power ≈ 0.1-0.2 (old unit) or 1-2 (newer unit)

6/9/20

1

Nate Lighthizer, O.D., F.A.A.OAssociate Professor, NSUOCO

Assistant Dean for Clinical Care ServicesDirector of CE

Chief of Specialty Care ClinicsChief of Electrodiagnostics Clinic

[email protected]

1

¨ Aerie Pharmaceuticals¨ Biotissue¨ Diopsys¨ Ellex¨ EyePromise¨ Ivantis¨ Maculogix¨ Nidek

¨ Nova Ocular¨ Novartis¨ Optovue¨ Quantel¨ Reichert¨ RevolutionEHR¨ Sight Sciences¨ Shire

2

3

¨ In the US, 1,500,000 new cases every year¨ 285,000,000 in the world (100,000,000 in the US)

¡ Glaucoma : 2,700,00 in the US

¨ In the US, 40% will develop diabetic retinopathy¡ Half of them don’t know about it until vision

problems

Diabetic changes in a blonde fundus.

4

¨ In 2015, 30.3 million Americans had diabetes¡ 9.4% of the population¡ 7.2 million are undiagnosed¡ Between 2015 and 2030 that number will increase to 55

million¨ Over the age of 65:

¡ 25.2% prevalence of DM¨ Pre-diabetes:

¡ 84.1 million Americans¨ 7th leading cause of death

¡ Probably underreported

5

¨ Most frequent cause of new cases of blindness among adults 20-74 in developed countries

¨ Rate of diabetic retinopathy:¡ 35.4%

ú Type 1 after 5 years – 25%ú Type 1 after 10 years – 60%ú Type 1 after 15 years – 80%ú Type 2 after 5 years – 40% taking insulin, 24% not taking

insulinú Type 2 after 10 years – 84% taking insulin, 53% not taking

insulin¨ Proliferative diabetic retinopathy:

¡ 7.5%¨ Glaucoma, cataracts and other disorders of the eye

occur earlier and more frequently in people with diabetes

6

6/9/20

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¨ Increased risk of cataracts¨ Increased risk of glaucoma¨ Diabetic retinopathy¨ Stroke

Middle-aged female with diabetic cataracts

and mild diabetic retinopathy. Noteworthy was the spoke-like character of the cataracts.

7

¨ Mild Nonproliferative¨ Moderate Nonproliferative¨ Severe Nonproliferative¨ Proliferative¨ Diabetic Macular Edema (can happen in any of

the above)

8

Stimulus Mini-ganzfeld

Flicker Electroretinogram(Flicker ERG)

Retinal signal recorded at the

lower lid in response to flash

stimuli of high frequency

9

Stimulus Mini-ganzfeld Photoreceptors & Bipolar

Flicker Electroretinogram(Flicker ERG)

Retinal signal recorded at the

lower lid in response to flash

stimuli of high frequency

10

¨ Tests the outer retina ¡ Photoreceptors (rod & cones)¡ Bipolar cells

¨ Test of overall retinal functioning¡ May not pick up small retinal issues

¨ Flash flicker stimulus

11

BCVA

2-3°

12

6/9/20

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13

BCVA

2-3°

14

OCT 12°

15

mfERG21°

16

Flicker ERG

Full Field

17

¨ Tests the outer retina ¡ Photoreceptors (rod & cones)¡ Bipolar cells

¨ Test of overall retinal functioning¡ May not pick up small retinal issues

¨ Flash flicker stimulus

18

6/9/20

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¨ ffERG indications:¡ DM & diabetic retinopathy

ú Monitoring progressionú Monitoring improvement with treatment

¡ Retinal dystrophies/diseaseú Rod/cone problems ú RP

¡ Pt symptoms:ú Color vision issuesú VF defectsú Decreased visionú Unexplained decreased vision

¡ Testing retinal function with significant media opacities¡ Indicator for prognosis following cataract surgery

ú Is the retina functioning well or not?

19

¨ Evaluation of retinal function

¨ Determining the of level of retinal ischemia

¨ Predicting post-treatment retinal function

¨ Evaluating post-treatment retinal function

20

ERG for Early Detection

21

ERG for Evaluating Retinal Dysfunction

22

23 24

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ERG vs FA : Predictive value of Vascularization

FA:82%ERG:94%

25

Flicker ERG is a good predictor of ischemia

Flicker ERG can be used to evaluate DR

Flicker ERG can be used to monitor patients and evaluate referals

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27 28

Healthy Dysfunction

29 30

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Healthy Dysfunction

31

Healthy Dysfunction

32

33

¨ No longer need to wait for structural damage¨ Multi-component nutritional supplement can

benefit these patients

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35 36

6/9/20

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37

Br J Ophthalmol 2015 e-published June 18

¨ 6 month double-blind placebo-controlled, randomized, controlled clinical trial of adults with type 1 diabetes or type 2 diabetes > 5 years

¨ No DR (2:1) and mild-moderate NPDR (1:1)¨ Daily use of a multi-component nutritional supplement

(zeaxanthin, lutein, vitamins D/C/E including tocotrienols, curcumin, benfotiamine, Pycnogenol™, lipoic acid, NAC, resveratrol, green tea & grapeseed extracts, O-3 FAs, CoQ10, Zn)

¨ Pre- and post- analysis of CSF, MPOD, color vision, macular perimetry, OCT, A1c, lipids, 25(OH) vitamin D3, hsCRP, TNF-a, NFL thickness and diabetic peripheral neuropathy symptom scores (DPNSS)

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Br J Ophthalmol 2015 e-published June 18

¨ Pre- and post- analysis of:¡ CSF¡ MPOD ¡ color vision ¡ macular perimetry¡ NFL thickness¡ OCT of macula¡ A1c ¡ lipids ¡ 25(OH) vitamin D3 ¡ hsCRP¡ TNF-a ¡ diabetic peripheral neuropathy symptom scores (DPNSS)

39

Diabetes & DR Affect Visual Function§ Snellen visual acuity is a 150+ yr old test

that does not always reflect real world visual function

§ DM/DR also impair: color perception, contrast sensitivity, visual field sensitivity

Graefes Arch Clin Exp Ophthalmol. 2012 Dec;250(12):Diabet Med. 2011 Jul;28(7):865-71Acta Opthalmol 2005; 82(5):574-80Graefes Arch Clin Exp Ophthalmol. 2001 Sep;239(9):643-8BJO 1996;80: 209-13IOVS 1997; 38(9): 1819-24Diabetes Care 1992; 15(5):620-25Graefes Arch Clin Exp Ophthalmol.1996 May;234(5):300-540

No statistically significant differences at baseline between Supplemented and Placebo groups

¨ 28-79 yo (mean = 56.1 yrs)¨ 30 with NPDR & 37 with no DR¨ 27 type 1 diabetes & 40 type 2 diabetes¨ HbA1c range 5.85 to 10.3% (mean 7.2%)¨ Diabetes duration 5-52 years (mean 16.1 yrs)¨ Both Placebo and Supplement Groups showed

similar and significant deficits in contrast sensitivity, color vision and visual field at baseline

41

Mean Change/SD in visual function measures, serum lipids, hsCRP, TNF-a, glycohemoglobin, foveal thickness and symptoms of diabetic peripheral neuropathy with 95% p-Values

Δ from baseline Suppl v. Plac p-ValueColor Error Score -20.55+24.37 +7.5+22.01 <0.00025-2 MD (db) +2.78+9.83 -0.75+0.98 <0.0001MPOD (du) +0.09+0.05 -0.01+0.03 < 0.0001LDL-C (mg/dl) -7.61+16.08 +0.82+10.15 0.01HDL-C (mg/dl) +3.82+6.24 -1.61+5.31 0.0004TGs (mg/dl) -10.46+28.48 +2.39 +11.56 0.01hsCRP (mg/L) -2.14+3 -0.28+1.83 0.01TNF-a (pg/ml) +0.78+5.04 +0.56+2.79 0.88HbA1c (%) -0.1+0.4 +0.1+0.4 0.06Foveal Thickness 2.66+11.25µm 0.34+3.48 µm 0.35DPNSS -30.7% +10.7% 0.0024

Fisher’s Exact Test

42

6/9/20

8

§ The DiVFuSS formula significantly improved visual function, diabetic peripheral neuropathy symptoms, blood lipids and hsCRPin patients with established diabetes - without significantly affecting blood sugar control

§ The DiVFuSS formula significantly increased MPOD

§ No adverse events occurred during the study

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¨ Adults with any degree of DR¨ Adults with DM and reduced visual function

and/or low macular pigment¨ Patients with sub-optimal blood glucose

control¨ Adults with DM > 5 years

¨ Every patient with diabetes???

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VEP FFERG1. Glaucoma & glaucoma

suspects2. Unexplained vision

loss3. Transient vision loss4. Unexplained VF

defects 5. Unreliable VF6. Optic neuropathies7. Optic neuritis/MS8. Amblyopia9. TBI

1. DM & retinopathy2. RP & its variants3. Cone dystrophies

& Rod monochromat

4. Symptoms:¡ “Night blindness”¡ Restricted

peripheral fields¡ Color vision

deficits¡ Unexplained

decreased vision

5. To get an idea of retinal functioning in a pt with media opacity

PERG1. Glaucoma &

glaucoma suspects2. Unexplained VF

defects 3. Unreliable VF4. Optic neuropathies5. Maculopathies

1. AMD2. Diabetic macular

edema3. High risk med use

(Plaquenil)4. Generalized DR

47

Nate Lighthizer, O.D., F.A.A.OAssociate Professor, NSUOCO

Assistant Dean for Clinical Care ServicesDirector of CE

Chief of Specialty Care ClinicsChief of Electrodiagnostics Clinic

[email protected]

48

1

Valerie M. Kattouf O.D.Chief, Pediatric/Binocular Vision Service

FAAO, FCOVDIllinois College of Optometry

Associate Professor

The Neuro-Ophthalmology Of Concussion:The Evaluation and Management of Vision and

Visual-Motor Abnormalities

Lecture Goals

Geared toward the primary care optometrist

Will review:◼ presentation of concussion

◼ Important facts to know for well rounded care

Determine optometric testing sequence and intervention options

Giza CC, et al. Neurology 2013

Definitions Traumatic Brain Injury (TBI) – results from acute

impact to the head causing brain dysfunction

Concussion - a form of mild traumatic brain injury (TBI) owing to structural, metabolic and functional changes involving white mater tracts of the central nervous system in the absence of macroscopic findings

Giza CC, et al. Neurology 2013

StatisticsFrom The Concussion Legacy Foundation

CDC estimates 3.8 million concussions each year

Only 1 in 6 concussions are diagnosed

91 of 95 former professional football players have been diagnosed with CTE at the VA-BU-CLF Brain Bank

Concussion Legacy Foundation MissionThe Concussion Legacy Foundation (formerly the Sports

Legacy Institute) is dedicated to advancing the study, treatment and prevention of the effects of brain trauma in

athletes and other at-risk groups.

Concussion Significant short and long term issues Early diagnosis and treatment are key to recovery Visual symptoms and signs are common during and post

recovery

Affects◼ Balance◼ Cognition◼ Vision

Vision involves ½ of the brain’s systems Many of the areas of the brain housing visual systems are

susceptible to impact

Concussion Facts

Functional rather than structural injury

Axonal predilection – Diffuse axonal injury

Loss of consciousness in less than 10%

Johnson VE, et al. Exp Neurol 2012

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What does the primary care practitioner need to know?

The Cocussion Tool Box: the Role of Vision in the Assessment of ConcussionSemin Neurol. 2015 Oct;35(5):599-606

Concussion can lead to subtle changes in brain functionTests of the visual system probe higher cortical functioning and increase our sensitivity in detecting these changes

Neuro – ophthalmologic FindingsAccommodation

ConvergenceExtraocular motility

Stereo acuityPursuitsSaccades

Vestibulo-ocular reflexBalance

CognitionVision

Concussion Epidemiology

300,000 to 4 million per year

Nearly 85% of concussions may go undiagnosed◼ Multiple studies suggest rate on rise

Sports most affected◼ Boys’ High school football◼ Followed by girls' soccer

Girls have a higher rate of concussion

CDC Report 2007 JAMA 2010

High School Concussions (per 100,000)

Football: Between 60 and 76Girl's soccer: Between 33 and 35Boys' lacrosse: Between 30 and 46Girls' lacrosse: Between 20 and 31Boys' soccer: Between 17 and 19

Boys' wrestling: Between 17 and 23Girls' basketball: Between 16 and 18

Softball: Between 11 and 16Boys' basketball: Between 11 and 21

Girls' field hockey: Between 10 and 24Cheerleading: 11

Girls' volleyball: Between 5 and 8Boys' baseball: Between 4 and 6

Halstead M, et al. Pediatrics 2010Meehan WP. Et al. Am J Sports Med 2011

Concussion in Youth Sports

Children are more susceptible to head injury than adults and require a longer

period of recovery than adults

Kirkwood MJ, et al. Pediatrics 2006

Age of First Exposure to Football and Later-Life Cognitive Impairment in Former NFL Players

(DETECT study)

Analysis of cognitive function among 42 former NFL players based-on age of first

exposure (AFE) to tackle football

o AFE <12 years o associated with greater later-life cognitive impairment

o vs. o AFE >12 years

o Repetitive head trauma during critical period of brain development may lead to later-life cognitive impairment

Stamm JM, et al. Neurology 2015

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What happens to the brain with concussion?

Biomechanics of Concussion…”Brain in a Box”

• Direct injury to brain at point of contact (coup)

• Injury opposite the point of impact (contrecoup)

• Rotational forces with shearing/stretching of axons

• “wash-over” effect (blast injuries)

Maruta J, et al. Ann NYAcad Sci 2010

Linear Acceleration

Rotational Acceleration

Case #115 year old male

Concussion 2 months prior◼ Jumped down stairs → fell backwards → hit head

Seen by neurologist specializing in concussion◼ Constant headaches◼ Fatigue

Visual symptoms◼ Difficulty focusing on things up close◼ Intermittent diplopia (horizontal) with near work

Clears immediately with blink

School has allowed him to d/c homework and tests

Case #215 year old female

Concussion 2 months prior◼ Hit with softball under Left eye

Broken nose Concussion Whiplash

Seen by neurologist specializing in concussion◼ Fatigue◼ Difficulty concentrating◼ Headaches (variable pattern)◼ Photophobia, worse with fluorescent lighting◼ Nausea throughout day

Visual symptoms◼ Non specific◼ SCL wearer x 4 years

Complications of Concussion

• Second-impact syndrome (SIS)

• Postconcussion syndrome (PCS)

• Chronic traumatic encephalopathy (CTE)

Second-Impact Syndrome• Sustaining a second concussion before

“recovery” from first concussion

• Majority in pediatric/adolescent populations (< 20 yrs.)

• Loss of cerebral autoregulation with enhancement of cerebrovascular congestion– Diffuse cerebral edema / transtentorial herniation

– 90% mortality (within minutes to days!)

Cantu RC, et al. Phys Sportsmed 1995Weinstein E, et al. J Neurosurg Pediatr

2013

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Postconcussion Syndrome• 2-5% of all concussions

• > 1 month(s) duration of three or more of the following:• Fatigue• Disordered sleep• Irritability / aggressiveness• Anxiety / depression• Personality changes / apathy• Impaired attention / memory• Impaired eye tracking

Diagnostic and Statistical Manual of Mental Disorders. Fourth EditionHeitger MH et al. Brain 2009

CTEChronic Traumatic Encephalopathy

CTE is a progressive degenerative brain disease found in athletes, military veterans, and others with a history of repetitive brain trauma. Brain trauma can cause a build-up of an abnormal type of a protein called tau, which slowly kills brain cells. Once started, these changes in the brain appear to continue to progress even after exposure to brain trauma has ended.

Historical Perspective of CTE Martland – “Punch drunk”◼ JAMA 1928

Millspaugh – “Dementia pugilistica”◼ US Naval Medical Bulletin 1937

Critchley – “Medical aspects of boxing particularly from a neurological standpoint”◼ Psychological Bulletin 1957

Corsellis – neuropathology of CTE among boxers◼ Psychological Medicine 1973

Photophobia

Accommodative dysfunction

Binocular Vision dysfunction(Convergence insufficiency)

Saccadic dysfunction

Vision Problems Associated with Concussion

Photophobia




Vision Problems Associated with Concussion Photophobia

Photophobia/ Photosensitivity: an elevated sensitivity to light in the absence of ocular inflammation or infection◼ Reported in between 20-40% in those with TBI who are NOT visually-

symptomatic ◼ Reported in nearly 50% of those with TBI who ARE visually-

symptomatic

Types of photosensitivity may be: 1) generalized to all types of lighting2) selective to fluorescent lighting

Craig SB, Kapoor N, Ciuffreda KJ, Suchoff IB, Han ME, and Rutner D. (2008) Profile of selected aspects of visually-symptomatic individuals with

acquired brain injury: a retrospective study. Journal of Behavioral Optometry 19 (1): 7-10.

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Photophobia EtiologyWhat causes it?

Du T, Ciuffreda KJ, Kapoor N. (2005) Elevated dark adaptation thresholds in traumatic brain injury. Brain Inj. 19:1125 -38

Chang TT, Ciuffreda KJ, and Kapoor N. (2007) Critical flicker frequency and related symptoms in mild traumatic brain injury. Brain Injury. 21 (10): 1055-1062.

Schrupp L, Ciuffreda K, Kapoor N. (2009) Foveal versus eccentric retinal critical flicker frequency in mild traumatic brain injury. Optometry. 80 (11): 642-650.

Patel R, Ciuffreda KJ, Tannen B, Kapoor N. (2011) Elevated coherent motion thresholds in mild traumatic brain injury. Optometry. 82 (5): 284-9.

ConclusionsThe results of these four papers led Ciuffreda’s research team to hypothesize that

anomalous cortical or subcortical regulation of response to changes in illumination and visual-spatial patterns, possibly mediated by the dorsal visual pathway, may

be contributing to the perception of photosensitivity on those with TBI.

Photophobia

Chronic / persistent photophobia seen with post concussion syndrome

◼ Post-concussion syndrome is a complex disorder in which various symptoms — such as headaches and dizziness — last for weeks and sometimes months after the injury that caused the concussion

◼ In most people, post-concussion syndrome symptoms occur within the first seven to 10 days and go away within three months, though they can persist for a year or more.

Photophobia Treatment in TBI Patients

Tinted lensesColored overlaysBrimmed caps

Often a subjective determinationResearch looking for a more systematic determination

Colorimetrymeans of determining the precise hue resulting in

reduced visual stress for the patient

Photophobia




Vision Problems Associated with Concussion

Cross-sectional study of 100 subjects post concussion (mean age = 14.5 yrs)

69% with one or more binocular vision problems◼ Accommodative disorders (51%)◼ Convergence insufficiency (49%)◼ Saccadic dysfunction (29%)

Highest prevalence if within 1 month of concussion

Master CL, et al. Clin Pediatr 2016

Not a lot of new information here

Optometric Exam Sequencein the primary care practice

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Four General Areas of Visual Function

Accommodative Vergence SystemSystem

Oculomotor Ocular AlignmentSystem

Vestibular-Ocular Reflex System

A Visual Efficiency Testing ”Handbook”

Binocular Vision DisordersBinocular Vision Disorders

EXO Deviations◼ Convergence Insufficiency◼ Basic exo deviations◼ Divergence Excess

ESO Deviations◼ Convergence Excess◼ Basic eso deviations◼ Divergence Insufficiency

DUANE’S CLASSIFICATIONS

EXO Deviations N = near fixation distance / F = far fixation distance

<D AC/AConvergence Insufficiency N>F LowBasic EXO deviation N=F NormalDivergence Excess F>N High

DUANE’S CLASSIFICATIONS

ESO Deviations N = near fixation distance / F = far fixation distance

<D AC/AConvergence Excess N>F HighBasic ESO deviation N=F NormalDivergence Insufficiency F>N Low

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Clinical Vergence DisordersSoft Binocular Vision Problems

Scheiman/Wick

Phoria NormsCover test and phoropter measurements

Distance ortho - 2 ∆ exophoria

Near ortho - 6 ∆ exophoria

How to record Smooth Vergence Measurements

Blur / break / recovery

Blur – patient reports blur

Break – patient reports diplopia

Recovery – patient reports fusion (diplopia is eliminated)

How to record Smooth Vergence Measurements

Blur / break / recovery Blur

◼ Fusional vergence is used up◼ Accommodation adjusting to maintain fusion

Measures amount of fusional vergence free of accommodation◼ Should not be noted when testing distance vergences

Break ◼ Patient uses up all vergence sources

Measures total amount of fusional and accommodative vergence

Recovery ◼ Point where patient can re-access vergence system to regain single vision/fusion

Image may still be blurry


Scheiman/Wick

VergencesSmooth / Phoropter

Near

Base In 11/19/10

Base Out 14/18/7

Distance

Base In x/6/3

Base Out 7/15/8


Scheiman/Wick

VergencesPrism Bar Vergences/Step Vergence ADULTS

Near

Base In x/13/10

Base Out x/19/14

Distance

Base In x/7/4

Base Out x/11/7


Scheiman/Wick

VergencesPrism Bar Vergences/Step Vergence CHILDREN

Near

Base In x/12/7

Base Out x/23/16

Distance

Base In None established

Base Out None established

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Near Point of Convergence Testing

NPCNear Point of Convergence

Children Break 6 cm

Adults

Accommodative target

5cm/8cm(break/recovery)

Red lens / transilluminator


Accommodative Disorders

Accommodative Disorders Accommodative Insufficiency

◼ Insufficient amplitude of accommodation to afford clear imagery of a stimulus object at a specified distance, usually the normal or desired reading distance

Accommodative Excess◼ Accommodation in excess of the amount required for

sharpest imagery of the stimulus object

Accommodative Infacility (inertia of accommodation)◼ Slow or difficult accommodative response to dioptric

change in stimulus; especially sluggish accommodative response to changes in fixation distance

Accommodative Testing

Note: for amplitudes always be aware of even a small difference between the 2 eyes that is repeatable◼ If this is backed up by symptoms there may be an accommodative problem

Accommodative TestingTest Normative Value Standard Deviation

Push up/Pull away amplitudes

15- ¼ age +/- 2.00D

NRA +2.00 D +/- 0.50 DPRA -2.37D +/- 1.00 D

Minus lens amplitudes

15- ¼ age – 2D

MEM (monocular estimation method)

+0.50 D +/- 0.25 D

Fused X-cylinder +0.50 D +/- 0.25 D

Accommodative Facility

Accommodative Facility Testing

Test type Population Normative Value

Binocular Children (7-12) 5.0 cpm

Adults 8.0 cpm

Monocular Children 7-12 7.0 cpm

Adults 11-12 cpm

Binocular Vision Disorder Summaries

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Convergence Insufficiency Fusional Vergence Dysfunction

Convergence Excess

Accommodative Disorder Summaries

Accommodative Excess

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Optometric Exam Sequence

Refraction Assessment of Accommodative Skills

◼ Minus lens amplitudes◼ Flipper Facility as needed

Assessment of Binocular Vision Status◼ Cover test – distance and near◼ Vergences – typically near, distance as needed◼ NPC – Near Point of Convergence◼ Vergence Facility

Ocular Motility evaluation◼ King Devick Test◼ DEM – Developmental Eye Movement Test

Accommodative DisordersAccommodative Dysfunction with TBI

Alvarez et al. 2012: 24%Ciuffreda et al. 2007: 41%Stelmack et al. 2009: 47%

General population: 6-9%

Alvarez TL, et al. Optom Vis Sci 2013Ciuffreda KJ, et al. Optometry 2007Stelmack JA, et al. Optometry 2009Porcar E, et al. Optom Vis Sci 1997

Hokoda SC, et al. J Am Optom Assoc 1985

The Accommodative Neural Circuit The afferent limb of the circuit includes the

◼ Retina - the retinal ganglion axons in the optic nerve, chiasm and tract◼ lateral geniculate body - axons in the optic radiations◼ visual cortex

visual association in the cortex determines if the image is "out-of-focus"

Recommended clinical evaluation for accommodative testing:◼ Accommodative amplitude ◼ Accommodative lens flipper facility fatigue◼ Stimulus AC/A ratio◼ Horizontal near heterophoria◼ NRA / PRA

We can simplify this…

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Symptoms of Accommodative ProblemsClinical Signs of Accommodative Problems

Hyperopic Rx has benefits◼ May improve near symptoms◼ May not tolerate Rx at distance

Retinoscopy reflex fluctuates◼ Often see A/R astigmatism◼ Myopia

Subjective > retinoscopy

Variable acuity / may not achieve level expected as per findings

Optometric Findings in Accommodative Insufficiency

Visual Acuity “mushy”Reduced distance VA

Reduced near VA

Areas of Accommodation to Measure

Accommodative Amplitudes◼ Push-up / Pull –away amplitudes (Donder’s)◼ Minus Lens Amplitudes

Accommodative Response◼ NRA/PRA◼ Monocular Estimation Method (MEM)

Accommodative Facility◼ Flipper Facility with +/- 2 D lenses

Let’s keep it Simple

Minus Lens Amplitudesmeasures “power” of the accommodative system

Must determine age norm


Note: for amplitudes always be aware of even a small difference between the 2 eyes that is repeatable

If this is backed up by symptoms there may be an accommodative problem

Accommodative TestingTest Normative Value Standard

Deviation

Push up/Pull away amplitudes

15- ¼ age +/- 2.00D

NRA +2.00 D +/- 0.50 DPRA -2.37D +/- 1.00 D

Minus lens amplitudes

15- ¼ age – 2D

MEM (monocular estimation method)

+0.50 D +/- 0.25 D

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Control Rx = +2.50 sphereMinus Lens Amplitudes

Control lenses Near PD / Phoropter converged / stand lamp Using nearpoint rod/ target at 16”

◼ One line larger than patients near VA◼ Normed for 20/40

Test monocularly Add minus lenses in 0.25 D increments to first sustained blur

◼ Alternative end points Target goes “in and out” of clarity Target is to small to read

To obtain the amplitude in diopters add 2.50 D for the 40 cm WD

Target for Minus lens Amplitudes Minus Lens Amplitudes

To obtain the amplitude in diopters add 2.50 D for the 40 cm WD

Baseline +2.50 D

OD → -2.004.50 + 2.50 = 7.00D

OS → -2.505.00 + 2.50 = 7.50D


Accommodative Facility Testing

Test type Population Normative Value


Adults 8.0 cpm


Adults 11-12 cpm


Modified facility testing

20/40 letter / line of letters

+2.00 D OU compared to -2.00 D OU

Is there blur?Is one side more difficult than the other?

Which side is more difficult in Accommodative Insufficiency?

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1) Minus Lens Amplitudes

2) Flipper Facility +2.00 D OU compared to -2.00 D OU

3) Trial Frame Plus at near Start with +1.00 - +1.25

Subjective response

4) Take Distance VA OU with Near RxCan patient tolerate the plus at distance

Single vision vs bifocal Rx


Concussion 2 months prior◼ Hit with softball under Left eye

Broken nose Whiplash

Seen by neurologist specializing in concussion◼ Fatigue◼ Difficulty concentrating◼ Headaches (variable pattern)◼ Photophobia, worse with fluorescent lighting◼ Nausea throughout day

Visual symptoms◼ Non specific◼ SCL wearer x 4 years


Case findingsSnellen VA sc Distance

OD OS Near

OD OS20/20 20/20 20/20 20/20

Pupils / CF / EOM normal

Stereopsis (+) Forms / 25 sec

Refraction -3.50 sph 20/20-3.50 sph 20/20

Dilated exam unremarkable


Initial FindingsCover Test cc Distance

Ortho Near2 XP

Near Prism Bar Vergences cc

Base Inx/26/10

Base Outx/30/14

NPC 6 cm/9 cm5cm/8cm

Minus Lens Amplitudes

6.00 D OD and OSNorm = 9.25 D

NRA/PRA +2.25 / -1.25

Flippers Able to clear + 2.00 D and unable to clear -2.00D

King Devick Test Age appropriate findingsNo ocular motor deficits


Accommodative Insufficiency◼ Progressive lens prescribed over soft contact

lenses to alleviate asthenopia with near work◼ Will not address photophobia with indoor

tinted lenses at this time recommended brimmed hat

◼ RTC 1 month One month follow up◼ Patient notes great improvement in visual

symptoms with Rx

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Binocular Vision Disorders

Convergence Insufficiency with TBI

• Alvarez et al. 2012: 23%• Ciuffreda et al. 2007: 42%• Brahm et al. 2009: 46%

• General population: 4-6%

Alvarez TL, et al. Optom Vis Sci 2013Ciuffreda KJ, et al. Optometry 2007Brahm KD, et al. Optom Vis Sci 2009

Convergence Insufficiency


Scheiman/Wick

VergencesSmooth / Phoropter

Near

Base In 11/19/10

Base Out 14/18/7

Distance

Base In x/6/3

Base Out 7/15/8


Scheiman/Wick

VergencesPrism Bar Vergences/Step Vergence ADULTS

Near

Base In x/13/10

Base Out x/19/14

Distance

Base In x/7/4

Base Out x/11/7

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How to record Step Vergence Measurements Base IN


x/20/12

Norm: NBI x/13/10

How to record Step Vergence Measurements Base OUT


x/20/12

Norm: NBO x/19/14


Scheiman/Wick

VergencesPrism Bar Vergences/Step Vergence CHILDREN

Near

Base In x/12/7

Base Out x/23/16

Distance

Base In None established

Base Out None established

Near Point of Convergence TestingNPC

Near Point of Convergence

Children Break 6 cm

Adults

Accommodative target


Red lens / transilluminator


Concussion Recovery as a Function of NPC

Prospective analysis of concussion symptoms and NPC among 28 collegiate athletes with sports-related concussion

❑ Shortened (improved) NPC with resolution of symptoms

Figler R, et al. AAN Sports Concussion Conference 2014

Analysis of 78 athletes s/p sports-related concussion (ave. 6 days) Assessment of NPC, neurocognitive function (ImPACT) & post

concussion symptoms score (PCSS) 42% of concussed athletes had CI Athletes with CI had worse neurocognitive impairment and higher

symptom scores than did those with normal NPC

Pearce KL, et al. Am J Sports Med 2015

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Concussion 2 months prior◼ Jumped down stairs → fell backwards → hit head

Seen by neurologist specializing in concussion◼ Constant headaches◼ Fatigue

Visual symptoms◼ Difficulty focusing on things up close◼ Intermittent diplopia (horizontal) with near work

Clears immediately with blink

School has allowed him to d/c homework and tests


Case findingsSnellen VA sc Distance

OD OS Near

OD OS20/20 20/30 20/20 20/20



Refraction Pl – 0.50 x 180 20/20-0.25 -1.00 x 180 20/20




Ortho Near

12 XP


Base In18/30/8

Base Outx/24/10


Further receded after 5 x and red lens


5.75 D OD and OSNorm = 9.25D

NRA/PRA +2.50 / -1.50

Flippers Able to clear (+) and difficulty clearing (-) 2.00Definite affinity for plus



Accommodative Insufficiency and Convergence Insufficiency◼ Bifocal Rx prescribed to alleviate asthenopia with near

work Pl -0.50 x 005 +1.25 Pl -1.00 x 005 +1.25

◼ Convergence insufficiency noted, will re-evaluate findings at follow up Consider therapy at follow up

◼ RTC 1 month

Binocular Vision Testing Summary

1)Cover test – Distance and Near

2) Stereopsis

3)Vergence Evaluation – Base IN and base OUT

4) NPC

Additional Assessment Tool

5) Vergence Facility Testing

Vergence Facility Vergence facility attempts to capture the ability of the fusional vergence

system to respond rapidly and accurately to changing vergence demands over time

Purpose/Goal of testing: To determine the ability to make large rapid changes in fusional vergence

Can address typical binocular vision symptoms

AND can aid diagnosis in the absence of reduced binocular vision signs

Excellent tool in symptomatic traumatic brain injury (TBI) patients findings significantly lower in the visually symptomatic post concussion group as compared

to visually normal group

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Vergence Facility Vergence Facility 20/30 target Hold target in primary gaze at 40 cm Prism Flipper over ONE EYE 12BO/3BI used Instruct patient that target may appear double and to

make it single quickly - say NOW when single vision is achieved

Perform for 1 minute alternating BI / BO◼ Record the number of cycles per minute (cpm)

One cycle = clearing BO prism and BI prism

Expected values◼ Vergence Facility using 12∆BO/3∆BI = 15cpm (Adult)

Failure = < 15 cpm

Vergence FacilityVergence Facility with Stereoscopic and Nonstereoscopic Targets

Optometry and Vision Science Issue: Volume 91(5), May 2014, p 522–527Momeni-Moghaddam, Hamed*; Goss, David A.†; Dehvari, Abubakr

The highest vergence facility was obtained with a nonstereo target and the lowest was obtained with a stereo-global target. High sensitivity with all three targets means that there are few false-negative results with them, and the high specificity is indicative of low false-positive results. Hence, the vergence facility predictive value would be high in diagnosing binocular symptomatic patients using a 3[DELTA] BI/12[DELTA] BO prism flipper at near and a response cutoff of about 10 cycles per minute or less.

Vergence FacilityOptom Vis Sci. 1998 Oct;75(10):731-42.

Vergence facility: establishing clinical utility.Gall R1, Wick B, Bedell H.

In addition to providing valuable normative data, this study indicates that the vergence system nearly resets its "zero point" at any distance and sheds further light on the results of dynamic convergence and divergence stimulation on the accommodative-vergence system. From a clinical standpoint, the results improve the diagnosis of binocular vision abnormalities. The recommended near vergence facility test is

easily implemented, using a commonly available flip prism (3 delta BI/12 delta BO) and having a clinical failure criterion that is easily recalled (15 cpm, sum of the BI and BO magnitudes).

Optometry. 2003 May;74(5):309-22.The symptomatic patient with normal phorias at distance and near: what tests detect a binocular vision

problem?Gall R1, Wick B.

Given a patent with asthenopia, normal phorias, and visual acuity, a differential diagnosis may be made based primarily on using vergence facility and accommodative facility testing. From a clinical

standpoint, the results expedite diagnosis of binocular vision abnormalities and direct treatment.

Case # 352 year old male firefighter

Case findingsC/O diplopia, asthenopia, difficulty reading, photophobia, headache, depth and

balance issuesH/O head trauma after being hit on head 2 years prior

Not on active duty, desk only and driving but wants to stop driving

Snellen VA sc Distance OD OS

NearOD OS

20/20 20/20 20/20 20/20



Refraction OD -3.25 -1.00 x 090OS -3.25 -1.00 x 090


Case #352 year old male firefighter


12Δ IAET Near

8 IAXT

Distance Prism Bar Vergences cc

Base Inx/8/4

Base Outx/4/2


Base Inx/10/8

Base Out0/2/unable


Vergence Facility 12BO/3BI: 0cpm/ Unable to clear BO Norm = 15 cpm

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Treatment

Single Vision Rx◼ Distance Rx = 3 Δ BO ◼ Near Rx = 4Δ BI

Began Office Based Vergence Training

Binocular Vision Testing


2) Stereopsis


4) NPC

Optional: Vergence Facility Testing

Oculomotor DisordersSaccade and Pursuit Dysfunction

Prospective analysis of 36 PCS subjects vs. healthy controlsPCS associated with worsening of anti-saccades, self-paced saccades,

memory-guided sequences & smooth pursuitsEye movement dysfunction showed higher correlation with symptom load

as compared to neuro-psych testingBiological substrate for concussion-related symptoms

Oculomotor DisordersSaccade and Pursuit Dysfunction

Optometric Evaluation Tool

King Devick TestRapid Number Naming

Test of saccades, verbalization & recall

High levels of test-retest reliability High levels of validity for concussion identification

Test Card 1 Test Card 2 Test Card 3

Galetta KM, et al. Concussion 2015

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High reliability

Designed originally as a reading test for kids◼ Easy◼ takes less than a minute◼ anyone can do it!

The athlete is asked to read three test cards with numbers as quickly as possible, and total time is the baseline or pre-season score.

> ½ of the brain’s pathways go into vision and reading, we anticipated that athletes with concussion would take longer to read the cards compared to a pre-season or pre-competition baseline.


Has been examined in a range of athletes at various ages, may be useful in ID of concussion

Worsening of baseline K-D test at the time of the injury indicates a 5x greater risk of concussion

Reliable when administered by trained personnel and lay person

Sensitive (86%) and specific (90%) for the detection of concussion

Subjective analysis of patient symptom provocation following various eye movements

Headache, nausea fogginess, dizziness Some expertise required (not possible for most teams and

level of play) Symptoms provoked in 33 to 61% (VOR best) Misses motility problems that could be detected by objective

exam Not validated on sidelines

Mucha A, et al. AJSM 2014

University of Florida study of K-D test, SAC & BESS in the sideline assessment of concussion◼ SAC - Standardized Assessment of Concussion ◼ BESS - Balance Error Scoring System

N=217 athletes (men’s football, women’s soccer, and women’s lacrosse with 30 concussions)

Marinides Z, et al. Neurology Clin Prac 2014

Standardized Assessment of Concussion(SAC)

The SAC takes approximately 5 minutes to administer and includes measures of:

◼ Orientation (month, date, day of week, year, time)◼ Immediate Memory◼ Neurologic Screening◼ Loss of consciousness◼ Amnesia◼ Strength◼ Sensation◼ Coordination◼ Concentration◼ Exertional Maneuvers◼ Delayed Recall

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BESS - Balance Error Scoring System (BESS)

The BESS is a portable, cost-effective and objective method of assessing static postural stability. Takes approximately 10 minutes to conduct.◼ The balance-testing regime consists three stances on

two different surfaces◼ Three Stances

double leg stance single leg stance tandem stance

◼ Two Surfaces firm (ground) foam surface.

Results

52% of concussions detected with SAC

79% of concussion detected with K-D test

80% of concussion detected with BESS

95% of concussions detected with combination of K-D & BESS

100% of concussions detected with combination of K-D, SAC & BESS

Marinides Z, et al. Neurology Clin Prac 2014

BESS - Balance Error Scoring System (BESS)

The BESS is a portable, cost-effective and objective method of assessing static postural stability. Takes approximately 10 minutes to conduct.◼ The balance-testing regime consists three stances on

two different surfaces◼ Three Stances

double leg stance single leg stance tandem stance

◼ Two Surfaces firm (ground) foam surface.


Test of saccades, verbalization & recall

High levels of test-retest reliability High levels of validity for concussion identification

Test Card 1 Test Card 2 Test Card 3

Galetta KM, et al. Concussion 2015

Treatment of Oculomotor Disorders

In office Vision Therapy

King-Devick Recovery Acceleration Program

K-D TEST PRO MONITORING

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K-D Test Pro Monitoring is a post-injury evaluation tool used to monitor the patient’s oculomotor function during the concussion recovery process

following identification of concussive injury. K-D Test Pro Monitoring may be used when a pre-injury K-D Test baseline is not available. The program uses charts and graphs to display K-D Test scores over the

course of recovery.

For clinical use only Standard-sized iPad App Quick, objective patient progress

monitoring For serial post-injury testing Unlimited testing per patient for one

year Purchase patient activations as

needed◼ $20/patient◼ Minimal initial set-up required

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CONCUSSIONS: REHABILITATION

• For clinical or home use• Standard-sized iPad or laptop computer

• Requires Wi-Fi/internet

• Corrects deficits in eye movements and alleviates symptoms for many who have

suffered a concussion • Set goals and tailor programs for individual

patients• Real-time outcome measures to determine

patient compliance and progress• Patient has access to program for one year• Patient activation costs - $65/patient; 10

code minimum• Resell code to patient – SRP $90

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King-Devick Recovery Acceleration Program is a computer and tablet based oculomotor

concussion rehabilitation program for patients suffering from persistent symptoms.


$650 training package of 10 subjects activations ($65 unit cost) Retail $90 / subject

◼ $125 when combined office therapy Guidance, compliance, real time follow up

Evidence based training protocol: ◼ 20 minutes/ day◼ 3 days / week◼ 6 weeks

Totals = 6 hours training

www.kingdevicktest.com◼ More information about sideline concussion screening◼ KD Team assists with on-boarding, training and implementation◼ General pricing questions, seek out sales and account management

Additional New Technology

Oculomotor assessment

“RightEye is the world’s first commercialized eye-tracking solution for general healthcare and wellness. It is nothing

like traditional vision tests. It is a proven, easy-to-use tool, steeped in science and applicable for optometry, medicine

and sports. Every day. For every body.”

9 yo Reading disability / post vision therapy treatment

Functional Vision Assessment

11 year old Functional Vision Assessment

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9 year old reading disability

reading assessment

11 year oldReading Assessment

Return to Play

McAvoy AAN SCC 2015

Risks of Premature Return to Play

❑ Risk of second impact syndrome❑ Repeat impact before normalization of brain

function ❑ “window of vulnerability”

❑ Chronic headaches❑ Depression❑ Long-term cognitive deficits❑ Post-traumatic encephalopathy (CTE)

2013 NCAA survey of 789 athletic trainers and 111 team physicians (530 institutions)

64.4% pressure from athletes 53.7% pressure from coaches

Greater pressure if female clinicians or if under supervisory purview of athletic department

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Graduated Return to Play ProtocolOver days… weeks… months…

AAN Clinical Practice Reference Sheet for Clinicians, 2011.

Rehabilitation Stage Functional Exercise at Each Stage of Rehabilitation

(1) No activity Complete physical, cognitive rest

(2) Light aerobic exercise Walking, swimming, stationary bike

(3) Sport-specific exercise Running drills in soccer, skating drills in hockey, etc.

(4) Noncontact drills More complex training drills, may start resistance training

(5) Full-contact practice With medical clearance, participate in normal training activities

(6) Return to play Normal game play

88 individuals (age 11-22 years) with ED presentation for acute concussion

Initial neurocognitive and balance assessments with daily record of post-concussive symptoms

Randomized to:◼ strict rest (5 days) vs. ◼ 1-2 days rest followed by step-wise return to activity

No difference between groups regarding NC/balance outcomes Increased symptoms among strict rest group

Thomas DG, et al. Pediatrics 2015

Return to LearnReturn to Learn

❑ Return to learn must precede return to play

❑ Return to school when symptoms are tolerable for 30-45 min ❑ usually within 2-4 days of concussion

❑ Schools/teacher should make adjustments to incorporate 5-10 min. of rest/hour

Halstead ME, et al. Pediatrics 2013

The Optometrists Role…. Photophobia




A Vision exam geared to rule out….

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Treatment Approaches

Lenses◼ Plus for near

Determine bifocal vs single vision option

Prism◼ When applicable for diplopia issues◼ Consider Fresnel if temporary condition

Orthoptic / Vision therapy◼ Scientific basis for therapeutic value◼ Addition to traditional vestibular and cognitive

rehabilitation

Vision Therapy Templates


Concussion at soccer game ◼ September 2018 (9 months prior)◼ Severe symptoms at the time of the incident◼ Did not loose consciousness, but does not recall incident

Seen by neurologist specializing in concussion◼ Has completed vestibular therapy◼ post concussion syndrome, patient has significant headaches and asthenopia that start at

work◼ Long hours of computer use, patient is a consultant◼ neurologist has limited patient to 10 hours daily of computer use his work demands 15◼ visual symptoms ONLY occur on weekdays patient is symptom free on weekends◼ Discussed option of therapy to treat CI and AI◼ No IXT noted today superb fusion with significant phoria, superb convergence as well◼ Concussion

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Case Example24 year old male

Case findingsSnellen VA cc Distance

OD OS Near

OD OS20/20 20/20 20/20 20/20

Habitual Rx OD -1.00 -1.00 x 180OS -1.50 -1.50 x 180



Refraction No change




Ortho Near

12 XP


Base Inx/25/16

Base Outx/25/20

NPC To Nose

To nose with red lens


5.50 D OD and OSNorm = 7.00D

Flippers Able to clear (+) and difficulty clearing (-) 2.00Definite affinity for plus



◼ Diagnosis


Accommodative Insufficiency

◼ Treatment

Has completed vestibular therapy

Vision Therapy – 9 sessions◼ Complete resolution of symptoms

Concussion Response

Concussion Legacy FoundationRecognizeConsultRecover

Encourage

Beyond the Science… Team Up Against Concussion

◼ Team Up Against Concussions is a free 30 minute concussion education program for schools, community centers, and athletic programs

◼ Trained volunteers educate student-athletes about concussions through discussion, video, and interactive games, teaching them that successful athletes play hard and play smart. Using an evidence-based bystander intervention model, the program focuses on empowering student-athletes with the knowledge they need to take concussions seriously and foster a safer concussion culture

◼ Aimed at grades 4-12

https://www.youtube.com/watch?v=Efpnm158y64

Concussion Response

Recover◼ return to play protocol to gradually re-

introduce the athlete to activity

Encourage◼ recovery can be a long and frustrating

process ◼ When it comes to concussion recovery,

toughness means sticking to the recovery plan and not rushing back into play

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Concussion Response

Recognize◼ When in doubt, sit them out◼ Concussions present with unique symptoms◼ If a concussion is suspected immediately remove the

athlete from play. ◼ Athletes must not return to play the same day it is

confirmed or suspected they are suffering from a concussion

Consult◼ It is critical the athlete is evaluated by a medical

professional experienced with managing concussions as soon as possible after the injury occurs.

There’s No Such Thing As A Tough Brain!®

King-Devick Test® (K-D Test®) All Rights Reserved. © 2015, 2014, 2013, 2012, 2011, 2010, 1983. Patent Pending. Unauthorized duplication is prohibited and a violation of applicable laws. www.kingdevicktest.com

Questions ??…… Thank You

[email protected]

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iStrain: What effect do today's tablets and devices

have on vision?Valerie M. Kattouf O.D., F.A.A.O., F.C.O.V.D

Associate Professor, Illinois College of Optometry

Chief, Pediatrics/Binocular Vision Department, Illinois Eye Institute

Clin Exp Optom. 2019 Sep;102(5):463-477. Ocular and visual discomfort associated with smartphones, tablets and computers: what we do and do not know.

Jaiswal S1, Asper L1, Long J1, Lee A1, Harrison K1, Golebiowski B1.

• Smartphone and tablet use in Australia and worldwide is reaching saturation levels and associated visual and ocular discomfort such as headaches, eyestrain, dry eyes and sore eyes are widespread.

• Literature review

• Handheld devices differ from computers in viewing position and distance, screen size and luminance, and patterns of use. • Accommodation is altered with handheld device use, with increased lag and decreased amplitude.

• Smartphone and tablet use results in reduced fusional convergence and possibly a receded near point of convergence.

• The available literature does not conclusively link eye and visual discomfort symptoms reported with handheld digital devices, with changes in binocular vision, blinking or ocular surface.

• However, there is a gap in our understanding of symptoms which occur with smartphone and tablet use in the context of how these devices are used.

• In addition, studies are required in high users such as teenagers, and in patients with dry eye or accommodative/binocular vision anomalies, all of whom may have a higher risk of symptoms.

Lecture Goals for

the“brain”

Discuss digital media use and it’s effect on vision

Share information which provide parents with updates, research and guidance

Develop “Device Advice”

Lecture Goals

“heart”

Help families to create balance in your home around technology

Allow PARENTS to be in charge of the way technology is integrated into their family’s life

Inspire parents to not give up their “parent power”

“The Big Disconnect”

“parenting in the digital age challenges in ways the human brain --- AND heart --- can hardly process fast enough”

“we do not want to surrender ourselves unquestioningly to adapt to technology”

What do we love about technology?• Communicating with ease… family, long

distance, up close and personal• Visually impaired• Grabbing a recipe• Learning math facts• Learning disabled children / education

potential• Research

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Book Titles

Screenwise: Helping Kids Thrive (and Survive) in Their Digital World

iRules: What Every Tech-Healthy Family Needs to Know about Selfies, Sexting, Gaming, and Growing up

The Big Disconnect: Protecting Childhood and Family Relationships in the Digital Age

AND SO ON

8 Reasons Why Children Should

Not Use Handheld Devices

Frequently

1. Children are not turning their brains on.2. Children may be exposed to too much

radiation.3. Children are not getting enough sleep.4. Children will take ages to do homework.5. Toddlers’ brain development may be at risk.6. Children may be at increased risk of mental

illness.7. Children may become couch potatoes.8. Children may suffer from eye strain.

"Without data, you are just another person with an opinion".

Andreas Schleicher developer of the PISA, Program for International Student Assessment

Screenagers Tech Talk Tuesday

SUBSCRIBE

http://www.screenagersmovie.com/

Some Tech Talk Tuesday Topics

“Hold That Text”

“The Art of Asking People to put their Phones Away”

“Sharing not Scaring is the Key to Managing Screen Time”

“Ending Bedtime Madness”

“Online Homework: The Biggest Challenge”

“Emotional Risks of an Online Life”

“E – readers or books? What is Best”

Common Sense Media Research 2018

• 95% of Teens in the U.S. Own a Mobile Device; 70% Check Social Media Several Times a Day

• Teens Prefer Texting to Talking as Their Favorite Way to Communicate

• 3 Out of 4 Teens Believe That Tech Companies Intentionally Manipulate Them

• Social Media Affects Teens' Social and Emotional Well-Being, But Not Necessarily in Negative Ways

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Common Sense Media 2017

M IS FOR MOBILE By Michael H. Levine

You may have heard that Sesame Street’s beloved Cookie Monster has learned some valuable lessons in delaying his gratification and eating right. He now knows that his favorite chocolate chip treat is a “sometime food,” part of a balanced diet of fruits, vegetables, and the occasional hubcap!

The same is true of children’s media diets. Some experiences may constitute “empty” calories that should certainly be limited, while others that are proven to be educational, like Sesame Street, are more substantive staples. But parents and educators cannot know what “balanced” means if they don’t have an understanding of how kids are actually spending their time with media.

Common Sense Media 2017

Percent of homes with a mobile device

Common Sense Media 20172011 – 2017

Mobile media time among 0-8 year olds tripledMedia Use Guidelines

American Academy of Pediatrics2013

• The AAP recommends that parents establish "screen-free" zones at home by making sure there are no televisions, computers or video games in children's bedrooms, and by turning off the TV during dinner. Children and teens should engage with entertainment media for no more than one or two hours per day, and that should be high-quality content. It is important for kids to spend time on outdoor play, reading, hobbies, and using their imaginations in free play.

Media Use GuidelinesAmerican Academy of Pediatrics, 2016

Pediatricians

• Start the conversation early. Ask parents of infants and young children about family media use, their children’s use habits, and media use locations.

• Help families develop a Family Media Use Plan (www.healthychildren.org/MediaUsePlan) with specific guidelines for each child and parent.

• Educate parents about brain development in the early years and the importance of hands-on, unstructured, and social play to build language, cognitive, and social-emotional skills.

• For children younger than 18 months, discourage use of screen media other than video-chatting.• For parents of children 18 to 24 months of age who want to introduce digital media, advise that they

choose high-quality programming/apps and use them together with children, because this is how toddlers learn best. Letting children use media by themselves should be avoided.

• Guide parents to resources for finding quality products (eg, Common Sense Media, PBS Kids, Sesame Workshop).

• In children older than 2 years, limit media to 1 hour or less per day of high-quality programming. Recommend shared use between parent and child to promote enhanced learning, greater interaction, and limit setting.

• Recommend no screens during meals and for 1 hour before bedtime.• Problem-solve with parents facing challenges, such as setting limits, finding alternate activities, and

calming children.


Families

• Do not feel pressured to introduce technology early; interfaces are so intuitive that children will figure them out quickly once they start using them at home or in school

• For children 2 to 5 years of age, limit screen use to 1 hour per day of high-quality programming, coviewwith your children, help children understand what they are seeing, and help them apply what they learn to the world around them.

• Avoid fast-paced programs (young children do not understand them as well), apps with lots of distracting content, and any violent content.

• Turn off televisions and other devices when not in use.• Avoid using media as the only way to calm your child. Although there are intermittent times (eg, medical

procedures, airplane flights) when media is useful as a soothing strategy, there is concern that using media as strategy to calm could lead to problems with limit setting or the inability of children to develop their own emotion regulation. Ask your pediatrician for help if needed.

• Monitor children’s media content and what apps are used or downloaded. Test apps before the child uses them, play together, and ask the child what he or she thinks about the app.

• Keep bedrooms, mealtimes, and parent–child playtimes screen free for children and parents. Parents can set a “do not disturb” option on their phones during these times.

• No screens 1 hour before bedtime, and remove devices from bedrooms before bed.

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Industry

• Work with developmental psychologists and educators to create design interfaces that are appropriate to child developmental abilities, that are not distracting, and that promote shared parent–child media use and application of skills to the real world. Cease making apps for children younger than 18 months until evidence of benefit is demonstrated.

• Formally and scientifically evaluate products before making educational claims.

• Make high-quality products accessible and affordable to low-income families and in multiple languages.

• Eliminate advertising and unhealthy messages on apps. Children at this age cannot differentiate between advertisements and factual information, and therefore, advertising to them is unethical.

• Help parents to set limits by stopping auto-advance of videos as the default setting. Develop systems embedded in devices that can help parents monitor and limit media use.

On any given day, American teenagers (13- to 18-year-olds)

average about NINE hours of entertainment media use,excluding time spent at school or for homework.

Tweens (8- to12-year-olds) use an average ofabout SIX hours’ worth

of entertainment media daily.

• Boys play video games 56 minutes / day vs 7 minutes for girls• Only 3% of tweens and teens time is spent on content creation• More parents are concerned about the type of media content their children use

than how much time they spend using it.• Many teens multitask with media while doing their homework, and most think this

has no effect on the quality of their work.• Teens from lower income families spend an average of 2:45 more with media per

day than teens from higher income families

18 year old female

• Referred due to suspected neurological cause of headaches

• All diagnostic testing normal• Headaches since June• Diffuse – entire head• 10/10 severity• Greatest when awaking• Random presentation – no noted association with

near work• No relief with oral pain meds• On leave from school since June – High School

Junior

• Convergence Insufficiency Diagnosis• Low minus Rx

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18 year old femaleAdditional questions….

What are you doing when you are not at school?On computer, developing videos on you tube, playing video games

Do you suffer the headaches at home like you do at school?Some, not as severe

What is your typical sleep schedule?4 AM – 8 AM

Do you sleep with devices in your bedroom YES

Do you exercise regularlyNO

Technology Use and Sleep Quality in Preadolescence and Adolescence

J Clin Sleep Med. 2015 Dec 15;11(12):1433-41. doi: 10.5664/jcsm.5282.Bruni O1, Sette S1, Fontanesi L1, Baiocco R1, Laghi F1, Baumgartner E1

RESULTS:Adolescents reported more sleep problems, a tendency toward eveningness, and an increase of Internet and phone

activities, as well as social network activities, while preadolescents were more involved in gaming console and television viewing. The regression analysis performed separately in the two age groups showed that sleep quality

was affected by the circadian preference (eveningness) in both groups. Adolescents' bad sleep quality was consistently associated with the mobile phone use and number of devices in the bedroom, while in

preadolescents, with Internet use and turning-off time.

CONCLUSIONS:The evening circadian preference, mobile phone and Internet use, numbers of other activities after 21:00 (9:00), late turning off time, and number of devices in the bedroom have different negative influence on sleep quality in

preadolescents and adolescents.

Sleep Health. 2019 Sep 12. Identifying drivers for bedtime social media use despite sleep costs: The adolescent perspective.

Scott H1, Biello SM2, Woods HC2.OBJECTIVES:

Bedtime social media use is associated with poor sleep during adolescence, which in turn contributes to poor mental health, impaired daytime functioning and lower academic achievement. However, the underlying drivers

for these bedtime social media habits remain understudied. This study adds an adolescent perspective on motivations for bedtime social media use and perceived impact on sleep.

METHODS:Adolescents aged 11-17 years (n = 24) participated in focus group discussions exploring their experiences of using

social media, particularly at night. Inductive reflexive thematic analysis produced themes that captured underlying drivers for social media use and associated impact on sleep.

RESULTS:Our analyses produced two overarching themes: Missing Out and Norms & Expectations. Adolescents' nighttime

social media use was driven by concerns over negative consequences for real-world relationships if they disconnected (often reporting delayed bedtimes, insufficient sleep and daytime tiredness). These concerns included

the risk of offline peer exclusion from missing out on online interactions, and the fear of social disapproval from violating norms around online availability and prompt responses.

CONCLUSIONS:These findings offer novel insight into why adolescents may choose to prioritize social media over sleep.

Researchers and practitioners can respond to the evolving needs of today's adolescents by approaching social media use not as a technology-based activity, but as an embedded social experience underpinned by the same concerns as

offline interactions.

Vision Issues related to Near Point Stress

Near Point Visual Stress

Birnbaum Theory

• Binocular Vision and Accommodative Disorders / Myopia onset

• Often stress induced conditions• Motivation for academic achievement• Career stress

• Results in: • refractive changes • disturbances of accommodation and convergence

• Many disorders (CI, AI, myopia) not primary problems = adaptive changes to near point stress

• CI and Myopia have been linked to personality and emotional factors which underly heightened sympathetic arousal

Use Abuse Theory

Birnbaum theory

Rapid rise in myopia from the 1970s to the early 2000s

66% increase

There is an adverse influence of the extensive near vision demands imposed by our society

The visual system is biologically unsuited for the sustained near work demands of our culture

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Near Point Visual Stress

How are digital devices affecting

this?

Clin Exp Optom. 2017 Mar;100(2):133-137

Viewing distance and eyestrain symptoms with prolonged viewing of smartphones.

Long J1, Cheung R1, Duong S1, Paynter R1, Asper L1.BACKGROUND:This paper investigates viewing distances and eyestrain symptoms in young adults reading from a smartphone for 60 minutes.

METHODS:A survey related to common asthenopic (eyestrain) symptoms was administered to subjects before and after they read an extract from a novel on a smartphone for 60 minutes. Subjects rated their symptoms on a scale from zero (not at all) to four (extremely). The viewing distance to the smartphone was measured on a photograph taken of the subject every minute. Each subject used the same smartphone and read the same text.

RESULTS:Subjects were 18 young adults (mean age: 21.5 ± 3.3 years) with self-reported good health, normal visual acuity and no accommodative or binocular vision disorders. The mean viewing distance while using a smartphone over 60 minutes was 29.2 ± 7.3 cm. Symptoms of tired eyes, uncomfortable eyes and blur increased significantly after 60 minutes of smartphone use There was a significant correlation between change in total symptom score and change in viewing distance (ρ = -0.51; p = 0.03).

CONCLUSION:Viewing distances are closer and eyestrain symptoms are greater after reading from a smartphone for 60 minutes. The viewing distances measured were closer than those previously reported in the literature.

Appl Ergon. 2018 Apr;68:12-17. Symptoms associated with reading from a smartphone in conditions of light and dark.

Antona B1, Barrio AR2, Gascó A3, Pinar A3, González-Pérez M3, Puell MC2.Author information

• Asthenopia symptoms were investigated in visually-normal subjects without computer-related vision symptoms

• After reading from the smartphone, total symptom scores and nine out of ten questionnaire symptoms were significantly worse than for the hardcopy

• blurred vision while viewing the text• blurred distance vision after the task• difficulty in refocusing from one distance to another• irritated or burning eyes, dry eyes• Eyestrain / tired eyes / eye discomfort• sensitivity to bright lights

• Mean total symptom scores and scores for "irritated or burning eyes" and "dry eyes" were significantly higher for the dark versus photopic conditions.

• In conclusion, prolonged smartphone reading could cause worse eyestrain symptoms than reading from a hardcopy under similar conditions.

• Symptoms could be even worse when reading from a smartphone in the dark.

Curr Eye Res. 2019 Oct 7:1-7Smartphone Use and Effects on Tear Film, Blinking and Binocular

Vision.Golebiowski B1, Long J1, Harrison K1, Lee A1, Chidi-Egboka N1, Asper L1.

Results: Eyestrain symptoms and ocular surface symptoms increased after smartphone use,

specifically comfort, tiredness and sleepiness items (p ≤ .02). Binocular accommodative facility decreased from a median of 11.3 (IQR 6.6)

cycles/min pre-task to 7.8 (2.5) cycles/min post-task (p = .01), but there was no significant change in fixation disparity or working distance.

There were no changes in NIBUT, lipid layer or tear meniscus height. Number of incomplete blinks per minute increased from a median of 6 blinks at 1 min to 15 at 60 min (p = .0049). Total blink rate (complete plus incomplete blinks) gradually increased

over time, but this trend was not significant (p = .08). A greater increase in incomplete blinks over 60 min of reading was associated with

worsening of the overall ocular surface symptoms score (ρ = -0.65, p = .02) and of the tiredness item (ρ = 0.70, p = .01).

Conclusions: Extended use of smartphones appears to have important implications for ocular

surface health and binocular function.

To summarize thus far:

Asthenopia develops due to:Accommodative IssuesDry Eye / Blink rate issues

Visual symptoms influenced by:Improper working distancePoor lightingPoor sleep due to digital device usage / presence

Consider printed material• Printed characters provide adequate visual information• Good contrast from ink color to paper color• Sharp transition - good edge definition• Our vision system is programmed to understand normal

printed material

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Pixels

• Present entirely different kind of image• Image is made up of pixels, not one full image• Pixels- picture and text drawn in little “pieces”• Pixels are brightest in center and dimmer

towards edge• Pixels are used on computers, iPads

New LCD Screens with higher resolution will likely cause fewer problems

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Computer Screen vs. HardcopyA comparison of symptoms after viewing text on a computer screen and

hardcopyOphthalmol Physiol Opt. 2011 Jan;31(1):29-32, Chu C, Rosenfield M., Portello JK, Benzoni JA, Collier JD

Symptoms following sustained computer use were significantly worse than those reported after hard copy fixation under similar viewing conditions.

Retina Display

Retina Display is a term coined by Apple to refer to their devices that have a

pixel density so high that the naked eye can’t see individual pixels. These options

offer a solution to pixelation, making them much “better for your eyes”

Retina Display = Sharper text is much easier on the eye and much more

pleasurable for reading.

Causes of Computer Vision Syndrome

Symptoms

• poor lighting• glare on the computer screen• improper viewing distances• poor seating posture• uncorrected vision problems• Excessive usage• a combination of these factors

One More thing….Blue Light

Blue Light

❑What is Blue light?

❑Visible light emitted by the sun comprises of a range of different colored light rays that contain different amounts of energy

Rays on the RED end of the visible light spectrum have longer wavelengths and, therefore, LESS energy

Rays on the BLUE end of the visible light spectrum have shorter wavelengths and, therefore, MORE energy

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Blue Light

❑Blue light is everywhere❑Man made sources of indoor blue light

❑Fluorescent lighting❑LED lighting❑Flat screen TV❑Screen displays of:

❑Computers❑E Readers❑Tablets❑Smartphones

❑Concern:❑Amount of time spent on devices❑Proximity of devices to the face❑The eye does not block blue light well

Blue Light

❑Concern: The eye does not block blue light well

The cornea and lens block UV rays from reaching the retina

Most visible blue light passes through the cornea and lens and reaches the retina

Blue light exposure may increase the risk of macular degeneration

Blue light contributes to digital eye strain

Blue Light

❑Preventative Methods:❑Blue light filters for digital devices❑iLLumiShield – iPhone ($8-10)❑retinaShield (tech Armour) – iPAD ($12)❑Retina Armor (tekide)❑Frabicon – same as above❑Cyxus – same as above

Blue Light

❑Spectacle Lens technology:❑amber lenses add additional contrast to

define shapes and sharpen detail for easier viewing

❑lens tints filter high frequency blue light emitted from digital devices to protect eyes

❑lens focusing power helps you hold focus on your screens and minimizes eye muscle fatigue

❑wrap-around patented lens design prevents dry eyes and irritation to ease eyestrain

❑anti-reflective coatings on front and back of the lenses eliminate visual distractions and filter blue light to the

Blue Light Studies

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Blue Light

Effects of blue light on the circadian system and eye physiology.Tosini G, Ferguson I, Tsubota K.Vol Vis. 2016 Jan 24;22:61-72. eCollection 2016. Review

Blue blocker glasses as a countermeasure for alerting effects of evening light-emitting diode screen exposure in male teenagers.van der Lely S, Frey S, Garbazza C, Wirz-Justice A, Jenni OG, Steiner R, Wolf S, Cajochen C, Bromundt V, Schmidt C.J Adolesc Health. 2015 Jan;56(1):113-9. doi: 10.1016/j.jadohealth.2014.08.002. Epub 2014 Oct 3.

Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness.Chang AM1, Aeschbach D2, Duffy JF3, Czeisler CA3.Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1232-7. doi: 10.1073/pnas.1418490112. Epub 2014 Dec 22

Bigger, Brighter, Bluer-Better?

Current Light-Emitting Devices - Adverse Sleep

Properties and Preventative Strategies.

Gringras P, Middleton B, Skene DJ, Revell VL.

Front Public Health. 2015 Oct 13;3:233. eCollection 2015.

RESULTS:

All the LE devices shared very similar enhanced short-wavelength peaks when displaying text. This included the output from the backlit Kindle Paperwhite device. The spectra when comparing text to the Angry Birds game were also very similar, although the text emissions were higher intensity. Both the orange-tinted glasses and the "sleep-aware" app significantly reduced short-wavelength emissions.

CONCLUSION:

The LE devices tested were all bright and characterized by short-wavelength enriched emissions. Since this type of light is likely to cause the most disruption to sleep as it most effectively suppresses melatonin and increases alertness, there needs to be the recognition that at night-time "brighter and bluer" is not synonymous with "better." Ideally future software design could be better optimized when night-time use is anticipated, and hardware should allow an automatic "bedtime mode" that shifts blue and green light emissions to yellow and red as well as reduce backlight/light intensity.


Accommodative Facility TestingTest type Population Normative Value


Adults 8.0 cpm


Adults 11-12 cpm

Case Report

Fatigueassociated with near

work

AsthenopiaAssociated with near

work

Distance blur

12 year old male

12 year old male

Initial Findings

Visual Acuity cc Distance Near

20/20 OD, OS 20/20 OD, OSRetinoscopy = Subjective -1.75 sph 20/20

-1.50 sph 20/20Cover Test cc ortho 20∆ IAXT

Near Prism Bar Vergences cc Base Inx/20/18

x/12/7

Base Outx/16/12x/23/16

NPC TN5cm/8cm

12 year old male

Initial FindingsMinus lens Amps = 5.50 OD, 5.25 OS

norm = 9-10 D

+/- 2.00 D Flippers

Difficulty clearing minus

Stereopsis = (+) RDS

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Diagnosis

• Convergence Insufficiency

• Accommodative Insufficiency

What visual disorders do optometrists encounter most due to increased near point demands on our population?

Binocular Vision and Accommodative Disorders


Case Example

11 year old male

Initial FindingsCase History Blurry distance vision

Blur at near after 10 minutes of reading5th grade, B/C student

No headaches, no diplopia

Visual Acuity sc Distance Near

20/20 OD, OS 20/25 OD, OS

Cover Test sc ortho orthoRetinoscopy Plano – 0.50 x 090 OD, OS

Near Prism Bar Vergences cc Base Inx/24/12

Base Outx/12/6

NPC TN

11 year old male

Accommodative TestingOD OS

Minus Lens Amplitude(age expected = 10.25D)

5.50D 4.50D

Binocular Accommodative Facility

Cannot clear - 2D

11 year old male

Additional questions….

How much time is spent with digital devices?

As per Mom…..

EXCESSIVE HOURS GAMING

Low A/R Cylinder –Birnbaum Theory

Onset of myopia often preceded by low A/R cyl(Hirsch 1964)

A/R cyl is an early adaptationLag of accommodation is present during near work

(Accommodation is localized beyond the plane of regard)

A/R cyl produces vertically oriented blur circles which permit resolution of the vertically oriented characters of

our language

A/R cyl permits one to accommodate less while maintaining adequate visual resolution at neat point with a minimum loss

of distance visual acuity

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Low A/R Cylinder –Birnbaum Theory

As Near point stress persists or visual efficiency is unsatisfactory

Myopia development may occur

We often see low A/R cyl reduce or disappear with plus lens treatment or

vision therapy

11 year old maleTreatment

• Accommodative Insufficiency

• SUPERB plus acceptance• Rx given for near and reading = +1.25 sph• Given in form of bifocal (DUO blended)• Discussed importance of time limits and

decreasing near demands


What are they going to say? Symptoms

What are you going to see?Clinical Findings

What are you going to do?Treatment Options


5 year old chief complaint of severe headaches

Patient is on iPAD from the time he wakes up in morning until he goes to bed at night per mom. Educated mom that headache is likely due to excessive near work on digital devices. Discussed need to balance time with digital devices and that children are unable to self limit and we must provide balance for them.Recommended keeping a record of when headaches occur and what activities caused them. Return on 2/12/2019 at 9:45 with Dr. Kattouf for near work up to rule out any accommodative or vergence disorder.

Clinical Signs of

Accommodative Problems

My view

Retinoscopy reflex fluctuates

Often see A/R astigmatismMyopia: Subjective may be > retinoscopy

Variable acuity / may not achieve level expected as per findings (“Mushy VA”)

Hyperopic Rx has benefits

May improve near symptomsMay not tolerate Rx at distance

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Accommodative InsufficiencyTreatment Options

Added Lenses• Refractive error as necessary• Optimize spectacle and/or contact lens

Rx

Plus lenses• need reflected in clinical signs

Orthoptics / Vision Therapy• generally requires 12-24 office visits• dependent upon age, motivation,

compliance


Treatment

Treatment of Accommodative Dysfunction in Children: results from a Randomized Clinical TrialOptometry and Vision Science, Vol. 88, No.11, November 2011,

Scheiman, M., Cotter S, et.al.

• 211 children ages 9-17 with symptomatic CI

• 74% had accommodative dysfunction• 29% had decreased amplitude of accommodation when

compared to age norms• 19% had decreased accommodative facility• 26% both

Conclusion: Vision therapy/orthoptics was effective for improving

decreased accommodative amplitude and accommodative facility

SUMMARY:

What visual disorders do optometrists

encounter most due to increased

near point demands on our

population?

Binocular Vision and Accommodative Disorders



Convergence Excess

With these visual issues what

symptoms will you notice in your

child?

Headaches

Eyestrain (may be blinking, eye rubbing)

Close working distance / gets close to page or device

Fatigue at end of day

Blur that comes and goes

Distance blur (even though the problems are at near)

Covers one eye while reading

Double vision

Avoidance of Near work

My advice to parents:

If your child experiences these visual symptoms

Comprehensive Eye Examination focus on the

binocular vision (eye teaming) and

accommodative (eye focusing) systems

Smaller eyeglass prescriptions mean more in today’s digital

world

Glasses for near / school reading tasks

may give support, eliminate symptoms

and may be preventative for future/additional

vision issues

Orthoptics / vision therapy

We can train the eye teaming and focusing

systems) to be stronger, more efficient and more flexible thus eliminating

symptoms and development of additional vision issues

Summary of the Optometric Evaluation

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1) Minus Lens Amplitudes

2) Flipper Facility +2.00 D OU compared to -2.00 D OU

3) Trial Frame Plus at near Start with +1.00 - +1.25Subjective response

4) Take Distance VA OU with Near RxCan patient tolerate the plus at distanceSingle vision vs bifocal Rx

Binocular Vision

Testing


2) Stereopsis


4) NPC

Not just “soft”BV and

accommodative disorders

BMC Ophthalmol. 2016; 16: 37.

Acute acquired comitantesotropia (AACE) related to excessive Smartphone

use

Hyo Seok Lee, Sang Woo Park, and Hwan Heo

BMC Ophthalmol. 2016; 16: 37.Acute acquired comitant esotropia (AACE) related to excessive Smartphone use

Hyo Seok Lee, Sang Woo Park, and Hwan Heo

In conclusion, excessive smartphone use at a close reading distance might influence the development of rarely occurring AACE in patients with myopia or mild hyperopia, good corrected visual acuity, and binocularity.

AACE can potentially be induced by increased tonus of the medial rectus muscles resulting from the sustained near work itself, and disrupted accommodation and vergence by VDT work.

In these cases, refraining from smartphone use can decrease the amount of esodeviation, and successful management of residual esotropia and restoration of binocularity can be achieved with bilateral medial rectus recession.

Further studies with larger sample sizes and long-term follow-up periods are warranted

Technology has become an ever present influence on our lives. Our children have the benefit of instant communication and easy access to information. This is a wonderful

thing……

Except when it isn’t

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This generations use of media is EXPONENTIAL

According to common Core State Standards Initiative …..keyboards

will soon replace pencils

Question:

What are the human costs of this “always connected” lifestyle, especially for our children?

Device AdviceParent Education

“The Big Disconnect”

“I believe that the digital life we now take for granted is taking a far greater toll on family cohesion and childhood itself than we imagine or perhaps than we want to allow ourselves to imagine”

“The Big Disconnect”Infant Development

• Research points to neurologic concerns that screen based activity stimulates visual processing more heavily than other sensory processing systems

• Near visual demands

• Early exposure to technology is negatively altering children’s intellectual, social and emotional development

• Digital devices are the 3rd party in the infant - parent relationship

• “Just because your baby CAN tap a touch screen to change a picture does not mean that he should, that it is developmentally useful or an appropriate activity for him”

Important Distinctions• The Three C’s of media use:

• Consumption – to take in or use media passively without contributing

• Creation – To produce and distribute something in a way that requires active engagement, acquired skills, and complex problem solving

• Communication – to use media to connect with another person

“After reading these sections no parent will be able to say they don’t have reason to limit their child’s media consumption and communication between 1-2 hours per day”

Advice to Parents who ask about limiting media consumption and

communication

• Multi-tasking

• Direct conflict between a child’s ability to multi task and a child’s ability to sustain attention and concentration

• For a child’s developing brain it is almost impossible to restrain themselves from responding to a text or checking social media feeds

• To avoid: • Have a cell phone SPOT in your home• Power down and place them there

before entering house

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5 year old maleonly child

Question: How many hours a day does your child use media?Answer: 2 hours

Reminded parent of all media devices owned reconstructed patient day and asked more

specialized questions……

5 hours and 55 minutes

Advice to Parents who ask about limiting media consumption and

communication

Media Tracking

Media consumption extends far beyond TVCell phones and tablets allow children to play

games and watch videos ANYWHERE

“Start by making a list of your media devices and your children’s. Track your children’s media use by device. You will be surprised

how quickly it adds up”

Media Creation

Play through technology is the way children learn to use technology.

“The goal for parents is to use media CREATION to both inspire and prepare

children for 21st-century skills.”

All combined research revealed that children are able to naturally regulate

themselves when it come to media creation

Media Creation

• Power point presentation

• Making videos• Creating animation• Learning touch typing• Learning apps

(reading and math, etc.)

• Texting• Surfing the web• Social media• Video Gaming

Media Communication

Device advice

New England Journal of medicine 2014: Too much screen time is part of the obesity

epidemic

Children need a moderate diet of food as well as a moderate media diet

Pediatrics. 2017 NovScreen Media Exposure and Obesity in Children and

Adolescents.Robinson TN1,2, Banda JA3, Hale L4, Lu AS5,6, Fleming-Milici F7, Calvert

SL8, Wartella E9.

Anxiety is a hallmark of children who spend too much time in front of screens

Too much screen time is a deterrent to learning social skills

A trend noticed by teachers in elementary schools

Gaming Addiction

June 2018

WHO adding GAMING DISORDERto the International

Classification of diseases

Gaming Disorder = increasing priority given to gaming over other activities to the extent that gaming takes precedence over other interests and daily activities and continuation or escalation of gaming despite the occurrence of negative

consequences

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Gaming Disorders

The American Psychiatric Association (APA) included internet game disorder (IGD) in section III of the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) on the condition that it guaranteed more clinical research and experience. The World Health Organization (WHO) also included Game Disorder (GD) in the 11th final revision of the International Classification of

Diseases (ICD-11) and recently recognized it as a diagnosis code

J Clin Med. 2019 Jun 28;8(7)Clinical Characteristics of Diagnosis for Internet Gaming Disorder: Comparison of DSM-5 IGD

and ICD-11 GD Diagnosis.Jo YS1,2, Bhang SY3, Choi JS4,5, Lee HK6, Lee SY7, Kweon YS8.

Tech Talk Tuesday“Fortnite, addiction and what to do about it”

• Former gaming addict, Cam Adair

• After nearly a decade of eating, sleeping, and gaming up to 16 hours a day, he quit and in January of 2015

• started the website GameQuitters

• What started as a way to help him find his purpose and keep him away from the consoles, has turned into a community 30,000 strong.

Q: What advice would you give parents?

Parents have to get more educated and firm with their children's relationship with technology. It's challenging these days because as a parent you are up against a billion-dollar tech industry that has a greater interest in selling

their technology than they do in your child's health. Games are different than they were when I was growing up, especially with the integration of gambling-like game design, loot boxes, and in-app purchases. If you notice technology causing problems in your home, or your child has mood swings without them, you must take action

immediately. You must set firm boundaries, and stay strong in them. Lastly, it's easy to feel a lot of shame and guilt as a parent, especially if your child is having challenges, but you must let go of that and open yourself up to help.

Parents need to come together more on this subject.

Case study: World renowned game creator / CEO

Has 5 children, no video games in home

Question: Are you aware of the statistics on video game and poor social skills in children?

P: Why do you think I do not let my kids play video games?

Question: Are you aware of how addictive video games are?

P: The goal of developers is to make the most complex, captivating addictive game possible. I don’t let my children play video games for exactly that reason”

Device advice• The Homework Habit

• Low sleep onset latency – falling asleep quickly• Research showed that increase in media use

contributes to trouble falling asleep• No media in bedrooms; limited media at other

times• No media or any distractions during homework

time• The 10 minute rule – 10 minutes of academic

homework per grade• Regular exercise• Daily family time including 30 minutes of media

free family activity (meals, games, talking, reading)

• Regular Household chores and bedtime• Screen time as a reward (after tasks are done,

never before)• Effective communication skills

Device advice• Family challenges

• “Swap Out”• Swap out 30 minutes of media

consumption or communication for a non-media activity (sports, board games, face to face conversation etc.)

• Cell phone STOP station• Leave phones in this area• Determine times that they can be used

• Media Time Out• Pick a block of extended time with no

media use• Reading Challenge

• Determine a 24 hour age appropriate reading goal for every member of the family

• Keep media out of children’s bedrooms

Visual Rules to help prevent

eyestrain for children

(and adults)

20-20-20 Rule

Choose a comfortable supportive chair so that the child’s feet are on the ground

Suggest that they limit leisure screen time to 2 hours/day (this includes TV watching, playing video games, and using mobile devices)

Take notice if children are squinting, rubbing eyes

Remind children to blink more regularly

Check for glare and reflections on the screen

Adjust lighting

Remember that kids do not have awareness of the time they spend on many media devices

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This is NOT true of digital taskskids do not have awareness of the time they spend on many media

devices

PARENTS must take charge of the regulation

Children self regulate on the

majority of tasks they partake in…

Visual Rules to help prevent

eyestrain for children

• Pre-school and Kindergarten aged children• Limit tech time to 2 hours or less daily• Increase font size

• Elementary school children• Cell phones for quick tasks only• Hold device at Harmon’s distance slightly below eye

level• Take frequent breaks

• Middle school and high school students• Place the screen 20-28 inches from your child’s eyes.

Align the top of the screen at eye level• Use small devices (phones) for quick tasks (texting)

do not use to read articles and documents • Build in breaks every hour• NO DEVICES IN BEDROOMS

Through Technology

is a way to inspire and learn, but when is it

Technology Advice to Help Prevent Eyestrain:

Our #1 Rule! Every 20 minutes, take a 20 second break and look 20 feet away.

• Choose a comfortable, supportive chair so that the child’s feet are on the ground • Limit leisure screen time to 2 hours/day- Media extends far beyond TV. Cell

phones are tablets allow children to play games and watch videos anywhere. o Track Your Media: Start by making a list of you and your children’s media

devices. Track their media use by device. You will be surprised how quickly it adds up.

• Take notice if children are squinting or rubbing their eyes • Remind children to blink more regularly • Check for glare and reflections on the screen • Adjust lighting • **Remember that kids do not have awareness of the time they spend on many media

devices

Working Distance

Use the “Harmon Distance” when reading, writing and doing other close work. The distance between the eyes and the task

is the distance between the elbow and the middle knuckle.

Dr. Darrell Boyd Harmon’s “Harmon Distance”

Advice to Parents about limiting media consumption

and communication

Common Sense

Flexibility

Awareness

Develop a plan/rules• Communicate these rules to your children• Enforce your rules

Develop some alternatives to media use

Keep Media OUT of children’s bedrooms

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Device Advice

Pediatrics. 2016 Nov,

Children and Adolescents and

Digital Media

Reid C, Radesky J, et al

• Early learning• Exposure to new ideas and knowledge• Increased opportunities for social contact and support• New opportunities to access health promotion messages and

information

Evidenced Based BENEFITS of digital and social media:

• Negative health effects on • Sleep• Attention• Learning

• Higher incidence of obesity and depression• Exposure to inaccurate inappropriate, unsafe content and contacts• Compromised privacy and confidentiality

Evidenced Based RISKS of digital and social media

Device Advice

Pediatrics. 2016 Nov

Children and Adolescents and

Digital media

Reid C, Radesky J, et al

Resources:Family Media Use Plan

www.healthychildren.org/MediaUsePlan

Individualize for child, teenager or familyIdentify and appropriate balance between

screen time and other activitiesSet boundaries for accessing content

Encourage age appropriate digital literacyEncourage age appropriate critical thinking

Support open family communicationSupport consistent rules about media use

Lecture Goals• Discuss digital media use and it’s effect on vision• Discuss how we diagnose these issues• Discuss how we treat these issues• Develop “Device Advice”

• How do we respond to the questions our parents and patients ask

Thank you!!!

Valerie M. Kattouf O.D., F.A.A.O., F.C.O.V.DAssociate Professor, Illinois College of Optometry

[email protected]

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JANUARY/FEBRUARY 2017 www.retinalphysician.com

UPDATE ON THE MANAGEMENT OF IOFBS

Dry AMD Masquerade SyndromesPETER BRACHA, MD • THOMAS A. CIULLA, MD, MBA

Using Genetics to Guide AMD Therapy: Are We There Yet?

JACLYN L. KOVACH, MD • INGRID U. SCOTT, MD, MPH

Posterior Staphyloma in Pathologic MyopiaKYOKO OHNO-MATSUI, MD, PHD

Diabetic Retinopathy: Halting and Reversing Progression

STEPHEN J. SMITH, MD • MARGARET A. GREVEN, MD • PRITHVI MRUTHYUNJAYA, MD, MH

R E T I N A L P H Y S I C I A N | J A N U A RY / F E B R U A RY 2 0 1 71

features16 Using Genetics to Guide AMD Therapy:

Are We There Yet?BY JACLYN L. KOVACH, MD • INGRID U. SCOTT, MD, MPH

21 Geographic Atrophy Now in Researchers’ SightsMany try varied approaches to confront this unmet need.BY JERRY HELZNER, CONTRIBUTING EDITOR

26 AMD Masquerade SyndromesPETER BRACHA, MD • THOMAS A. CIULLA, MD, MBA

35 Incorporating a Low Vision Rehabilitation Service into a Retinal PracticeDONALD C. FLETCHER, MD • JAY HOLMES • TRACY RUMMANS, OCS

38 Posterior Staphyloma in Pathologic MyopiaWhat it means for patient’s vision and how to detect it KYOKO OHNO-MATSUI, MD, PHD

44 Diabetic Retinopathy: Halting and Reversing ProgressionThe second of three partsSTEPHEN J. SMITH, MD • MARGARET A. GREVEN, MD

PRITHVI MRUTHYUNJAYA, MD, MH

48 Update on the Management of Intraocular Foreign BodiesThese patients require careful monitoring.AJAY E. KURIYAN, MD • ALEKSANDRA V. RACHITSKAYA, MD

54 CMV Retinitis: Evidence-based TreatmentALAA E. RADWAN, MD, FRCS OPHTH • ROWAYDA M. AMIN, MD, FICO, FRCS

OPHTH

departments58 CT Update

66 New Product Applications Laser system delivers treatment to preplanned locations.

67 Ad Index

67 Classifieds

4 UpfrontFrom the Editor in Chief

6 Subspecialty NewsOphthotech AMD Combo Fails in Phase 3; Trump’s Win Scuttles CMS Reimbursement Plan; Spark is Offering Free Genetic Testing; More Durable Retina Drugs in the Pipeline; and more

14 CodingWhat’s New for 2017?

JANUARY/FEBRUARY 2017 n VOLUME 14 n NUMBER 1

Flecks from Multifocal Pattern Dystrophy Simulating Fundus Flavimaculatus can mimic drusen from AMD.

Image courtesy of Thomas A. Ciulla, MD, MBA

1R E T I N A L P H Y S I C I A N .C O M | J A N U A RY / F E B R U A RY 2 0 1 7

26 R E T I N A L P H Y S I C I A N | J A N U A RY / F E B R U A RY 2 0 1 7

Dry AMD Masquerade Syndromes

PETER BRACHA, MD • THOMAS A. CIULLA, MD, MBA

The prevalence of nonexudative age-related macular degeneration (AMD) will dramatically increase with an aging population. By the year 2020, an esti-mated 196 million people globally will have AMD and 11 million will have significant vision loss.1

Whenever cases present with atypical features, ophthalmolo-gists should consider other diagnoses, as numerous retinal dis-eases have overlapping features with dry AMD. In this article, we present examples of pattern and cone-rod dystrophies, and maculopathies associated with medication toxicity or systemic disorders, all of which were referred to a retina clinic for assess-ment of dry AMD. These cases were ultimately diagnosed as other pathologies with the aid of ancillary testing. They all can be considered “Dry AMD-masquerade syndromes.”

CASESCuticular Drusen (Basal Laminar Drusen)A diagnosis of cuticular drusen (Figure 1) was originally considered distinct from AMD, with a more favorable prog-nosis, but more recently it has been considered a subtype of AMD. Despite numerous clinical and histological similarities, important differentiating features exist. On fundus examina-tion, cuticular drusen are small (25-75 microns), yellow-white and nodular. Macular OCT demonstrates these drusen to be blunted, triangular-shaped and below the RPE, giving a saw-tooth pattern.2 FA strikingly reveals innumerable hyperfluo-rescent drusen that significantly outnumber the drusen noted clinically, yielding the characteristic “stars-in-the-sky” appear-ance during the early arteriovenous phase.2 Interestingly, on FAF, these drusen are hypoautofluorescent when very small, but also present with a hypoautofluorescent center surrounded by a ring of hyperautofluorescence.2 Overall, the frequency of choroidal neovascularization seen with this AMD subtype ranges from 4% to 56% depending on the study.3-5 One-third of patients can develop geographic atrophy.6 In patients with early-onset, extensive cuticular drusen, a rare complement mutation is associated with an increased risk of developing choroidal neovascularization and type II membranoprolifera-tive glomerulonephritis.4,7,8 Close ocular and systemic moni-toring is warranted.

Peter Bracha, MD, is a resident and Thomas A. Ciulla, MD, MBA is on the clinical faculty at Indiana University Dept. of Ophthalmology in Indianapo-lis. Neither author reports any financial interests in products mentioned in this article. Dr Ciulla can be reached via e-mail at [email protected].

Figure 1. This 52-year-old female was referred with a 4 month history of progressive blurring of central vision and meta-morphopsia from her left eye (LE). Visual acuity (VA) mea-sured 20/20 both eyes (BE) and fundus examination revealed bilateral macular retinal pigment epithelial (RPE) mottling with patches of atrophy in the nasal macula (Figure A). Macular OCT demonstrated areas of outer retinal segment and RPE atrophy and fine sub-RPE drusen BE (Figure B). Fundus autofluores-cence (FAF) vividly demonstrated innumerable, punctate hyperautofluorescent lesions significantly outnumbering the drusen noted clinically, which is characteristic for this disorder. There were also patches of hypoautofluorescence correlating to RPE atrophy (Figure C). With the aid of multimodal imaging, a diagnosis of cuticular drusen with RPE atrophy was made. In addition to the examples from this case, in another case, a clas-sic appearance is depicted on fluorescein angiography (FA), on which these numerous punctate drusen stain discretely, result-ing in a “stars-in-the-sky” appearance (Figure D)

A

C

B

D

27 R E T I N A L P H Y S I C I A N | M AY 2 0 1 3 27

Gass first classified pattern dystrophies, which represent a group of autosomal dominant maculopathies involving pig-mentary abnormalities.9 They generally carry a more favorable prognosis than AMD.

Multifocal pattern dystrophy simulating fundus flavimacu-latusMultifocal pattern dystrophy simulating fundus flavimacula-tus (Figure 2) is one of five main pattern dystrophy categories that Gass classified.9 Patients develop mild-to-moderate visual disturbances in midlife which progress to severe vision loss in up to 50% of patients after the age 70 due to atrophy of the RPE-photoreceptor complex and/or development of choroidal neovascularization.10 Early in the course of the disease, patients have nonspecific pigmentary changes.4 Subsequently, they develop a variable number of irregularly shaped and/or elgon-gated, yellow-white flecks throughout the posterior pole and around retinal vascular arcades.10 FA reveals staining of these lesions and FAF demonstrates significantly increased autofluo-rescence of the flecks with a small, adjacent zone of decreased autofluorescence.10 Macular OCT shows moderately reflective deposits just anterior to the ellipsoid zone.11 Most patients have an abnormal electrooculogram and 50% have an abnormal ERG.10 Genetic testing can reveal a peripherin/RDS mutation but other mutations have been associated with this pathology.10

Adult-onset foveomacular vitelliform dystrophy Adult-onset foveomacular vitelliform dystrophy (Figure 3), another pattern dystrophy, typically presents with mild visual disturbances between 30 and 50 years of age.12 Vitelliform lesions are hyperautofluorescent on FAF and hypofluorescent on early FA frames with later staining.13,14 Macular OCT reveals a dome-shaped hyperreflective area between the RPE and ellipsoid zone.12,15 Genetic testing classically identifies a mutation in the peripherin 2 (PRPH2) gene, but other genetic mutations have been associated.13

Cone-rod dystrophy Cone-rod dystrophy (Figure 4) typically presents during child-hood with poor VA and severe color-vision loss.16 Fundus appearance can range from normal to a bull’s eye maculopathy with temporal pallor of the optic nerve.16 Goldman visual fields reveal a central scotoma.16 Full-field ERG, which is necessary for diagnosis, demonstrates progressively deteriorating cone amplitudes with comparatively normal rod amplitudes.16

Hydroxychloroquine toxicityHydroxychloroquine is used for many rheumatologic disor-ders. The toxicity risk is very low in patients who consume less than 5.0 mg/kg of real body weight and who have been on therapy for less than 10 years.17 When toxicity develops


Figure 2. This 38-year-old, asymptom-atic male was referred for bilateral maculopathy. VA measured 20/20 BE. Fundus examination revealed numerous elongated yellow flecks that were hyper-autofluorescent on FAF (Figures A and B). FA identified early, mild choroidal silence and staining of the yellow flecks (Figure C). Considering the excellent VA and lack of beaten bronze fundus appearance, Stargardt’s disease was ruled out and the diagnosis of multifocal pattern dystrophy simulating fundus flavimaculatus was made.

Figure 3. This 85-year-old, glaucomatous female was referred with a one-month his-tory of bilateral blurring of central vision. VA measured 20/200 RE and 20/30 LE and fundus examination revealed bilateral yellow foveal lesions with pigment clump-ing (Figure A). FA demonstrated central blocking defects in early frames without staining or leakage (Figure B). Red-free photographs provided great contrast of the lesions (Figure C). Her findings and symptoms were consistent with adult-onset foveomacular vitelliform dystrophy.

A

C

B

A

B

C

Figure 4. This 78-year-old male was referred with a one- year history of pro-gressive, bilateral central blurring. VA measured 20/40 RE and count fingers LE. Fundus examination revealed bilat-eral generalized RPE atrophy with optic nerve pallor LE, and FA demonstrated staining in a bull’s eye pattern (Figures A and C). Macular OCT identified bilateral outer retinal and RPE atrophy, and an epiretinal membrane RE (Figure B). The patient denied a history of hydroxychlo-roquine or chloroquine use. Cone-rod dystrophy was suspected and then confirmed when ERG showed a broadly diminished wave-form that was worse under photopic conditions.

A

C

B

28R E T I N A L P H Y S I C I A N .C O M | J U N E 2 0 1 3

(Figure 5), patients frequently complain of nyctalopia and paracentral scotomas. This paracentral scotoma can be identi-fied and tracked with visual fields, the most sensitive of which is a 10-2 Humphrey visual field. Early in the course of the dis-ease, fundus appearance is normal and in later stages a bull’s eye maculopathy develops. Macular OCT reveals a loss of the external limiting membrane, disruption of the ellipsoid zone, parafoveal thinning of the outer nuclear layer, and RPE dam-age.18 On multifocal ERG, paracentral, central or generalized amplitude reductions develop.19 FAF findings vary depending on disease severity: early pathology highlights a paracentral ring of increased autofluorescence; moderate severity shows a paracentral mottled hypoautofluorescence with an adjacent hyperautofluorescence; and advanced disease reveals a complete central loss of autofluorescence.19

Cancer Associated Retinopathy Cancer associated retinopathy (Figure 6) typically presents with subacute vision loss over weeks to months.20 Symptoms vary depending on the degree of rod and cone involvement; patients frequently present with symptoms of shimmering or flicker-ing lights.20 On clinical examination, patients show a normal appearing fundus early in the course of the disease, but with progression, they develop retinal arteriolar attenuation, retinal pigment epithelial mottling and optic disc pallor.20,21 Goldman visual field testing can identify a generalized depression or a central, paracentral, arcuate or ring scotoma.22 ERG is a sen-sitive diagnostic test early in the course of disease and dem-onstrates a depression of a- and b-waves on either phototopic and/or scotopic conditions depending on the degree of rod or cone involvement.22 FAF can reveal abnormal hyperautofluo-rescence surrounding a parafoveal region of normal autofluo-rescence.23 Macular OCT shows a loss of outer retinal complex


AMD MASQUERADE SYNDROMES

Figure 5. This 65-year-old female was referred with a 2-month history of bilateral blurring of central vision. VA measured 20/30 RE and 20/20 LE. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes and FAF demonstrated a bilateral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figures A and C). Macular OCT identi-fied parafoveal ellipsoid zone loss along with generalized reti-nal thinning (Figure B). After additional questioning regarding her current and past medications, she endorsed a 20-year his-tory of hydroxychloroquine use that was stopped several years prior to presentation. Despite no hydroxychloroquine use for a number of years, this patient most likely demonstrated symptomatic progression of hydroxychloroquine toxicity.

C

Figure 6. This 71-year-old male was referred with nyctalopia and with subacute blurring of central vision bilaterally. VA mea-sured 20/50 RE and 20/40 LE and fundus examination revealed parafoveal RPE mottling (Figure A). Macular OCT identified a generalized irregularity of the ellipsoid zone (Figure B). FA revealed staining of the RPE mottling only (Figure C). ERG was consistent with rod > cone dysfunction.

A

Figure 7. This 43-year-woman with a history of myotonic dystrophy was referred with blurring of central vision LE. VA measured 20/30 LE. Fundus examination revealed mild pigmentary changes in the macula (top left), corroborated on red-free fundus photography (top right). FA demon-strated patchy staining of the RPE mottling on early and late frames (bottom left and right respectively). These findings were consistent with myotonic dystrophy with pattern dys-trophy of the macula.

A B

C D

C

A

B

B


components.23 Immunohistochemistry can identify antiretinal antibodies, most common of which are antirecoverin and anti-alpha-enolase antibodies.20

Myotonic DystrophyThe classic ocular finding in myotonic dystrophy is the “Christmas tree cataract,” a posterior subcapsular, red and green, iridescent opacification of the lens. Patients can pres-ent with other ophthalmic findings including ocular hypotony and pigmentary retinopathy (Figure 7) that can be confused for AMD.24,25 The pathognomonic systemic feature is muscle weakness and myotonia of the distal legs, hands, neck and face.26 Fundus examination can reveal butterfly-shaped macu-lar pigmentary changes, peripheral reticular pigmentation and peripheral polygonal-shaped atrophy.27 FAF of the macular pigmentary changes demonstrates a branching linear pattern of mixed hyper- and hypoautofluorescence.28 Macular OCT of these changes identifies patches of inderdigitation zone hyper-reflectivity and ellipsoid zone hyporeflectivity.28

CONCLUSIONDespite the prevalence of dry AMD, it is important for ophthalmologists to consider less common diseases and multi-modal imaging to arrive at the correct diagnosis. As demonstrated in this series, numerous pathologies have over-lapping features with dry AMD, including pattern dystrophies, cone-rod dystrophies, medication toxicities, and systemic disor-ders associated with maculopathies. Other common disorders with overlapping features of dry AMD include inactive central serous retinopathy and other “pachychoroid”-related maculop-athies, particularly in older patients, as these entities can cause macular pigmentary changes. Historical and exam features that raise suspicion of “Dry AMD-masquerade syndromes” include younger age, suspect medications and systemic disorders, family history, highly symmetric macular pathology and lack of typi-cal drusen. Cuticular drusen and flecks, as demonstrated above, as well as dominant drusen (Malattia Leventinese), and even crystalline retinopathies such as tamoxifen maculopathy, could mimic drusen. Ancillary testing with red-free photography, FA, FAF, macular OCT and ERG can be helpful in further charac-terizing the retinal pathology. Newer techniques such as OCT with enhanced depth imaging can be used to demonstrate thickened choroid, which is characteristic of central serous reti-nopathy and other “pachychoroid”-related maculopathies. In the future, genetic testing will become commonplace, and will further delineate many of these maculopathies. RP

REFERENCES

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet Global health. 2014;2(2):e106-116.

2. Spaide RF, Curcio CA. Drusen characterization with multimodal imaging. Retina (Philadelphia, Pa). 2010;30(9):1441-1454.

3. Boon CJ, van de Ven JP, Hoyng CB, den Hollander AI, Klevering BJ. Cuticular drusen: stars in the sky. Progress in retinal and eye research. 2013;37:90-113.

4. Boon CJ, Klevering BJ, Hoyng CB, et al. Basal laminar drusen caused by compound heterozygous variants in the CFH gene. American journal of human genetics. 2008;82(2):516-523.

5. Cohen SY, Meunier I, Soubrane G, Glacet-Bernard A, Coscas GJ. Visual function and course of basal laminar drusen combined with vitelliform macular detachment. The British journal of ophthalmology. 1994;78(6):437-440.

6. Khan KN, Mahroo OA, Khan RS, et al. Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes. Progress in retinal and eye research. 2016;53:70-106.

7. Leys A, Vanrenterghem Y, Van Damme B, Snyers B, Pirson Y, Leys M. Fundus chang-es in membranoproliferative glomerulonephritis type II. A fluorescein angiographic study of 23 patients. Graefe’s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 1991;229(5):406-410.

8. van de Ven JP, Boon CJ, Fauser S, et al. Clinical evaluation of 3 families with basal laminar drusen caused by novel mutations in the complement factor H gene. Archives of ophthalmology (Chicago, Ill : 1960). 2012;130(8):1038-1047.

9. Gass JDM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. Mosby; 1997.

10. Boon CJ, van Schooneveld MJ, den Hollander AI, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. The British journal of ophthalmology. 2007;91(11):1504-1511.

11. Roy R, Kumar S, Chandrasekharan DP, Ghose A, Sharma P. Multimodal imaging in multifocal pattern dystrophy simulating fundus flavimaculatus. Indian journal of ophthalmology. 2016;64(5):395-396.

12. Rocha Bastos R, Ferreira CS, Brandao E, Falcao-Reis F, Carneiro AM. Multimodal Image Analysis in Acquired Vitelliform Lesions and Adult-Onset Foveomacular Vitel-liform Dystrophy. Journal of ophthalmology. 2016;2016:6037537.

13. Chowers I, Tiosano L, Audo I, Grunin M, Boon CJ. Adult-onset foveomacular vitelliform dystrophy: A fresh perspective. Progress in retinal and eye research. 2015;47:64-85.

14. Grob S, Yonekawa Y, Eliott D. Multimodal imaging of adult-onset foveomacular vitelliform dystrophy. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society. 2014;28(2):104-110.

15. Querques G, Forte R, Querques L, Massamba N, Souied EH. Natural course of adult-onset foveomacular vitelliform dystrophy: a spectral-domain optical coherence tomography analysis. American journal of ophthalmology. 2011;152(2):304-313.

16. Thiadens AA, Phan TM, Zekveld-Vroon RC, et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012;119(4):819-826.

17. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA ophthalmology. 2014;132(12):1453-1460.

18. Chen E, Brown DM, Benz MS, et al. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clinical ophthalmology (Auckland, NZ). 2010;4:1151-1158.

19. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Investigative ophthalmology & visual science. 2006;47(8):3531-3538.

20. Khan N, Huang JJ, Foster CS. Cancer associated retinopathy (CAR): An autoimmune-mediated paraneoplastic syndrome. Seminars in ophthalmology. 2006;21(3):135-141.

21. Grange L, Dalal M, Nussenblatt RB, Sen HN. Autoimmune retinopathy. American journal of ophthalmology. 2014;157(2):266-272.e261.

22. Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: evaluation and management. Survey of ophthalmology. 2013;58(5):430-458.

23. Pepple KL, Cusick M, Jaffe GJ, Mruthyunjaya P. SD-OCT and autofluorescence characteristics of autoimmune retinopathy. The British journal of ophthalmology. 2013;97(2):139-144.

24. Ikeda KS, Iwabe-Marchese C, Franca MC, Jr., Nucci A, Carvalho KM. Myotonic dys-trophy type 1: frequency of ophthalmologic findings. Arquivos de neuro-psiquiatria. 2016;74(3):183-188.

25. Rosa N, Lanza M, Borrelli M, et al. Low intraocular pressure resulting from ciliary body detachment in patients with myotonic dystrophy. Ophthalmology. 2011;118(2):260-264.

26. TD. B. Myotonic Dystrophy Type 1. In: Pagon RA, Adam MP, Ardinger HH, et al, edi-tors GeneReviews® [Internet]. 1999 Sep 17 [Updated 2015 Oct 22].(Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1165/).

27. Kimizuka Y, Kiyosawa M, Tamai M, Takase S. Retinal changes in myotonic dystrophy. Clinical and follow-up evaluation. Retina (Philadelphia, Pa). 1993;13(2):129-135.

28. Esteves F, Dolz-Marco R, Hernandez-Martinez P, Diaz-Llopis M, Gallego-Pinazo R. Pattern dystrophy of the macula in a case of steinert disease. Case reports in ophthalmology. 2013;4(3):129-133.

29R E T I N A L P H Y S I C I A N .C O M | J A N U A RY / F E B R U A RY 2 0 1 7

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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

Innovative therapies for neovascular age-relatedmacular degeneration

Hasenin Al-Khersan, Rehan M. Hussain, Thomas A. Ciulla & Pravin U. Dugel

To cite this article: Hasenin Al-Khersan, Rehan M. Hussain, Thomas A. Ciulla & Pravin U. Dugel(2019): Innovative therapies for neovascular age-related macular degeneration, Expert Opinion onPharmacotherapy, DOI: 10.1080/14656566.2019.1636031

To link to this article: https://doi.org/10.1080/14656566.2019.1636031

Published online: 12 Jul 2019.

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Innovative therapies for neovascular age-related macular degenerationHasenin Al-Khersana, Rehan M. Hussaina, Thomas A. Ciullab,c,d and Pravin U. Dugele,f

aDepartment of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; bDepartment ofOphthalmology, Indiana University School of Medicine, Indianapolis, IN, USA; cRetina Service, Midwest Eye Institute, Indianapolis, IN, USA;dClearside Biomedical, Alpharetta, GA, USA; eRetinal Consultants of Arizona, Phoenix, Arizona; fUSC Roski Eye Institute, Keck School of Medicine,University of Southern California, Los Angeles, CA, USA

ABSTRACTIntroduction: Investigational anti-VEGF treatments for neovascular age-related macular degeneration(nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-actingagents, combination strategies, topical agents, sustained-release, and genetic therapies.Areas covered: The authors provide a comprehensive review of investigational therapies for nAMD,focusing on therapies currently in clinical trial.Expert opinion: Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies,and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeatprotein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept – a fusion proteinof the VEGF receptor domains, KSI-301 – an anti-VEGF antibody biopolymer conjugate, and OPT-302 –an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGFinhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shownlimited efficacy and/or have not been advanced, although PAN-90806 continues to advance withpromising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, includethe ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305.Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGFexpression from the retina.

ARTICLE HISTORYReceived 7 March 2019Accepted 21 June 2019

KEYWORDSAge-related maculardegeneration; vascularendothelial growth factor;abicipar pegol;brolucizumab; conbercept;X-82; Tie-2 receptor;faricimab; nesvacumab;gene therapy; RGX-314;ADVM-022

1. Background

Age-related macular degeneration (AMD) is the leading causeof irreversible legal blindness in people ≥ 65 years of age inthe Western world, with projections to affect almost 3 millionpeople in the United States by 2020 [1]. In the UnitedKingdom, the prevalence of advanced-stage AMD in patients≥ 50 years of age has been reported at 2.4%, with an estima-tion of 679,000 cases by 2020 [2]. AMD has historically beenclassified into one of the two main subtypes: the non-neovascular (non-exudative or dry) form of the disease andthe neovascular (exudative or wet) form of the disease. Thenon-neovascular form of AMD accounts for approximately90% of all AMD cases and is often characterized by a slowdegeneration of the macula, resulting in atrophy of the cen-tral macula with gradual vision loss over a period of years [3].In contrast, neovascular AMD (nAMD), although less preva-lent, commonly causes acute and often substantial loss ofcentral vision, accounting for most cases of severe vision lossin this disease. This type of AMD is characterized by thegrowth of pathologic choroidal neovascularization (CNV)beneath the macula, which causes exudation of blood and/or fluid into the macula [4,5]. Ultimately, neovascular tissueand associated exudates develop into a destructive macularscar, leading to central blindness.

The aberrant vascular growth and exudation in nAMD aredriven by upregulation of one of the main cytokines involvedin angiogenesis, vascular endothelial growth factor-A (VEGF-A)[6]. This cytokine is also one of the most potent inducers ofpermeability and was, in fact, originally called vascular perme-ability factor [7]. The introduction of intravitreally administeredanti-VEGF-A agents has led to notably improved outcomes forpatients with nAMD.

2. Medical need

Despite the impressive advancements in nAMD treatment overthe past two decades, there are several practical limitations toanti-VEGF-A therapy, including the high cost of certain agents,need for frequent intravitreal injections, incomplete response,and/or failure to maintain response in some patients. Even withregularly repeated dosing of anti-VEGF therapy over 1 year,approximately 20% of patients lose vision, approximately 50%do not achieve 20/40 visual acuity (VA) (which is necessary foran unrestricted driver’s license in regions of the United Statesand in most European Union countries), and 2/3 or more do notachieve a VA gain of 3 or more ETDRS lines [8,9].

Although one recent international database observationalstudy showed that favorable visual outcomes could be

CONTACT Rehan M. Hussain [email protected] Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL 33136, USA

EXPERT OPINION ON PHARMACOTHERAPYhttps://doi.org/10.1080/14656566.2019.1636031

© 2019 Informa UK Limited, trading as Taylor & Francis Group

obtained with aflibercept dosed in a treat and extend manner[10], large ‘real world’ studies of anti-VEGF therapy in nAMD,based on chart reviews, electronic medical records (EMR) orclaims analyses, show visual outcomes that fall far short ofrandomized clinical trials (RCTs), possibly due to under-treatment and non-compliance [11–25]. Multiple reportshave suggested a relationship between the number of injec-tions and visual outcome, with fewer injections associatedwith worse VA [12–14,18,21,26,27].

Additionally, there are numerous barriers that posea challenge to patient compliance with frequent anti-VEGF-Ainjection such as patient anxiety/discomfort, financial burden,time constraints, and lack of transportation [28]. Due to thesebarriers, there is great interest in the development of long-acting anti-VEGF formulations.

Although anti-VEGF-A therapies initially improve vision byreducing leakage from neovascularization during the firstmonths of treatment, undoubtedly this is a complex physiolo-gic progress requiring inhibition of many more pathologicmechanisms. Ultimately, the formation of submacular scarlimits further visual benefit despite treatment; a recent large-randomized controlled study showed that submacular scardevelops in nearly 50% of subjects despite 2 years of anti-VEGF-A treatment [29]. For those patients with incompleteresponse to anti-VEGF-A therapy, there is great interest intargeting other molecules involved in angiogenesis.

3. Existing treatment

3.1. Previous nAMD treatments

Prior to the advent of anti-VEGF-A therapy, nAMD was treatedwith focal laser therapy, intravitreal steroids, photodynamic ther-apy with verteporfin, and surgical excision of choroidal

neovascular membranes. These treatments did not significantlyimprove vision and thus are not used frequently today [28]. The2004 United States Food and Drug Administration (US FDA)approval of Pegaptanib (Macugen, Eyetech) for the treatmentof nAMD ushered in the new era of anti-VEGF therapy. Currently,the most commonly utilized anti-VEGF agents include ranibizu-mab, aflibercept, and bevacizumab, which are summarized inTable 1.

4. Current research goals

Given the limitations of the efficacy of anti-VEGF-A therapyand the burden of repeated intravitreal injections, alternatetherapies and delivery systems are being developed. Anti-platelet-derived growth factor (anti-PDGF) therapy has beenan area of recent research focus, as several companies havedeveloped investigational therapies in this class with theintent to combine them with anti-VEGF-A therapy. Othernew therapies modulate the Tie-2 receptor kinase, whichwhen activated, reduces vascular permeability. The desire toreduce injection frequency has led to the development ofsustained-release formulations of anti-VEGF drugs, along withtopical and oral formulations. Gene therapy with viral vectorsholds the potential to produce continuous expression of anti-VEGF-A in the eye after only one administration.

5. Scientific rationale for anti-VEGF-A monotherapyand combination therapies

5.1. The role of VEGF

VEGF plays a key role in both angiogenesis and vascularpermeability [30]. The VEGF family of proteins includes VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E, and placental growthfactor (PLGF) [31]. The actions of VEGF family members aremediated by the activation of tyrosine-kinase receptors. VEGF-A is a critical regulator of ocular angiogenesis and vascularpermeability; there are various isoforms of VEGF-A resultingfrom alternative mRNA splicing of exons, which determine itsheparin-binding ability and diffusibility through tissues [31].VEGF-A acts at VEGFR 1 and 2. VEGF-A mediates angiogenesisby promoting endothelial cell migration, proliferation, andsurvival [32]. VEGF-A also possesses inflammatory propertiesthrough its capacity to mediate microvascular permeabilityand increase adhesion of leukocytes [33].

5.2. The role of platelet-derived growth factor (PDGF)

Several studies suggested that limitations of anti-VEGF-A ther-apy may be related to pericytes [34–36]. Pericytes aremesenchymal cells that share a common basement membranewith endothelial cells, effectively covering them, while alsoproviding VEGF-A and other growth factors via paracrine sig-naling [37,38]. Hence, anti-PDGF therapy was aimed at strip-ping pericytes in order to increase the potency of anti-VEGF-Atherapy. Furthermore, PDGF may be involved in subretinalfibrosis, and anti-PDGF therapy was postulated to potentiallydecrease this cause of permanent vision loss in nAMD.

Article Highlights

● Despite impressive advancements in the treatment of neovascularage-related macular degeneration over the past two decades withanti-vascular endothelial growth factor (anti-VEGF) therapy, there isgreat need to reduce the treatment burden from frequent injections.

● Brolucizumab and abicipar pegol are two novel anti-VEGF agents thatdemonstrated promising results with 12-week dosing in phase 3clinical trials. Conbercept, another anti-VEGF agent that has beenapproved in China, is undergoing phase 3 trials in the United States.

● Faricimab is a bispecific antibody targeting both VEGF-A and angio-poietin-2, which is now in phase 3 trials after 12 and 16-week dosingwas non-inferior to monthly ranibizumab in phase 2 trials.

● Topical anti-VEGF therapy so far has failed to reduce the need forrescue intravitreal anti-VEGF injections in clinical trials, though PAN-90806 is currently being studied in phase 1/2 trials.

● The ranibizumab Port Delivery System is in phase 3 studies after thephase 2 LADDER study demonstrated the majority of patients weremaintained for 6 months or more without requiring an initial med-ication refill. Other sustained-release anti-VEGF delivery treatmentssuch as GB-102, hydrogel depot, Durasert, and ENV1305 are in earlierphase studies.

● Several viral vector-based genetic therapies under study aim torelieve the burden of persistent anti-VEGF therapy, with potentialfor a one-time treatment.

This box summarizes the key points contained in the article.

2 H. AL-KHERSAN ET AL.

5.3. The role of the Tie-2 receptor

Another target of interest in treating exudative vascular dis-eases of the retina is the Tie-2 tyrosine-kinase receptor, whichis expressed on endothelial cells. Tie-2 receptor activationresults in reinforcement of junctional proteins and stabiliza-tion of vasculature to limit permeability [39]. Angiopoietin-1(Ang-1) is a ligand that activates the Tie-2 receptor, therebylimiting vascular leakage [40] and promoting homeostasis.Angiopoietin-2 (Ang-2), which is upregulated in diseasestate, is a competitive antagonist to Ang-1, and hence ele-vated Ang-2 levels cause increased vascular leakage [41].Several new drugs have been designed to inhibit Ang-2,thus allowing the constitutively secreted Ang-1 to activatethe Tie-2 receptor. Another approach targets the enzyme,vascular endothelial protein tyrosine phosphatase (VE-PTP),which inactivates the Tie-2 receptor [42] and more directlyaffects the phosphorylation and activation of Tie-2.

6. Drugs and delivery systems in development

6.1. Future anti-VEGF medications

See Table 2 for a summary of anti-VEGF-A medications indevelopment.

6.1.1. BrolucizumabBrolucizumab (Novartis) is a 26 kDa, humanized single-chainantibody fragment that, like existing anti-VEGF therapy, tar-gets VEGF-A. However, brolucizumab is the first single-chainantibody to be developed for nAMD and is smaller thanranibizumab (48 kDa) and aflibercept (115 kDa). The smallermolecule size facilitates higher molar concentration, 11–13times greater than that of aflibercept.

The efficacy of brolucizumab in the treatment of nAMD wasevaluated in HAWK and HARRIER, two prospective, RCTs [43]. Inthe HAWK study, 1082 patients were enrolled with 1:1:1 rando-mization into treatment with brolucizumab 3 mg, brolucizumab6 mg, or aflibercept 2 mg. All groups received injections every 4weeks for the first 12 weeks. Beginning at week 16, the afliber-cept group received treatment every 8 weeks. The brolucizumabgroups received injections either every 8 or 12 weeks, dependingon functional and anatomical disease activity assessment bya masked physician. The HARRIER study was carried out concur-rently with two treatment arms, a brolucizumab 6 mg group andan aflibercept 2 mg group.

Brolucizumab met the primary efficacy objective of non-inferiority in BCVA from baseline to week 48 compared toaflibercept [44]. Additionally, brolucizumab demonstratedsuperiority in the secondary endpoints of the degree ofcentral subfield thickness (CST) and presence of retinalfluid. Two-year data demonstrated that fewer patients withnAMD had retinal fluid with brolucizumab 6 mg compared toaflibercept in HAWK (24% vs 37%, respectively, p = 0.0001)and HARRIER (24% vs 39%, respectively, p < 0.0001).Reduction in CST was also greater at 96 weeks in the 6 mgbrolucizumab group compared to aflibercept in both HAWK(−175 µm vs −149 µm, respectively, p = 0.0057) and HARRIER(−198 µm vs −155 µm, respectively, p,0.0001) [43].Ta

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EXPERT OPINION ON PHARMACOTHERAPY 3

Importantly, at 48 weeks, 57% of HAWK patients and 52%of HARRIER patients in the 6 mg brolucizumab group weremaintained on a 12-week treatment interval after the initialloading phase. At 96 weeks, among patients that completed48 weeks of treatment on a 12-week interval, 82% in theHAWK trial and 75% in HARRIER remained on a 12-week dos-ing interval through year two. A new drug application forBrolucizumab along with a priority review voucher was sub-mitted to the US FDA in 2019 for expedited review.

6.1.2. Abicipar pegolAbicipar pegol is a DARPin® (Designed Ankyrin Repeat Protein)based anti-VEGF drug being evaluated for the treatment ofnAMD. DARPin® therapeutics are a class of small proteins derivedfrom natural ankyrin repeat proteins, which bind to a singletarget. Abicipar was compared to ranibizumab in two Phase 3clinical trials (SEQUOIA and CEDAR) sponsored by Allergan andMolecular Partners [45]. Both the SEQUOIA and CEDAR trialsconsisted of three treatment arms: abicipar every 8 weeks, abici-par every 12 weeks, and the control, ranibizumab every 4 weeks.The 8-week abicipar arm received three monthly doses followedby the 8-week treatment interval. The 12-week abicipar armreceived twomonthly doses followed by the 12-week treatment.The primary endpoint was the proportion of treated patientswith stable vision in one year.

In the SEQUOIA study, the reported proportion of patientstreated with abicipar maintaining stable vision was 94.8% and91.3% in those dosed with abicipar every 8 and 12 weeks, respec-tively, at 52 weeks [45]. This was compared to 96% of patientsmaintaining stability with monthly dosed ranibizumab. In CEDAR,the proportion of patients with stable vision in the abicipar groups

was 91.7% and 91.2% when dosed every 8 and 12 weeks, respec-tively.Monthly dosed ranibizumabdemonstrated stability in 95.5%of patients.

While the results of SEQUOIA and CEDAR appear promising,with 6 or 8 injections of Abicipar showing similar efficacy to 13ranibizumab injections in the first year, the rates of intraocularinflammation were significantly higher in the abicipar groupscompared to ranibizumab. In SEQUOIA, 15.7% and 15.3% of theabicipar 8- and 12-week groups, respectively, demonstratedintraocular inflammation compared to 0.6% in the ranibizumabarm. In the CEDAR trial, reported rates of intraocular inflamma-tion rates were 15.1% and 15.4% in the 8- and 12-week abicipargroups, respectively, compared to 0% in the ranibizumab arm.The reason for this result is currently under investigation [45].A reformulated agent is being studied in the smaller MAPLEstudy [46] and in April 2019, Allergan announced topline safetyresults. In this open-label study, 123 nAMD patients receivedthree monthly 2 mg abicipar injections followed by 2 mg injec-tions every 8 weeks through week 28, with an incidence ofintraocular inflammation of 8.9% percent, mostly assessed asmild to moderate in severity. The incidence of severe inflam-mation was 1.6% with one reported case of iritis and onereported case of uveitis. There were no reported cases ofendophthalmitis or retinal vasculitis in MAPLE [47].

6.1.3. OPT-302OPT-302 (Opthea) targets VEGF-C and VEGF-D, which may playa complementary role in nAMD pathogenesis, in addition toanti-VEGF-A. A phase 1/2a study (NCT02543229) showed thatin treatment-naïve patients, intravitreal injections of bothOPT-302 2 mg and ranibizumab 0.5 mg administered every 4

Table 2. Summary of emerging drugs to treat neovascular age-related macular degeneration (nAMD).

Compound Company Stage of development Structure/mechanism of action

Brolucizumab Novartis Phase 3 completed Small MW humanized single-chain Fab anti-VEGF-AAbicipar pegol Allergan Phase 3 completed DARPin antagonist of VEGF-AOPT-302 Ophthea Phase 2b; outcomes pending Anti-VEGF-C/VEGF-DConbercept Chengdu Kanghong Biotech Co., Ltd. Phase 3 underway Anti-VEGFR1/2KSI-301 Kodiak Sciences Phase 1b underway Anti-VEGF antibody biopolymer conjugatePegpleranib (Fovista) Ophthotech Phase 3 did not meet endpoint Anti-PDGF-B aptamerRinucumab-aflibercept Regeneron Phase 2 did not meet endpoint Anti-PDGF-B/anti-VEGF co-formulationX-82 Tyrogenex Phase 2 completed Oral anti-VEGF-A/PDGFRNesvacumab-aflibercept Regeneron Phase 2 did not meet endpoint Ang-2/VEGF-A mAb co-formulationFaricimab Roche Phase 3 underway Bispecific Ang-2/VEGF-A antibodyARP-1536 Aerpio Preclinical Tie-2 receptor activation (via VE-PTP inhibition)Pazopanib GlaxoSmithKline Phase 2b results (2015) TKI of VEGFR/PDGFRSqualamine lactate Ohr Pharmaceuticals Phase 3 did not meet endpoint TKI of VEGF-A/PDGF/bFBFRegorafenib Bayer Healthcare Phase 2a did not meet endpoint TKI of VEGF-A/PDGFLHA510 Alcon Phase 2 completed VEGF-A inhibitorPAN-90806 PanOptica Phase 1/2 underway TKI of VEGF-A/PDGFRanibizumab PDS Genentech Phase 3 underway Refillable port of VEGF-A mAbGB-102 GrayBug Vision Phase 2b upcoming Bioerodible nanoparticles encapsulate TKI of VEGFR/PDGFRNT-503 ECT Neurotech Phase 2 terminated VEGF-A receptor fusion proteinHydrogel depot Ocular Therapeutix Phase 1 underway Sustained release anti-VEGF-ADurasert pSivida Preclinical TKI of VEGF-A/PDGFENV1305 Envisia Therapeutics Preclinical Sustained release anti-VEGF-AAVA-101 Adverum Biotechnologies Phase 2a completed AAV sFLTADVM-022/ADVM-032 Adverum Biotechnologies Phase 1 underway AAV encoding anti-VEGF-A cDNAAAV2-sFLT01 Genzyme (Sanofi) Phase 1 completed AAV sFLTRGX-314 Regenxbio Phase 2b upcoming AAV8 encoding anti-VEGF-ARetinostat Oxford Biomedica Phase 1 completed EIAV encoding endostatin and angiostatin

MW = molecular weight, Fab = fragment antibody, VEGF = vascular endothelial growth factor, DARPin = designed ankyrin repeat protein, PDGF = platelet-derivedgrowth factor, TKI = tyrosine-kinase inhibitor, Ang-2 = Angiopoietin-2, mAb = monoclonal antibody, VE-PTP = vascular endothelial-protein tyrosine phosphatase,PDGFR = platelet-derived growth factor receptor, bFBF = beta fibroblast growth factor, VEGFR = vascular endothelial growth factor receptor, AAV = adeno-associated virus, sFLT = soluble fms-like tyrosine-kinase 1, cDNA = complementary deoxyribonucleic acid.


weeks resulted in meaningful additional VA gain and reduc-tion in macular thickness compared to ranibizumab alone at12-week follow up. The proportion gaining ≥ 5, ≥ 10 or ≥ 15letters of vision from baseline to week 12 was 67%, 44%, and33%, respectively, in treatment-naïve subjects (baseline meanBCVA of 56.4 letters), while it was 53%, 16% and 0% forpatients previously treated with multiple anti-VEGF-A agents(baseline mean BCVA 64.5 letters). The difference of eightETDRS letters in baseline BCVA between these groups mayhave created a ceiling effect for the previously treated group.Of 13 participants who received OPT-302 monotherapy treat-ment, 54% did not require anti-VEGF-A rescue therapy overthe entire 12 weeks, with an additional 38% receiving only oneanti-VEGF-A rescue injection, while 1 subject received 2 rescueinjections. The mean time to first intravitreal injection of res-cue therapy (based on investigator discretion) was 58 days.Phase 2B trials have concluded enrollment and will compareranibizumab monotherapy with OPT-302 2 mg/ranibizumab0.5 mg, and OPT-302 0.5 mg/ranibizumab 0.5 mg in 351 treat-ment-naïve patients over 6 months. Outcomes are expected inlate 2019.

6.1.4. ConberceptConbercept (Chengdu Kanghong Biotech Co., Ltd.) isa recombinant fusion protein that is comprised of the secondIg domain of VEGFR1 and both the third and fourth Ig domains ofVEGFR2 on the Fc of human IgG1. The drug has been approvedfor the treatment of nAMD in China. The PHOENIX trial wasa Phase 3 52-week study conducted in China. One treatmentarm received conbercept 0.5 mg monthly for three monthsfollowed by 0.5 mg every three months compared to a delayedtreatment group, which had sham injections for three monthsfollowed by 0.5 mg conbercept monthly for three months andfinally quarterly injections until month 12. The immediate treat-ment group of conbercept demonstrated 9.9-letter improve-ment from baseline while the delayed treatment group showed8.8-letter improvement, both statistically significant [48].

Additional registration studies will compare conbercept tostandard of care. Specifically, two Phase 3 head-to-head stu-dies of conbercept and aflibercept (PANDA-1 and PANDA-2)(NCT03577899 and NCT03630952, respectively) will comparetwo doses of conbercept (0.5 mg and 1.0 mg) to 2.0 mgaflibercept. The primary outcome is mean change from base-line in VA at 36 weeks. The PANDA-1 trial is currently recruitingwith an estimated primary completion date of October 2020.

6.1.5. KSI-301KSI-301 (Kodiak Sciences) has developed a novel anti-VEGF anti-body biopolymer conjugate (ABC platform™) for the treatmentof nAMD and other retinal vascular diseases. In a small phase 1astudy of 9 patients with severe diabetic macular edema (DME),a single dose of KSI-301 was well tolerated and showed durationof response at 12 -week follow up, with a median of 9 ETDRSletter improvement across all dose groups. The highest dosetested, 5 mg, has been selected for advancement into futurestudies. A multiple-dose phase 1b study in patients with treat-ment-naïve nAMD, DME, and RVO is now recruiting patients

(NCT03790852). The phase 1b study for nAMD, which will com-pare 8-week dosing of aflibercept with 12, 16, and 20-weekdosing of KSI-301, is expected to have an interim readout ofthe data in 2020 [49].

6.2. Anti-VEGF plus anti-PDGF combination therapy

As noted above, pericytes may play a role in limiting theefficacy of anti-VEGF-A therapy. Consequently, combinationsof anti-PDGF therapies, which target pericytes, and anti-VEGF-A therapies were thought to have potential for enhancedefficacy over anti-VEGF-A mono-therapy. However, as of thewriting of this review, combination therapy has not provensuperiority to monotherapy in phase 3 randomized clinicaltrials as discussed below.

6.2.1. PegpleranibPegpleranib (Fovista®, Ophthotech) is a 32-mer pegylated DNAaptamer that selectively binds to PDGF-BB homodimers andPDGF-AB heterodimers to prevent their binding with PDGF tyr-osine-kinase receptors expressed on pericytes. The phase 2bstudy enrolled 449 treatment-naïve patients with nAMD andshowed that the 1.5 mg pegpleranib/0.5 mg ranibizumab com-bination therapy regimen outperformed ranibizumabmonother-apy, supporting advancement to phase 3 [50]. However, anOphthotech/Novartis press release from December 2016announced that phase 3 trials (NCT01944839) of combinationtherapy did not meet its primary endpoint, and further develop-ment of pegpleranib was halted [51,52].

6.2.2. RinucumabRinucumab (Regeneron) is an anti-PDGF receptor-β antibody. Ithas been co-formulated with aflibercept for a single injectionthat was studied in the phase 2 CAPELLA trial (NCT02418754).At 12-week follow up, rinucumab/aflibercept failed to meet itsprimary endpoint of improved BCVA compared to afliberceptalone as announced in September 2016 [52,53].

6.2.3. X-82X-82 (Tyrogenex) is an oral anti-PDGF and VEGF-A inhibitor. Inthe Phase 1 dose-escalation study (NCT02348359), 10 of 35patients (29%) did not complete the 24-week endpoint, withsix (17%) withdrawing due to adverse events. The most com-mon adverse events were diarrhea (n = 6), nausea (n = 5),fatigue (n = 5), and elevated transaminase enzymes (n = 4)that reversed with cessation of X-82. Twenty four of the 25patients that completed the 24-week trial showed stable orimproved VA (mean +3.8 letters), and 15 of 25 (60%) did sowithout need for rescue ranibizumab injections. Mean centralsubfield thickness was reduced by a mean of 50 μm [54]. ThePhase 2 APEX study (NCT02348359) tested X-82 at doses of50 mg, 100 mg, and 200 mg with as-needed anti-VEGF com-pared to placebo and as-needed anti-VEGF. The primary out-come was the change in VA from baseline to 52 weeks. Thestudy was terminated after an interim analysis. Participants inthe 200 mg arm gained a mean of 1.7 letters while those inthe placebo arm lost a mean of 0.3 letters.


6.3. Anti-VEGF-A plus Tie-2 receptor modulatorcombination therapy

As noted above, activation of the Tie-2 receptor stabilizes vas-culature and limits permeability. Consequently, modulating theTie-2 receptor in combination with anti-VEGF-A therapy mayprovide enhanced efficacy over anti-VEGF-A monotherapy.

6.3.1. NesvacumabNesvacumab (Regeneron) is an Ang-2 inhibitor that, whencombined with aflibercept, was thought to have potential toincrease the duration of aflibercept’s anti-permeability effects.Nesvacumab-aflibercept was well tolerated by 20 patients ina phase 1 trial sponsored by Regeneron. VA and anatomicalimprovements at all dose levels were encouraging [55,56]. Thephase 2 ONYX study (NCT02713204) compared nesvacumaband aflibercept combination therapy to aflibercept monother-apy [52]. The primary endpoint was change in BCVA at 12 and36 weeks. Regeneron announced in November 2017 that theresults of the trial failed to show significant differentiation anddid not warrant a Phase 3 evaluation.

6.4. Faricimab

Faricimab (Roche/Genentech) is a bispecific antibody targetingboth VEGF-A and angiopoietin-2 (Ang-2). The AVENUE trial,a phase 2, 273-patient study, compared treatment with ranibizu-mab 0.5 mg every 4 weeks, faricimab 1.5 mg every 4 weeks,faricimab 6mg every 4 weeks, faricimab 6mg every 8 weeks, andfaricimab 6 mg/ranibizumab 0.5 mg combination therapy (threeranibizumab injections every 4 weeks, followed by faricimabevery 4 weeks) in treatment-naïve nAMD. The primary outcomewasmean change in BCVA frombaseline at 36weeks. The 1.5mgfaricimab arm given every 4 weeks demonstrated the best gainsof +9.1 letters at 36 weeks. All arms showed significant decreasesin CST, with the combination therapy arm demonstrating thelargest reduction of −185 µm [57].

Another phase 2 trial, STAIRWAY, was a 52-week study thatcompared faricimab 6 mg given either every 12 or 16 weekscompared to ranibizumab 0.5 mg every 4 weeks in 76 treatment-naïve patients with nAMD [58]. In the two faricimab groups,patients initially received 4 monthly injections followed by far-icimab 6mg either every 12 or 16 weeks. The ranibizumab groupreceived monthly treatment. At 24 weeks, disease activity wasassessed using protocol-defined criteria including BCVA, OCT,and clinical examination. If patients were found to have activedisease, they were moved from the 16-week faricimab group tothe 12-week group. This assessment at 12 weeks showed that65% of patients treated with farcicimab had no protocol-definedactivity 12weeks after their last injection. At 52weeks, patients inthe 12-week group gained 10.08 letters, those in the 16-weekgroup gained 11.42 letters, and the ranibizumab group hadamean gain of 9.59 letters. Phase 3 trials (LUCERNE) are expectedto conclude in August 2021 (NCT03823300).

6.5. ARP-1536

ARP-1536 (Aerpio Therapeutics) is a novel monoclonal anti-body that activates the Tie-2 receptor by an alternative

pathway. VE-PTP is the most downstream negative regulatorof Tie-2. ARP-1536 is administered by intravitreal injection andbinds to the extracellular domain of VE-PTP, inhibiting it, andthus causing increased activation of the Tie-2 receptor. Pre-clinical studies have established biologic activity. AKB-9778,Aerpio’s other VE-PTP inhibitor, is administered by subcuta-neous injection. Most recently, it was assessed in the TIME-2bPhase 2 clinical trial, which enrolled patients with moderate tosevere non-proliferative diabetic retinopathy (NPDR) withoutDME; the company recently announced that this study did notreach its primary endpoint of ≥2-step improvement in diabeticretinopathy severity score at 48 weeks, but other endpointssuggested improved intraocular pressure and renal function inthose patients treated with AKB-9778.

7. Topical treatments

7.1. Pazopanib

Pazopanib (GlaxoSmithKline) is a topical VEGF-A tyrosine-kinase inhibitor (TKI) that inhibits both VEGF-A and PDGF.Phase 2b trial results were released in 2015. In a 510-patientstudy, at the 52-week endpoint, Pazopanib QID combinedwith as-needed ranibizumab was found to be non-inferior toranibizumab dosed as-needed or monthly; however, the addi-tion of pazopanib did not decrease the number of as-neededranibizumab injections by >50% (the prespecified minimumcriterion of efficacy). There was no significant difference inretinal thickness and size of lesion between groups [59]. Noannouncement for further development of pazopanib hasbeen announced by GlaxoSmithKline since these results wereannounced.

7.2. Squalamine lactate

Squalamine lactate eyedrops (Ohr Pharmaceutical) preventdownstream signaling of multiple angiogenic factors (VEGFreceptor-1, VEGF receptor-2, PDGF receptor, and b-FGF receptor).The phase 2 IMPACT study (NCT02511613) compared squala-mine drops twice daily plus ranibizumab as needed with placeboplus ranibizumab as needed. The trial did not meet its primaryendpoint goal of decreasing the frequency of ranibizumab injec-tions and did not show a significant difference in BCVA in thosewho completed the trial. In January 2018, Ohr Pharmaceuticalannounced that the MAKO study (NCT02727881), a phase 3study evaluating the efficacy of topical squalamine in combina-tionwithmonthly ranibizumab, failed tomeet its primary efficacyendpoint. Patients in the combination squalamine/ranibizumabarm achieved mean gains of 8.33 letters from baseline comparedto 10.58 letters with ranibizumab monotherapy at nine months.No plans to continue development have been announced.

7.3. Regorafenib

Regorafenib (Bayer Healthcare) is a multi-kinase inhibitor thatacts on intracellular signaling of VEGF-A and PDGF receptors.It was developed as a topical eyedrop given three times dailyto treat nAMD. The Phase 2a DREAM study (NCT02222207) didnot show efficacy that was comparable to previously existing


nAMD treatments, and all 21 enrolled patients required res-cue ranibizumab treatments. Studies on regorafenib werehalted [60].

7.4. LHA510

Alcon has developed a topical anti-VEGF-A medication,LHA510, which has been tested as maintenance therapy forpatients with nAMD. The phase 2 study (NCT02355028) com-pared initial ranibizumab plus topical LHA510 for 84 daysversus initial ranibizumab plus placebo, with the primary end-point being the number of patients requiring rescue ranibizu-mab injections before day 84. Results demonstrated that75.8% of subjects in the treatment arm required ranibizumabrescue compared to 67.6% in the placebo arm [61]. There havenot been any updates provided since the completion of thephase 2 study, to the best of the authors’ knowledge.

7.5. PAN-90806

PAN-90806 (PanOptica), another VEGF-A inhibitor eyedrop, hasbeen shown to produce an anti-VEGF-A response comparable tocurrently available anti-VEGF-A therapies in half of 50 treatment-naïve nAMD patients, according to a phase 1/2 study(NCT02022540) presented at the 2016 American Academy ofOphthalmology Retina Subspecialty Day. A new phase 1/2 clin-ical trial of an updated formulation for patients with nAMDdosedthe first patient in mid-2018 (NCT03479372). This newer suspen-sion was designed to reduce the incidence of punctate kerato-pathy as a side effect [62]. The estimated study completion dateis June 2019.

8. Sustained delivery treatments

8.1. Ranibizumab port delivery system

The need for frequent intravitreal injections has spurred severalcompanies to develop sustained-release anti-VEGF-A devices.The ranibizumab Port Delivery System (PDS), which isa nonbiodegradable port fixed to the sclera, has a 0.05 ml reser-voir that can be refilled in the office. Phase 1 results indicatedthat it improved VA comparable to monthly ranibizumab injec-tions as reported in the MARINA and ANCHOR studies [63]. The20 patients in the trial gained amean of 10 ETDRS letters and hada mean of 4.8 refills given at 12-month follow up. Three seriousadverse events (related to the implantation procedure) werereported, including endophthalmitis and persistent vitreoushemorrhage.

The phase 2 LADDER trial randomized 179 patients toimplantation of the PDS with doses of ranibizumab of either10, 40, or 100 mg/mL [64]. Among the PDS group with the100 mg/mL ranibizumab dose, approximately 80% were main-tained for 6 months or more without needing an initial medica-tion refill. In the 10 and 40 mg/mL groups, 63.5% and 71.3%,respectively, went 6 months or more without a refill. A phase 3(NCT03677934) trial is currently underway and expected to becompleted in 2021 [64].

8.2. GB-102

GB-102 (GrayBug Vision) is Sunitinib maleate, a multitargetedTKI with activity against both VEGF-A and PDGF. It is aninjectable depot designed for twice per year formulation.The drug is encapsulated within bioerodable polymer nano-particles that slowly degrade over time. The patented GrayBugformulation is designed to avoid the inflammatory responseseen with other nanoparticles, and the nanoparticles are toremain at the injection site to avoid clouding the visual axis.Phase 1/2a study (ADAGIO) results were announced inJanuary 2019. The study met its primary endpoint of safetyand tolerability, with no dose-limiting toxicities or ocular ser-ious adverse events. There was durable pharmacodynamiceffect with 3 and 6-month dosing duration achieved in 88%and 68% of patients, respectively. However, there was micro-particle-related anterior chamber migration and mild ocularhypertension, which was self-limited. A phase 2b study in wetAMD will initiate in 2019 with a new GB-102 manufacturingprocess optimized to eliminate particle dispersion [65].

8.3. NT-503 encapsulated cell therapy (ECT) implant

NT-503 (Neurotech) is essentially a reversible gene therapy.ECT is an intravitreal implant inserted through a 3 mm scleralincision, which houses an RPE cell line genetically engineeredto produce several therapeutically active biologics for at least2 years. NT-503 is a novel VEGF-A receptor fusion protein thatis continuously secreted by the platform. A Neurotech pressrelease announced that the phase II study (NCT02228304) wasdiscontinued due to a larger than expected number of parti-cipants requiring rescue medication in the treatment arm [66].

8.4. Hydrogel anti-VEGF depot

Ocular Therapeutix developed a hydrogel depot that uses poly-ethylene glycol to create a sustained drug delivery system for anti-VEGF-A that can last for six months. The hydrogel creates a tightmeshwork that contains the anti-VEGF-A particles and graduallydissolves, allowing the medication to diffuse. The released anti-VEGF-A particles have been stable and have not demonstratedchemical changes. Phase I studies of the hydrogel depot are inprocess; the first patient was dosed in February 2019 [67].

8.5. Durasert

The Durasert™ Bioerodible TKI (EyePoint Pharmaceuticals) isa sustained-release implant that delivers tyrosine-kinase inhi-bitors that inhibit both VEGF-A and PDGF. IND-enabling stu-dies with the Durasert implant are underway [68].

8.6. ENV1305

ENV1305 (Envisia Therapeutics) is a sustained-release anti-VEGF-A that utilizes PRINT® nanoparticle technology, which isa proprietary system capable of engineering highly precise nano-particle systems, with potential for better control of drug release.The rights to the PRINT® nanoparticle technology were acquiredby Aerie Pharmaceuticals, Inc. in October 2017. Per company


reports, Aerie plans to use the technology to manufacture inject-able implants containing a pre-clinical product, AR-13154, aninhibitor of Rho kinase and Protein kinase C.

9. Gene therapy

Recently, the eye has become a target for investigational genetherapy due to the monogenic nature of many inherited retinaldiseases (IRDs), its accessibility, tight blood-ocular barrier, theability to non-invasively monitor for functional and anatomicoutcomes, as well as its relative immune-privileged state. Genetherapy for nAMD offers the promise of long-term continuousexpression of anti-VEGF-A protein with a single administration.Viral vectors are conduits for transferring desired genetic infor-mation to host cells. Vectors currently used in ocular genetherapy clinical trials include adeno-associated virus (AAV),small single-stranded DNA viruses of the parvovirus family, andlentivirus, RNA viruses of the retrovirus family. After successfultransduction, the target cells transcribe and translate the viralgenetic material into therapeutic protein, which then modulatesthe pathogenesis of the targeted disease process.

9.1 rAAV.sFLT-1 (AVA-101)

Avalanche Biotechnology assessed rAAV.sFLT-1 (also calledAVA-101) in a ‘biofactory approach’ to transfect retinal cellsfor chronic secretion of the natural anti-VEGF-A inhibitor,soluble fms-like tyrosine kinase-1 (sfLT-1). The phase I study(NCT01494805) results were published in 2015, with three-yearoutcomes published in 2017 [69,70]. In the phase IIa RCT,patients were randomized to either subretinal rAAV.sFLT-1gene therapy (n = 21) or to the control group (n = 11), andthere was no meaningful improvement in VA [71].

9.2. ADVM-022/ADVM-032

Following the disappointing results from this phase IIa trial,Avalanche Biotechnologies merged with AnnapurnaTherapeutics to become Adverum Biotechnologies. Theirnext generation gene therapy products for nAMD, ADVM-022and ADVM-032 utilize an AAV vector (AAV.7 m8) that has beenoptimized for intravitreal injection of vectors carrying anti-VEGF cDNA, leading to the expression of aflibercept and rani-bizumab, respectively. According to publicly disclosed corpo-rate materials, both ADVM-022 and ADVM-032 inhibit laser-induced CNV in a primate model at day 28, comparable inextent to intravitreal injections of aflibercept and ranibizumab,respectively, and expression was sustained for approximatelytwo years post-dose. ADVM-022 has been selected to advance,and a Phase I trial (OPTIC) (NCT03748784) is underway with anexpected completion date of June 2020. The multi-center,open-label, phase 1, dose-escalation trial will enroll 18 patientswith nAMD who are responsive to anti-VEGF treatment. InNovember 2018, Adverum announced that the first patienthad been dosed. In May 2019, the company announced thatno patient in the first cohort experienced a serious adverseevent (SAE), with the first patient completing the 24-week (6months) assessment, and that the FDA and the DataMonitoring Committee cleared dose escalation. Also, the

company noted that, based on a robust preliminary anatomi-cal response in the first cohort (n = 6), it will begin dosingthe second cohort at a three-times lower dose than in the firstcohort [72].

9.3. AAV2-sFLT01

Sanofi Genzyme investigated intravitreal delivery of AAV2-sFLT01 (NCT01024998). The sFLT1 produced by this company issimilar to that used in the Avalanche studies, except that it isa fusion protein of the sFLT-1 domain 2 with the Fc domain ofIgG1. In a phase I, dose-escalation trial, 19 patients withadvanced nAMD were treated with a single 100 μL intravitrealinjection of AAV2-SFLT01. The therapy was generally welltolerated, though there was a high degree of variability inexpression and anti-permeability activity among the 19patients [73]. The company has not expressed any plans tocontinue development of this therapy.

9.4. RGX-314

Regenxbio is developing a novel AAV8 vector, RGX-314, whichexpresses a soluble anti-VEGF monoclonal antibody fragment,similar to ranibizumab, in transduced retinal cells. The com-pany suggests that their proprietary gene delivery platform(NAV® Technology Platform) may yield higher levels of anti-VEGF expression than earlier generation AAV vectors. In non-human primates, maximal expression of therapeutic protein inthe anterior chamber treated with RGX-314 measured 4,992ng/ml, compared to 528 and 0.217 ng/ml for the Genzymeand Avalanche therapies, respectively, [74].

RGX-314 is to be administered via subretinal injection duringvitrectomy and a phase I, open-label dose-escalation trial(NCT03066258) is underway. The primary endpoint involvessafety assessments at 26 weeks. Secondary endpoints, assessedat 106 weeks, include change in BCVA, change in central retinalthickness, mean number of rescue anti-VEGF injections, meanchange in area of CNV and leakage. Interim results, announced inOctober 2018, showed dose-dependent protein expressionlevels and dose-dependent reductions in anti-VEGF injections,as well as maintenance of central retinal thickness and vision. Insubjects treated with the 6 x 1010 (Cohort 3) genome copies/eyedose, 50% did not require anti-VEGF injections at 6 months. Inthis same cohort, RGX-314 protein expression continued to bedetected in all subjects at sixmonths. In January 2019, Regenxbioannounced the expansion to a Phase IIa trial to include additionalsubjects in two higher-dose cohorts and anticipates initiatinga larger, randomized, controlled Phase IIb clinical trial in late2019 [75]. In May 2019, it announced continued tolerance withno drug-related SAEs. At one year after administration of RGX-314, Cohort 3 subjects continued to demonstrate sustained anti-VEGF protein expression levels, mean BCVA improvement of +5letters from baseline and a mean of 2.3 anti-VEGF injections overone year versus over 35 anti-VEGF injections, since diagnosis,prior to RGX-314 treatment; 50% of subjects (3/6) in Cohort 3continue to remain injection-free at one year with persistentlystable BCVA (+10 letters from baseline) and CST (−59 μm frombaseline). In addition, the study has completed dosing thehigher-dose Cohort 4 subjects and is nearing completion of


Cohort 5 enrollment, with expectations of top-line data by theend of 2019. Importantly, Regenxbio announced plans to filea new IND for a Phase II trial evaluating RGX-314 in subjectswith diabetic retinopathy (DR) in the second half of 2019 [76].

9.5. Retinostat

Retinostat (Oxford Biomedica) is a lentivector platform basedon the recombinant equine infectious anemia virus (EIAV). It isdelivered by subretinal injection and encodes the anti-angiogenic proteins endostatin and angiostatin [77].A bicistronic expression cassette leads to production of bothmolecules from one lentivirus vector. This approach derivesfrom preclinical work demonstrating that direct intravitrealinjections of either AAV-endostatin, AAV-angiostatin, or lenti-viral vector-angiostatin significantly inhibited a neonatal mur-ine model of proliferative retinopathy [78,79]. The phase 1‘Gene transfer of Endostatin/angiostatin for Macular degen-eration’ (GEM) trial (NCT01301443) enrolled 21 patients withadvanced nAMD (poorly responsive to anti-VEGF-A therapy)to receive three dosing cohorts over a 48-week period.Overall, there were no adverse effects related to the lentivec-tor platform. There were sustained high levels of angiostatinand endostatin expressed in the eye throughout the study, asdetermined by direct sampling from the anterior chamber.A reduction in leakage on FA occurred in 71% of patients, butonly one patient showed a significant reduction in intraret-inal/subretinal fluid compared to baseline [80]. These resultsmay have been limited by advanced nAMD disease.

10. Potential development issues

In addition to the issues described above, anti-VEGF-A therapyhas some associated ocular and systemic risks, both real andtheoretical. Some feel that there may be an increase in arter-iothrombotic events (stroke and myocardial infarction) asso-ciated with anti-VEGF-A injections [81]. Repeated injectionsmay also place patients at higher risk of developing complica-tions such as endophthalmitis, retinal pigment epitheliumatrophy and tears, retinal tears, traumatic cataract, and ocularhypertension [81–85]. The high cost of some of the currentlyavailable anti-VEGF-A treatment options, along with largevolume of patients requiring indefinite injections, placesa strain on the health-care system. As additional therapeuticoptions become available, cost of treatment will undergocareful scrutiny in determining the most appropriate manage-ment for patients.

11. Conclusion

The development of anti-VEGF-A therapy has revolutionizedthe treatment of nAMD. Landmark trials such as the ANCHORstudy demonstrated superiority of anti-VEGF-A injections overphotodynamic therapy for preserving and recovering VA [86].The most widely used anti-VEGF-A medications include bev-acizumab, ranibizumab, and aflibercept. Undoubtedly thesemedications have significantly reduced the worldwide inci-dence of blindness caused by nAMD, although many new

drugs are in development to address the shortcomings of anti-VEGF-A treatment.

Drugs in the pipeline aim to modulate synergistic targetssuch as the Tie-2 receptor, Ang-2, and PDGF, with hopes ofoutperforming anti-VEGF-A monotherapy. Other drugs utilizesustained-release therapy, nanoparticle technology, and smal-ler molecular size in order to extend the duration of anti-VEGF-A effect. Topical and systemic anti-VEGF-A/PDGF therapieshave been explored in attempt to minimize the need forfrequent injections. Gene therapy holds the potential to resultin continuous production of VEGF-A via the retina’s own cel-lular apparatus.

12. Expert opinion

The management of nAMD can be onerous for both thephysician and patient. While anti-VEGF-A injections havebeen monumental in reducing severe vision loss in countlesspatients, this current paradigm requires a major commitmentto continue treatment, possibly indefinitely in some cases.Anti-VEGF-A maintenance therapy poses a treatment burdenon patients, families, and the health-care system, andpatients need to be counseled that preservation of vision isconsidered a success. It is well documented that real-worldoutcomes of anti-VEGF-A treatment fall short of thoseobtained in landmark clinical trials due to inadequate num-bers of injections to optimize visual gains. One approach toreduce the treatment burden of frequent injections has beenthe ‘treat-and-extend’ regimen, in which injections are gra-dually spaced out until a recurrence of fluid occurs. While thisregimen appears to perform relatively well in practice basedmainly on retrospective studies, including one randomizedstudy of 441 patients (LUCAS) [87] and one randomized studyof 60 patients (TREX) [88], the level of evidence is not asstrong without largescale, controlled trials.

Current clinical research seeks to improve visual outcomesfor nAMD, address the treatment ceiling of anti-VEGF-A ther-apy, and reduce the treatment burden of long-term mainte-nance. While anti-VEGF-A/anti-PDGF combination therapyinitially appeared promising, results of the trials of intravitrealrinucumab/aflibercept and pegpleranib/ranibizumab broughtdisappointment. The phase III trial of the topical VEGF-A andPDGF inhibitor, squalamine lactate, subsequently failed tomeet its primary endpoint. Other topical anti-VEGF-A/anti-PDGF therapies for nAMD so far have been unsuccessful inreducing the need for rescue intravitreal injections, as evi-denced by the trials of pazopanib and regorafenib. PAN-90806 still has an ongoing phase 1/2 trial, with hopes that itsnew formulation with higher bioavailability in the centralretina and choroid will outperform the other anti-VEGF topicaltherapies [62].

Despite the underwhelming results of anti-PDGF trials, sev-eral other drugs and drug delivery systems under investiga-tion continue to offer promise. Brolucizumab and abiciparpegol are the two drugs furthest along in development. Theresults of the HAWK and HARRIER phase III trials indicated thatbrolucizumab 6.0 mg dosed every 12 weeks after 3 monthlyloading doses was non-inferior to aflibercept dosed every 8weeks. Recent two-year data demonstrated that the reduction


in CST was greater at 96 weeks in the 6 mg brolucizumabgroup compared to aflibercept in both the HAWK andHARRIER trials. The drug is currently under evaluation by theFDA. If brolucizumab becomes the first anti-VEGF-A drugapproved for 12-week dosing, it could represent a threat toaflibercept’s dominant role in the global anti-VEGF market (ina similar manner to how ranibizumab’s role has declinedrecently). However, given the remarkable economic efficiencyof bevacizumab compared to other available anti-VEGF treat-ments, it seems likely that bevacizumab would continue to bea first line treatment for most VEGF-mediated diseases, withthe newly approved products of the future being utilized inrefractory cases or in VEGF-dependent patients.

Further disruption of this market could occur due to abici-par, which showed noninferiority when dosed every 12 weekscompared to aflibercept dosed every 8 weeks. However, theissue of increased intraocular inflammation with the use ofabicipar compared to ranibizumab is a critical concern thatAllergan continues to address.

Clinical research has continued to broaden the physiologi-cal scope of drug development to include drugs that influencethe Tie-2 receptor pathway, including nesvacumab, faricimab,and ARP-1536. Of these, nesvacumab did not show sufficientlypromising results in Phase II trials for further advancement.Faricimab is the furthest under development. In the phase IISTAIRWAY trial, at 52 weeks, patients in the 12-week faricimabgroup gained 10.08 letters, those in the 16-week group gained11.42 letters, and the ranibizumab monthly dosed group hada mean gain of 9.59 letters. Phase III trials are currentlyunderway.

Regarding extended release formulations of anti-VEGF-Atherapy, the ranibizumab Port Delivery System is the furthestin development. The phase II LADDER trial demonstratedpromising results as approximately 80% of patients dosedwith the 100 mg/mL ranibizumab PDS were maintained for 6months or more without requiring an initial medication refill.

In theory, gene therapy with viral vectors could representthe ultimate form of sustained anti-VEGF-A treatment, as theeye could develop its own anti-VEGF-A secretory mechanismthat would diminish the need for intravitreal injections. Whilethere are many gene therapies in development, none are inphase 3 study yet.

In summary, the pathogenesis of CNV formation in nAMD iscomplex and includes a wide variety of factors that could betargeted in future treatments. Emerging therapies that targetthese pathways, along with novel anti-VEGF-A therapies thataddress treatment burden, will provide the retina communitywith better options for managing nAMD.

Acknowledgments

This work was undertaken in Dr. Ciulla’s role as Volunteer Clinical Professorat Indiana University School of Medicine, and does not reflect the views oropinions of Clearside Biomedical or management.

Funding

This manuscript has not been funded.

Declaration of interest

T Ciulla is an employee of Clearside Biomedical and was formerly employedby Spark Therapeutics and Ophthotech. PU Dugel is on the scientific advisoryboard of Alcon Surgical, Genentech, MacuSight, Novartis, NeoVista, ArticDx,Alcon Pharmaceutical, AMO, Novartis, Thrombogenics, Santen, Ophthotech,Lux BioScience, Digisight, Roche, Acucela, Stealth Biotherapeutics, Lutronic,Avalanche, TrueVision, Alimera, Orbis International, Annidis, Neurotech,Aerpio, DOSE Medical, Omeros, Shire Human Genetics, Opthea, GraybugVision, CDR-Life, and Clearside Biomedical. He has also acted asa consultant for Bausch and Lomb Surgical and Medical, Genentech, AlconSurgical and Pharmaceutical, NeoVista, MacuSight, ArticDx, ORA, Novartis,Allergan, Regeneron, Santen Inc, QLT, Inc., Abbott/AMO, Thrombogenics,Ophthotech, Lux Bioscience, DigiSight,Genentech, Roche, TopCon, Acucela,Pentavision, ORA, Stealth Biotherapeutics, Annidis, Clearside Biomedical,Optovue, Neurotech, Lutronic, Alimera Sciences, DOSE Medical, Aerpio,Omeros, Shire Human Genetics, Ophthea, Spark Therapeutics, GraybugVision, Zeiss Group, Irenix, ByeOnics, Clearside Biomedical, PanOptica,Chengdu Kanghong Biotechnology, SciFluor Life Sciences, BoehringerIngelheim, Kodiak Sciences, Oculis SA, pSivida Corporation, Amgen Inc,Aerie Pharmaceutical, Pieris Pharmaceutical, Gemini Pharmaceutical, Ionis,RegenexBio, Reneuron and Abfero. He is also aminor stockholder for Alimera,Aerpio, Annidis, ArctixDx, Digisight, Irenix, Ophthotech, Clearside Biomedical,PanOptica, and TrueVision. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with a financial interestin or financial conflict with the subject matter or materials discussed in themanuscript apart from those disclosed.

Reviewer disclosures

One referee has received lecture fees and consultancy honoraria fromAllergan, Alimera, Bayer, Novartis, Roche. They also participate in studiesconducted by Samsung, Novartis, and GlaxoSmithKline. Another refereegives presentations for Bayer, Novartis and Heidelberg Engineering andhas served on advisory boards for Bayer and Novartis. Peer reviewers onthis manuscript have no other relevant financial relationships or otherwiseto disclose.

References

Papers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.

1. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence ofage-related macular degeneration in the United States. ArchOphtalmol. 2004 Apr;122(4):564–572.

2. Owen CG, Jarrar Z, Wormald R, et al. The estimated prevalence andincidence of late stage age related macular degeneration in the UK.Br J Ophthalmol. 2012 May;96(5):752–756.

3. Ferris FL III, Fine SL, Hyman L. Age-related macular degenerationand blindness due to neovascular maculopathy. Arch Ophtalmol.1984;102(11):1640–1642.

4. Donald J, Gass M. Pathogenesis of disciform detachment of theneuroepithelium: I. general concepts and classification. AmJ Ophthalmol. 1967 Mar 01;63(3, Part 2):573/1–85/13.

5. Green WR, Enger C. Age-related macular degeneration histopatholo-gic studies: the 1992 Lorenz E. Zimmerman Lecture. Ophthalmology.1993;100(10):1519–1535.

6. Leung D, Cachianes G, Kuang W, et al. Vascular endothelial growthfactor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–1309.

7. Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascularpermeability factor that promotes accumulation of ascites fluid.Science. 1983 Feb 25;219(4587):983–985.

8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovas-cular age-related macular degeneration. N Engl J Med. 2006 Oct05;355(14):1419–1431.

9. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGFtrap-eye) in wet age-related macular degeneration. Ophthalmology.2012 Dec;119(12):2537–2548.


•• Registration trial for aflibercept that led to its FDA approvalfor neovascular AMD.

10. Barthelmes D, Nguyen V, Daien V, et al. Two year outcomes of“Treat and Extend” intravitreal therapy using aflibercept preferen-tially for neovascular age-related macular degeneration. Retina.2018 Jan;38(1):20–28.

11. Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab forchoroidal neovascularization in age-related macular degeneration:5-year results of The Pan-American Collaborative Retina StudyGroup. Retina. 2016 May;36(5):859–867.

12. Cohen SY, Mimoun G, Oubraham H, et al. Changes in visual acuityin patients with wet age-related macular degeneration treated withintravitreal ranibizumab in daily clinical practice: the LUMIEREstudy. Retina. 2013 Mar;33(3):474–481.

13. Hjelmqvist L, Lindberg C, Kanulf P, et al. One-year outcomes usingranibizumab for neovascular age-related macular degeneration:results of a prospective and retrospective observational multicen-tre study. J Ophthalmol. 2011;405724.

14. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience ofanti-vascular endothelial growth factor therapy for wet age-relatedmacular degeneration. Br J Ophthalmol. 2015 Feb;99(2):220–226.

15. Kruger Falk M, Kemp H, Sorensen TL. Four-year treatment results ofneovascular age-related macular degeneration with ranibizumaband causes for discontinuation of treatment. Am J Ophthalmol.2013 Jan;155(1):89–95 e3.

16. Rakic JM, Leys A, Brie H, et al. Real-world variability in ranibizumabtreatment and associated clinical, quality of life, and safety outcomesover 24 months in patients with neovascular age-related maculardegeneration: the HELIOS study. Clin Ophthalmol. 2013;7:1849–1858.

17. Rasmussen A, Bloch SB, Fuchs J, et al. A 4-year longitudinalstudy of 555 patients treated with ranibizumab for neovascularage-related macular degeneration. Ophthalmology. 2013Dec;120(12):2630–2636.

18. Souied EH, Oubraham H, Mimoun G, et al. Changes in visual acuityin patients with wet age-related macular degeneration treated withintravitreal ranibizumab in daily clinical practice: the TWIN study.Retina. 2015 Sep;35(9):1743–1749.

19. Talks JS, Lotery AJ, Ghanchi F, et al. First-year visual acuity out-comes in the United Kingdom of providing aflibercept according tothe VIEW study protocol for age-related macular degeneration.Ophthalmology. 2016 Feb;123(2):337–343.

20. van Asten F, Evers-Birkenkamp KU, van Lith-Verhoeven JJ, et al.A prospective, observational, open-label, multicentre study toinvestigate the daily treatment practice of ranibizumab in patientswith neovascular age-related macular degeneration. ActaOphthalmol. 2015 Mar;93(2):126–133.

21. Writing Committee for the U. K. Age-Related Macular DegenerationE.M. R. Users Group. The neovascular age-relatedmacular degenerationdatabase: multicenter study of 92 976 ranibizumab injections: report 1:visual acuity. Ophthalmology. 2014 May;121(5):1092–1101.

22. Zarranz-Ventura J, Liew G, Johnston RL, et al. The neovascularage-related macular degeneration database: report 2: incidence,management, and visual outcomes of second treated eyes.Ophthalmology. 2014 Oct;121(10):1966–1975.

23. Ross AH, Donachie PH, Sallam A, et al. Which visual acuity measure-ments define high-quality care for patients with neovascularage-related macular degeneration treated with ranibizumab? Eye(Lond). 2013 Jan;27(1):56–64.

24. Rao P, Lum F, Wood K, et al. Real-world vision in age-related maculardegeneration patients treated with single anti-VEGF drug type for1 year in the IRIS registry. Ophthalmology. 2018;125:522–528.

25. Ciulla TA, Hussain RM, Pollack JS, et al. Visual Acuity outcomes andanti-vascular endothelial growth factor therapy intensity in neovas-cular AMD patients: a “Real World” analysis in 49,485 eyes.Ophthalmol Retina. 2019. [Epub ahead of print]

26. Dadgostar H, Ventura AA, Chung JY, et al. Evaluation of injectionfrequency and visual acuity outcomes for ranibizumab monotherapyin exudative age-relatedmacular degeneration. Ophthalmology. 2009Sep;116(9):1740–1747.

27. Hussain RM, Hariprasad SM, Ciulla TA. Treatment burden in neo-vascular AMD:visual acuity outcomes are associated with anti-VEGFinjection frequency. Ophthalmic Surg Lasers Imaging Retina. 2017Oct 1;48(10):780–784.

28. Smith AG, Kaiser PK. Emerging treatments for wet age-relatedmacular degeneration. Expert Opin Emerg Drugs. 2014 Mar;19(1):157–164.

29. Daniel E, Toth CA, Grunwald JE, et al. Risk of scar in the comparison ofage-related macular degeneration treatments trials. Ophthalmology.2014 Mar;121(3):656–666.

30. Miller JW, Le Couter J, Strauss EC, et al. Vascular endothelial growthfactor a in intraocular vascular disease. Ophthalmology. 2013Jan;120(1):106–114.

31. Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF)family: angiogenic factors in health and disease. Genome Biol.2005;6(2):209.

32. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelialgrowth factor regulates endothelial cell survival through the phos-phatidylinositol 3ʹ-kinase/Akt signal transduction pathway.Requirement for Flk-1/KDR activation. J Biol Chem. 1998 Nov13;273(46):30336–30343.

33. Kim I, Moon SO, Kim SH, et al. Vascular endothelial growth factorexpression of intercellular adhesion molecule 1 (ICAM-1), vascularcell adhesion molecule 1 (VCAM-1), and E-selectin through nuclearfactor-kappa B activation in endothelial cells. J Biol Chem. 2001 Mar09;276(10):7614–7620.

34. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growthfactor B signaling enhances the efficacy of anti-vascular endothelialgrowth factor therapy in multiple models of ocularneovascularization. Am J Pathol. 2006 Jun;168(6):2036–2053.

35. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGFand PDGF signaling enforces tumor vessel regression by interferingwith pericyte-mediated endothelial cell survival mechanisms. FasebJ. 2004 Feb;18(2):338–340.

36. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vesselremodelling is defined by pericyte coverage of the preformedendothelial network and is regulated by PDGF-B and VEGF.Development. 1998 May;125(9):1591–1598.

37. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyteinteractions. Circ Res. 2005 Sep 16;97(6):512–523.

38. Hellstrom M, Kalen M, Lindahl P, et al. Role of PDGF-B andPDGFR-beta in recruitment of vascular smooth muscle cells andpericytes during embryonic blood vessel formation in the mouse.Development. 1999 Jun;126(14):3047–3055.

39. Davis S, Yancopoulos GD. The angiopoietins: yin and Yang inangiogenesis. Curr Top Microbiol Immunol. 1999;237:173–185.

40. Bhattacharya D, Chaudhuri S, MK S, et al. T11TS inhibitsAngiopoietin-1/Tie-2 signaling, EGFR activation and Raf/MEK/ERKpathway in brain endothelial cells restraining angiogenesis inglioma model. Exp Mol Pathol. 2015 june 01;98(3):455–466.

41. Hansen TM, Singh H, Tahir TA, et al. Effects of angiopoietins-1 and−2 on the receptor tyrosine kinase Tie2 are differentially regulatedat the endothelial cell surface. Cell Signal. 2010 Mar;22(3):527–532.

42. Fachinger G, Deutsch U, Risau W. Functional interaction of vascularendothelial-protein-tyrosine phosphatase with the angiopoietinreceptor Tie-2. Oncogene. 1999 Oct 21;18:5948. online.

43. Dugel PU. Phase 3, randomized, double-masked, multicenter trialsof brolucizumab vs. aflibercept for neovascular AMD: ninety-six-week results from the HAWK and HARRIER studies. Chicago:American Academy of Ophthalmology;2018.

44. Dugel PU. HAWK & HARRIER: 48-week results of 2 multi-centered,randomized, double-masked trials of brolucizumab versus afliber-cept for neovascular AMD. New Orleans: American Academy ofOphthalmology; 2017.

45. Allergan and molecular partners announce two positive phase 3clinical trials for abicipar pegol 8 and 12-week regimens for thetreatment in patients with neovascular age-related maculardegeneration; 2019. Available from: https://www.molecularpartners.


com/allergan-and-molecular-partners-announce-two-positive-phase-3-clinical-trials-for-abicipar-pegol-8-and-12-week-regimens-for-the-treatment-in-patients-with-neovascular-age-related-macular-degeneration/

46. Kirker RM. CLINICAL TRIAL CLOSEUP: A deeper dive into abicipartrials; 2018. [cited 2019 Jun 10]. Available from: http://www.retina-specialist.com/article/a-deeper-dive-into-abicipar-trials

47. Allergan and Molecular Partners Announce Topline Safety Resultsfrom MAPLE study of Abicipar pegol; 2019. [cited 2019 Jun 10].Available from: https://www.allergan.com/news/news/thomson-reuters/allergan-and-molecular-partners-announce-topline-s.aspx

48. Liu K, Song Y, Xu G, et al. Conbercept for Treatment of NeovascularAge-related Macular Degeneration: results of the RandomizedPhase 3 PHOENIX Study. Am J Ophthalmol. 2019;197:156–167.

49. Kodiak sciences announces completion of 12-week phase 1a studyof KSI-301 in patients with diabetic macular edema demonstratingsafety and durability of responses following single dose of intravi-treal anti-VEGF antibody biopolymer conjugate; 2018. [cited 2019Mar 17]. Available from: https://www.prnewswire.com/news-releases/kodiak-sciences-announces-completion-of-12-week-phase-1a-study-of-ksi-301-in-patients-with-diabetic-macular-edema-demonstrating-safety-and-durability-of-responses-following-single-dose-of-intravitreal-anti-vegf-antibody-biopolymer-300770093.html

50. Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual Antagonism of PDGF andVEGF in neovascular age-related macular degeneration: A phase IIb,multicenter, randomized controlled trial. Ophthalmology. 2017Feb;124(2):224–234.

51. Ophthotech announces results from pivotal phase 3 trials ofFovista® in wet age-related macular degeneration; 2016 [cited2017 Feb 27]. Available from: http://investors.ophthotech.com/releasedetail.cfm?ReleaseID=1003651

52. Dunn EN, Hariprasad SM, Sheth VS. An overview of the Fovista andrinucumab trials and the fate of anti-PDGF medications. OphthalmicSurg Lasers Imaging Retina. 2017 Feb 01;48(2):100–104.

53. Regeneron announces phase 2 study of aflibercept co-formulatedwith rinucumab (anti-PDGFR-beta) shows no benefit over afliber-cept alone in neovascular age-related macular degeneration; 2016.[cited 2019 Feb 26]. Available from: http://investor.regeneron.com/releasedetail.cfm?releaseid=991601

54. Jackson TL, Boyer D, Brown DM, et al. Oral tyrosine kinase inhibitorfor neovascular age-related macular degeneration: A phase 1dose-escalation study. JAMA Ophthalmol. 2017 Jun 01;135:761.

55. Brown DM. Phase 1 study of combination therapy with nesvacu-mab and aflibercept for neovascular AMD and diabetic macularedema. American Academy of Ophthalmology annual meeting;2016; Chicago, IL.

56. Boyer DS. Aflibercept combination therapies: rinucumab/afliber-cept and nesvacumab/aflibercept. Chicago, IL: American Academyof Ophthalmology; 2016.

57. Helzner J. Faricimab Shows Potential for 16-Week Dosing. RetinPhysician. 2018 September.

58. Khanani AM. Simultaneous inhibition of VEGF and Ang-2 withfaricimab in neovascular AMD: STAIRWAY phase 2 results.Chicago: American Academy of Ophthalmology; 2018.

59. Csaky KG, Dugel PU, Pierce AJ, et al. Clinical evaluation of pazopanibeye drops versus ranibizumab intravitreal injections in subjects withneovascular age-related macular degeneration. Ophthalmology.2015 Mar;122(3):579–588.

60. Joussen A, Wolf S, Kaiser PK. A combined phase 2a/b study of theefficacy, safety, and tolerability of repeated topical doses of regor-afenib eye drops in treatment-naïve patients with neovascular age-related macular degeneration (nAMD). Seattle, WA: Association forResearch in Vision and Ophthalmology; 2016.

61. LHA510 proof-of-concept study as a maintenance therapy forpatients with wet age-related macular degeneration. [cited 2019

Jan 19]. Available from: https://clinicaltrials.gov/ct2/show/NCT02355028

62. Panoptica doses first patient with new formulation of PAN-90806,a novel, topical anti-VEGF eye drop, in phase 1/2 clinical trial; 2018.[cited 2019 Mar 22]. Available from: http://www.panopticapharma.com/wp-content/uploads/2018/05/PanOptica-New-Formulation-First-Patient-Dosed-News-Release-Final-May-17-2018.pdf

63. Rubio RG. Long-acting anti-VEGF delivery. Retina Today. 2014 July/August.

64. LADDER trial of the port delivery system for ranibizumab: prelimin-ary study results. Vancouver: American Society of Retina Specialists;2018.

65. Graybug vision presents top line results of phase 1/2a ADAGIO studyat Hawaiian eye & retina 2019; 2019. [cited 2019 Mar 24]. Availablefrom: https://graybug.com/graybug-vision-presents-top-line-results-of-phase-1-2a-adagio-study-at-hawaiian-eye-retina-2019/

66. NT-503 ECT. [cited 2019 Mar 25]. Available from: http://www.neurotechusa.com/nc-503-ect.html

67. Pipeline - Ocular Therapeutix. [cited 2019 Mar 05]. Available from:https://www.ocutx.com/research/pipeline/

68. Lurker N. pSivida corp. Ophthalmic Innoviations Summit atAmerican Academy of Ophthalmology meeting; 2016; Chicago, IL.

69. Rakoczy EP, Lai CM, Magno AL, et al. Gene therapy with recombi-nant adeno-associated vectors for neovascular age-related maculardegeneration: 1 year follow-up of a phase 1 randomised clinicaltrial. Lancet. 2015 Dec 12;386(10011):2395–2403.

70. Constable IJ, Lai CM, Magno AL, et al. Gene therapy in neo-vascular age-related macular degeneration: three-yearfollow-up of a phase 1 randomized dose escalation trial. AmJ Ophthalmol. 2017;177:150–158.

71. Constable IJ, Pierce CM, Lai CM, et al. Phase 2a randomized clinical trial:safety and Post Hoc Analysis of subretinal rAAV.sFLT-1 for wetage-related macular degeneration. EBioMedicine. 2016 Dec;14:168–175.

• Phase 2a trial results of a subretinal rAAV.sFLT-1 gene therapy,which was deemed to be a safe and promising approach totreat neovascular AMD.

72. Adverum Biotechnologies provides update on OPTIC phase 1 trialfor ADVM-022 in wet AMD; 2019. [cited 2019 Mar 25]. Availablefrom: http://investors.adverum.com/news-releases/news-release-details/adverum-biotechnologies-provides-update-optic-phase-1-trial-advm

73. Heier JS, Kherani S, Desai S, et al. Intravitreous injection ofAAV2-sFLT01 in patients with advanced neovascular age-relatedmacular degeneration: a phase 1, open-label trial. Lancet. 2017Jul 1;390(10089):50–61.

74. Corporate Presentation. 2019. [cited 2019 Jun 03]. Available from:https://regenxbio.gcs-web.com/static-files/3e73040c-8f46-4353-9653-7e643f3bc59d

75. REGENXBIO REPORTS CONTINUED PROGRESS ACROSS PROGRAMSIN YEAR-END 2018 CORPORATE UPDATE; 2019. [cited 2019 Feb 23].Available from: https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-reports-continued-progress-across-programs-year-end

76. REGENXBIO ANNOUNCES COMPLETION OF DOSING FOR PHASE I/IIA CLINICAL TRIAL OF RGX-314 IN WET AMD; 2019. [cited 2019 Jun04]. Available from: https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-completion-dosing-phase-iiia-clinical-trial

77. Binley K, Widdowson PS, Kelleher M, et al. Safety and biodistribu-tion of an equine infectious anemia virus-based gene therapy,RetinoStat((R)), for age-related macular degeneration. Hum GeneTher. 2012 Sep;23(9):980–991.

78. Lai CM, Estcourt MJ, Himbeck RP, et al. Preclinical safety evaluationof subretinal AAV2.sFlt-1 in non-human primates. Gene Ther. 2012Oct;19(10):999–1009.


79. Igarashi T, Miyake K, Kato K, et al. Lentivirus-mediated expression ofangiostatin efficiently inhibits neovascularization in a murine pro-liferative retinopathy model. Gene Ther. 2003 Feb;10(3):219–226.

80. Campochiaro PA, Lauer AK, Sohn EH, et al. Lentiviral vector genetransfer of endostatin/angiostatin for macular degeneration (GEM)study. Hum Gene Ther. 2017 Jan;28(1):99–111.

81. Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of bevacizumabversus ranibizumab for neovascular age-related macular degeneration.Cochrane Database Syst Rev. 2014 Sep;15(9):CD011230.

82. Bracha P, Moore NA, Ciulla TA, et al. The acute and chronic effects ofintravitreal anti-vascular endothelial growth factor injections on intrao-cular pressure: A review. Surv Ophthalmol. 2018 May–Jun;63(3):281–295.

83. Baek SU, Park IW, Suh W. Long-term intraocular pressure changesafter intravitreal injection of bevacizumab. Cutan Ocul Toxicol.2016 Dec;35(4):310–314.

84. Rayess N, Rahimy E, Storey P, et al. Postinjection endo-phthalmitis rates and characteristics following intravitreal

Bevacizumab, ranibizumab, and aflibercept. Am J Ophthalmol.2016;165:88–93.

85. Chang LK, Sarraf D. Tears of the retinal pigment epithelium: anold problem in a new era. Retina. 2007 Jun;27(5):523–534.

86. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verte-porfin for neovascular age-related macular degeneration. N EnglJ Med. 2006 Oct 05;355(14):1432–1444.

• Landmark trial demonstrating superiority of intravitreal rani-bizumab injections over photodynamic therapy to treat neo-vascular AMD.

87. Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizu-mab and bevacizumab for neovascular age-related maculardegeneration according to LUCAS treat-and-extend protocol.Ophthalmology. 2015 Jan;122(1):146–152.

88. Wykoff CC, Croft DE, Brown DM, et al. Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related maculardegeneration: TREX-AMD 1-year results. Ophthalmology. 2015Dec;122(12):2514–2522.


TThe 2017 U.S. FDA approval of the first gene therapy for a genetic disease launched a promising new cycle of innovation in ophthalmic therapies.1 The retina is a prime target for gene therapy research given the large number of monogenic disorders, accessi-bility to target cell delivery, the noninvasive ability to monitor for disease progression or therapeutic response as well as relative immune-privilege that limits inflammatory response.2-4 However, beyond inherited retinal dystrophies (IRDs), gene therapy is even being explored to treat common chronic disor-ders, such as neovascular AMD, geographic atrophy, uveitis and some corneal dystrophies.

This article reviews some of the basic principles of gene therapy, as the ophthalmology community prepares for the future.

GENETIC TESTING With more than 260 genes known to cause IRDs,5 a basic understanding of genetic testing is essential to remain current. Genetic testing is recommended by the AAO when clinical findings indicate retinal dystrophy that is possibly associated with genetic mutations.6 Genetic testing can confirm suspi-cion of an IRD, provide an accurate diagnosis and information about prognosis and management and assist in counseling of families, including assessing risk in family members.7

Unfortunately, ordering and interpretation of genetic test results is complex, but a facility with the basics of interpretation is useful. While single-gene testing is inexpensive, it requires a working clinical diagnosis and, consequently, has limited utility in many cases, given the nonspecific nature of clini-cal findings in many IRDs.8 Gene panels are more commonly used, and generally focused on diagno-ses associated with multiple genes.8 Whole genome/exome sequencing is the most comprehensive but

generates a high number of variants of uncertain significance (VUSs).8

Genetic testing results are not binary and involve a ranking system of each identified mutation based on standards released by American College of Medical Genetics and Genomics (pathogenic, likely pathogenic, VUS, likely benign, benign).9 Pathogenicity is determined by multiple factors, including the effect on gene coding, protein struc-ture/function, variant association with disease in the population and in vitro/in vivo functional stud-ies.9 VUSs can be especially difficult to address. A VUS involves a mutation variant for which there is a lack of affirmative data of pathogenicity or non-pathogenicity. A VUS may be reclassified in the future as more information accumulates.

Genetic counselors can assist patients in select-ing genetic tests, interpretation of genetic test results and family planning. Fortunately, insurance can cover their services, and some providers are available for patients via a telemedicine interaction.

TYPES OF GENE THERAPYThe major categories of gene therapy include:• Gene augmentation — adding a gene to a cell• Gene editing — revising the existing genetic

code• Gene inactivation — silencing a gene, often a

dominant negative one• Selective toxicity — as in chimeric antigen

receptor (CAR)-T cells to recognize cancer cells

• RNA therapeutics — targeting RNA, instead of DNA within the gene

Ocular gene therapy has mostly involved gene augmentation. Recessive single-gene disorders are the most amenable to gene augmentation, because

A review of genetic testing and basics of gene therapy.

By Thomas A. Ciulla, MD, MBA

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hor

Thomas A. Ciulla, MD, MBA, is volunteer clinical professor of ophthalmology at Indiana University School of Medicine, a board member of Midwest Eye Institute, Indianapolis, and chief medical officer at Clearside Biomedical. He previously served a VP role as medical strategy lead-ophthalmology at Spark Therapeutics..

Introduction to gene therapy

30 J U LY 2 0 1 9 • OP H T HA L M OL O G Y M A NAG E M E N T

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the mutations causing the dis-ease generally lead to loss-of-function of the gene product and, therefore, total absence or near absence of functional protein. In these cases, gene augmentation can correct the lost function by delivery of the normal gene. Also, in some instances, restoring a small percentage of the normal level of the gene product is suffi-cient to revert the phenotype.

The majority of gene thera-pies to treat inherited ocular diseases target autosomal recessive diseases. For example, RPE65 mutation-associated retinal dys-trophy is a recessive monogenic disorder in which Luxturna (Spark Therapeutics), the only FDA-approved ocular gene therapy, corrects the lost function. In contrast, gain-of-function mutations produce dominant phenotypes. These diseases may be less amenable to gene therapy treatment, as one gene copy expresses an abnormal product that has to be suppressed while the other expresses a protein that functions normally.10 Consequently, develop-ing a gene therapy for autosomal dominant RP has been more challenging.

In addition to addressing genetic mutations in native genes, gene therapy can be utilized in a “bio-factory approach” to produce non-native proteins. In neovascular AMD, gene therapy is already being assessed using a biofactory approach to chronically express anti-angiogenic proteins such as pigment epithelium-derived factor, soluble fms-like tyro-sine kinase-1 (sFLT-1) as well as aflibercept (Eylea, Regeneron), ranibizumab (Lucentis, Genentech), angiostatin and endostatin. The complement sys-tem is also a target for gene therapy in AMD. In humans, deposition of membrane attack complex in Bruch’s membrane and choriocapillaris increases significantly with aging and with AMD,11 and some gene therapies are being developed to inhibit com-ponents of the complement cascade.

Another gene therapy approach involves opto-genetic technology that may render retinal ganglion cells responsive to light. This therapy comprises a vector encoding a photosensitive protein, belonging to the subfamily of channelrhodopsins, which functions as sensory photoreceptors in green algae. Once this protein is expressed, it confers a photoreceptor-like function to the target ganglion

cells. As noted above, an additional form of gene therapy is RNA therapeutics, which involves target-ing RNA, instead of DNA within the gene. Current trials are assessing intravitreal antisense oligonucle-otides in IRD.

DELIVERY METHODSA variety of viral and non-viral gene delivery meth-ods have been developed over the past two decades.

The viral vectors most extensively used include the adenovirus, adeno-associated virus (AAV), gamma-retrovirus and lentivirus. The choice of viral vector is specific to each application and depends on a combination of factors, such as tis-sue tropism, cloning capacity of the vector (which determines the size of the expression cassette that can be accommodated in the genome of the virus) and safety concerns (inflammatory responses and genotoxicity/insertional oncogenesis).

AAVs are small, single-stranded DNA viruses of the parvovirus family (See Figure).12 AAV vectors transduce quiescent tissues, and their genome is primarily maintained as extrachromosomal mono-meric and concatemeric circles. More than 100 dif-ferent AAV serotypes have been described, each of them displaying enhanced tropism for a specific set of tissues. To date, AAV is the most common viral vector utilized in retinal genetic therapy. AAV sero-types 2, 5 and 8 have been commonly used in retinal gene therapy applications, transducing photore-ceptors and/or retinal pigment epithelium (RPE). Multiple features make it an excellent vector choice for these diseases, including the non-integrating nature, low inflammatory potential, low immuno-genicity, low retinal toxicity at appropriate doses, non-pathogenic nature, ability to transduce non-dividing cells and excellent track record of safety

Figure. Gene therapy using an adenovirus vector can poten-tially be used as one-time treatment for certain genetic diseases.

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in human trials.13 AAV vectors do have limitations, which include having a restricted transgene capac-ity (4.5-5.0 kb) and the risk of being eliminated by the humoral immune response in patients who have previously been exposed to the virus.14 However, the risk for immunogenicity with AAV vectors is low when targeting relatively immune-privileged tissues such as the retina.15

Lentiviruses are RNA viruses of the retrovirus family. Commonly used lentiviral vectors derive from the human immunodeficiency virus 1 (HIV1) or the equine infectious anemia virus (EIAV).16 Lentivirus vectors efficiently integrate their genome into the host cell genome and do not require cell divi-sion for integration.17 An added attractive feature is the cloning capacity, up to 10 kb.18 Lentiviruses have recently become a popular choice because they have improved safety features relative to gamma-retrovi-ruses, as the vector genome does not preferentially integrate in the proximity of oncogenes.19

Other nonviral delivery methods are being investigated and have potential for titratable and repeat dosing according to clinical need. In addi-tion to antisense oligonucleotides, DNA-compacted nanoparticles, which are single DNA molecules, compacted polyethylene glycol-substituted polyly-sine 30-mers (CK30PEG) have been explored. This nonviral gene therapy technique would incur less risk of immune response in patients with preexisting viral immunity and can transfer large genes beyond the carrying capacity of AAV or even lentivirus.

The safety and potential utility of the nanopar-ticles has been demonstrated in the lung, with introduction of the cystic fibrosis transmembrane conductance regulator through an intranasal route in a Phase 1 clinical trial.20 In the retina, DNA nanoparticle-mediated ABCA4 delivery has been shown to rescue several IRDs, including Stargardt dystrophy in mouse models,21 and reporter genes have been expressed in RPE as long as two years.22

Since DNA nanoparticles have been found to have lower transduction efficiency per vector genome than AAV, higher vector amounts may be compensated and repeated dosing may be required after one to two years, which would not be practical via vitrectomy with subretinal injection.23 However, intravitreal or even suprachoroidal administra-tion could circumvent this problem, as these routes are conducive to repeat minimally invasive treat-ment. As with intravitreally-administered antisense oligonucleotides, this paradigm could facilitate titration to clinical response or need, as opposed to a

one-time treatment with chronic protein expression using current viral vector-based techniques.

PRODUCTION OF GENE THERAPYViral gene therapies are complex, requiring more complicated processing than pharmaceuticals because virus capsids are developed within cell lines. Unlike nonviral gene therapies such as DNA nanoparticles or oligonucleotides, cell lines serve as “biofactories” to produce viral vectors.

With AAV2, for example, these cell lines typically undergo “triple transfection” with three plasmid constructs carrying expression cassettes encoding the therapeutic transgene (including regulatory ele-ments such as promoters and enhancers), the AAV (rep and cap genes) and helper virus sequences (to replicate and pack the recombinant AAV with ther-apeutic transgene). Multiple purification steps ensue to extract the viral capsids from the cell media.

ADMINISTRATION OF OCULAR GENE THERAPYVector delivery to the target retinal tissue involves several potential methods. The most commonly investigated method involves pars plana vitrec-tomy followed by retinotomy and injection of the viral vector with genetic material into the subreti-nal space. This method creates a temporary retinal detachment but allows for direct delivery to the cells of interest. The virus then “infects” or enters the retinal pigment epithelial cells or photoreceptors, ultimately causing the host cell’s own translational machinery to express the protein.

Alternatively, injection of the vector into the vitreous cavity has been attempted. Although this method may be less invasive and potentially have fewer procedure-related complications, the penetra-tion of viral vector to the target tissue has histori-cally been perceived as inferior to that of subretinal injections.24 Additionally, animal models have dem-onstrated an induced humoral immune response to intravitreally delivered viral vectors that was not observed with subretinally delivered viral vectors. However, techniques such “directed evolution” of viral vectors may enhance intravitreal delivery, and at least one such promising intravitreally adminis-tered vector employing an anti-VEGF biofactory approach is currently in clinical trial. Furthermore, clinic-based intravitreal or suprachoroidal delivery may circumvent some of the logistic issues of oper-ating room-based subretinal delivery.

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OPTIMIZATION AND REGULATIONBeyond selection of vector, numerous factors are involved in optimizing gene therapy. Within the vector, the gene is actually complementary DNA or cDNA with no introns, only the coding exons. Codon optimization involves the introduction of synonymous mutations into recombinant genes, changing rare codons to common codons to improve protein translation efficiency. Also, there are regulatory elements such as promoters and enhancers, which partially determine where and how robustly the gene is expressed as well as optimization of the translational start site (eg, Kozak sequence).

In addition to optimizing the vector, the gene itself, regulatory elements, delivery method and location, an immunomodulatory regimen may be used to limit the risk of immune response. These parameters all factor into differentiation, in which two gene therapies carrying the same transgene may have differing safety and efficacy profiles.

In the future, there may be “regulate-able” gene therapy, in which small, orally adminis-

tered molecules turn protein production on and off as needed. For example, preclinical studies have demonstrated the efficacy of a tetracycline-responsive “OFF-type” riboswitch in regulating aflibercept expression in the mouse retina fol-lowing AAV delivery of a gene encoding afliber-cept.25 Transgene regulation by physiological condition may be possible in the future. One group developed a hypoxia-regulated gene ther-apy (using hypoxia inducible factor-1 response elements) to drive expression of endostatin in the same hypoxic/inflammatory conditions that drive VEGF expression and growth of choroidal neovascularization in a murine model.26

CONCLUSIONGene therapy has proven to be relatively safe in a multitude of small clinical trials. With the potential for continued optimization and rapid therapeutic innovation in gene therapy, ophthalmology has an exciting future. However, to remain current, oph-thalmologists must understand genetic testing and the basic aspects of gene therapy. OM

For references, see the online version of this article.

Gene therapy, continued from page 32

a single intravitreal injection. At six months, 68% of participants were without rescue treatment.

One concern that emerged was in relation to non-aggregation of the drug once in the vitreous cavity, resulting in particle dispersion. Nine of 32 subjects experienced related symptoms, includ-ing eye pain, photophobia and blurriness.25 The manufacturing process is being optimized to allow improved aggregation of the micropar-ticles, according to the company. The Phase 2b study PRELUDE, comparing two dose levels of sunitinib to aflibercept in a randomized study, is anticipated. Also, development of GB-103, which aims for once-a-year dosing, is in the pipeline.

VEGF C/D TRAP THERAPYOPT-302 (Opthea) is a VEGF receptor 3 mol-ecule engineered for intravitreal injection that traps and inhibits VEGF-C and -D. This mole-cule can be combined with inhibitors of VEGF-A to achieve a more complete blockade of VEGF drive. Opthea’s six-month Phase 2b trial ran-domized 366 participants with treatment-naive

neovascular AMD to monotherapy or in combi-nation with ranibizumab.26 The final patient visit for the trial was completed in May 2019, after which the company reported that top-line results were expected within the coming months.27

A PIPELINE OF POSSIBILITIESAlthough the current anti-VEGF therapies have resulted in drastically improved patient outcomes, they require frequent injections and monitoring visits, and a subset of patients do not fully respond. Improved efficacy and durability are much needed. Thankfully, the pipeline for new therapeutic possi-bilities is packed with exciting potential.

Numerous other promising agents are on the way. They include other mechanisms of action, such as HMR59 (Hemera Biosciences) gene therapy that expresses CD59,28 RNAi technologies and biosimilar molecules amongst many other exciting developments in the dynamic field of neovascular AMD therapeutics. OM

For references, see the online version of this article.

AMD, continued from page 29

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‘Real world’ OCT: Subtle findings, critical implications

Peter Bracha, MD, and Thomas A. Ciulla, MD, MBA

UUltra-high resolution optical coherence tomog-raphy (OCT) systems can generate superb atlas-grade images that readily highlight macular pathology. However, instead of reviewing atlas-grade images, clinicians must become comfort-able with rapidly and accurately interpreting “real world” OCT images in busy clinic settings, with typical limitations involving system capabilities, operator skill, ocular media clarity and patient cooperation.

This real-world OCT case series, derived from a typical retina clinic setting, demonstrates com-mon but subtle findings that carry prognostic significance and/or impact management. This

case series is organized by anatomic location of findings, from inner ret-ina to outer retina.

Specifically, this series reviews OCT findings commonly mistaken for cystoid macular edema, OCT depictions of ellipsoid zone disruptions corre-lating with symptomatic functional vision loss, and OCT demonstra-tions of the variations in retinal pigment epithe-lial (RPE) elevations that carry diagnostic, prog-nostic and therapeutic implications.

1. OCT FINDINGS COMMONLY MISTAKEN FOR CYSTOID MACULAR EDEMANot all hyporeflective intraretinal spaces convey an active exudative process requiring treatment.

Pseudo-cysts in macular telangiectasia type 2 A 75-year-old female presented with a progres-sive blurring of central vision bilaterally. She had a 15-year history of diabetes but never required treatment for diabetic retinopathy. Her visual acuity (VA) measured 20/50 bilaterally and mod-erate cataracts were noted in both eyes (BE). Fluorescein angiography (FA) revealed staining temporal to the foveal avascular zone in both eyes (Figure 1A) in the location of fine telangiec-tatic capillaries and dilated venules (Figure 1B). Macular OCT identified pseudocysts without significant neurosensory thickening BE and some ellipsoid zone disruption in the right eye (RE) (Figure 1C). Observation was recommended.

Differentiating pseudocysts from cystoid macular edema (CME) of other etiologies has important clinical implications as antivascular endothelial growth factor (anti-VEGF) therapy is not convincingly effective in treating macular tel-angiectasia type 2 and may unnecessarily expose patients to risks of intravitreal injection.1 Type 2 macular telangiectasia is a rare, degenerative bilateral condition that typically presents in the fifth to sixth decade of life with the variable find-ings of reduced retinal transparency, crystalline deposits, mildly ectatic capillaries and blunted, slightly dilated venules. As disease advances, atrophy can develop as well as lamellar or full

Case studies underscore need to know what separates, image-wise, common vs. more uncommon diagnoses.

thickness holes and neovascularization. Macular OCT classically reveals pseudocysts,

which are atrophic hyporeflective spaces that do not show neurosensory thickening and are not associated with angiographic leakage or pooling of fluorescein dye. These pseudocysts are likely due to retinal degeneration and are pathophysi-ologically analogous to spaces in X-linked reti-noschisis.1 Other macular OCT findings include ellipsoid zone disruption, and in advanced dis-ease, atrophy of the neurosensory retina and sequelae from neovascularization.

Outer retinal tubulation in neovascular AMDAn 87-year-old male presented with a several-year history of progressive bilateral metamor-phopsia and scotoma. He had been treated with numerous anti-VEGF injections in his RE. VA measured 20/70 RE and 20/400 left eye (LE), and fundus examination revealed bilateral advanced geographic atrophy (GA), drusen and pigment clumping (Figure 2A). Macular OCT demon-strated outer retinal tubulation RE (red arrow, Figure 2B) as well as bilateral RPE atrophy with increased signal penetration into the choroid (blue arrows, Figure 2B).

Incidentally, the nerve fiber layer of the macu-lopapillary bundle is denoted by the yellow arrow (yellow arrow, Figure 2B). Due to disease inac-tivity, observation was recommended with close follow-up.

Differentiating outer retinal tubulation (ORT) from solitary cystoid spaces secondary to neovas-cular age-related macular degeneration (AMD) is important as ORT is not an indication to treat with anti-VEGF therapy. ORT is an OCT find-ing characterized by a hyporeflective cavity sur-rounded by a hyper-reflective wall and is found in the outer nuclear layer.

Histologically, this correlates with a sphere of surviving cones surrounded by Muller cell pro-cesses; the finding portends worse visual acuity outcomes.2,3 Most commonly found in advanced AMD, ORT can also be found in hereditary reti-nal degenerations.

Geographic atrophy, which was also noted in this case, is recognized as discrete areas of increased signal penetration into the choroid, and is a common finding in both non-neovascu-lar AMD and neovascular AMD. Laser photoco-agulation scars, which atrophy over time, can also yield multiple discrete areas of increased signal

penetration into the choroid.

2. ELLIPSOID ZONE DISRUPTIONS CORRELATING WITH SYMPTOMATIC FUNCTIONAL VISION LOSSThe ellipsoid zone represents the regularly oriented, inner portion of the photoreceptor layer that is densely packed with mitochondria, and has unique, clinically useful functional significance.

Parafoveal ellipsoid zone loss from hydroxychloroquine retinopathyA 65-year-old female presented with a two-month history of bilateral central vision loss. VA measured 20/30 RE and 20/20 LE. She endorsed a 20-year history of hydroxychloroquine use that was stopped several years prior to presentation. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes (Figure 3A) while fun-dus autofluorescence (FAF) demonstrated a bilat-eral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figure 3B). Macular OCT identified parafoveal ellipsoid zone loss (leaving the central ellipsoid zone intact, reminiscent of a “flying saucer” and hence the “flying saucer sign”) along with generalized retinal thinning (Figure 3C, red arrows depicting the edge of intact foveolar ellip-soid zone). Even though she had not taken hydroxy-chloroquine for a number of years, this patient d e m o n s t r a t e d progression of hydroxychloro-quine toxicity.

Macular OCT should be included among the tests for hydroxychlo-IM

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Figure 1. Pseudo-cysts in macular tel-angiectasia type 2.

Figure 2. Outer retinal tubulation in neovascular AMD.

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Figure 3. Parafoveal ellipsoid zone loss from hydroxychloro-quine retinopathy.

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THE DIAGNOSTICS ISSUE

‘Real world’ OCT: Subtle findings, critical implications

Peter Bracha, MD, and Thomas A. Ciulla, MD, MBA

UUltra-high resolution optical coherence tomog-raphy (OCT) systems can generate superb atlas-grade images that readily highlight macular pathology. However, instead of reviewing atlas-grade images, clinicians must become comfort-able with rapidly and accurately interpreting “real world” OCT images in busy clinic settings, with typical limitations involving system capabilities, operator skill, ocular media clarity and patient cooperation.

This real-world OCT case series, derived from a typical retina clinic setting, demonstrates com-mon but subtle findings that carry prognostic significance and/or impact management. This

case series is organized by anatomic location of findings, from inner ret-ina to outer retina.

Specifically, this series reviews OCT findings commonly mistaken for cystoid macular edema, OCT depictions of ellipsoid zone disruptions corre-lating with symptomatic functional vision loss, and OCT demonstra-tions of the variations in retinal pigment epithe-lial (RPE) elevations that carry diagnostic, prog-nostic and therapeutic implications.

1. OCT FINDINGS COMMONLY MISTAKEN FOR CYSTOID MACULAR EDEMANot all hyporeflective intraretinal spaces convey an active exudative process requiring treatment.

Pseudo-cysts in macular telangiectasia type 2 A 75-year-old female presented with a progres-sive blurring of central vision bilaterally. She had a 15-year history of diabetes but never required treatment for diabetic retinopathy. Her visual acuity (VA) measured 20/50 bilaterally and mod-erate cataracts were noted in both eyes (BE). Fluorescein angiography (FA) revealed staining temporal to the foveal avascular zone in both eyes (Figure 1A) in the location of fine telangiec-tatic capillaries and dilated venules (Figure 1B). Macular OCT identified pseudocysts without significant neurosensory thickening BE and some ellipsoid zone disruption in the right eye (RE) (Figure 1C). Observation was recommended.

Differentiating pseudocysts from cystoid macular edema (CME) of other etiologies has important clinical implications as antivascular endothelial growth factor (anti-VEGF) therapy is not convincingly effective in treating macular tel-angiectasia type 2 and may unnecessarily expose patients to risks of intravitreal injection.1 Type 2 macular telangiectasia is a rare, degenerative bilateral condition that typically presents in the fifth to sixth decade of life with the variable find-ings of reduced retinal transparency, crystalline deposits, mildly ectatic capillaries and blunted, slightly dilated venules. As disease advances, atrophy can develop as well as lamellar or full

Case studies underscore need to know what separates, image-wise, common vs. more uncommon diagnoses.

thickness holes and neovascularization. Macular OCT classically reveals pseudocysts,

which are atrophic hyporeflective spaces that do not show neurosensory thickening and are not associated with angiographic leakage or pooling of fluorescein dye. These pseudocysts are likely due to retinal degeneration and are pathophysi-ologically analogous to spaces in X-linked reti-noschisis.1 Other macular OCT findings include ellipsoid zone disruption, and in advanced dis-ease, atrophy of the neurosensory retina and sequelae from neovascularization.

Outer retinal tubulation in neovascular AMDAn 87-year-old male presented with a several-year history of progressive bilateral metamor-phopsia and scotoma. He had been treated with numerous anti-VEGF injections in his RE. VA measured 20/70 RE and 20/400 left eye (LE), and fundus examination revealed bilateral advanced geographic atrophy (GA), drusen and pigment clumping (Figure 2A). Macular OCT demon-strated outer retinal tubulation RE (red arrow, Figure 2B) as well as bilateral RPE atrophy with increased signal penetration into the choroid (blue arrows, Figure 2B).

Incidentally, the nerve fiber layer of the macu-lopapillary bundle is denoted by the yellow arrow (yellow arrow, Figure 2B). Due to disease inac-tivity, observation was recommended with close follow-up.

Differentiating outer retinal tubulation (ORT) from solitary cystoid spaces secondary to neovas-cular age-related macular degeneration (AMD) is important as ORT is not an indication to treat with anti-VEGF therapy. ORT is an OCT find-ing characterized by a hyporeflective cavity sur-rounded by a hyper-reflective wall and is found in the outer nuclear layer.

Histologically, this correlates with a sphere of surviving cones surrounded by Muller cell pro-cesses; the finding portends worse visual acuity outcomes.2,3 Most commonly found in advanced AMD, ORT can also be found in hereditary reti-nal degenerations.

Geographic atrophy, which was also noted in this case, is recognized as discrete areas of increased signal penetration into the choroid, and is a common finding in both non-neovascu-lar AMD and neovascular AMD. Laser photoco-agulation scars, which atrophy over time, can also yield multiple discrete areas of increased signal

penetration into the choroid.

2. ELLIPSOID ZONE DISRUPTIONS CORRELATING WITH SYMPTOMATIC FUNCTIONAL VISION LOSSThe ellipsoid zone represents the regularly oriented, inner portion of the photoreceptor layer that is densely packed with mitochondria, and has unique, clinically useful functional significance.

Parafoveal ellipsoid zone loss from hydroxychloroquine retinopathyA 65-year-old female presented with a two-month history of bilateral central vision loss. VA measured 20/30 RE and 20/20 LE. She endorsed a 20-year history of hydroxychloroquine use that was stopped several years prior to presentation. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes (Figure 3A) while fun-dus autofluorescence (FAF) demonstrated a bilat-eral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figure 3B). Macular OCT identified parafoveal ellipsoid zone loss (leaving the central ellipsoid zone intact, reminiscent of a “flying saucer” and hence the “flying saucer sign”) along with generalized retinal thinning (Figure 3C, red arrows depicting the edge of intact foveolar ellip-soid zone). Even though she had not taken hydroxy-chloroquine for a number of years, this patient d e m o n s t r a t e d progression of hydroxychloro-quine toxicity.

Macular OCT should be included among the tests for hydroxychlo-IM

AG

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Figure 1. Pseudo-cysts in macular tel-angiectasia type 2.

Figure 2. Outer retinal tubulation in neovascular AMD.

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Figure 3. Parafoveal ellipsoid zone loss from hydroxychloro-quine retinopathy.

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roquine (Plaquenil,Sanofi-Synthelabo, Inc.) maculopathy, as it can reveal disruption of the parafoveal ellipsoid zone (which can correlate with paracentral vision loss), as well as a loss of the external limiting mem-brane, parafoveal thin-ning of the outer nuclear layer, and RPE atrophy.4 Hydroxychloroquine is

used for a number of rheumatologic disorders. The risk of toxicity is very low in patients who consume less than 5.0 mg/kg of real body weight and who have been on therapy for less than 10 years.5 Early in the course of the disease, fundus appearance is normal and in later stages a bull’s eye maculopathy develops. Other tests that can help identify early pathology include a multifo-cal electroretinography (ERG), 10-2 Humphrey visual field testing and FAF. Early identification of pathologic changes is crucial because this pro-gressive retinopathy is irreversible and patients should stop therapy.

Subtle ellipsoid zone disruption with subsequent improvement after laser pointer injuryA 13-year-old male presented with a one-month history of an RE central scotoma following a laser injury. VA measured 20/20 bilaterally, and fun-dus and red-free macular evaluation were grossly normal (Figure 4A). His symptoms were difficult to explain until macular OCT revealed a subtle disruption of the foveal ellipsoid zone RE (Red

arrows, Figure 4B), cor-relating to his functional complaints. The patient was observed without treatment and had a slow resolution of the scotoma over the ensuing six weeks with partial resolution of the ellipsoid zone irregu-larity (Figure 4C).

Ellipsoid zone disrup-tion correlates with symp-tomatic functional vision loss and, in some disorders, can improve over time, correlating with improv-

ing symptoms. Laser retinal injuries have become more common with the widespread availability of inexpensive and high-energy, handheld laser pointers. Important variables in determining the degree of ophthalmic injury include the amount of energy delivered, the duration of exposure and the location of retinal involvement.6 Fundus examination can be normal with mild injury, and in more severe cases yellowing or whitening of the retina or a macular hole can develop. Macular OCT changes range from subtle disruption of the ellipsoid zone and inner retinal hyper-reflectiv-ity to subretinal hemorrhage and macular hole formation in severe cases. Steroid treatment for laser retinal injury has been advocated by some authors, but the efficacy in humans and in pre-clinical models remains controversial.7

Ellipsoid and interdigitation zone atrophy from solar maculopathy A 52-year-old schizophrenic male presented with a one-year history of bilateral, central, progres-sive scotomas after prolonged periods of staring at the sun. VA measured 20/20 RE and 20/30 LE and fundus examination revealed bilateral foveal atrophy with pigment clumping (Figure 5A). FA demonstrated central hypofluorescence with sur-rounding staining (Figure 5B) and macular OCT identified foveolar ellipsoid zone and interdigi-tation zone atrophy (Figure 5C; ELM [External limiting membrane], EZ [Ellipsoid zone], IDZ [Interdigitation zone], RPE [Retinal pigment epithelium]), accounting for his symptoms. Note that the external limiting membrane and RPE remain intact centrally.

Macular OCT is a sensitive test in identifying outer neurosensory retinal abnormalities, such as ellipsoid zone disruption, as well as RPE atrophy.8 A history of prolonged sun gazing can often be difficult to elicit from patients with an underlying psychiatric condition and the degree of pathol-ogy is primarily determined by the duration of exposure.9 Early fundus changes include areas of yellow pigmentation surrounded by a faint gray irregularity, which then progresses to reddish lesions, and eventually neurosensory retinal and RPE atrophy with scar formation.8-10

3. VARIATIONS OF RPE ELEVATIONS WITH DIAGNOSTIC, PROGNOSTIC AND THERAPEU-TIC IMPLICATIONSIn addition to the most commonly encountered

serous and fibrovascular PEDs in AMD, RPE elevations have numerous variations, which carry differing diagnostic, prognostic and therapeutic implications.

Retinal pigment epithelial tear in neovascular AMDAn 85-year-old female presented with a six-month history of a central blur in her RE, for which she had previously received numerous anti-VEGF injections for neovascular AMD. VA measured 20/200 RE and 20/60 LE, and fundus examination revealed a moderate RPE tear in her RE along with bilateral drusen and RPE changes. FA demonstrated a large window defect in the exposed area of the RPE tear along with an area of hypofluorescence from blockage by the heaped-up RPE in her RE, and bilateral staining consis-tent with drusen and RPE changes (Figure 6A). Macular OCT revealed an irregularly elevated and corrugated area of RPE (Figure 6B) adjacent to a denuded area of atrophy RE with increased signal penetration into the choroid (Figure 6B), along with bilateral drusen and a small area of cystoid macular edema LE (Figure 6B). Anti-VEGF therapy was continued in the RE and the patient was monitored closely.

RPE tears are a complication of pigment epi-thelial detachments (PED) and can occur sponta-neously or be precipitated by anti-VEGF therapy. They are associated with a poor visual prognosis when the fovea is involved. Fundus examina-tion reveals an area of bare choroid adjacent to retracted RPE, which is best delineated with fun-dus autofluorescence. Macular OCT shows a dis-ruption of the RPE layer with adjacent increased signal penetration into the choroid; the elevated RPE is irregular, corrugated and hyper-reflective overlying a hyporeflective shadow. The differen-tial diagnosis for RPE tears include GA due to advanced AMD and various etiologies of PED; the history and corrugated appearance of RPE on OCT can differentiate these pathologies. Anti-VEGF therapy should be continued in these patients despite the possibility that the therapy initially precipitated the tear, until the disappear-ance of underlying evidence of active choroidal neovascularization (CNV).11

Polyp in polypoidal choroidal vasculopathyAn 89-year-old African-American female pre-sented with a two-week history of central blurring in her RE, and VA measured 20/40 RE and 20/25

LE. Posterior pole evaluation revealed a hemorrhagic PED and suggested a polyp temporal to the optic disc in the RE, with a normal left poste-rior pole (Figure 7A). Macular OCT demonstrated a large area of sub-retinal fluid as well as a likely polyp with steeply elevated contours (White arrow, Figure 7B). Monthly anti-VEGF therapy was initiated and the patient experienced an improvement in visual acuity and anatomic resolution of exudation.

Macular OCT can frequently identify pol-yps and other findings of polypoidal choroidal vasculopathy (PCV), such as dilated choroidal vessels. Identifying polyps in PCV and differen-tiating them from other forms of choroidal neo-vascularization has clinical implications, as the EVEREST trial found that combination therapy (photodynamic therapy with VEGF blockade) was superior to anti-VEGF therapy alone.12 PCV is a variation of AMD characterized by polypoi-dal lesions resulting in serous and serosanguine-ous detachments of the neurosensory retina and RPE. Polyps can sometimes be seen on posterior pole examination, but are best identified with indocyanine green angiography. En face macular OCT can identify polyp networks and also reveal the “hematocrit sign”, in which blood settles into serous and red blood cell components.13 A sharp PED peak (as in this case), a PED notch and a hyporeflective PED lumen within a hyper-reflec-tive lesion adherent to the outer surface of the RPE are characteristics that can help differentiate PCV from serous PEDs.14

Adult-onset foveo-macular vitelliform dystrophy An 85-year-old, g l a u c o m a t o u s female presented with a one-month history of bilateral central blurring.

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Figure 4. Subtle el-lipsoid zone disrup-tion with subse-quent improvement after laser pointer injury.

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Figure 5. Ellipsoid and interdigitation zone atrophy from solar maculopathy.

Figure 6. Retinal pig-ment epithelial tear in neovascular AMD.

Figure 7. Polyp in polypoidal choroidal vasculopathy.


THE DIAGNOSTICS

ISSUE


roquine (Plaquenil,Sanofi-Synthelabo, Inc.) maculopathy, as it can reveal disruption of the parafoveal ellipsoid zone (which can correlate with paracentral vision loss), as well as a loss of the external limiting mem-brane, parafoveal thin-ning of the outer nuclear layer, and RPE atrophy.4 Hydroxychloroquine is

used for a number of rheumatologic disorders. The risk of toxicity is very low in patients who consume less than 5.0 mg/kg of real body weight and who have been on therapy for less than 10 years.5 Early in the course of the disease, fundus appearance is normal and in later stages a bull’s eye maculopathy develops. Other tests that can help identify early pathology include a multifo-cal electroretinography (ERG), 10-2 Humphrey visual field testing and FAF. Early identification of pathologic changes is crucial because this pro-gressive retinopathy is irreversible and patients should stop therapy.

Subtle ellipsoid zone disruption with subsequent improvement after laser pointer injuryA 13-year-old male presented with a one-month history of an RE central scotoma following a laser injury. VA measured 20/20 bilaterally, and fun-dus and red-free macular evaluation were grossly normal (Figure 4A). His symptoms were difficult to explain until macular OCT revealed a subtle disruption of the foveal ellipsoid zone RE (Red

arrows, Figure 4B), cor-relating to his functional complaints. The patient was observed without treatment and had a slow resolution of the scotoma over the ensuing six weeks with partial resolution of the ellipsoid zone irregu-larity (Figure 4C).

Ellipsoid zone disrup-tion correlates with symp-tomatic functional vision loss and, in some disorders, can improve over time, correlating with improv-

ing symptoms. Laser retinal injuries have become more common with the widespread availability of inexpensive and high-energy, handheld laser pointers. Important variables in determining the degree of ophthalmic injury include the amount of energy delivered, the duration of exposure and the location of retinal involvement.6 Fundus examination can be normal with mild injury, and in more severe cases yellowing or whitening of the retina or a macular hole can develop. Macular OCT changes range from subtle disruption of the ellipsoid zone and inner retinal hyper-reflectiv-ity to subretinal hemorrhage and macular hole formation in severe cases. Steroid treatment for laser retinal injury has been advocated by some authors, but the efficacy in humans and in pre-clinical models remains controversial.7

Ellipsoid and interdigitation zone atrophy from solar maculopathy A 52-year-old schizophrenic male presented with a one-year history of bilateral, central, progres-sive scotomas after prolonged periods of staring at the sun. VA measured 20/20 RE and 20/30 LE and fundus examination revealed bilateral foveal atrophy with pigment clumping (Figure 5A). FA demonstrated central hypofluorescence with sur-rounding staining (Figure 5B) and macular OCT identified foveolar ellipsoid zone and interdigi-tation zone atrophy (Figure 5C; ELM [External limiting membrane], EZ [Ellipsoid zone], IDZ [Interdigitation zone], RPE [Retinal pigment epithelium]), accounting for his symptoms. Note that the external limiting membrane and RPE remain intact centrally.

Macular OCT is a sensitive test in identifying outer neurosensory retinal abnormalities, such as ellipsoid zone disruption, as well as RPE atrophy.8 A history of prolonged sun gazing can often be difficult to elicit from patients with an underlying psychiatric condition and the degree of pathol-ogy is primarily determined by the duration of exposure.9 Early fundus changes include areas of yellow pigmentation surrounded by a faint gray irregularity, which then progresses to reddish lesions, and eventually neurosensory retinal and RPE atrophy with scar formation.8-10

3. VARIATIONS OF RPE ELEVATIONS WITH DIAGNOSTIC, PROGNOSTIC AND THERAPEU-TIC IMPLICATIONSIn addition to the most commonly encountered

serous and fibrovascular PEDs in AMD, RPE elevations have numerous variations, which carry differing diagnostic, prognostic and therapeutic implications.

Retinal pigment epithelial tear in neovascular AMDAn 85-year-old female presented with a six-month history of a central blur in her RE, for which she had previously received numerous anti-VEGF injections for neovascular AMD. VA measured 20/200 RE and 20/60 LE, and fundus examination revealed a moderate RPE tear in her RE along with bilateral drusen and RPE changes. FA demonstrated a large window defect in the exposed area of the RPE tear along with an area of hypofluorescence from blockage by the heaped-up RPE in her RE, and bilateral staining consis-tent with drusen and RPE changes (Figure 6A). Macular OCT revealed an irregularly elevated and corrugated area of RPE (Figure 6B) adjacent to a denuded area of atrophy RE with increased signal penetration into the choroid (Figure 6B), along with bilateral drusen and a small area of cystoid macular edema LE (Figure 6B). Anti-VEGF therapy was continued in the RE and the patient was monitored closely.

RPE tears are a complication of pigment epi-thelial detachments (PED) and can occur sponta-neously or be precipitated by anti-VEGF therapy. They are associated with a poor visual prognosis when the fovea is involved. Fundus examina-tion reveals an area of bare choroid adjacent to retracted RPE, which is best delineated with fun-dus autofluorescence. Macular OCT shows a dis-ruption of the RPE layer with adjacent increased signal penetration into the choroid; the elevated RPE is irregular, corrugated and hyper-reflective overlying a hyporeflective shadow. The differen-tial diagnosis for RPE tears include GA due to advanced AMD and various etiologies of PED; the history and corrugated appearance of RPE on OCT can differentiate these pathologies. Anti-VEGF therapy should be continued in these patients despite the possibility that the therapy initially precipitated the tear, until the disappear-ance of underlying evidence of active choroidal neovascularization (CNV).11

Polyp in polypoidal choroidal vasculopathyAn 89-year-old African-American female pre-sented with a two-week history of central blurring in her RE, and VA measured 20/40 RE and 20/25

LE. Posterior pole evaluation revealed a hemorrhagic PED and suggested a polyp temporal to the optic disc in the RE, with a normal left poste-rior pole (Figure 7A). Macular OCT demonstrated a large area of sub-retinal fluid as well as a likely polyp with steeply elevated contours (White arrow, Figure 7B). Monthly anti-VEGF therapy was initiated and the patient experienced an improvement in visual acuity and anatomic resolution of exudation.

Macular OCT can frequently identify pol-yps and other findings of polypoidal choroidal vasculopathy (PCV), such as dilated choroidal vessels. Identifying polyps in PCV and differen-tiating them from other forms of choroidal neo-vascularization has clinical implications, as the EVEREST trial found that combination therapy (photodynamic therapy with VEGF blockade) was superior to anti-VEGF therapy alone.12 PCV is a variation of AMD characterized by polypoi-dal lesions resulting in serous and serosanguine-ous detachments of the neurosensory retina and RPE. Polyps can sometimes be seen on posterior pole examination, but are best identified with indocyanine green angiography. En face macular OCT can identify polyp networks and also reveal the “hematocrit sign”, in which blood settles into serous and red blood cell components.13 A sharp PED peak (as in this case), a PED notch and a hyporeflective PED lumen within a hyper-reflec-tive lesion adherent to the outer surface of the RPE are characteristics that can help differentiate PCV from serous PEDs.14

Adult-onset foveo-macular vitelliform dystrophy An 85-year-old, g l a u c o m a t o u s female presented with a one-month history of bilateral central blurring.

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Figure 4. Subtle el-lipsoid zone disrup-tion with subse-quent improvement after laser pointer injury.

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Figure 5. Ellipsoid and interdigitation zone atrophy from solar maculopathy.

Figure 6. Retinal pig-ment epithelial tear in neovascular AMD.

Figure 7. Polyp in polypoidal choroidal vasculopathy.


THE DIAGNOSTICS

ISSUE


Her VA measured 20/200 RE (chronically poor) and 20/30 LE and she had a history of severe glau-coma in her RE necessitat-ing tube shunt placement. Fundus examination iden-tified symmetric yellow foveal lesions with pigment clumping (Figure 8A) and FA demonstrated an early bilateral blocking defect without staining or leakage (Figure 8B). Red-free pho-tographs provided greater contrast of the lesions (Figure 8C) and macular OCT identified bilateral hyper-reflective subretinal material underlying a mot-

tled ellipsoid zone in the LE (Figure 8D). Differentiating adult-onset foveomacular vitel-

liform dystrophy (AOFVD) from PEDs of neo-vascular AMD is important because these lesions are typically indolent and only require treatment if secondary neovascularization develops in chronic cases. AOFVD typically presents with mild visual disturbances between the ages of 30 and 50.15 The natural history of a classical AOFVD lesion is the development of an “egg-yolk” spot with subsequent degradation leading to a pseudohypopyon and eventually an area of atrophic neurosensory retina and RPE.15 Macular OCT identifies a dome-shaped, hyper-reflective subretinal mass with overlying ellipsoid-zone mottling during the vitelliform stage, and progressive degradation of the hyper-reflective material as the lesion involutes.15,16 The disease can also be differentiated from Best disease by a normal electro-oculogram (EOG) along with a nonpediat-ric or young-adult onset.

CONCLUSIONThis case series is limited in that space con-straints precluded a comprehensive review of the rich variation in OCT findings, particularly in infectious, inflammatory and neoplastic dis-orders. Still, this real-world OCT case series, derived from a typical retina clinic setting with its inherent limitations, demonstrates common but subtle findings that can impact management. Major themes include findings commonly mis-taken for CME not requiring treatment, ellipsoid

zone disruptions correlating with symptomatic functional vision loss, and variations of RPE elevations with diagnostic, prognostic and thera-peutic implications.

In the future, with rising clinic volumes, new imaging technologies such as OCT angiogra-phy and complex in-office treatments, rapid and accurate interpretation of real-world imaging will be increasingly important. OM

REFERENCES1. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Progress in retinal and eye research. 2013;34:49-77.2. Lee JY, Folgar FA, Maguire MG, et al. Outer retinal tubulation in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2014;121:2423-2431.3. Schaal KB, Freund KB, Litts KM, Zhang Y, Messinger JD, Curcio CA. Outer retinal tubulation in advanced age-related macular degeneration: Optical Coherence Tomographic Findings Correspond to Histology. Retina (Philadelphia, Pa). 2015;35:1339-1350.4. Chen E, Brown DM, Benz MS, et al. Spectral domain optical co-herence tomography as an effective screening test for hydroxychlo-roquine retinopathy (the “flying saucer” sign). Clinical Ophthalmol-ogy (Auckland, NZ). 2010;4:1151-1158.5. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmology. 2014;132:1453-1460.6. Xu K, Chin EK, Quiram PA, Davies JB, Parke DW, 3rd, Almeida DR. Retinal injury secondary to laser pointers in pediatric patients. Pediatrics. 2016;138(4).7. Barkana Y, Belkin M. Laser eye injuries. Survey of Ophthalmology. 2000;44:459-478.8. Birdsong O, Ling J, El-Annan J. Solar Retinopathy. Ophthalmology. 2016;123:570.9. Rai N, Thuladar L, Brandt F, Arden GB, Berninger TA. Solar retinopathy. A study from Nepal and from Germany. Documenta Ophthalmologica Advances in Ophthalmology. 1998;95:99-108.10. Brue C, Mariotti C, De Franco E, Fisher Y, Guidotti JM, Giovan-nini A. Solar retinopathy: a multimodal analysis. Case Reports in Ophthalmological Medicine. 2013;2013:906920.11. Ersoz MG, Karacorlu M, Arf S, Sayman Muslubas I, Hocaoglu M. Retinal pigment epithelium tears: Classification, pathogenesis, predictors, and management. Survey of Ophthalmology. 2017.12. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina (Philadelphia, Pa). 2012;32:1453-1464.13. Imamura Y, Engelbert M, Iida T, Freund KB, Yannuzzi LA. Polyp-oidal choroidal vasculopathy: a review. Survey of Ophthalmology. 2010;55:501-515.14. De Salvo G, Vaz-Pereira S, Keane PA, Tufail A, Liew G. Sensitivity and specificity of spectral-domain optical coherence tomography in detecting idiopathic polypoidal choroidal vasculopathy. American Journal of Ophthalmology. 2014;158:1228-1238.e1221.15. Rocha Bastos R, Ferreira CS, Brandao E, Falcao-Reis F, Carneiro AM. Multimodal image analysis in acquired vitelliform lesions and adult-onset foveomacular vitelliform dystrophy. Journal of Ophthal-mology. 2016;2016:6037537.16. Querques G, Forte R, Querques L, Massamba N, Souied EH. Natural course of adult-onset foveomacular vitelliform dystrophy: a spectral-domain optical coherence tomography analysis. American journal of ophthalmology. 2011;152:304-313.

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Figure 8. Adult-onset foveomacular vitel-liform dystrophy.

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Peter Bracha, MD, is a resident andThomas A. Ciulla, MD, MBA, is a volunteer clinical professor of Ophthalmology at Indiana University School of Medicine. Dr. Ciulla is on the Board of Directors of Midwest Eye Institute, an ophthalmic subspecialty tertiary center. He can be reached via e-mail at [email protected].

Neither author reports any financial interests in products mentioned in this article.

24 J U N E 2 0 1 7 • OP H T HA L M OL O G Y M A NAG E M E N T

THE DIAGNOSTICS

ISSUE

Vitreous Pathology

Peter Bracha, Gian Paolo Giuliari, and Thomas A. Ciulla

Abstract The vitreous is involved in a wide variety of pathologies. The vitreo-retinal interface is the site of adhesion between the posterior vitreous cortex andthe retina’s internal limiting membrane, and a pathological interaction betweenthese two surfaces accounts for pathologies including vitreomacular traction,macular holes, epiretinal membranes, retinal tears and detachments, and macularedema. The vitreous has a structural role in retinal neovascularization, in particularproliferative diabetic retinopathy, retinopathy of prematurity, and familial exudativevitreoretinopathy. Metabolic disorders of the vitreous include amyloidosis andasteroid hyalosis. These diseases of the vitreous and vitreoretinal interface will bediscussed in this chapter.

As discussed in a prior chapter, the vitreous is composed of 99% water with theremainder comprised of collagen, which forms the fibrillary component, and theglycoaminoglycosides (GAGs) hyaluronan and chondroitin sulfate. The vitreoreti-nal interface is the site of adhesion between the posterior vitreous cortex and theretina’s internal limiting membrane (ILM), and includes laminin and fibronectin,which have high affinity for collagen. The vitreous and vitreoretinal interface havenumerous roles in the physiology and pathology of the human eye. However,the “transparent by design” nature of the vitreous has historically made study ofits pathophysiologic roles a challenging issue. Advances in imaging, particularlyoptical coherence tomography, has clarified the precise interaction between thevitreous and retina in various disease states, improving our understanding andmanagement of vitreoretinal pathology. Diseases of the vitreous and vitreoretinalinterface will be discussed in this chapter.

P. Bracha · G. P. GiuliariDepartment of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA

T. A. Ciulla (�)Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA

Midwest Eye Institute, Indianapolis, IN, USA

© Springer Nature Switzerland AG 2019G. Guidoboni et al. (eds.), Ocular Fluid Dynamics, Modeling and Simulation inScience, Engineering and Technology, https://doi.org/10.1007/978-3-030-25886-3_11

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1 Developmental Abnormalities

1.1 Stickler Syndrome

The vitreous collagen forms the fibrillary component of the vitreous, and consistsof types V and XI in the core, type II surrounding this core, and type IX on itsoutermost surface. The vitreoretinal interface includes the retina’s internal limitingmembrane, which is composed of type IV collagen [1]. Stickler syndrome isa genetic connective tissue disorder with mutations in genes encoding collagensubunits, resulting in malformation of primarily type II collagen, but also types IXand XI. Autosomal dominant variants can be caused by mutations in COL2A1 (80–90% of cases), COL11A1 (10–20% of cases), or COL11A2. Autosomal recessivevariants can be due to mutations in COL9A1, COL9A2, or COL9A3. Clinically,patients have an optically empty vitreous with a thin layer of cortical vitreousimmediately posterior to the lens (membranous subtype) or threadlike, avascularmembranes that adhere circumferentially to the retina (beaded congenital vitreousanomaly). Patients classically have high myopia and equatorial and perivascularlattice degeneration, placing them at high risk of rhegmatogenous retinal detach-ment. Patients are at increased risk of open-angle glaucoma and premature cataractformation.

Stickler syndrome can be classified into syndromic and ocular-only subtypes,determined by the underlying genetic mutation. Genetic testing is available and canhelp with both diagnosis and prognosis.

Syndromic variants, which are more common than the ocular-only subtypes,are associated with midfacial flattening, oral clefting, and Pierre Robin sequence,features which can help clue practitioners to the right diagnosis. Musculoskeletalmanifestations are common and include femoral head failure, precocious arthritis,and mild spondyloepiphyseal dysplasia. Both conductive and sensorineural hearingloss are common.

Management of the associated systemic conditions is important, as craniofacialand hearing issues can be amenable to treatment. Anesthesiologists should beinformed of the diagnosis so that they can be prepared for variations duringintubation. Amblyopic refractive errors can be treated with spectacles or contacts,and retinal detachment should be treated in standard fashion. Genetic counselingcan be offered and screening of potentially affected family members should beconsidered [2, 3].

1.2 Wagner Syndrome

As noted above, the vitreous glycoaminoglycosides (GAGs) include hyaluronan andchondroitin sulfate, with the former being more abundant [1]. Wagner syndromeis an autosomal dominant disease caused by a mutation in the chondroitin sulfate

Vitreous Pathology 279

proteoglycan 2 gene (CSPG2), and is clinically and pathologically distinct fromocular-only variants of Stickler’s syndrome, despite a similarly optically emptyvitreous with myopia. The CSPG2 gene encodes a core protein of the proteoglycanversican, a key vitreous structural protein. Classical features include vitreoussyneresis, posterior strands and veils in the vitreous cavity, and avascular mem-branes. Patients may also have subnormal rod and cone responses on ERG, earlycataract formation, age-dependent chorioretinal atrophy, and peripheral tractionalretinal detachment from a progressive and extensive vitreoretinopathy. Unlikein classical Stickler syndrome, Wagner syndrome rarely has associated systemicmanifestations [4].

1.3 Persistent Fetal Vasculature

Persistent fetal vasculature, also known as persistent hyperplastic primary vitreous,is a unilateral developmental anomaly that typically presents as a white retrolentalmass at birth. It is caused by the persistence of the anterior hyaloid artery, whichis the first embryological source of nutrients to the anterior eye. Typically it isassociated with the ocular findings of microphthalmos, elongated ciliary processes,and lenticular opacification. Other associated findings include a shallow anteriorchamber, glaucoma, and vitreous hemorrhage; pathologic neuroophthalmic devel-opmental sequelae include amblyopia and strabismus. The precise pathogenesis ispoorly understood. Most cases are sporadic, but autosomal dominant and recessiveinheritance patterns have been described [5].

2 Normal Aging

The normal vitreous undergoes changes with age that can result in symptomaticfloaters. Proteins can aggregate into visible masses that can result in light scatteringand shadowing, most noticeable in brighter light. Liquefaction of the vitreous bodyoccurs initially in a patchy fashion. The resulting lacunae can cause light scatter,contributing to the sensation of floaters. The liquefaction of vitreous typically startsaround the age of four, increases in volume with age, and results in approximately50% liquefaction of the gel in septuagenarians [6]. Syneresis and synchysis arecontroversial terms used to describe the process of vitreous liquefaction and proteinaggregation; the precise terminology in literature is conflicting, with some authorsdescribing syneresis as liquefaction and other authors describing syneresis as proteinaggregation [7, 8]. Due to the conflicting terminology, this book chapter usesdescriptive terms, vitreous liquefaction, and vitreous protein aggregation.


3 Posterior Vitreous Detachment

Posterior vitreous detachment (PVD) is a very common process where the typicallyadherent vitreous cortex separates from the neurosensory retina. Aging and patho-logic processes lead to liquefaction and condensation of proteins within the bodyof the vitreous and weakening of adhesions between the posterior vitreous cortexand the internal limiting membrane (ILM). These biochemical changes combinedwith mechanical forces of a rotating globe lead to a separation of the posteriorhyaloid from the ILM (Fig. 1). This typically starts in the macula, and separationplanes between the vitreous cortex and neurosensory retina allow chronic or acuteprogression of the detachment anteriorly. Firm points of attachment between thecortex and the ILM include the fovea, optic nerve, and vitreous base, as well asmajor blood vessels, border of lattice degeneration, and chorioretinal scars. Thesefirm points of attachment punctuate the four stages of PVD. Stage 1 PVD involvesa partial PVD in the macula, with persistent cortical attachment to the fovea, opticnerve, and midperipheral retina. Stage 2 PVD involves a partial PVD progressingperifoveally, with persistent cortical attachment to the fovea, optic nerve, andmidperipheral retina. Stage 3 PVD involves further progression through the fovea,with persistent cortical attachment to the optic nerve and midperipheral retina. Stage4 PVD is considered a total PVD, with a visible Weiss Ring and persistent corticalattachment to the vitreous base only [9].

Fig. 1 Posterior vitreous detachment. This B-scan ultrasound image clearly reveals the posteriorhyaloid, detached from the retina. Vitreous debris are noted


Firm points of attachment between the vitreous cortex and retinal structures alsocontribute to vitreoretinal disorders, when accelerated vitreous liquefaction outpacesthe age-related decline in vitreoretinal adhesion, resulting in pathologic separationof cortex from retina. When the vitreous cortex separates, the mechanical forces canresult in symptomatic flashes and condensation of cortex can result in floaters. Ifthese large floaters are very symptomatic, a pars plana vitrectomy (PPV) or, morerecently, as an investigational option, YAG vitreolysis can be considered [9].

4 Anomalous Posterior Vitreous Detachment

4.1 Vitreomacular Traction

Vitreomacular traction (VMT) is a spectrum of disease where the vitreous cortexdoes not separate normally from the macula. Vitreomacular adhesion (VMA) is theleast severe stage of disease, where a partial PVD is present but foveal attachmentpersists without distortion of the normal retinal contour (i.e., a stage 2 PVD, partof normal PVD evolution). In one observational, cross-sectional study of 335 eyesin 271 patients examined by OCT and ultrasonography, vitreofoveal adhesion waspresent in 19% of eyes, as assessed by OCT. As expected, the prevalence ofvitreofoveal adhesion decreased with age, affecting 26% of patients <70 years ofage compared to 9% of patients >80 years of age [10].

In VMT, as traction progresses in the setting of a firm vitreous cortex-fovealadhesion, the foveal anatomy becomes increasingly distorted by centripetal vit-reoretinal traction. Patients typically present during the sixth to eighth decade oflife and experience metamorphopsia and central visual blur when forces result indistortion of the normal foveal contour. In early stages, the anomalous adhesionspontaneously resolves in 50% of cases. If symptomatic and chronic, practitionerscan consider ocriplasmin, a protease, to degrade proteins, including laminin whichis a key component of the vitreomacular interface. Patients with focal adhesionstend to respond better to this chemical vitreolysis [11]. Alternatively, surgical lysisof the vitreomacular adhesion can be considered.

4.2 Idiopathic Macular Hole

An idiopathic macular hole is hypothesized to be a sequelae of vitreomaculartraction, resulting from avulsion of the vitreous cortex from the macula and theformation of a partial- to full-thickness neurosensory retinal break [12]. Patientsare variably symptomatic, from a mild central blur and metamorphopsia to a largecentral scotoma. Macular holes can be also staged according to their appearance,with stage 0 being an anomalous PVD with persistent foveal attachment. A stage


1 hole is either a foveal detachment (1A) or an isolated break in the outer fovea(1B). A stage 1A macular hole appears ophthalmoscopically as a central yellowspot with loss of foveolar depression and represents early serous detachment offoveolar retina. It can sometimes be mistaken for a solitary foveal soft druse onclinical exam. A stage 1B macular hole appears ophthalmoscopically as a 250-µmyellow ring forming an irregular slightly elevated ridge and results from centrifugalaccumulation of foveolar xanthophyll [13]. A stage 2 hole is an eccentric orsmall, round full-thickness defect <400 µm in diameter. In many of these cases,an eccentric tear forms in the contracted prefoveolar vitreous cortex, producing apseudo-operculum [13]. In the past, these tears have been thought to represent full-thickness retinal flap tears, or true opercula. A stage 3 hole is a full-thickness hole>400 µm in diameter and is typically surrounded by a small rim of thickened andlocalized detached perifoveal retina. It can be accompanied by an overlying, freepseudo-operculum. Yellow, clumped RPE deposits can be noted in the base of thehole [13]. Finally, a stage 4 hole is a full-thickness hole with a complete PVD.

Macular holes are treated based upon their symptomology, stage, chronicity, andetiology. Stage 1 holes have a 50% chance of spontaneous resolution followingvitreofoveolar separation. Stage 2 through 4 holes have less than a 10% chanceof spontaneous resolution, therefore a PPV with gas tamponade and ILM peel canbe considered for symptomatic patients. ILM peeling is thought to reduce the riskof hole recurrence through elimination of a scaffolding for cellular proliferation andsubsequent mechanical tangential traction [14].

4.3 Epiretinal Membrane

An epiretinal membrane (ERM) is a fibrocellular proliferation at the vitreoretinalinterface that results in distortion of the underlying retina and can cause visualsymptoms ranging from asymptomatic to debilitating central metamorphopsia andreduced acuity [15]. The membrane is composed of retinal and extraretinal cells andextracellular matrix components. The cellular source for the membrane includesglial cells, hyalocytes, macrophages, retinal pigment epithelial cells, fibroblasts,and myofibroblasts. Epithelial mesenchymal transition (EMT) of retinal pigmentepithelium (RPE) cells that escape through retinal breaks is one potential sourcethat may play a role in ERM [16]. The transdifferentiation of various cell typesinto myofibroblasts makes the precise origin of the cellular component difficult todetermine. The cellular proliferation produces excessive and disorganized collagenand other extracellular matrix components, and contraction of the fibrocellularmembrane results in distortion of the underlying retina [17]. Therapeutically, anERM can be surgically removed through PPV, with or without the removal of theunderlying ILM.


4.4 Vitreous Hemorrhage

Vitreous cortex has increased adherence to retinal vessels and as the vitreousdetaches, tractional forces can cause blood vessels to shear and then bleed into thevitreous. Smaller vitreous hemorrhages tend to resolve spontaneously, but largerhemorrhages often need to be cleared through PPV. Ocular ultrasonography isindicated for vitreous hemorrhage to rule out retinal tear or detachment, either ofwhich would prompt urgent PPV and repair. A unique sequela of vitreous hem-orrhage, particularly in eyes with severe and chronic pathology, is cholersterolosisbulbi (alternatively known as synchysis scintillans), in which cholesterol crystalsaccumulate subretinally, within the vitreous body or anterior chamber followingresolution of the hemorrhage [18].

4.5 Retinal Tears and Detachments

Strong adhesion between the vitreous and peripheral retina can result in a retinaltear with the progression of a posterior vitreous detachment. Tears are typicallysymptomatic with flashes and floaters, and vision can significantly decline ifvitreous hemorrhage or retinal detachment occurs. Early recognition and timelytreatment with laser barricade is essential to prevent the development of a retinaldetachment. If retinal detachment occurs, the status of macular attachment andchronicity dictate the urgency of repair. When the macula is attached and the onsetis acute, urgent repair is indicated; following macular detachment, the urgency ofimmediate repair diminishes.

5 Macular Edema

Vitreous cortex may play a role in macular edema from various etiologies, includingpseudophakic cystoid macular edema (Irvine-Gass syndrome), diabetic macularedema, retinal vein occlusion, uveitis, and vitreomacular traction syndrome [19].It is thought that traction on macular vasculature can compromise vessel integrity,leading to increased permeability and macular edema. Another hypothetical mech-anism for vascular instability includes the sequestration of permeability factors inthe gelatinous, native vitreous. Several authors have reported case series suggestingbenefit of PPV with posterior hyaloid excision in the treatment of diabetic macularedema, especially those cases in which OCT suggests traction [20]. However,medical treatment with anti-vascular endothelial growth factor (anti-VEGF) therapyor steroids has a more favorable risk–benefit profile, and PPV plays a role only inrecalcitrant cases and instances of vitreomacular traction.


6 The Role of Vitreous in Retinal Neovascularization

6.1 Proliferative Diabetic Retinopathy

The vitreous acts as a scaffold for retinal neovascularization (NV), which growsinto the vitreous, instead of in the plane of the retina, in ischemic retinopathies,most commonly in proliferative diabetic retinopathy (PDR). The vitreous cortexcan shift during PVD, causing traction on the NV, which shears and hemorrhagesinto the vitreous. In addition, NV in the vitreous cortex can fibrose, contract, andlead to tractional retinal detachment. In more severe cases of PDR, specificallythose with tractional retinal detachment or severe non-clearing vitreous hemorrhage,PPV is indicated. Pars plana vitrectomy is clearly beneficial for the treatment ofadvanced active PDR, not only excising the vitreous scaffold on which NV growsbut also excising the vitreous cortex which plays a role in NV traction and vitreoushemorrhage.

6.2 Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a developmental pathology of retinal vascu-logenesis, where peripheral retinal ischemia results in neovascularization and insevere cases retinal detachment. Retinal vascular development begins at the opticdisc at 16 weeks gestation and normally reaches the nasal and temporal ora serrataat 36 and 40 weeks, respectively. Suboptimal oxygenation and comorbid conditions,such as sepsis, result in premature closure of peripheral capillaries and preventnormal vascular development. The pathogenesis is complex, but principal factorsinclude suboptimal postnatal retinal oxygenation and abnormal systemic growthfactor production, both of which are a result of extreme prematurity, multi-organinsufficiency, and resuscitative efforts. This peripheral retinal ischemia can result incharacteristic vascular changes, the early stages of which are a retinal demarcationline (Stage 1 ROP) that can develop into a ridge, with height and width (Stage 2ROP). As disease progresses, neovascularization develops at this ridge and bloodvessels extend into the vitreous (Stage 3 ROP). The blood vessels can then fibroseand contract, which results in a subtotal retinal detachment (Stage 4 ROP) andcan culminate in a total retinal detachment (Stage 5 ROP). Early identification ofROP is crucial for early treatment and a reduction in the risk of development ofretinal detachment. Peripheral retinal ablation of ischemic retina, either with laseror cryotherapy, increases the chances of favorable outcomes in select patients [21].Anti-VEGF therapy has also demonstrated efficacy, but the ideal dosage, injectionfrequency, and follow-up remain unclear [22].


6.3 Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy is a genetic condition caused by mutations ingenes that promote retinal vasculogenesis. The hallmark of FEVR is the failure ofthe temporal retina to properly vascularize, resulting in peripheral ischemia withensuing VEGF-driven exudation and fibrovascular proliferation. As in PDR, thisabnormal tissue can result in vitreous hemorrhage, retinal folds, tractional andexudative retinal detachment as well as a large positive angle kappa due to draggingof the macula. The phenotype is similar to retinopathy of prematurity (ROP), andthe two can typically be distinguished by the premature birth and early criticalcare found in ROP. It is typically inherited in an autosomal dominant manner, butautosomal recessive and X-linked recessive forms have also been described. Severalcausative genes have been identified, but remain unidentified in numerous othercases, and the function of the known genes has not been fully elucidated. Four ofthe five implicated genes affect the Norrin/Frizzled4 signaling pathway, suggestingan important role in retinal vascular development.

Diagnosis is facilitated by wide field fluorescein angiography, which can visu-alize capillary loss typical of ischemic retina. Treatment depends on the stageof disease. Mild disease, without neovascularization or exudation, is typicallyobserved. Neovascular disease is typically treated with peripheral retinal photocoag-ulation in the area of ischemic retina. Fibrovascular traction, resulting in detachmentor significant distortion of the retina, can be treated surgically. Referral to ageneticist should be considered for possible genetic testing and counseling of familymembers. If the LRP5 mutation is identified, dual energy X-ray absorptiometry(DEXA) scans should be performed to assess bone mineral density due to the highrate of associated osteopenia and osteoporosis [23].

7 Metabolic Disorders

7.1 Asteroid Hyalosis

Asteroid hyalosis is a benign and frequently asymptomatic accumulation of small10–100 nm clumps of fat, phospholipids, and calcium in the vitreous. The pathogen-esis is poorly understood. The vitreous aggregates, if in large enough quantity, canobscure visualization of the posterior pole, and fluorescein angiography can providesuperior visualization of the retina over indirect ophthalmoscopy due to the lackof reflectance of the fluorescent wavelength coming from the retinal vasculature.In contrast, the wavelengths of light from the indirect headset reflect off of thecalcified deposits, significantly reducing image contrast of underlying retina. Ifsignificantly affecting quality of vision or obscuring underlying retina from effectiveand necessary monitoring, PPV can remove asteroid hyalosis.


7.2 Amyloidosis

Amyloid deposits are aggregates of low-molecular-weight proteins with a beta-pleated sheet conformation in which the adjacent strands of polypeptides run inopposite directions (“anti-parallel”). Deposition of amyloid can occur in almostany organ to result in a myriad of diseases, each possessing a constellation ofclinical findings. Clinicians have classified amyloidoses as follows: (1) primaryamyloidosis, with no coexisting systemic disease; (2) multiple myeloma-associatedamyloidosis; (3) secondary or reactive amyloidosis associated with chronic infec-tious disease or chronic inflammatory disease; (4) heredofamilial amyloidosisassociated with some cardiovascular, renal, or neuropathic syndromes, or withfamilial Mediterranean fever; (5) local amyloidosis, resulting in single organ systemdeposition without systemic disease; (6) aging associated amyloidosis, often in thebrain and heart.

Amyloid can affect the eye and adjacent structures in many ways. A hereditaryform of systemic amyloidosis, designated as familial amyloidotic polyneuropathy(FAP), involves the vitreous and the peripheral nerves. FAP had been traditionallysubdivided into four types. Type I FAP includes vitreous amyloidosis with an auto-nomic and peripheral neuropathy affecting the lower extremities most frequently.Type II FAP also develops vitreous amyloidosis and peripheral neuropathy, but theupper extremities, instead of the lower extremities, are affected first, and there isoften an associated cardiomyopathy. Carpal tunnel syndrome can be present. FAPtypes I and II are caused by accumulation of mutant transthyretin. Patients with typeIII and IV FAP do not develop vitreous opacities.

The vitreous opacities can mimic infectious, inflammatory, and neoplastic etiolo-gies. Pars plana vitrectomy can be employed diagnostically and therapeutically forvitreous amyloidosis. It is indicated when the vitreous deposits substantially reducevisual acuity.

References

1. Schneider, E.W. and M.W. Johnson, Emerging nonsurgical methods for the treatment ofvitreomacular adhesion: a review. Clin Ophthalmol, 2011. 5: p. 1151-65.

2. Snead, M.P., et al., Stickler syndrome, ocular-only variants and a key diagnostic role for theophthalmologist. Eye (Lond), 2011. 25(11): p. 1389-400.

3. Robin, N.H., R.T. Moran, and L. Ala-Kokko, Stickler Syndrome, in GeneReviews(R), M.P.Adam, et al., Editors. 1993, University of Washington, Seattle

4. Meredith, S.P., et al., Clinical characterisation and molecular analysis of Wagner syndrome.Br J Ophthalmol, 2007. 91(5): p. 655-9.

5. Shastry, B.S., Persistent hyperplastic primary vitreous: congenital malformation of the eye.Clin Exp Ophthalmol, 2009. 37(9): p. 884-90.

6. Milston, R., M.C. Madigan, and J. Sebag, Vitreous floaters: Etiology, diagnostics, andmanagement. Surv Ophthalmol, 2016. 61(2): p. 211-27.

7. Sebag, J., Age-related changes in human vitreous structure. Graefes Arch Clin Exp Ophthal-mol, 1987. 225(2): p. 89-93.


8. Le Goff, M.M. and P.N. Bishop, Adult vitreous structure and postnatal changes. Eye (Lond),2008. 22(10): p. 1214-22.

9. Johnson, M.W., Posterior vitreous detachment: evolution and complications of its early stages.Am J Ophthalmol, 2010. 149(3): p. 371-82.e1.

10. Schwab, C., et al., Prevalence of early and late stages of physiologic PVD in emmetropicelderly population. Acta Ophthalmol, 2012. 90(3): p. e179-84.

11. Neffendorf, J.E., et al., Ocriplasmin for symptomatic vitreomacular adhesion. CochraneDatabase Syst Rev, 2017. 10: p. Cd011874.

12. Gass, J.D., Idiopathic senile macular hole. Its early stages and pathogenesis. Arch Ophthalmol,1988. 106(5): p. 629-39.

13. Krzystolik, M.G., T.A. Ciulla, and A.R. Frederick, Jr., Evolution of a full-thickness macularhole. Am J Ophthalmol, 1998. 125(2): p. 245-7.

14. Bainbridge, J., E. Herbert, and Z. Gregor, Macular holes: vitreoretinal relationships andsurgical approaches. Eye (Lond), 2008. 22(10): p. 1301-9.

15. Ciulla, T.A. and R.D. Pesavento, Epiretinal fibrosis. Ophthalmic Surg Lasers, 1997. 28(8): p.670-9.

16. Shu, D.Y. and F.J. Lovicu, Myofibroblast transdifferentiation: The dark force in ocular woundhealing and fibrosis. Prog Retin Eye Res, 2017.

17. Bu, S.C., et al., Idiopathic epiretinal membrane. Retina, 2014. 34(12): p. 2317-35.18. Wand, M., T.R. Smith, and D.G. Cogan, Cholesterosis bulbi: the ocular abnormality nown as

synchysis scintillans. Am J Ophthalmol, 1975. 80(2): p. 177-83.19. Golan, S. and A. Loewenstein, Surgical treatment for macular edema. Semin Ophthalmol,

2014. 29(4): p. 242-56.20. Haller, J.A., et al., Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular

traction. Ophthalmology, 2010. 117(6): p. 1087-1093.e3.21. Revised indications for the treatment of retinopathy of prematurity: results of the early

treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol, 2003. 121(12): p.1684-94.

22. Mintz-Hittner, H.A., K.A. Kennedy, and A.Z. Chuang, Efficacy of intravitreal bevacizumab forstage 3+ retinopathy of prematurity. N Engl J Med, 2011. 364(7): p. 603-15.

23. Gilmour, D.F., Familial exudative vitreoretinopathy and related retinopathies. Eye (Lond),2015. 29(1): p. 1-14.

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