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1. Schwartz-Matsuo syndrome: An important cause of secondary glaucoma

Author

Tyler Etheridge, Jennifer C. Larson, T. Michael Nork, and Anna C. Momont

Subjects
Ophthalmology, RE1-994
Abstract

Purpose: We report a case of Schwartz-Matsuo syndrome that highlights the pathophysiology, diagnostic challenges, and management considerations of this rare disease. Observations: 31-year-old man with a history of left eye cataract presented with left eye photophobia and elevated intraocular pressure (IOP) of 64 mm Hg. Visual acuity 20/40. Open angles with an increased pigment of trabecular meshwork by gonioscopy, 2 + anterior chamber (AC) cell, superior retinal detachment, and 0.6 cup-to-disc ratio. Electron microscopy of AC fluid demonstrated outer segments of photoreceptors. IOP was lowered with oral and topical ophthalmic antihypertensives. Retinal detachment was treated with pars plana vitrectomy with endolaser, gas tamponade, and AC paracentesis. Follow-up VA 20/20 with normal IOP. Conclusions and importance: Schwartz-Matsuo syndrome is characterized by elevated IOP with marked fluctuations, open angles, aqueous cells, and retinal detachment. Diagnosis is supported by electron microscopy of AC fluid with outer segments of photoreceptors. Treatment includes retinal detachment repair and antihypertensive therapy. Keywords: Schwartz-Matsuo syndrome, Retinal detachment, Open-angle glaucoma

Published
2020
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2. Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

Author

Jenna R Rosinski, Lauren E Raasch, Patrick Barros Tiburcio, Meghan E Breitbach, Phoenix M Shepherd, Keisuke Yamamoto, Elaina Razo, Nicholas P Krabbe, Mason I Bliss, Alexander D Richardson, Morgan A Einwalter, Andrea M Weiler, Emily L Sneed, Kerri B Fuchs, Xiankun Zeng, Kevin K Noguchi, Terry K Morgan, Alexandra J Alberts, Kathleen M Antony, Sabrina Kabakov, Karla K Ausderau, Ellie K Bohm, Julia C Pritchard, Rachel V Spanton, James N Ver Hoove, Charlene B Y Kim, T Michael Nork, Alex W Katz, Carol A Rasmussen, Amy Hartman, Andres Mejia, Puja Basu, Heather A Simmons, Jens C Eickhoff, Thomas C Friedrich, Matthew T Aliota, Emma L Mohr, Dawn M Dudley, David H O'Connor, and Christina M Newman

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Published
2023
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4. Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Author

Michelle R Koenig, Elaina Razo, Ann Mitzey, Christina M Newman, Dawn M Dudley, Meghan E Breitbach, Matthew R Semler, Laurel M Stewart, Andrea M Weiler, Sierra Rybarczyk, Kathryn M Bach, Mariel S Mohns, Heather A Simmons, Andres Mejia, Michael Fritsch, Maria Dennis, Leandro B C Teixeira, Michele L Schotzko, T Michael Nork, Carol A Rasmussen, Alex Katz, Veena Nair, Jiancheng Hou, Amy Hartman, James Ver Hoeve, Charlene Kim, Mary L Schneider, Karla Ausderau, Sarah Kohn, Anna S Jaeger, Matthew T Aliota, Jennifer M Hayes, Nancy Schultz-Darken, Jens Eickhoff, Kathleen M Antony, Kevin Noguchi, Xiankun Zeng, Sallie Permar, Vivek Prabhakaran, Saverio Capuano, Thomas C Friedrich, Thaddeus G Golos, David H O'Connor, and Emma L Mohr

Subjects
Medicine, Science
Abstract

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

Published
2020
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5. Prediction for 2-Year Vision Outcomes Using Early Morphologic and Functional Responses in the Comparison of Age-related Macular Degeneration Treatments Trials

Author

Katie Xue, Peiying Hua, Maureen G. Maguire, Ebenezer Daniel, Glenn J. Jaffe, Juan E. Grunwald, Gui-shuang Ying, David F. Williams, Sara Beardsley, Steven Bennett, Herbert Cantrill, Carmen Chan-Tram, Holly Cheshier, Kathyrn Damato, John Davies, Sundeep Dev, Julianne Enloe, Gennaro Follano, Peggy Gilbert, Jill Johnson, Tori Jones, Lisa Mayleben, Robert Mittra, Martha Moos, Ryan Neist, Neal Oestreich, Polly Quiram, Robert Ramsay, Edwin Ryan, Stephanie Schindeldecker, John Snater, Trenise Steele, Dwight Selders, Jessica Tonsfeldt, Shelly Valardi, Gary Edd Fish, Hank A. Aguado, Sally Arceneaux, Jean Arnwine, Kim Bell, Tina Bell, Bob Boleman, Patricia Bradley, David Callanan, Lori Coors, Jodi Creighton, Timothy Crew, Kimberly Cummings, Christopher Dock, Karen Duignan, Dwain Fuller, Keith Gray, Betsy Hendrix, Nicholas Hesse, Diana Jaramillo, Bradley Jost, Sandy Lash, Laura Lonsdale, Michael Mackens, Karin Mutz, Michael Potts, Brenda Sanchez, William Snyder, Wayne Solley, Carrie Tarter, Robert Wang, Patrick Williams, Stephen L. Perkins, Nicholas Anderson, Ann Arnold, Paul Blais, Joseph Googe, Tina T. Higdon, Cecile Hunt, Mary Johnson, James Miller, Misty Moore, Charity K. Morris, Christopher Morris, Sarah Oelrich, Kristina Oliver, Vicky Seitz, Jerry Whetstone, Bernard H. Doft, Jay Bedel, Robert Bergren, Ann Borthwick, Paul Conrad, Amanda Fec, Christina Fulwylie, Willia Ingram, Shawnique Latham, Gina Lester, Judy Liu, Louis Lobes, Nicole M. Lucko, Holly Mechling, Lori Merlotti, Keith McBroom, Karl Olsen, Danielle Puskas, Pamela Rath, Maria Schmucker, Lynn Schueckler, Christina Schultz, Heather Shultz, David Steinberg, Avni Vyas, Kim Whale, Kimberly Yeckel, David H. Orth, Linda S. Arredondo, Susan Brown, Barbara J. Ciscato, Joseph M. Civantos, Celeste Figliulo, Sohail Hasan, Belinda Kosinski, Dan Muir, Kiersten Nelson, Kirk Packo, John S. Pollack, Kourous Rezaei, Gina Shelton, Shannya Townsend-Patrick, Marian Walsh, H. Richard McDonald, Nina Ansari, Amanda Bye, Arthur D. Fu, Sean Grout, Chad Indermill, Robert N. Johnson, J. Michael Jumper, Silvia Linares, Brandon J. Lujan, Ames Munden, Meredith Persons, Rosa Rodriguez, Jennifer M. Rose, Brandi Teske, Yesmin Urias, Stephen Young, Richard F. Dreyer, Howard Daniel, Michele Connaughton, Irvin Handelman, Stephen Hobbs, Christine Hoerner, Dawn Hudson, Marcia Kopfer, Michael Lee, Craig Lemley, Joe Logan, Colin Ma, Christophe Mallet, Amanda Milliron, Mark Peters, Harry Wohlsein, Joel A. Pearlman, Margo Andrews, Melissa Bartlett, Nanette Carlson, Emily Cox, Robert Equi, Marta Gonzalez, Sophia Griffin, Fran Hogue, Lance Kennedy, Lana Kryuchkov, Carmen Lopez, Danny Lopez, Bertha Luevano, Erin McKenna, Arun Patel, Brian Reed, Nyla Secor, Iris R. Sison, Tony Tsai, Nina Varghis, Brooke Waller, Robert Wendel, Reina Yebra, Daniel B. Roth, Jane Deinzer, Howard Fine, Flory Green, Stuart Green, Bruce Keyser, Steven Leff, Amy Leviton, Amy Martir, Kristin Mosenthine, Starr Muscle, Linda Okoren, Sandy Parker, Jonathan Prenner, Nancy Price, Deana Rogers, Linda Rosas, Alex Schlosser, Loretta Studenko, Thea Tantum, Harold Wheatley, Michael T. Trese, Thomas Aaberg, Denis Bezaire, Craig Bridges, Doug Bryant, Antonio Capone, Michelle Coleman, Christina Consolo, Cindy Cook, Candice DuLong, Bruce Garretson, Tracy Grooten, Julie Hammersley, Tarek Hassan, Heather Jessick, Nanette Jones, Crystal Kinsman, Jennifer Krumlauf, Sandy Lewis, Heather Locke, Alan Margherio, Debra Markus, Tanya Marsh, Serena Neal, Amy Noffke, Kean Oh, Clarence Pence, Lisa Preston, Paul Raphaelian, Virginia R. Regan, Peter Roberts, Alan Ruby, Ramin Sarrafizadeh, Marissa Scherf, Sarita Scott, Scott Sneed, Lisa Staples, Brad Terry, Matthew T. Trese, Joan Videtich, George Williams, Mary Zajechowski, Daniel P. Joseph, Kevin Blinder, Lynda Boyd, Sarah Buckley, Meaghan Crow, Amanda Dinatale, Nicholas Engelbrecht, Bridget Forke, Dana Gabel, Gilbert Grand, Jennifer Grillion-Cerone, Nancy Holekamp, Charlotte Kelly, Ginny Nobel, Kelly Pepple, Matt Raeber, P. Kumar Rao, Tammy Ressel, Steven Schremp, Merrilee Sgorlon, Shantia Shears, Matthew Thomas, Cathy Timma, Annette Vaughn, Carolyn Walters, Rhonda Weeks, Jarrod Wehmeier, Tim Wright, Daniel M. Berinstein, Aida Ayyad, Mohammed K. Barazi, Erica Bickhart, Tracey Brady, Lisa Byank, Alysia Cronise, Vanessa Denny, Courtney Dunn, Michael Flory, Robert Frantz, Richard A. Garfinkel, William Gilbert, Michael M. Lai, Alexander Melamud, Janine Newgen, Shamekia Newton, Debbie Oliver, Michael Osman, Reginald Sanders, Manfred von Fricken, Pravin Dugel, Sandra Arenas, Gabe Balea, Dayna Bartoli, John Bucci, Jennifer A. Cornelius, Scheleen Dickens, Don Doherty, Heather Dunlap, David Goldenberg, Karim Jamal, Norma Jimenez, Nicole Kavanagh, Derek Kunimoto, John Martin, Jessica Miner, Sarah Mobley, Donald Park, Edward Quinlan, Jack Sipperley, Carol Slagle, Danielle Smith, Miguelina Yafchak, Rohana Yager, Christina J. Flaxel, Steven Bailey, Peter Francis, Chris Howell, Thomas Hwang, Shirley Ira, Michael Klein, Andreas Lauer, Teresa Liesegang, Ann Lundquist, Sarah Nolte, Susan K. Nolte, Scott Pickell, Susan Pope, Joseph Rossi, Mitchell Schain, Peter Steinkamp, Maureen D. Toomey, Debora Vahrenwald, Kelly West, Baker Hubbard, Stacey Andelman, Chris Bergstrom, Judy Brower, Blaine Cribbs, Linda Curtis, Jannah Dobbs, Lindreth DuBois, Jessica Gaultney, Deborah Gibbs, Debora Jordan, Donna Leef, Daniel F. Martin, Robert Myles, Timothy Olsen, Bryan Schwent, Sunil Srivastava, Rhonda Waldron, Andrew N. Antoszyk, Uma Balasubramaniam, Danielle Brooks, Justin Brown, David Browning, Loraine Clark, Sarah Ennis, Susannah Held, Jennifer V. Helms, Jenna Herby, Angie Karow, Pearl Leotaud, Caterina Massimino, Donna McClain, Michael McOwen, Jennifer Mindel, Candace Pereira, Rachel Pierce, Michele Powers, Angela Price, Jason Rohrer, Jason Sanders, Robert L. Avery, Kelly Avery, Jessica Basefsky, Liz Beckner, Alessandro Castellarin, Stephen Couvillion, Jack Giust, Matthew Giust, Maan Nasir, Dante Pieramici, Melvin Rabena, Sarah Risard, Robert See, Jerry Smith, Lisha Wan, Sophie J. Bakri, Nakhleh Abu-Yaghi, Andrew Barkmeier, Karin Berg, Jean Burrington, Albert Edwards, Shannon Goddard, Shannon Howard, Raymond Iezzi, Denise Lewison, Thomas Link, Colin A. McCannel, Joan Overend, John Pach, Margaret Ruszczyk, Ryan Shultz, Cindy Stephan, Diane Vogen, Reagan H. Bradford, Vanessa Bergman, Russ Burris, Amanda Butt, Beth Daniels, Connie Dwiggins, Stephen Fransen, Tiffany Guerrero, Darin Haivala, Amy Harris, Sonny Icks, Ronald Kingsley, Lena Redden, Rob Richmond, Brittany Ross, Kammerin White, Misty Youngberg, Trexler M. Topping, Steve Bennett, Sandy Chong, Mary Ciotti, Tina Cleary, Emily Corey, Dennis Donovan, Albert Frederick, Lesley Freese, Margaret Graham, Natalya Gud, Taneika Howard, Mike Jones, Michael Morley, Katie Moses, Jen Stone, Robin Ty, Torsten Wiegand, Lindsey Williams, Beth Winder, Carl C. Awh, Michelle Amonette, Everton Arrindell, Dena Beck, Brandon Busbee, Amy Dilback, Sara Downs, Allison Guidry, Gary Gutow, Jackey Hardin, Sarah Hines, Emily Hutchins, Kim LaCivita, Ashley Lester, Larry Malott, MaryAnn McCain, Jayme Miracle, Kenneth Moffat, Lacy Palazzotta, Kelly Robinson, Peter Sonkin, Alecia Travis, Roy Trent Wallace, Kelly J. Winters, Julia Wray, April E. Harris, Mari Bunnell, Katrina Crooks, Rebecca Fitzgerald, Cameron Javid, Corin Kew, Erica Kill, Patricia Kline, Janet Kreienkamp, Maricruz Martinez, Roy Ann Moore, Egbert Saavedra, LuAnne Taylor, Mark Walsh, Larry Wilson, Thomas A. Ciulla, Ellen Coyle, Tonya Harrington, Charlotte Harris, Cindi Hood, Ingrid Kerr, Raj Maturi, Dawn Moore, Stephanie Morrow, Jennifer Savage, Bethany Sink, Tom Steele, Neelam Thukral, Janet Wilburn, Joseph P. Walker, Jennifer Banks, Debbie Ciampaglia, Danielle Dyshanowitz, Jennifer Frederick, A. Tom Ghuman, Richard Grodin, Cheryl Kiesel, Eileen Knips, Jonathan McCue, Maria Ortiz, Crystal Peters, Paul Raskauskas, Etienne Schoeman, Ashish Sharma, Glenn Wing, Rebecca Youngblood, Suresh R. Chandra, Michael Altaweel, Barbara Blodi, Kathryn Burke, Kristine A. Dietzman, Justin Gottlieb, Gene Knutson, Denise Krolnik, T. Michael Nork, Shelly Olson, John Peterson, Sandra Reed, Barbara Soderling, Guy Somers, Thomas Stevens, Angela Wealti, Srilaxmi Bearelly, Brenda Branchaud, Joyce W. Bryant, Sara Crowell, Sharon Fekrat, Merritt Gammage, Cheala Harrison, Sarah Jones, Noreen McClain, Brooks McCuen, Prithvi Mruthyunjaya, Jeanne Queen, Neeru Sarin, Cindy Skalak, Marriner Skelly, Ivan Suner, Ronnie Tomany, Lauren Welch, Susanna S. Park, Allison Cassidy, Karishma Chandra, Idalew Good, Katrina Imson, null Sashi, null Kaur, Helen Metzler, Lawrence Morse, Ellen Redenbo, Marisa Salvador, David Telander, Mark Thomas, Cindy Wallace, Charles C. Barr, Amanda Battcher, Michelle Bottorff, Mary Chasteen, Kelly Clark, Diane Denning, Debra Schoen, Amy Schultz, Evie Tempel, Lisa Wheeler, Greg K. Whittington, Thomas W. Stone, Todd Blevins, Michelle Buck, Lynn Cruz, Wanda Heath, Diana Holcomb, Rick Isernhagen, Terri Kidd, John Kitchens, Cathy Sears, Ed Slade, Jeanne Van Arsdall, Brenda VanHoose, Jenny Wolfe, William Wood, John Zilis, Carol Crooks, Larry Disney, Mimi Liu, Stephen Petty, Sandra Sall, James C. Folk, Tracy Aly, Abby Brotherton, Douglas Critser, Connie J. Hinz, Stefani Karakas, Valerie Kirschner, Cheyanne Lester, Cindy Montague, Stephen Russell, Heather Stockman, Barbara Taylor, Randy Verdick, Jean Walshire, John T. Thompson, Barbara Connell, Maryanth Constantine, John L. Davis, null Gwen Holsapple, Lisa Hunter, C. Nicki Lenane, Robin Mitchell, Leslie Russel, Raymond Sjaarda, David M. Brown, Matthew Benz, Llewellyn Burns, JoLene G. Carranza, Richard Fish, Debra Goates, Shayla Hay, Theresa Jeffers, Eric Kegley, Dallas Kubecka, Stacy McGilvra, Beau Richter, Veronica Sneed, Cary Stoever, Isabell Tellez, Tien Wong, Ivana Kim, Christopher Andreoli, Leslie Barresi, Sarah Brett, Charlene Callahan, Karen Capaccioli, William Carli, Matthew Coppola, Nicholas Emmanuel, Claudia Evans, Anna Fagan, Marcia Grillo, John Head, Troy Kieser, Elaine Lee, Ursula Lord, Edward Miretsky, Kate Palitsch, Todd Petrin, Liz Reader, Svetlana Reznichenko, Mary Robertson, Justin Smith, Demetrios Vavvas, John Wells, Cassie Cahill, W. Lloyd Clark, Kayla Henry, David Johnson, Peggy Miller, LaDetrick Oliver, Robbin Spivey, Tiffany Swinford, Mallie Taylor, Michael Lambert, Kris Chase, Debbie Fredrickson, Joseph Khawly, Valerie Lazarte, Donald Lowd, Pam Miller, Arthur Willis, Philip J. Ferrone, Miguel Almonte, Rachel Arnott, Ingrid Aviles, Sheri Carbon, Michael Chitjian, Kristen DAmore, Christin Elliott, David Fastenberg, Barry Golub, Kenneth Graham, AnnMarie Lavorna, Laura Murphy, Amanda Palomo, Christina Puglisi, David Rhee, Juan Romero, Brett Rosenblatt, Glenda Salcedo, Marianne Schlameuss, Eric Shakin, Vasanti Sookhai, Richard Kaiser, Elizabeth Affel, Gary Brown, Christina Centinaro, Deborah Fine, Mitchell Fineman, Michele Formoso, Sunir Garg, Lisa Grande, Carolyn Herbert, Allen Ho, Jason Hsu, Maryann Jay, Lisa Lavetsky, Elaine Liebenbaum, Joseph Maguire, Julia Monsonego, Lucia O’Connor, Lisa Pierce, Carl Regillo, Maria Rosario, Marc Spirn, James Vander, Jennifer Walsh, Frederick H. Davidorf, Amanda Barnett, Susie Chang, John Christoforidis, Joy Elliott, Heather Justice, Alan Letson, Kathryne McKinney, Jeri Perry, Jill A. Salerno, Scott Savage, Stephen Shelley, Lawrence J. Singerman, Joseph Coney, John DuBois, Kimberly DuBois, Gregg Greanoff, Dianne Himmelman, Mary Ilc, Elizabeth McNamara, Michael Novak, Scott Pendergast, Susan Rath, Sheila Smith-Brewer, Vivian Tanner, Diane E. Weiss, Hernando Zegarra, Lawrence Halperin, Patricia Aramayo, Mandeep Dhalla, Brian Fernandez, Cindy Fernandez, Jaclyn Lopez, Monica Lopez, Jamie Mariano, Kellie Murphy, Clifford Sherley, Rita Veksler, Firas Rahhal, Razmig Babikian, David Boyer, Sepideh Hami, Jeff Kessinger, Janet Kurokouchi, Saba Mukarram, Sarah Pachman, Eric Protacio, Julio Sierra, Homayoun Tabandeh, Adam Zamboni, Michael Elman, Jennifer Belz, Tammy Butcher, Theresa Cain, Teresa Coffey, Dena Firestone, Nancy Gore, Pamela Singletary, Peter Sotirakos, JoAnn Starr, Travis A. Meredith, Cassandra J. Barnhart, Debra Cantrell, RonaLyn Esquejo-Leon, Odette Houghton, Harpreet Kaur, Fatoumatta NDure, Ronald Glatzer, Leonard Joffe, and Reid Schindler

Subjects
Ophthalmology
Published
2023

6. Outcomes of Rhegmatogenous Retinal Detachment Repair When Comparing Surgeon Continuity in a Team-Based Practice

Author

Michael S. Ip, Jonathan S. Chang, Justin L. Gottlieb, Michael R. Lasarev, Elaine Downie, Michael M. Altaweel, T Michael Nork, Joseph Raevis, and Zackery Oakey

Subjects
Surgeons, medicine.medical_specialty, Visual acuity, business.industry, Extramural, Significant difference, Retinal Detachment, Retinal detachment repair, Retinal detachment, Retrospective cohort study, medicine.disease, Article, eye diseases, Surgery, Scleral Buckling, Treatment Outcome, Time of day, Vitrectomy, Time to surgery, Humans, Medicine, medicine.symptom, business, Retrospective Studies
Abstract

BACKGROUND AND OBJECTIVE: To facilitate timely surgery and efficient use of operating room time, our practice uses a team-based approach so patients may undergo primary rhegmatogenous retinal detachment (RRD) surgery with a different surgeon instead of the diagnosing surgeon. PATIENTS AND METHODS: This was a retrospective cohort study of 331 eyes that underwent RRD surgery. Patients were divided into two groups: RRD surgery performed by the diagnosing surgon, and RRD surgery performed by a different surgeon. RESULTS: Of 331 eyes, 200 eyes (60.4%) were repaired by the diagnosing surgeon and 131 eyes (39.6%) were repaired by a different surgeon. Primary anatomic success (PAS) rates at 3 months postoperatively were equivalent between the two groups (87.0% and 87.8% in the diagnosing surgeon and different surgeon groups, respectively [ P = .83]). There was no significant difference in preoperative ( P = .08) or final ( P = .28) visual acuity between the groups. Time between diagnosis and RRD repair was shorter in the different surgeon group (median of 1.5 days [IQR: 1.0–3.6] in the surgeon group versus 2.2 days [IQR: 0.8–5.7] in the diagnosing surgeon group) ( P = .03). Logistic regression analysis gave no evidence to suggest that PAS rates depended on day of week, time of day surgery was performed, group, or the interaction between those factors ( P = .93). CONCLUSIONS: Visual and anatomic success in RRD repair are equivalent when surgery is performed by either the diagnosing surgeon or a surgical colleague because time to surgery is reduced. Neither time of day nor day of the week had any influence on the outcomes. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:560–566.]

Published
2021

7. Nonsurgical Resolution of Full Thickness Macular Holes without Vitreomacular Traction

Author

Paige J, Richards, Amol D, Kulkarni, T Michael, Nork, Monique, Leys, David, Hinkle, Karina A, Conlin, Stanley, Chang, and Jonathan S, Chang

Subjects
Ophthalmology, General Medicine
Abstract

To report a case series of full-thickness macular holes without vitreomacular traction that resolved without surgery.Retrospective case series of 11 patients who demonstrated closure of full-thickness macular holes without surgical intervention.All full-thickness macular holes closed, with all patients having improvement in visual acuity. All but one of the cases had acuity better than 20/40 at last recorded visit. Most cases presented with associated epiretinal membrane (73%), cystoid changes (64%), defects150 microns (80%) and resolved within 2 months (91%). Topical anti-inflammatory drops were used in 7/11 cases, and dorzolamide was used in 1 case.Full-thickness macular holes can develop in eyes without the presence of vitreomacular traction. Topical therapy without vitrectomy may be particularly helpful in closure of full-thickness macular holes with associated cystoid macular edema. Holes with a lamellar hole component may spontaneously resolve as part of a retinal remodeling process.

Published
2022

8. Impact of COVID-19 Restrictions on Retinal Detachment: A Multicenter Experience

Author

Jesse J. Jung, Jonathan S. Chang, Patrick R. Oellers, Mohsin H. Ali, Brian K. Do, Joseph J. Tseng, Roberto Roizenblatt, Rajeev H. Muni, Christina Y. Weng, Zackery B. Oakey, Sean W. Tsao, Soraya Rofagha, Xavier Chan, Quan V. Hoang, Daniel Russ Richardson, Jaime Toledo-Corral, Hemang K. Pandya, Victor T. Copeland, Gowtham Jonna, Sarwar Zahid, James Lin, Aristomenis Thanos, Isaac Ezon, Asadolah Movahedan, Sidney A. Schechet, Mitul C. Mehta, Hesham Hamli, Sidharth Puri, Chirag D. Jhaveri, Jamison R. Ridgeley, Alan T. Sheyman, Jonathan Hu, Stephanie Y. Lu, Andrew W. Browne, Lynn L. Huang, Yewlin E. Chee, Solly Elmann, Khurram M. Chaudhary, Nitish Mehta, Philip Kurochkin, Genti Gjyzeli, Michael M. Altaweel, T. Michael Nork, Anne Zeng, Isabella Q. Loh, and Hong Yi Lin

Subjects
sulfurhexafluoride, (SF6), perfluoropropane, (C3F8), rhegmatogenous retinal detachment, (RRD), Retinal Detachment, Visual Acuity, COVID-19, Best-corrected visual acuity, (BCVA), postoperative month, (POM), Ophthalmology, Treatment Outcome, proliferative vitreoretinopathy, (PVR), Communicable Disease Control, coronavirus disease 2019, (COVID-19), pars plana vitrectomy, (PPV), Humans, scleral buckle, (SB), percentage point, (%p), single surgery anatomic success, (SSAS), pneumatic retinopexy, (PR), Retrospective Studies, Reports
Abstract

In this retrospective, multicenter study of 261 eyes (259 patients), patients who underwent rhegmatogenous retinal detachment repair during the coronavirus disease 2019 (COVID-19) post-lockdown period experienced an additional 22-day delay, leading to significantly more epiretinal membrane and proliferative vitreoretinopathy and lower single-surgery anatomic success rates. During lockdown, perfluoropropane gas was used more commonly, and pneumatic retinopexy was used more commonly in COVID-19-positive patients.

Published
2022

9. Accommodative movements of the choroid in the optic nerve head region of human eyes, and their relationship to the lens

Author

Mary Ann Croft, John Peterson, Christopher Smith, Julie Kiland, T. Michael Nork, Jared P. Mcdonald, Alexander Katz, Scott Hetzel, Elke Lütjen-Drecoll, and Paul L. Kaufman

Subjects
Adult, Adolescent, Choroid, Optic Disk, Accommodation, Ocular, Middle Aged, Macaca mulatta, Sensory Systems, Young Adult, Cellular and Molecular Neuroscience, Ophthalmology, Lens, Crystalline, Animals, Humans, Tomography, Optical Coherence
Abstract

The ciliary muscle (CM) powers the accommodative response, and during accommodation the CM pulls the choroid forward in the region of the ora serrata. Our goal was to elucidate the accommodative movements of the choroid in the optic nerve region in humans and to determine whether these movements are related to changes in the lens dimensions that occur with aging, in the unaccommodated and accommodated state. Both eyes of 12 human subjects (aged 18-51 yrs) were studied. Homatropine (1 drop/5%) was used to relax the ciliary muscle (unaccommodated or "resting" eye) and pilocarpine was used to induce the maximum accommodative response (2 drops/4%) (accommodated eye). Images of the fundus and choroid were collected in the region of the optic nerve (ON) via Spectralis OCT (infrared and EDI mode), and choroidal thickness was determined. Ultrasound biomicroscopy (UBM; 50 MHz, 35 MHz) images were collected in the region of the lens/capsule and ciliary body. OCT and UBM images were collected in the resting and accommodated state. The unaccommodated choroidal thickness declined significantly with age (p = 0.0073, r = 0.73) over the entire age range of the subjects studied (18-51 years old). The choroidal thickness was significantly negatively correlated with lens thickness in the accommodated (p = 0.01) and the unaccommodated states (p = 0.005); the thicker the lens the thinner the choroid. Choroid movements around the optic nerve during accommodation were statistically significant; during accommodation the choroid both thinned and moved centrifugally (outward/away from the optic nerve head). The accommodative choroid movements did not decline significantly with age and were not correlated with accommodative amplitude. Measurement of the choroidal thickness is possible with the Spectralis OCT instrument using EDI mode and can be used to determine the accommodative changes in choroidal thickness. The choroidal thickness decreased with age and during accommodation. It may be that age-related choroidal thinning is due to changes in the geometry of the accommodative apparatus to which it is attached (i.e., ciliary muscle/lens complex) such that when the lens is thicker, the choroid is thinner. Accommodative decrease in choroidal thickness and stretch of the retina/choroid may indicate stress/strain forces in the region of the optic nerve during accommodation and may have implications for glaucoma.

Published
2022

10. Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration

Author

Jeannette J. Yu, Elvira Agrón, Traci E. Clemons, Amitha Domalpally, Freekje van Asten, Tiarnan D. Keenan, Catherine Cukras, Emily Y. Chew, Frederick L. Ferris, John Paul SanGiovanni, Traci Clemons, Anne Lindblad, Robert Lindblad, Nilay Shah, Robert Sperduto, Wendy McBee, Gary Gensler, Molly Harrington, Alice Henning, Katrina Jones, Kumar Thotapally, Diana Tull, Valerie Watson, Kayla Williams, Christina Gentry, Francine Kaufman, Chris Morrison, Elizabeth Saverino, Sherrie Schenning, Barbara Blodi, Ronald P. Danis, Matthew Davis, Kathy Glander, Gregory Guilfoil, Larry D. Hubbard, Kristine Johnson, Ronald Klein, Barbara Nardi, Michael Neider, Nancy Robinson, Eileen Rosensteel, Hugh Wabers, Grace Zhang, Alan J. Ruby, Antonio Capone, Bawa Dass, Kimberly Drenser, Bruce R. Garretson, Tarek S. Hassan, Michael Trese, George A. Williams, Jeremy Wolfe, Tina Bell, Mary Zajechowski, Dennis Bezaire, Fran McIver, Anthony Medina, Jackie Pagett, Stephanie Hatch Smith, Lynn Swartz, Tom Treuter, Andrew Antoszyk, Justin Brown, David J. Browning, Walter Holland, Angella Karow, Kelly Stalford, Angela Price, Sarah Ennis, Sherry Fredenberg, Jenna Herby, Uma Balasubramaniam, Loraine Clark, Donna McClain, Michael McOwen, Lynn Watson, Michael Klein, Steven T. Bailey, Thomas J. Hwang, Andreas Lauer, J. Timothy Stout, Patty McCollum, Milt Johnson, Patrick B. Rice, Ivana Kim, John Loewenstein, Joan Miller, Lucia Sobrin, Lucy Young, Jacqueline Sullivan, Patricia Houlihan, Linda Merry, Ann Marie Lane, Ursula Lord Bator, Claudia Evans, Sarah Brett, Charleen Callahan, Marcia Grillo, David Walsh, Kamella Lau Zimmerman, Gary Edd Fish, Rajiv Anand, Lori E. Coors, Dwain G. Fuller, Rand Spencer, Robert C. Wang, Karen Duignan, Sally Arceneaux, Hank Aguado, Nicholas Hesse, Michael Mackens, Brian Swan, Wai T. Wong, Monica Dalal, Naima Jacobs-El, Catherine Meyerle, Benjamin Nicholson, Henry Wiley, Katherine Hall Shimel, Angel Garced, Janice Oparah, Greg Short, Alana Temple, Babilonia Ayukawa, Guy Foster, Darryl Hayes, Dessie Koutsandreas, Roula Nashwinter, John Rowan, Michael Bono, Denise Cunningham, Marilois Palmer, Alicia Zetina, David H. Orth, Kourous Rezaei, Joseph Civantos, Sohail Hasan, Kirk Packo, Celeste Figliulo, Pam Stanberry, Tara Farmer, Kiersten Nelson, Shannya Townsend-Patrick, Philip Rosenfeld, Royce Chen, Rishi Doshi, Sander Dubovy, Brian T. Kim, Matthew Lowrance, Andrew Moshfeghi, Zayna Nahas, Gary Schienbaum, John Vishak, Christina Weng, Zohar Yehoshua, Belen Rodriguez, Jose Rebimbas, Jane Gleichauf, Mike Kicak, Jason Mena, Tim Odem, Elizabeth Sferza-Camp, Alicia Disgdiertt, Jim Oramas, Isabel Rams, Stephanie Thatcher, Susan B. Bressler, Neil M. Bressler, Daniel Finkelstein, Steven H. Sherman, Sharon Solomon, Howard S. Ying, Rita Denbow, Deborah Phillips, Elizabeth Radcliffe, Judy Belt, Dennis Cain, David Emmert, Mark Herring, Jacquelyn McDonald, G. Baker Hubbard, Chris S. Bergstrom, Blaine Cribbs, Andrew Hendrick, Brandon Johnson, Philip Laird, Sonia Mehta, Timothy Olsen, Justin Townsend, Jion Yan, Steven Yeh, Linda Curtis, Judy Brower, Hannah Yi, Jannah Rutter Dobbs, Debbie Jordan, Michael J. Elman, Robert A. Liss, JoAnn Starr, Jennifer Belz, Charlene Putzulo, Teresa Coffey, Ashley Davis, Pamela Singletary, Giorya Shabi Andreani, Theresa Cain, Daniel Ketner, Peter Sotirakos, Suresh Chandra, Barbara A. Blodi, Michael M. Altaweel, Justin L. Gottlieb, Michael Ip, T. Michael Nork, Thomas S. Stevens, Kathryn Burke, Shelly Olson, Kristine Dietzman, Barbara Soderling, Guy Somers, Angie Wealti, Denise Krolnik, John Peterson, Sandra Reed, Thomas Friberg, Andrew Eller, Denise Gallagher, Leanne Labriola, Melissa Pokrifka, Aron Gedansky, Natalie Anthony, Cassandra Grzybowski, Dawn Matthews, Sharon Murajda-Jumba, Jessica Toro, David G. Callanan, Wayne A. Solley, Patrick Williams, Sandy Lash, Bob Boleman, Chris Dock, Michel Shami, Brenda Arrington, Ashaki Meeks, Alan R. Margherio, Paul Raphaelian, Debra Markus, Justin Langdon, Elizabeth Truax, Sandy Lewis, Brad Terry, Amy Noffke, Kean Oh, Ramin Sarrafizadeh, Scott Sneed, Julie Hammersley, Serena Neal, Mary Doran, Nan Jones, Lisa Preston, Heather Jessick, Tanya Tracy Marsh, Michael Tolentino, Adam Berger, Richard Hamilton, David Misch, Suk Jin Moon, Dawn Sutherland, Vera Dilts, Sara Henderson, Esmeralda Medina, Donald Trueman, Laura Holm, Jason Strickland, Darmakusuma Ie, Jeffrey L. Lipkowitz, Kekul B. Shah, Susan Geraghty, Beverly Sannazzaro, Morgan Harper, Krista Bayer, Mary B. Lansing, Lauren B. Fox, Rebecca Lee, Jay B. Stallman, Michael Jacobson, Sean Koh, Scott Lampert, John Miller, Mark Rivellese, Atul Sharma, Robert A. Stoltz, Stephanie Vanderveldt, Leslie Marcus, Starr Hendricks, Ryan Hollman, Grethel Betanzos, Leslie Ellorin, Shelly Fulbright, Debbie McCormick, Paul A. Edwards, Julianne Hall, Mary Monk, Melanie Gutkowski, Melina Mazurek, Janet Murphy, Katherine Gusas, Crystal Moffett, David Burley, Nicole Chesney, Katie Kilgo, Brian Rusinek, Bradley Stern, Tracy Troszak, Rhonda Baker-Levingston, Carl W. Baker, Tracey Caldwell, Tammy Walker, Lynnette F. Lambert, Tracey Martin, Mary Jill Palmer, Tana Williams, Michael A. Novak, Joseph Coney, David G. Miller, Scott Pendergast, Lawrence Singerman, Nicholas Zakov, Hernando Zegarra, Kim DuBois, Susan Rath, Lori Revella, Tammy Brink, Kim Drury, Lisa Hogue, Mary Ilc, Connie Keller, Elizabeth McNamara, Vivian Tanner, Tamara Cunningham, John DuBois, Gregg Greanoff, Trina Nitzsche, Sheila Smith-Brewer, Ricky D. Isernhagen, John W. Kitchens, Thomas W. Stone, William J. Wood, Diana Holcomb, Virginia Therrien, Michelle Buck, Jeanne Van Arsdall, Edward Slade, Todd E. Schneiderman, David J. Spinak, Jackie Gaedke, Heather Davis Brown, Dan Helgren, Jenifer Garrison Pangelinan, Lawrence Halperin, Scott Anagnoste, Mandeep Dhalla, Krista Rosenberg, Barry Taney, W. Scott Thompson, Jaclyn Lopez, Monica Hamlin, Monica Lopez, Jamie Mariano, Evelyn Quinchia, Patricia Aramayo, Rita Veksler, Michael Lee, Richard Dreyer, Irvin Handelman, Colin Ma, Mark Peters, Stephen Hobbs, Amanda Milliron, Marcia Kopfer, Michele Connaughton, A. Christine Hoerner, R. Joseph Logan, Harry J. Wohlsein, David Boyer, Thomas G. Chu, Pouya Dayani, David Liao, Roger L. Novack, Firas M. Rahhal, Richard Roe, Homayoun Tabandeh, Janet Bayramyan, Tammy Gasparyan, Connie Hoang, Janet Kurokouchi, Tammy Eileen Lo, Richard Ngo, Mary Ann Nguyen, Michael Peyton, Charles Yoon, Julio Sierra, Adam Zamboni, Jeff Kessinger, Eric Protacio, Adam Smucker, Pamela Rath, Robert Bergren, Bernard Doft, Judy Liu, Karl Olsen, Lori Merlotti, Willia Ingram, Kellianne Marfisi, Kimberly Yeckel, Heather Schultz Carmelo, Amanda Fec, Keith McBroom, David Steinberg, Marc Levy, Jody Abrams, Melvin Chen, Waldemar Torres, Peggy Jelemensky, Mark Prybylski, Tara Raphael, Diana Appleby, Charlotte Rodman, Mark Sneath, Robert H. Rosa, Vanessa Hoelscher, Adelia Castano, Jocelyn Parker, John Hoskins, Nicholas Anderson, Joseph Googe, Tod A. McMillan, James Miller, Stephen Perkins, Kristina Oliver, Jennifer Beerbower, Bruce Gilliland, Cecile Hunt, Mike Jacobus, Raul Lince, Christopher Morris, Sarah Oelrich, Jerry Whetstone, Clement K. Chan, Steven Lin, Kim Walther, Tiana Gonzales, Lenise Myers, Kenneth Huff, David M. Brown, Eric Chen, Matthew S. Benz, Richard H. Fish, Rosa Y. Kim, James Major, Tien Pei Wong, Charles Wycoff, Cassandra Cone, Debbie Goates Gilaspia, Nubia Landaverde, Robert Smith, Deneva Zamora, Veronica Sneed, Melina Vela, Eric Kegley, Craig Greven, Shree Kurup, Charles Richards, Madison Slusher, Cara Everhart, Joan Fish, Mark Clark, David Miller, Marshall Tyler, J. Michael Jumper, Arthur D. Fu, Robert N. Johnson, Brandon Lujan, H. Richard McDonald, Rosa Rodriguez, Nina Ansari, Jeanifer Joaquin, Silvia Linares, Lizette Lopez, Jessica Sabio, Sean Grout, Chad Indermill, Yesmin Urias, Roberto Zimmerman, Linda Margulies, Sara J. Schmidt, Joy L. Meier, Sherry L. Hadley, William Rosenthal, Barbara Johnson, Lois Swafford, Richard Shields, R. Scott Varner, Richard Rosen, Ronald Gentile, Melissa Rivas, Katy W. Tai, Wanda Carrasquillo-Boyd, Robert Masini, Glenn Stoller, Ken Carnevale, Diane M. LaRosa, Barbara Burger, Tereza Conway, Carla Del Castillo, Julissa Diaz, Susan Jones, Nina Mondoc, Charlene Balfour, C.H. Vitha, Jennifer Lutz, Barbara McGinley, Fadi El Baba, Ann Marie Lavorna, Renee Jones, Jean Lewis, Ruth Tenzler, Mary Salvas-Mladek, Diane Van Kesteren, W. Copley McLean, W. Zachery Bridges, Cameron Stone, Denise Ammons, Mary Lamy, Andrea Menzel, Lea Doll Raymer, Barbara Campbell, Lisa Hawkins, Leslie Rickman, Lorraine Sherlin, Paula Price, Albert Sinyai, Ronald Kingsley, Reagan H. Bradford, Robert E. Leonard, Sonny Icks, Vanessa Bergman, Brittany Ross, Russ Burris, Amanda Butt, Rob Richmond, Alice Lyon, Manjot Gill, Lee Jampol, Rukhsana Mizra, Zuzanna Rozenbajgier, Jeremy Chapman, Lori Kaminski, Andrea Degillio, Evica Simjanoski, Jeffrey Heier, Hyung Cho, Tina Scheufele Cleary, Darin Goldman, Chirag Shah, Trexler Topping, Marissa Weber, Torsten Wiegand, Jeremy Schindelheim, Joy Bankert, Jennifer Stone, Alison Nowak, Sandy Chong, Lindsay Williams, Steven Bennett, Dennis Donovan, Margaret Graham, Cullen Jones, Anne Fung, Jan-Kristine Bayabo, Razelda Bosch, Esperanza Cruz, Ashley Emerson, Alycia Fleming, Denice Barsness, Jorge Rodriguez, Marina Soboleva, Ingrid U. Scott, Esther Bowie, Kimberly A. Neely, David A. Quillen, Laura Walter, Timothy Bennett, James Strong, John Wells, Lloyd Clark, David Johnson, Peggy Miller, Mallie Taylor, Tiffany Swinford, Robbin Spivey, Michael Banach, Lawrence Ho, Richard Lanning, Thomas R. Pheasant, Jay G. Prensky, Steven Truong, Julia Teatsworth, Michelle Dietrich, Ann Wasilus, Ann Miller, Megan Rakes, Teresa Slagle, Michelle Richards, Patricia Schuessler, Lacy Stover, Paul Beer, Naomi S. Falk, Mary Beth Shannon, Jeannie Olmeda, Don Berdeen, Joseph F. Fisher, James Folk, Stephen Russell, Barbara Taylor, Connie Hinz, Jean Walshire, Heather Stockman, Bruce Critser, Stefani Karakas, Cindy Montague, Randy Verdick, Omesh Gupta, Joseph Maguire, Christopher Brady, Francis Char DeCroos, Michael Dollin, Sunir Garg, Adam Gerstenblith, Julia Haller, Allen C. Ho, Jason Hsu, Richard Kaiser, John Pitcher, Carl Regillo, Rajiv Shah, Marc Spirn, William Tasman, James Vander, Noga Senderowitsch, Michele Formoso, Michelle Markun, Cedric George, Christina Centinaro, Lisa Grande, Stefanie Carey, Elaine Liebenbaum, SriniVas Sadda, Mark Humayun, Rachel Sierra, Elizabeth Corona, Margaret Padilla, Moonseok Nu, Sylvia Ramos, Cullen Barnett, Glenn Currie, Cornelia Gottlieb, Richard Garfinkel, Daniel Berinstein, Marcus Colyer, William Deegan, Michael Min-Shyue Lai, Robert Murphy, Michael Osman, Michael Rivers, Reginald Sanders, Manfred A. von Fricken, Debbie Oliver, Jeanne Kirshon, Tanya Alexander Snowden, Thomas Blondo, Alysia Cronise, Vanessa Denny, Kylie Mendez, Janine Newgen, Justin Davis, Mike Flory, Robert Frantz, Bryan Murphy, Steve Rauch, Judy E. Kim, Jane Bachman, Thomas B. Connor, Dennis P. Han, Kimberly Stepian, David V. Weinberg, William J. Wirostko, Krissa Packard, Tracy Kaczanowski, Vesper Williams, Vicki Barwick, Judy Flanders, Dennis Backes, Joe Beringer, Kristy Keller, Kathy Selchert, Paul Bernstein, Michael Teske, Albert Vitale, Susan Allman, Bonnie Carlstrom, Kimberley Wegner, Anne Haroldsen, Deborah Harrison, Cyrie Fry, James Gilman, Glen Jenkins, Paula Morris, Michael Rauser, Joseph Fan, Mukesh Suthar, Gisela Santiago, Kara Rollins Halsey, Christy Quesada, William Kiernan, Jesse Knabb, Richard Alan Lewis, Cindy Dorenbach, Steven Spencer, Dana Barnett, Joseph Morales, Barron C. Fishburne, Jeffrey G. Gross, Michael A. Magee, Amy Flowers, Angie McDowell, Randall Price, Suber Huang, Johnny Tang, Shawn Wilker, Cherie Hornsby, Lisa Ferguson, Kirk Krogstad, Riva Adamovsky, Peggy Allchin, Kathleen Carlton, Claudia Clow, Kelly Sholtis, Stephanie Burke, Mark Harrod, Stacie Hrvatin, Geoffrey Pankhurst, Nelson R. Sabates, Michael Cassell, Komal Desai, Abraham Poulose, Felix Sabates, Yin Chen, Gary Gallimore, Yolanda Konior, Nicola Kim, Sami Uwaydat, Deborah Troillett, Karen Aletter, Robert N. Frank, Gary Abrams, James Puklin, Asheesh Tewari, Cheryl Milanovic, Melanie Bailey, David Griffith, Dena McDonald, Kit Morehead, Zlatan Sadikovic, Lisa Schillace, Elizabeth Silvis, Brian Joondeph, Nancy Christmas, Alan Kimura, Mimi Liu, Stephen Petty, John Zilis, Jenny Benitez, Cassandra Berryman Catlett, Eric Fluegel, Shane Mowry, Hoang Nguyen, David Reflow, Odette M. Houghton, Seema Garg, Maurice B. Landers, Travis Meredith, Sandy Barnhart, Megha Karmalkar, Debra Cantrell, Rona Lyn Esquejo-Leon, Linda Manor, Sue Pope, David Stines, Amelia Stokely, Dean Hainsworth, Dyann Helming, Debbie Eichelberger, Mary Paige Leaton, Chuck Hamm, Edward Chaum, Alessandro Iannaccone, Barbara Jennings, Tracy Murray, Joe Mastellone, Robert Millay, Brian Kim, Theresa Goddard, Liza Jarrett Beaudette, Nina Changelian-Aitken, Fernando Corrada, Jason Dubuque, Raymond Iezzi, Sophie J. Bakri, Jose S. Pulido, Diane Vogen, Rebecca Nielsen, Karin Berg, Jean Burrington, Shannon Howard, Joan Overend, Zbigniew Krason, Denise Lewison, Thomas Link, Kevin J. Blinder, Nicholas E. Engelbrecht, M. Gilbert Grand, Daniel P. Joseph, Gaurav K. Shah, Bradley Smith, Matthew Thomas, Rhonda Weeks, Lynda Boyd, Dana Gabel, Ron Adelman, John Huang, James Kempton, Aaron Parnes, Jennifer Dupont, Elizabeth Perotti, Victoria Donaldson, Kenneth Fong, Pamela Ossorio, Anita Agarwal, Paul Sternberg, Sandy Owings, Tony Adkins, Elaine Lok, Garvin Munn, Buddy Skellie, Neelakshi Bhagat, Monique S. Roy, Marco Zarbin, Catherine Fay, Michael Lazar, Beth Malpica, Tatiana Mikheyav, Lawrence Ulanski, Jennifer Lim, Marcia Niec, Tametha Johnson, Yesenia Ovando, Catherine Nail Carroll, Mark Janowicz, Steven Schwartz, David Cupp, Michael Gorin, Gad Heilweil, Hamid Hosseini, Jean-Pierre Hubschman, Allan Kreiger, Tara Young McCannel, Carolyn Pan, David Sarraf, Irena Tsui, Joshua Udoetek, Vinad Voleti, Logan Hitchcock, Rosaleen Ostrick, Melissa Chun, Jennie Kageyama, Nilo Davila, Kristin Lipka, Christina Shin, Cynthia Owsley, Michael Albert, Richard Feist, John Mason, Martin Thomley, Angelia Johnson, Tracy Emond, Joanna Hamela, Angela Marsh, Karen Searcey, Kia Rookard, Yu-Guang He, Rafael L. Ufret-Vincenty, Mike Molai, William Anderson, John Horna, Alan Letson, Colleen Cebulla, Susie Chang, Fred Davidorf, Jill Salerno, Laura Sladoje, Christina Stetson, Jeri Perry, Scott Savage, Cynthia Toth, Glenn Jaffe, Stefanie Schuman, Neeru Sarin, Jim Crowell, Tiffanie Keaton, Michael Kelly, Brian Lutman, Marriner Skelly, Lauren Welch, Lawrence Morse, Allan Hunter, Susanna Soon-Chun Park, Cynthia Wallace, Ember Dhillon, Marisa Salvador, Barbara Holderreed, Karishma Chandra, Sashi Kaur, Ellen Redenbo, Smiley Hom, Michael Cooney, Irene Barbazetto, James M. Klancnik, John A. Sorenson, Lawrence Yannuzzi, Maria Scolaro, Eugene Agresta, Nancy Gonzalez, Sandeep Grover, K.V. Chalam, Shailesh Gupta, Christopher Lyons, Wenhua Li, Chirag Patel, Jose Carrion, Henry Ferreyra, Amberly Rodriguez, Iliana Molina, Gabriel Balea, Pam Emory, Marlene Rico, Giorgio Siqueiros, Alexander J. Brucker, Joshua Dunaief, Juan Grunwald, Benjamin Kim, Albert M. Maguire, Brian VanderBeek, Sheri Drossner, Joan DuPont, Rebecca Salvo, Jim Berger, Cheryl Devine, Bill Nyberg, Laurel Weeney, David DiLoreto, Mina Chung, Valerie Davis, Peter MacDowell, George O. Gara, Daniel Castillo, Andrea Czubinski, Melissa Keim, Brandi Hardy, Rachel Grunhaus Hollar, Lynn Schueckler, Alice T. Lyon, Aaron Weinberg, Mira Shiloach, Nicole Pelkofer, Qin Zhou, Laura McPoland, Rajendra Apte, P. Kumar Rao, Sam Pistorius, Jamie Kambarian, Eve Adcock, Sarah Gould, Melanie Quinn, Rhonda Curtis, Amy Frost, Charla Meyer, and Greg Rathert

Subjects
0303 health sciences, medicine.medical_specialty, Visual acuity, genetic structures, business.industry, Eye disease, Hazard ratio, Age-Related Eye Disease Study, Retrospective cohort study, Fundus (eye), Macular degeneration, medicine.disease, eye diseases, 03 medical and health sciences, Ophthalmology, 0302 clinical medicine, 030221 ophthalmology & optometry, medicine, sense organs, medicine.symptom, Prospective cohort study, business, 030304 developmental biology
Abstract

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Published
2019

11. Progression of Geographic Atrophy in Age-related Macular Degeneration

Author

Tiarnan D. Keenan, Elvira Agrón, Amitha Domalpally, Traci E. Clemons, Freekje van Asten, Wai T. Wong, Ronald G. Danis, SriniVas Sadda, Philip J. Rosenfeld, Michael L. Klein, Rinki Ratnapriya, Anand Swaroop, Frederick L. Ferris, Emily Y. Chew, John Paul SanGiovanni, Traci Clemons, Anne Lindblad, Robert Lindblad, Nilay Shah, Robert Sperduto, Wendy McBee, Gary Gensler, Molly Harrington, Alice Henning, Katrina Jones, Kumar Thotapally, Diana Tull, Valerie Watson, Kayla Williams, Christina Gentry, Francine Kaufman, Chris Morrison, Elizabeth Saverino, Sherrie Schenning, Barbara Blodi, Ronald P. Danis, Matthew Davis, Kathy Glander, Gregory Guilfoil, Larry D. Hubbard, Kristine Johnson, Ronald Klein, Barbara Nardi, Michael Neider, Nancy Robinson, Eileen Rosensteel, Hugh Wabers, Grace Zhang, Alan J. Ruby, Antonio Capone, Bawa Dass, Kimberly Drenser, Bruce R. Garretson, Tarek S. Hassan, Michael Trese, George A. Williams, Jeremy Wolfe, Tina Bell, Mary Zajechowski, Dennis Bezaire, Fran McIver, Anthony Medina, Jackie Pagett, Stephanie Hatch Smith, Lynn Swartz, Tom Treuter, Andrew Antoszyk, Justin Brown, David J. Browning, Walter Holland, Angella Karow, Kelly Stalford, Angela Price, Sarah Ennis, Sherry Fredenberg, Jenna Herby, Uma Balasubramaniam, Loraine Clark, Donna McClain, Michael McOwen, Lynn Watson, Michael Klein, Steven T. Bailey, Thomas J. Hwang, Andreas Lauer, J. Timothy Stout, Patty McCollum, Milt Johnson, Patrick B. Rice, Ivana Kim, John Loewenstein, Joan Miller, Lucia Sobrin, Lucy Young, Jacqueline Sullivan, Patricia Houlihan, Linda Merry, Ann Marie Lane, Ursula Lord Bator, Claudia Evans, Sarah Brett, Charleen Callahan, Marcia Grillo, David Walsh, Kamella Lau Zimmerman, Gary Edd Fish, Rajiv Anand, Lori E. Coors, Dwain G. Fuller, Rand Spencer, Robert C. Wang, Karen Duignan, Sally Arceneaux, Hank Aguado, Nicholas Hesse, Michael Mackens, Brian Swan, Catherine Cukras, Monica Dalal, Naima Jacobs-El, Catherine Meyerle, Benjamin Nicholson, Henry Wiley, Katherine Hall Shimel, Angel Garced, Janice Oparah, Greg Short, Alana Temple, Babilonia Ayukawa, Guy Foster, Darryl Hayes, Dessie Koutsandreas, Roula Nashwinter, John Rowan, Michael Bono, Denise Cunningham, Marilois Palmer, Alicia Zetina, David H. Orth, Kourous Rezaei, Joseph Civantos, Sohail Hasan, Kirk Packo, Celeste Figliulo, Pam Stanberry, Tara Farmer, Kiersten Nelson, Shannya Townsend-Patrick, Philip Rosenfeld, Royce Chen, Rishi Doshi, Sander Dubovy, Brian T. Kim, Matthew Lowrance, Andrew Moshfeghi, Zayna Nahas, Gary Schienbaum, John Vishak, Christina Weng, Zohar Yehoshua, Belen Rodriguez, Jose Rebimbas, Jane Gleichauf, Mike Kicak, Jason Mena, Tim Odem, Elizabeth Sferza-Camp, Alicia Disgdiertt, Jim Oramas, Isabel Rams, Stephanie Thatcher, Susan B. Bressler, Neil M. Bressler, Daniel Finkelstein, Steven H. Sherman, Sharon Solomon, Howard S. Ying, Rita Denbow, Deborah Phillips, Elizabeth Radcliffe, Judy Belt, Dennis Cain, David Emmert, Mark Herring, Jacquelyn McDonald, G. Baker Hubbard, Chris S. Bergstrom, Blaine Cribbs, Andrew Hendrick, Brandon Johnson, Philip Laird, Sonia Mehta, Timothy Olsen, Justin Townsend, Jion Yan, Steven Yeh, Linda Curtis, Judy Brower, Hannah Yi, Jannah Rutter Dobbs, Debbie Jordan, Michael J. Elman, Robert A. Liss, JoAnn Starr, Jennifer Belz, Charlene Putzulo, Teresa Coffey, Ashley Davis, Pamela Singletary, Giorya Shabi Andreani, Theresa Cain, Daniel Ketner, Peter Sotirakos, Suresh Chandra, Barbara A. Blodi, Michael M. Altaweel, Justin L. Gottlieb, Michael Ip, T. Michael Nork, Thomas S. Stevens, Kathryn Burke, Shelly Olson, Kristine Dietzman, Barbara Soderling, Guy Somers, Angie Wealti, Denise Krolnik, John Peterson, Sandra Reed, Thomas Friberg, Andrew Eller, Denise Gallagher, Leanne Labriola, Melissa Pokrifka, Aron Gedansky, Natalie Anthony, Cassandra Grzybowski, Dawn Matthews, Sharon Murajda-Jumba, Jessica Toro, David G. Callanan, Wayne A. Solley, Patrick Williams, Sandy Lash, Bob Boleman, Chris Dock, Michel Shami, Brenda Arrington, Ashaki Meeks, Alan R. Margherio, Paul Raphaelian, Debra Markus, Justin Langdon, Elizabeth Truax, Sandy Lewis, Brad Terry, Amy Noffke, Kean Oh, Ramin Sarrafizadeh, Scott Sneed, Julie Hammersley, Serena Neal, Mary Doran, Nan Jones, Lisa Preston, Heather Jessick, Tanya Tracy Marsh, Michael Tolentino, Adam Berger, Richard Hamilton, David Misch, Suk Jin Moon, Dawn Sutherland, Vera Dilts, Sara Henderson, Esmeralda Medina, Donald Trueman, Laura Holm, Jason Strickland, Darmakusuma Ie, Jeffrey L. Lipkowitz, Kekul B. Shah, Susan Geraghty, Beverly Sannazzaro, Morgan Harper, Krista Bayer, Mary B. Lansing, Lauren B. Fox, Rebecca Lee, Jay B. Stallman, Michael Jacobson, Sean Koh, Scott Lampert, John Miller, Mark Rivellese, Atul Sharma, Robert A. Stoltz, Stephanie Vanderveldt, Leslie Marcus, Starr Hendricks, Ryan Hollman, Grethel Betanzos, Leslie Ellorin, Shelly Fulbright, Debbie McCormick, Paul A. Edwards, Julianne Hall, Mary Monk, Melanie Gutkowski, Melina Mazurek, Janet Murphy, Katherine Gusas, Crystal Moffett, David Burley, Nicole Chesney, Katie Kilgo, Brian Rusinek, Bradley Stern, Tracy Troszak, Rhonda Baker-Levingston, Carl W. Baker, Tracey Caldwell, Tammy Walker, Lynnette F. Lambert, Tracey Martin, Mary Jill Palmer, Tana Williams, Michael A. Novak, Joseph Coney, David G. Miller, Scott Pendergast, Lawrence Singerman, Nicholas Zakov, Hernando Zegarra, Kim DuBois, Susan Rath, Lori Revella, Tammy Brink, Kim Drury, Lisa Hogue, Mary Ilc, Connie Keller, Elizabeth McNamara, Vivian Tanner, Tamara Cunningham, John DuBois, Gregg Greanoff, Trina Nitzsche, Sheila Smith-Brewer, Ricky D. Isernhagen, John W. Kitchens, Thomas W. Stone, William J. Wood, Diana Holcomb, Virginia Therrien, Michelle Buck, Jeanne Van Arsdall, Edward Slade, Todd E. Schneiderman, David J. Spinak, Jackie Gaedke, Heather Davis Brown, Dan Helgren, Jenifer Garrison Pangelinan, Lawrence Halperin, Scott Anagnoste, Mandeep Dhalla, Krista Rosenberg, Barry Taney, W. Scott Thompson, Jaclyn Lopez, Monica Hamlin, Monica Lopez, Jamie Mariano, Evelyn Quinchia, Patricia Aramayo, Rita Veksler, Michael Lee, Richard Dreyer, Irvin Handelman, Colin Ma, Mark Peters, Stephen Hobbs, Amanda Milliron, Marcia Kopfer, Michele Connaughton, A. Christine Hoerner, R. Joseph Logan, Harry J. Wohlsein, David Boyer, Thomas G. Chu, Pouya Dayani, David Liao, Roger L. Novack, Firas M. Rahhal, Richard Roe, Homayoun Tabandeh, Janet Bayramyan, Tammy Gasparyan, Connie Hoang, Janet Kurokouchi, Tammy Eileen Lo, Richard Ngo, Mary Ann Nguyen, Michael Peyton, Charles Yoon, Julio Sierra, Adam Zamboni, Jeff Kessinger, Eric Protacio, Adam Smucker, Pamela Rath, Robert Bergren, Bernard Doft, Judy Liu, Karl Olsen, Lori Merlotti, Willia Ingram, Kellianne Marfisi, Kimberly Yeckel, Heather Schultz Carmelo, Amanda Fec, Keith McBroom, David Steinberg, Marc Levy, Jody Abrams, Melvin Chen, Waldemar Torres, Peggy Jelemensky, Mark Prybylski, Tara Raphael, Diana Appleby, Charlotte Rodman, Mark Sneath, Robert H. Rosa, Vanessa Hoelscher, Adelia Castano, Jocelyn Parker, John Hoskins, Nicholas Anderson, Joseph Googe, Tod A. McMillan, James Miller, Stephen Perkins, Kristina Oliver, Jennifer Beerbower, Bruce Gilliland, Cecile Hunt, Mike Jacobus, Raul Lince, Christopher Morris, Sarah Oelrich, Jerry Whetstone, Clement K. Chan, Steven Lin, Kim Walther, Tiana Gonzales, Lenise Myers, Kenneth Huff, David M. Brown, Eric Chen, Matthew S. Benz, Richard H. Fish, Rosa Y. Kim, James Major, Tien Pei Wong, Charles Wycoff, Cassandra Cone, Debbie Goates Gilaspia, Nubia Landaverde, Robert Smith, Deneva Zamora, Veronica Sneed, Melina Vela, Eric Kegley, Craig Greven, Shree Kurup, Charles Richards, Madison Slusher, Cara Everhart, Joan Fish, Mark Clark, David Miller, Marshall Tyler, J. Michael Jumper, Arthur D. Fu, Robert N. Johnson, Brandon Lujan, H. Richard McDonald, Rosa Rodriguez, Nina Ansari, Jeanifer Joaquin, Silvia Linares, Lizette Lopez, Jessica Sabio, Sean Grout, Chad Indermill, Yesmin Urias, Roberto Zimmerman, Linda Margulies, Sara J. Schmidt, Joy L. Meier, Sherry L. Hadley, William Rosenthal, Barbara Johnson, Lois Swafford, Richard Shields, R. Scott Varner, Richard Rosen, Ronald Gentile, Melissa Rivas, Katy W. Tai, Wanda Carrasquillo-Boyd, Robert Masini, Glenn Stoller, Ken Carnevale, Diane M. LaRosa, Barbara Burger, Tereza Conway, Carla Del Castillo, Julissa Diaz, Susan Jones, Nina Mondoc, Charlene Balfour, C.H. Vitha, Jennifer Lutz, Barbara McGinley, Fadi El Baba, Ann Marie Lavorna, Renee Jones, Jean Lewis, Ruth Tenzler, Mary Salvas-Mladek, Diane Van Kesteren, W. Copley McLean, W. Zachery Bridges, Cameron Stone, Denise Ammons, Mary Lamy, Andrea Menzel, Lea Doll Raymer, Barbara Campbell, Lisa Hawkins, Leslie Rickman, Lorraine Sherlin, Paula Price, Albert Sinyai, Ronald Kingsley, Reagan H. Bradford, Robert E. Leonard, Sonny Icks, Vanessa Bergman, Brittany Ross, Russ Burris, Amanda Butt, Rob Richmond, Alice Lyon, Manjot Gill, Lee Jampol, Rukhsana Mizra, Zuzanna Rozenbajgier, Jeremy Chapman, Lori Kaminski, Andrea Degillio, Evica Simjanoski, Jeffrey Heier, Hyung Cho, Tina Scheufele Cleary, Darin Goldman, Chirag Shah, Trexler Topping, Marissa Weber, Torsten Wiegand, Jeremy Schindelheim, Joy Bankert, Jennifer Stone, Alison Nowak, Sandy Chong, Lindsay Williams, Steven Bennett, Dennis Donovan, Margaret Graham, Cullen Jones, Anne Fung, Jan-Kristine Bayabo, Razelda Bosch, Esperanza Cruz, Ashley Emerson, Alycia Fleming, Denice Barsness, Jorge Rodriguez, Marina Soboleva, Ingrid U. Scott, Esther Bowie, Kimberly A. Neely, David A. Quillen, Laura Walter, Timothy Bennett, James Strong, John Wells, Lloyd Clark, David Johnson, Peggy Miller, Mallie Taylor, Tiffany Swinford, Robbin Spivey, Michael Banach, Lawrence Ho, Richard Lanning, Thomas R. Pheasant, Jay G. Prensky, Steven Truong, Julia Teatsworth, Michelle Dietrich, Ann Wasilus, Ann Miller, Megan Rakes, Teresa Slagle, Michelle Richards, Patricia Schuessler, Lacy Stover, Paul Beer, Naomi S. Falk, Mary Beth Shannon, Jeannie Olmeda, Don Berdeen, Joseph F. Fisher, James Folk, Stephen Russell, Barbara Taylor, Connie Hinz, Jean Walshire, Heather Stockman, Bruce Critser, Stefani Karakas, Cindy Montague, Randy Verdick, Omesh Gupta, Joseph Maguire, Christopher Brady, Francis Char DeCroos, Michael Dollin, Sunir Garg, Adam Gerstenblith, Julia Haller, Allen C. Ho, Jason Hsu, Richard Kaiser, John Pitcher, Carl Regillo, Rajiv Shah, Marc Spirn, William Tasman, James Vander, Noga Senderowitsch, Michele Formoso, Michelle Markun, Cedric George, Christina Centinaro, Lisa Grande, Stefanie Carey, Elaine Liebenbaum, Mark Humayun, Rachel Sierra, Elizabeth Corona, Margaret Padilla, Moonseok Nu, Sylvia Ramos, Cullen Barnett, Glenn Currie, Cornelia Gottlieb, Richard Garfinkel, Daniel Berinstein, Marcus Colyer, William Deegan, Michael Min-Shyue Lai, Robert Murphy, Michael Osman, Michael Rivers, Reginald Sanders, Manfred A. von Fricken, Debbie Oliver, Jeanne Kirshon, Tanya Alexander Snowden, Thomas Blondo, Alysia Cronise, Vanessa Denny, Kylie Mendez, Janine Newgen, Justin Davis, Mike Flory, Robert Frantz, Bryan Murphy, Steve Rauch, Judy E. Kim, Jane Bachman, Thomas B. Connor, Dennis P. Han, Kimberly Stepian, David V. Weinberg, William J. Wirostko, Krissa Packard, Tracy Kaczanowski, Vesper Williams, Vicki Barwick, Judy Flanders, Dennis Backes, Joe Beringer, Kristy Keller, Kathy Selchert, Paul Bernstein, Michael Teske, Albert Vitale, Susan Allman, Bonnie Carlstrom, Kimberley Wegner, Anne Haroldsen, Deborah Harrison, Cyrie Fry, James Gilman, Glen Jenkins, Paula Morris, Michael Rauser, Joseph Fan, Mukesh Suthar, Gisela Santiago, Kara Rollins Halsey, Christy Quesada, William Kiernan, Jesse Knabb, Richard Alan Lewis, Cindy Dorenbach, Steven Spencer, Dana Barnett, Joseph Morales, Barron C. Fishburne, Jeffrey G. Gross, Michael A. Magee, Amy Flowers, Angie McDowell, Randall Price, Suber Huang, Johnny Tang, Shawn Wilker, Cherie Hornsby, Lisa Ferguson, Kirk Krogstad, Riva Adamovsky, Peggy Allchin, Kathleen Carlton, Claudia Clow, Kelly Sholtis, Stephanie Burke, Mark Harrod, Stacie Hrvatin, Geoffrey Pankhurst, Nelson R. Sabates, Michael Cassell, Komal Desai, Abraham Poulose, Felix Sabates, Yin Chen, Gary Gallimore, Yolanda Konior, Nicola Kim, Sami Uwaydat, Deborah Troillett, Karen Aletter, Robert N. Frank, Gary Abrams, James Puklin, Asheesh Tewari, Cheryl Milanovic, Melanie Bailey, David Griffith, Dena McDonald, Kit Morehead, Zlatan Sadikovic, Lisa Schillace, Elizabeth Silvis, Brian Joondeph, Nancy Christmas, Alan Kimura, Mimi Liu, Stephen Petty, John Zilis, Jenny Benitez, Cassandra Berryman Catlett, Eric Fluegel, Shane Mowry, Hoang Nguyen, David Reflow, Odette M. Houghton, Seema Garg, Maurice B. Landers, Travis Meredith, Sandy Barnhart, Megha Karmalkar, Debra Cantrell, Rona Lyn Esquejo-Leon, Linda Manor, Sue Pope, David Stines, Amelia Stokely, Dean Hainsworth, Dyann Helming, Debbie Eichelberger, Mary Paige Leaton, Chuck Hamm, Edward Chaum, Alessandro Iannaccone, Barbara Jennings, Tracy Murray, Joe Mastellone, Robert Millay, Brian Kim, Theresa Goddard, Liza Jarrett Beaudette, Nina Changelian-Aitken, Fernando Corrada, Jason Dubuque, Raymond Iezzi, Sophie J. Bakri, Jose S. Pulido, Diane Vogen, Rebecca Nielsen, Karin Berg, Jean Burrington, Shannon Howard, Joan Overend, Zbigniew Krason, Denise Lewison, Thomas Link, Kevin J. Blinder, Nicholas E. Engelbrecht, M. Gilbert Grand, Daniel P. Joseph, Gaurav K. Shah, Bradley Smith, Matthew Thomas, Rhonda Weeks, Lynda Boyd, Dana Gabel, Ron Adelman, John Huang, James Kempton, Aaron Parnes, Jennifer Dupont, Elizabeth Perotti, Victoria Donaldson, Kenneth Fong, Pamela Ossorio, Anita Agarwal, Paul Sternberg, Sandy Owings, Tony Adkins, Elaine Lok, Garvin Munn, Buddy Skellie, Neelakshi Bhagat, Monique S. Roy, Marco Zarbin, Catherine Fay, Michael Lazar, Beth Malpica, Tatiana Mikheyav, Lawrence Ulanski, Jennifer Lim, Marcia Niec, Tametha Johnson, Yesenia Ovando, Catherine Nail Carroll, Mark Janowicz, Steven Schwartz, David Cupp, Michael Gorin, Gad Heilweil, Hamid Hosseini, Jean-Pierre Hubschman, Allan Kreiger, Tara Young McCannel, Carolyn Pan, David Sarraf, Irena Tsui, Joshua Udoetek, Vinad Voleti, Logan Hitchcock, Rosaleen Ostrick, Melissa Chun, Jennie Kageyama, Nilo Davila, Kristin Lipka, Christina Shin, Cynthia Owsley, Michael Albert, Richard Feist, John Mason, Martin Thomley, Angelia Johnson, Tracy Emond, Joanna Hamela, Angela Marsh, Karen Searcey, Kia Rookard, Yu-Guang He, Rafael L. Ufret-Vincenty, Mike Molai, William Anderson, John Horna, Alan Letson, Colleen Cebulla, Susie Chang, Fred Davidorf, Jill Salerno, Laura Sladoje, Christina Stetson, Jeri Perry, Scott Savage, Cynthia Toth, Glenn Jaffe, Stefanie Schuman, Neeru Sarin, Jim Crowell, Tiffanie Keaton, Michael Kelly, Brian Lutman, Marriner Skelly, Lauren Welch, Lawrence Morse, Allan Hunter, Susanna Soon-Chun Park, Cynthia Wallace, Ember Dhillon, Marisa Salvador, Barbara Holderreed, Karishma Chandra, Sashi Kaur, Ellen Redenbo, Smiley Hom, Michael Cooney, Irene Barbazetto, James M. Klancnik, John A. Sorenson, Lawrence Yannuzzi, Maria Scolaro, Eugene Agresta, Nancy Gonzalez, Sandeep Grover, K.V. Chalam, Shailesh Gupta, Christopher Lyons, Wenhua Li, Chirag Patel, Jose Carrion, Henry Ferreyra, Amberly Rodriguez, Iliana Molina, Gabriel Balea, Pam Emory, Marlene Rico, Giorgio Siqueiros, Alexander J. Brucker, Joshua Dunaief, Juan Grunwald, Benjamin Kim, Albert M. Maguire, Brian VanderBeek, Sheri Drossner, Joan DuPont, Rebecca Salvo, Jim Berger, Cheryl Devine, Bill Nyberg, Laurel Weeney, David DiLoreto, Mina Chung, Valerie Davis, Peter MacDowell, George O. Gara, Daniel Castillo, Andrea Czubinski, Melissa Keim, Brandi Hardy, Rachel Grunhaus Hollar, Lynn Schueckler, Alice T. Lyon, Aaron Weinberg, Mira Shiloach, Nicole Pelkofer, Qin Zhou, Laura McPoland, Rajendra Apte, P. Kumar Rao, Sam Pistorius, Jamie Kambarian, Eve Adcock, Sarah Gould, Melanie Quinn, Rhonda Curtis, Amy Frost, Charla Meyer, and Greg Rathert

Subjects
0301 basic medicine, medicine.medical_specialty, genetic structures, business.industry, Eye disease, Incidence (epidemiology), Fundus (eye), Macular degeneration, medicine.disease, eye diseases, Confidence interval, Geographic atrophy, 03 medical and health sciences, Ophthalmology, 030104 developmental biology, 0302 clinical medicine, Age related, 030221 ophthalmology & optometry, medicine, sense organs, Prospective cohort study, business
Abstract

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Published
2018

12. Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus

Author

Heather A. Simmons, Jiancheng Hou, Saverio Capuano, Jennifer M. Hayes, Emma L. Mohr, Andrea M. Weiler, Laurel M. Stewart, Michael K. Fritsch, Ann Mitzey, David H. O’Connor, Andres Mejia, Mariel S. Mohns, Carol A. Rasmussen, Alex Katz, Mary L. Schneider, Sarah Kohn, Elaina Razo, Anna S. Jaeger, Kevin K. Noguchi, Matthew R Semler, Xiankun Zeng, Dawn M. Dudley, Leandro B. C. Teixeira, Thomas C. Friedrich, Michele L Schotzko, Kathryn M. Bach, Sierra Rybarczyk, Matthew T. Aliota, Michelle R Koenig, Vivek Prabhakaran, Thaddeus G. Golos, Veena A. Nair, T Michael Nork, Maria Dennis, Jens C. Eickhoff, Christina M. Newman, Meghan E. Breitbach, C. B. Y. Kim, James N. Ver Hoeve, Karla Ausderau, Kathleen M. Antony, Sallie R. Permar, Nancy Schultz-Darken, and Amy Hartman

Subjects
Sensory Receptors, Maternal Health, Placenta, Social Sciences, Disease, Monkeys, Pathology and Laboratory Medicine, Zika virus, 0302 clinical medicine, Animal Cells, Pregnancy, Psychology, Hearing Disorders, Mammals, Neurons, Zika Virus Infection, Delayed onset, Pregnancy Outcome, Eukaryota, Bioassays and Physiological Analysis, Medical Microbiology, Viral Pathogens, Prenatal Exposure Delayed Effects, Medicine, Cellular Types, Macaque, Primates, medicine.medical_specialty, Imaging Techniques, Science, Vision Disorders, Neurophysiology, Nervous System Malformations, Microbiology, 03 medical and health sciences, biology.animal, Microbial Pathogens, Flaviviruses, Organisms, Reproductive System, medicine.disease, 030104 developmental biology, Eyes, Histopathology, Clinical Medicine, 030217 neurology & neurosurgery, Neuroscience, Developmental Biology, 0301 basic medicine, RNA viruses, Photoreceptors, Pediatrics, Embryology, Future studies, Vision, Physiology, Medicine and Health Sciences, Pregnancy Complications, Infectious, Clinical Neurophysiology, Brain Mapping, Multidisciplinary, biology, Obstetrics and Gynecology, Electroencephalography, Electrophysiology, Brain Electrophysiology, Vertebrates, Viruses, Fetal Demise, Neuropathogenesis, Sensory Perception, Female, Pathogens, Anatomy, Research Article, Signal Transduction, Neuroimaging, Research and Analysis Methods, Ocular System, Old World monkeys, medicine, Animals, Biology and life sciences, business.industry, Electrophysiological Techniques, Visual-Evoked Potentials, Cognitive Psychology, Afferent Neurons, Zika Virus, Cell Biology, biology.organism_classification, Macaca mulatta, Retinal structure, Animals, Newborn, Cellular Neuroscience, Amniotes, Cognitive Science, Women's Health, Perception, business, Zoology, Head
Abstract

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

Published
2020

13. Alcohol Pads and Nonsterile Gloves in Preparation of Aflibercept

Author

Justin L. Gottlieb, Mihai Mititelu, Jonathan S. Chang, Michael M. Altaweel, Barbara A Blodi, Kimberly E Stepien, T Michael Nork, and Kathleen A. Regan

Subjects
medicine.medical_specialty, Ethanol, business.industry, Recombinant Fusion Proteins, technology, industry, and agriculture, Angiogenesis Inhibitors, medicine.disease, Vial, Article, Surgery, body regions, Ophthalmology, Endophthalmitis, Receptors, Vascular Endothelial Growth Factor, Intravitreal Injections, medicine, Humans, Alcohol pads, business, Gloves, Protective, Aflibercept, medicine.drug, Hand Disinfection
Abstract

Use of nonsterile gloves and an alcohol pad does not significantly impact the contamination of the rubber septum of the aflibercept vial. Other contamination points might instead be explored for endophthalmitis risk.

Published
2020

14. EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL

Author

Jay M. Stewart, Joshua Horvath, Vladimir Bantseev, T Michael Nork, Chris Schuetz, Ellison Bentley, William R. Freeman, Helen Booler, Kristof Hovaten, Signe Erickson, and Giulio Barteselli

Subjects
Male, Vascular Endothelial Growth Factor A, genetic structures, Swine, medicine.medical_treatment, Visual Acuity, Angiogenesis Inhibitors, Fundus (eye), Ophthalmology & Optometry, 0302 clinical medicine, Drug Delivery Systems, animal surgical model, Homeostasis, Original Study, Drug Implants, 0303 health sciences, General Medicine, Dissection, medicine.anatomical_structure, Cauterization, Swine, Miniature, Sclera, medicine.drug, Pars plana, medicine.medical_specialty, 03 medical and health sciences, Opthalmology and Optometry, Ophthalmology, Ranibizumab, medicine, Animals, anti-vascular endothelial growth factor, Intraocular Pressure, Port Delivery System, 030304 developmental biology, vitreous hemorrhage, business.industry, Diathermy, medicine.disease, eye diseases, Vitreous Body, Disease Models, Animal, Vitreous hemorrhage, 030221 ophthalmology & optometry, anti–vascular endothelial growth factor, Implant, sense organs, retinal disease, business, Follow-Up Studies
Abstract

Supplemental Digital Content is Available in the Text. This minipig model of vitreous hemorrhage demonstrated that scleral dissection followed by thorough laser ablation of the pars plana before the pars plana incision could mitigate vitreous hemorrhage during Port Delivery System with ranibizumab implant insertion surgery., Purpose: To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant. Methods: Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated. Results: Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus). Conclusion: In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.

Published
2020

15. Schwartz-Matsuo syndrome: An important cause of secondary glaucoma

Author

Jennifer C. Larson, Anna C. Momont, T Michael Nork, and Tyler Etheridge

Subjects
Pars plana, medicine.medical_specialty, Visual acuity, Open angle glaucoma, genetic structures, medicine.medical_treatment, Case Report, Vitrectomy, 03 medical and health sciences, 0302 clinical medicine, lcsh:Ophthalmology, Ophthalmology, Gonioscopy, medicine, Schwartz-Matsuo syndrome, Open-angle glaucoma, medicine.diagnostic_test, business.industry, Retinal detachment, medicine.disease, eye diseases, 3. Good health, medicine.anatomical_structure, lcsh:RE1-994, 030221 ophthalmology & optometry, Trabecular meshwork, Tamponade, sense organs, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Purpose: We report a case of Schwartz-Matsuo syndrome that highlights the pathophysiology, diagnostic challenges, and management considerations of this rare disease. Observations: 31-year-old man with a history of left eye cataract presented with left eye photophobia and elevated intraocular pressure (IOP) of 64 mm Hg. Visual acuity 20/40. Open angles with an increased pigment of trabecular meshwork by gonioscopy, 2 + anterior chamber (AC) cell, superior retinal detachment, and 0.6 cup-to-disc ratio. Electron microscopy of AC fluid demonstrated outer segments of photoreceptors. IOP was lowered with oral and topical ophthalmic antihypertensives. Retinal detachment was treated with pars plana vitrectomy with endolaser, gas tamponade, and AC paracentesis. Follow-up VA 20/20 with normal IOP. Conclusions and importance: Schwartz-Matsuo syndrome is characterized by elevated IOP with marked fluctuations, open angles, aqueous cells, and retinal detachment. Diagnosis is supported by electron microscopy of AC fluid with outer segments of photoreceptors. Treatment includes retinal detachment repair and antihypertensive therapy. Keywords: Schwartz-Matsuo syndrome, Retinal detachment, Open-angle glaucoma

Published
2020

16. TWO CASES OF ACUTE RETINAL NECROSIS DUE TO VARICELLA ZOSTER DESPITE PRIOR SHINGLES VACCINATION

Author

Pimkwan Jaru-ampornpan, Eric Weinlander, Michael M. Altaweel, T Michael Nork, and Angeline L. Wang

Subjects
Male, 0301 basic medicine, Herpesvirus 3, Human, medicine.medical_specialty, viruses, Eye Infections, Viral, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Chart review, medicine, Herpes Zoster Vaccine, Humans, Viral etiology, integumentary system, business.industry, Vaccination, Varicella zoster virus, Antiviral therapy, virus diseases, Retinal Necrosis Syndrome, Acute, General Medicine, Middle Aged, Eye infection, medicine.disease, Dermatology, Virology, Ophthalmology, 030104 developmental biology, 030221 ophthalmology & optometry, Acute retinal necrosis, business, Shingles
Abstract

Purpose To review two cases of acute retinal necrosis in adults due to varicella zoster virus despite prior shingles vaccination. Methods Retrospective chart review. Patients A 62-year-old man and a 64-year-old man with unilateral acute retinal necrosis who had shingles vaccinations 16 and 7 months before their ocular symptoms. Results Polymerase chain reaction confirmation of varicella zoster virus in the anterior chambers of both patients. Both patients had good responses to oral antiviral therapy and topical and/or oral steroids. Discussion These two cases demonstrate that singles vaccination is not an absolute protection against varicella zoster virus-related acute retinal necrosis. However, such vaccination may reduce the severity of the acute retinal necrosis.

Published
2019

17. Determination of a No Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Cynomolgus Monkeys

Author

Brian J Christian, Aija McKenzie, Vladimir Bantseev, Helen Booler, Evan A Thackaberry, T Michael Nork, Carol A. Rasmussen, and Paul E. Miller

Subjects
0301 basic medicine, Intraocular pressure, medicine.medical_specialty, genetic structures, Fundus (eye), Peripheral blood mononuclear cell, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, Dose group, Photography, Medicine, Animals, Pharmacology (medical), Pharmacology, Inflammation, business.industry, Anatomical pathology, Intravitreal administration, Original Articles, Uveitis, Anterior, eye diseases, Posterior segment of eyeball, Endotoxins, Macaca fascicularis, 030104 developmental biology, Tolerability, Acute Disease, Intravitreal Injections, 030221 ophthalmology & optometry, Female, sense organs, business, Tomography, Optical Coherence
Abstract

Purpose: To characterize the inflammatory response and determine the no-observable-effect level (NOEL) in cynomolgus monkey eyes after intravitreal (ITV) injection of endotoxin. Methods: The inflammatory response to endotoxin was assessed in a single-dose study in monkeys at doses of 0.01 to 0.51 endotoxin units (EU)/eye. Tolerability was assessed by clinical ophthalmic examinations, intraocular pressure measurements, fundus color photography, optical coherence tomography, and anatomic pathology. Results: ITV injection of endotoxin at ≥0.04 EU/eye resulted in a dose-related anterior segment inflammatory response. No aqueous flare or cell was noted in the 0.01 EU/eye dose group. A more delayed posterior segment response characterized by vitreous cell was observed beginning on day 5, peaking on day 15, and decreasing in some groups. Microscopic findings of mononuclear cell infiltrates in the vitreous were observed in eyes given ≥0.21 EU/eye. Conclusion: The NOEL for ITV endotoxin in cynomolgus monkeys was 0.01 EU/eye, suggesting that this species is as sensitive as rabbits to the effects of endotoxin. The vitreous cavity also appears more sensitive to endotoxin than the anterior segment/aqueous chamber. Overall, the magnitude of the inflammatory response at ≥0.04 EU/eye suggests that dose-response curve in monkeys is steeper than in rabbits. These data highlight the importance of assessing endotoxin level in ITV formulations, as levels as low as 0.04 EU/eye may confound the safety evaluations of ITV therapeutics in cynomolgus monkeys.

Published
2019

18. Cone-Specific Promoters for Gene Therapy of Achromatopsia and Other Retinal Diseases

Author

Jeffrey D. Chulay, Jim Peterson, Guo-jie Ye, William W. Hauswirth, Nader Sheibani, Shannon E. Boye, Sanford L. Boye, Ewa Budzynski, Zafer Gurel, T Michael Nork, and Peter Sonnentag

Subjects
0301 basic medicine, Achromatopsia, genetic structures, Genetic enhancement, Genetic Vectors, Green Fluorescent Proteins, Gene Expression, Color Vision Defects, Biology, Green fluorescent protein, Mice, 03 medical and health sciences, Dogs, Retinal Diseases, Gene expression, Genetics, medicine, Animals, Humans, Vector (molecular biology), Promoter Regions, Genetic, Molecular Biology, Gene, Research Articles, Gene Transfer Techniques, Rod Opsins, Promoter, Genetic Therapy, Dependovirus, medicine.disease, eye diseases, Cell biology, 030104 developmental biology, Retinal Cone Photoreceptor Cells, Molecular Medicine, sense organs, Transducin
Abstract

Adeno-associated viral (AAV) vectors containing cone-specific promoters have rescued cone photoreceptor function in mouse and dog models of achromatopsia, but cone-specific promoters have not been optimized for use in primates. Using AAV vectors administered by subretinal injection, we evaluated a series of promoters based on the human L-opsin promoter, or a chimeric human cone transducin promoter, for their ability to drive gene expression of green fluorescent protein (GFP) in mice and nonhuman primates. Each of these promoters directed high-level GFP expression in mouse photoreceptors. In primates, subretinal injection of an AAV-GFP vector containing a 1.7-kb L-opsin promoter (PR1.7) achieved strong and specific GFP expression in all cone photoreceptors and was more efficient than a vector containing the 2.1-kb L-opsin promoter that was used in AAV vectors that rescued cone function in mouse and dog models of achromatopsia. A chimeric cone transducin promoter that directed strong GFP expression in mouse and dog cone photoreceptors was unable to drive GFP expression in primate cones. An AAV vector expressing a human CNGB3 gene driven by the PR1.7 promoter rescued cone function in the mouse model of achromatopsia. These results have informed the design of an AAV vector for treatment of patients with achromatopsia.

Published
2016

19. 2784. Increased Frontal Lobe Volume and Density in Macaques Exposed to Zika Virus In Utero

Author

Vivek Prabhakaran, Andres Mejia, Leandro B. C. Teixeira, Kathryn M. Bach, Andrea M. Weiler, Nancy Schultz-Darken, T Michael Nork, Emma L. Mohr, Xiankun Zeng, Sarah Kohn, Jennifer M. Hayes, M. Shahriar Salamat, Christina M. Newman, Thaddeus G. Golos, Dawn M. Dudley, Thomas C. Friedrich, Karla Ausderau, Alex Katz, Ann Mitzey, Michele L Schotzko, Amy Hartman, Kevin K. Noguchi, C. B. Y. Kim, James N. Ver Hoeve, Chrysanthy Ikonomidou, Jiancheng Hou, Matt Semler, Heather A. Simmons, Meghan E. Breitbach, Matthew T. Aliota, Elaina Razo, Saverio Capuano, Laurel M. Stewart, Carol A. Rasmussen, Mary L. Schneider, Michelle R Koenig, Kathleen M. Antony, Mariel S. Mohns, David H. O’Connor, and Sierra Rybarczyk

Subjects
Pathology, medicine.medical_specialty, biology, business.industry, Viremia, biology.organism_classification, medicine.disease, Fetal brain, Zika virus, Abstracts, Infectious Diseases, medicine.anatomical_structure, Oncology, Frontal lobe, In utero, Poster Abstracts, Brain mri, Vertical Disease Transmission, Medicine, business, Motor cortex
Abstract

Background In utero Zika virus (ZIKV) infection causes birth defects and neurodevelopmental deficits in neonates. We reasoned that a translational macaque model of congenital ZIKV infection could define disease pathophysiology not possible in human clinical studies. Methods We inoculated 5 pregnant rhesus macaques with a Puerto Rican isolate of ZIKV (ZIKV-PRVABC59) during the first trimester, monitored infection with plasma viral RNA (vRNA) loads, and evaluated infants for birth defects and neurodevelopmental deficits during their first week of life. Assessments included neurobehavioral assessments, ophthalmic examinations, optical coherence tomography, electroretinography with visual evoked potentials, hearing examinations, brain magnetic resonance imaging (MRI), and tissue histopathological analyses. Results All five pregnant dams demonstrated plasma viremia and seroconversion following ZIKV inoculation. One of the five pregnancies resulted in a stillbirth. All liveborn infants had decreased feeding volumes and weight gain compared with control infants. A comprehensive voxel-based morphometric comparison of ZIKV-exposed and control infant brain MRIs identified increased gray matter volume and density in the frontal lobe in the ZIKV-exposed infant group, which corresponds to the pharyngeal motor cortex responsible for coordinating swallowing. Ocular studies identified differences between ZIKV-exposed and control infants in retinal layer thicknesses (inner plexiform, outer nuclear layers, photoreceptor outer segment) and visual evoked potentials (increased amplitude of waveforms). While ZIKV vRNA was detected in the decidua of 2/5 pregnancies, no ZIKV vRNA was identified in infant tissues and none of the infants developed an anti-ZIKV IgM response. Conclusion In utero ZIKV exposure resulted in decreased feeding volumes and weight gain, which may be related to the gray matter changes identified in the pharyngeal motor cortex. Changes in retinal layer thicknesses and increased cortical visual pathway waveform amplitude suggest vision may be impaired. These changes occurred despite the lack of evidence of vertical transmission, suggesting that ZIKV exposure without measurable vertical transmission affects fetal brain development. Disclosures All authors: No reported disclosures.

Published
2019

20. Biomechanical, ultrastructural, and electrophysiological characterization of the non-human primate experimental glaucoma model

Author

Joshua T. Morgan, James N. Ver Hoeve, J. Seth Eaton, Carol A. Rasmussen, Paul E. Miller, Haiyan Gong, T Michael Nork, Paul Russell, Brian J Christian, Vijay Krishna Raghunathan, Christopher J. Murphy, and Chen-Yuan Charlie Yang

Subjects
0301 basic medicine, Intraocular pressure, Aging, genetic structures, Proteome, Nerve fiber layer, Glaucoma, lcsh:Medicine, Neurodegenerative, Eye, chemistry.chemical_compound, 0302 clinical medicine, Models, Medicine, Primate, lcsh:Science, Softening, Multidisciplinary, biology, medicine.anatomical_structure, Hypertension, Models, Animal, Primates, medicine.medical_specialty, Article, 03 medical and health sciences, Trabecular Meshwork, Ophthalmology, biology.animal, Animals, Humans, Eye Disease and Disorders of Vision, Intraocular Pressure, business.industry, Animal, Lasers, lcsh:R, Neurosciences, Retinal, medicine.disease, eye diseases, Electrophysiological Phenomena, Electrophysiology, 030104 developmental biology, chemistry, 030221 ophthalmology & optometry, lcsh:Q, Trabecular meshwork, sense organs, business
Abstract

Laser-induced experimental glaucoma (ExGl) in non-human primates (NHPs) is a common animal model for ocular drug development. While many features of human hypertensive glaucoma are replicated in this model, structural and functional changes in the unlasered portions of trabecular meshwork (TM) of laser-treated primate eyes are understudied. We studied NHPs with ExGl of several years duration. As expected, ExGl eyes exhibited selective reductions of the retinal nerve fiber layer that correlate with electrophysiologic measures documenting a link between morphologic and elctrophysiologic endpoints. Softening of unlasered TM in ExGl eyes compared to untreated controls was observed. The degree of TM softening was consistent, regardless of pre-mortem clinical findings including severity of IOP elevation, retinal nerve fiber layer thinning, or electrodiagnostic findings. Importantly, this softening is contrary to TM stiffening reported in glaucomatous human eyes. Furthermore, microscopic analysis of unlasered TM from eyes with ExGl demonstrated TM thinning with collapse of Schlemm’s canal; and proteomic analysis confirmed downregulation of metabolic and structural proteins. These data demonstrate unexpected and compensatory changes involving the TM in the NHP model of ExGl. The data suggest that compensatory mechanisms exist in normal animals and respond to elevated IOP through softening of the meshwork to increase outflow.

Published
2017

21. Single ocular injection of a sustained-release anti-VEGF delivers 6months pharmacokinetics and efficacy in a primate laser CNV model

Author

Justyna Korczynska, Lemy Tsikna, Zoe Hughes-Thomas, Richard Haworth, Christopher J. Roberts, John Warrack, Steven D. Sorden, Irene Papanicolaou, Rodd Polsky, Eric Dobrzynski, Edit Kurali, Timothy Streit, Thomas Wilde, Jeffery J Prusakiewicz, Brian J Christian, Peter C. Adamson, T Michael Nork, Ian Richard Catchpole, Craig Struble, Caroline Sychterz, James Walford, Chi-Man Tang, Daniel Gibson, Ruud Verrijk, Paul E. Miller, Fiona Cook, and Jos Smal

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, medicine.medical_treatment, Polyesters, Pharmaceutical Science, 02 engineering and technology, Pharmacology, Antibodies, Article, Polyethylene Glycols, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, In vivo, medicine, Animals, Humans, Particle Size, Aflibercept, Drug Carriers, Chemistry, Growth factor, Lasers, Non-human primate eyes, 021001 nanoscience & nanotechnology, Sustained-release delivery, VEGF, eye diseases, In vitro, Choroidal Neovascularization, Microspheres, Surgery, Immunoglobulin Fc Fragments, Vascular endothelial growth factor A, Drug Liberation, Macaca fascicularis, Choroidal neovascularization, Delayed-Action Preparations, Immunoglobulin G, Intravitreal Injections, 030221 ophthalmology & optometry, Wet Macular Degeneration, Choroidal neovascularisation, Rabbits, Intraocular injection, medicine.symptom, 0210 nano-technology, Drug carrier, medicine.drug
Abstract

A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in ocular VEGF-driven efficacy models in vivo. The dual dAb is highly potent, showing a lower IC50 than aflibercept in VEGF receptor binding assays (RBAs) and retaining activity upon release from microparticles over 12months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6months at sufficient levels to protect Cynomolgus against laser-induced grade IV choroidal neovascularisation (CNV). This demonstrates proof of concept for delivery of an anti-VEGF molecule within a sustained-release system, showing protection in a pre-clinical primate model of wet AMD over 6months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.

Published
2016

22. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Author

Roberto Calcedo, Paul E. Miller, Jeffrey D. Chulay, James N. Ver Hoeve, David R. Knop, Ewa Budzynski, Guo-jie Ye, Alok K. Sharma, Leia M. Smith, Paulette M. Robinson, William W. Hauswirth, Chantelle Gaskin, Peter Sonnentag, T Michael Nork, and Tara Arndt

Subjects
0301 basic medicine, Male, Intraocular pressure, medicine.medical_specialty, Biodistribution, Pathology, Achromatopsia, Genetic Vectors, DNA, Recombinant, Cyclic Nucleotide-Gated Cation Channels, Color Vision Defects, Biology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Endophthalmitis, law, Internal medicine, medicine, Animals, Humans, Vector (molecular biology), Research Articles, Genetics (clinical), Hematology, Genetic Therapy, Dependovirus, medicine.disease, Posterior segment of eyeball, Macaca fascicularis, 030104 developmental biology, 030221 ophthalmology & optometry, Recombinant DNA, Female, Injections, Intraocular
Abstract

Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated viral (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n = 2 males and 2 females per group) received a subretinal injection in one eye of 300 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 10(11) or 4 × 10(12) vector genomes/ml) and were evaluated over a 3-month period before being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on study day 5, based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

Published
2016

23. Safety and Biodistribution Evaluation in CNGB3-deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia

Author

Peter Sonnentag, William W. Hauswirth, James N. Ver Hoeve, Savitri Mandapati, Roberto Calcedo, Ewa Budzynski, Leslie E McPherson, Jeffrey D. Chulay, David R. Knop, Paulette M. Robinson, Tara Arndt, Guo-jie Ye, Leia M. Smith, T Michael Nork, and Paul E. Miller

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Biodistribution, Retinal Disorder, Achromatopsia, genetic structures, Genetic Vectors, DNA, Recombinant, Cyclic Nucleotide-Gated Cation Channels, Color Vision Defects, 030105 genetics & heredity, Retina, Virus, law.invention, Mice, 03 medical and health sciences, law, Animals, Humans, Medicine, Research Articles, Genetics (clinical), medicine.diagnostic_test, Clinical pathology, business.industry, Genetic Therapy, Dependovirus, medicine.disease, eye diseases, 030104 developmental biology, Recombinant DNA, Female, sense organs, Injections, Intraocular, business, Erg, Electroretinography
Abstract

Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 × 10(12) or 4.2 × 10(12) vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

Published
2016

24. Toluene inhalation exposure for 13 weeks causes persistent changes in electroretinograms of Long–Evans rats

Author

Laura L. Degn, Paul A. Evansky, Charles Pinckney, Andrew M. Geller, William K. Boyes, Philip J. Bushnell, Jean-Claude Mwanza, Tracey E. Beasley, Mark Bercegeay, and T Michael Nork

Subjects
Male, medicine.medical_specialty, Time Factors, Light, genetic structures, 010501 environmental sciences, Toxicology, 01 natural sciences, Article, Contrast Sensitivity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Electroretinography, medicine, Animals, Rats, Long-Evans, 0105 earth and related environmental sciences, Inhalation exposure, Inhalation Exposure, Retina, Dose-Response Relationship, Drug, Inhalation, Chemistry, Ophthalmoscopes, General Neuroscience, Retinal, eye diseases, Rats, medicine.anatomical_structure, Endocrinology, Visual cortex, Inner nuclear layer, Linear Models, Solvents, Evoked Potentials, Visual, sense organs, Erg, Color Perception, Photic Stimulation, 030217 neurology & neurosurgery, Toluene, Photopic vision
Abstract

Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000 ppm toluene by inhalation (6 hr/d, 5 d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not significantly changed by toluene exposure. Four to five weeks after completion of exposure, rats were dark-adapted overnight, anesthetized, and several sets of electroretinograms (ERG) were recorded. In dark-adapted ERGs recorded over a 5-log (cd-s/m 2 ) range of flash luminance, b-wave amplitudes were significantly reduced at high stimulus luminance values in rats previously exposed to 1000 ppm toluene. A second set of rats, exposed concurrently with the first set, was tested approximately one year after the termination of 13 weeks of exposure to toluene. Again, dark-adapted ERG b-wave amplitudes were reduced at high stimulus luminance values in rats previously exposed to 1000 ppm toluene. A third set of rats was exposed to the same concentrations of toluene for only 4 weeks, and a fourth set of rats exposed to 0 or 1000 ppm toluene for 4 weeks were tested approximately 1 year after the completion of exposure. No statistically significant reductions of ERG b-wave amplitude were observed in either set of rats exposed for 4 weeks. No significant changes were observed in ERG a-wave amplitude or latency, b-wave latency, UV- or green-flicker ERGs, or in photopic flash ERGs. There were no changes in the density of rod or M-cone photoreceptors. The ERG b-wave reflects the firing patterns of on-bipolar cells. The reductions of b-wave amplitude after 13 weeks of exposure and persisting for 1 year suggest that alterations may have occurred in the inner nuclear layer of the retina, where the bipolar cells reside, or the outer or inner plexiform layers where the bipolar cells make synaptic connections. These data provide experimental evidence that repeated exposure to toluene may lead to subtle persistent changes in visual function. The fact that toluene affected ERGs, but not VEPs, suggests that elements in the rat retina may be more sensitive to organic solvent exposure than the rat visual cortex.

Published
2016
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26. The effect of pentobarbital sodium and propofol anesthesia on multifocal electroretinograms in rhesus macaques

Author

James N. Ver Hoeve, Charlene B. Y. Kim, and T Michael Nork

Subjects
Pentobarbital, genetic structures, Sodium, chemistry.chemical_element, Signal-To-Noise Ratio, Retina, Article, Physiology (medical), Electroretinography, medicine, Animals, Hypnotics and Sedatives, Propofol anesthesia, Anesthesia, Ketamine, Propofol, Chemistry, Extramural, Macaca mulatta, eye diseases, Sensory Systems, Ophthalmology, Anesthetic, Evoked Potentials, Visual, Female, Anesthetics, Intravenous, Retinoscopy, medicine.drug
Abstract

We compared the suitability of pentobarbital sodium (PB) and propofol (PF) anesthetics for multifocal electroretinograms (mfERGs) in rhesus macaques. mfERGs were collected from 4 ocularly normal rhesus macaques. All animals were pre-anesthetized with intramuscular ketamine (10-15 mg/kg). Intravenous PB induction/maintenance levels were 15 mg/kg/2-10 mg/kg and for PF, 2-5 mg/kg/6-24 mg/kg/h. There were 3 testing sessions with PB anesthesia and 5-7 testing sessions with PF anesthesia. All PB sessions were carried out before PF. First-order (K1) and second-order (first slice) kernels (K2.1) response density amplitude (RDA), implicit time (IT), and root mean square signal-to-noise ratios (RMS SNR) of the low-frequency (LFC) and high-frequency (HFC) components were evaluated. The use of PF or PB anesthesia resulted in robust, replicable mfERGs in rhesus macaques; however, RMS SNR of K1 LFC in ring and quadrant analyses was significantly larger for PF than for PB. Additionally, K1 RDA under PF was significantly larger than under PB for N1, P1, and P2 components (ring and quadrant) and for N2 (quadrant). PF IT was significantly prolonged (

Published
2011

27. Comparison of the distribution of glial fibrillary acidic protein, heat shock protein 60, and hypoxia-inducible factor-1α in retinas from glaucomatous and normal canine eyes

Author

Richard R. Dubielzig, T Michael Nork, and Caitlin A. Savagian

Subjects
Pathology, medicine.medical_specialty, genetic structures, Glaucoma, Retina, Dogs, Heat shock protein, Glial Fibrillary Acidic Protein, medicine, Animals, Distribution (pharmacology), Dog Diseases, General Veterinary, Glial fibrillary acidic protein, biology, Chronic glaucoma, Chaperonin 60, General Medicine, medicine.disease, eye diseases, Staining, Hypoxia-inducible factors, biology.protein, Immunohistochemistry, Hypoxia-Inducible Factor 1, sense organs
Abstract

Objective—To determine the effect of acute (clinical history of glaucoma for ≤ 2 days) and chronic (clinical history of glaucoma for 7 days) goniodysgenesis-related glaucoma on various stress-inducible proteins in canine retinas. Sample Population—15 canine retinas (5 from control eyes, 5 from eyes with acute glaucoma, and 5 from eyes with chronic glaucoma). Procedures—Globes were obtained from the Comparative Ocular Pathology Laboratory of Wisconsin. Eyes were characterized on the basis of clinical history. The distribution of glial fibrillary acidic protein (GFAP), heat shock protein (HSP) 60, and hypoxia-inducible factor (HIF)-1α was determined by use of immunohistochemical analysis. Results—Intensity of GFAP staining increased with temporal progression of glaucoma. In specimens from eyes with acute glaucoma, staining for HSP 60 was more variable among eyes, compared with that of the control eyes, whereas specimens from eyes with chronic glaucoma typically had less HSP 60 staining than was evident in the control eyes. Neither the control eyes nor specimens from the eyes with acute glaucoma had nuclear staining for HIF-1α in the retinas. Four of 5 specimens from eyes with chronic glaucoma had nuclear staining for HIF-1α in cells of the outer nuclear layer. Staining for HIF-1α was distributed segmentally in regions of more severe atrophy and disorganization. Conclusions and Clinical Relevance—Results of the study reported here supported a clinically evident, rapidly progressive disease with a shift in cell regulation between acute and chronic glaucoma and also supported ischemia as a mechanism of retinal injury in this disease.

Published
2008

28. 199. Initial Safety Evaluation of rAAV-hCNGB3 Vectors in Nonhuman Primates

Author

Ewa Budzynski, James N. VerHoeve, Peter Sonnentag, T Michael Nork, Leslie E McPherson, Jeffrey D. Chulay, Paul E. Miller, and Guo-jie Ye

Subjects
Pharmacology, genetic structures, business.industry, Genetic enhancement, Physiology, Dose level, Severe inflammation, Test article, Drug Discovery, Homologous chromosome, Genetics, Medicine, Molecular Medicine, Evoked potential, business, Erg, Molecular Biology, Ocular inflammation
Abstract

Both AAV2tYF-hCNGB3 and AAV5-hCNGB3 were well tolerated after subretinal injection in in NHPs at a dose level of 4 × 10^10 or 4 × 10^11 vg/eye. Test article related findings included dose-dependent ocular inflammation that resolved by Study Week 12. No test article-related ERG or cortical visual evoked potential (VEP) effects were observed. In contrast to the severe inflammation noted in dogs receiving high dose of AAV5-hCNGB3 that usually resulted in involuntary early termination of the animals, the milder test article-related findings in macaques receiving AAV-hCNGB3 vectors that expresses a highly homologous xenogeneic human protein is helpful for guiding future development of rAAV-CNGB3 gene therapy for human patients.

Published
2015
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29. Subretinal Hyperreflective Material in the Comparison of Age-Related Macular Degeneration Treatments Trials

Author

Alex S. Willoughby, Gui-shuang Ying, Cynthia A. Toth, Maureen G. Maguire, Russell E. Burns, Juan E. Grunwald, Ebenezer Daniel, Glenn J. Jaffe, David F. Williams, Sara Beardsley, Steven Bennett, Herbert Cantrill, Carmen Chan-Tram, Holly Cheshier, Kathyrn Damato, John Davies, Sundeep Dev, Julianne Enloe, Gennaro Follano, Peggy Gilbert, Jill Johnson, Tori Jones, Lisa Mayleben, Robert Mittra, Martha Moos, Ryan Neist, Neal Oestreich, Polly Quiram, Robert Ramsay, Edwin Ryan, Stephanie Schindeldecker, John Snater, Trenise Steele, Dwight Selders, Jessica Tonsfeldt, Shelly Valardi, Gary Edd Fish, Hank A. Aguado, Sally Arceneaux, Jean Arnwine, Kim Bell, Tina Bell, Bob Boleman, Patricia Bradley, David Callanan, Lori Coors, Jodi Creighton, Timothy Crew, Kimberly Cummings, Christopher Dock, Karen Duignan, Dwain Fuller, Keith Gray, Betsy Hendrix, Nicholas Hesse, Diana Jaramillo, Bradley Jost, Sandy Lash, Laura Lonsdale, Michael Mackens, Karin Mutz, Michael Potts, Brenda Sanchez, William Snyder, Wayne Solley, Carrie Tarter, Robert Wang, Patrick Williams, Stephen L. Perkins, Nicholas Anderson, Ann Arnold, Paul Blais, Joseph Googe, Tina T. Higdon, Cecile Hunt, Mary Johnson, James Miller, Misty Moore, Charity K. Morris, Christopher Morris, Sarah Oelrich, Kristina Oliver, Vicky Seitz, Jerry Whetstone, Bernard H. Doft, Jay Bedel, Robert Bergren, Ann Borthwick, Paul Conrad, Amanda Fec, Christina Fulwylie, Willia Ingram, Shawnique Latham, Gina Lester, Judy Liu, Louis Lobes, Nicole M. Lucko, Holly Mechling, Lori Merlotti, Keith McBroom, Karl Olsen, Danielle Puskas, Pamela Rath, Maria Schmucker, Lynn Schueckler, Christina Schultz, Heather Shultz, David Steinberg, Avni Vyas, Kim Whale, Kimberly Yeckel, David H. Orth, Linda S. Arredondo, Susan Brown, Barbara J. Ciscato, Joseph M. Civantos, Celeste Figliulo, Sohail Hasan, Belinda Kosinski, Dan Muir, Kiersten Nelson, Kirk Packo, John S. Pollack, Kourous Rezaei, Gina Shelton, Shannya Townsend-Patrick, Marian Walsh, H. Richard McDonald, Nina Ansari, Amanda Bye, Arthur D. Fu, Sean Grout, Chad Indermill, Robert N. Johnson, J. Michael Jumper, Silvia Linares, Brandon J. Lujan, Ames Munden, Meredith Persons, Rosa Rodriguez, Jennifer M. Rose, Brandi Teske, Yesmin Urias, Stephen Young, Richard F. Dreyer, Howard Daniel, Michele Connaughton, Irvin Handelman, Stephen Hobbs, Christine Hoerner, Dawn Hudson, Marcia Kopfer, Michael Lee, Craig Lemley, Joe Logan, Colin Ma, Christophe Mallet, Amanda Milliron, Mark Peters, Harry Wohlsein, Joel A. Pearlman, Margo Andrews, Melissa Bartlett, Nanette Carlson, Emily Cox, Robert Equi, Marta Gonzalez, Sophia Griffin, Fran Hogue, Lance Kennedy, Lana Kryuchkov, Carmen Lopez, Danny Lopez, Bertha Luevano, Erin McKenna, Arun Patel, Brian Reed, Nyla Secor, Iris R. Sison, Tony Tsai, Nina Varghis, Brooke Waller, Robert Wendel, Reina Yebra, Daniel B. Roth, Jane Deinzer, Howard Fine, Flory Green, Stuart Green, Bruce Keyser, Steven Leff, Amy Leviton, Amy Martir, Kristin Mosenthine, Starr Muscle, Linda Okoren, Sandy Parker, Jonathan Prenner, Nancy Price, Deana Rogers, Linda Rosas, Alex Schlosser, Loretta Studenko, Thea Tantum, Harold Wheatley, Michael T. Trese, Thomas Aaberg, Denis Bezaire, Craig Bridges, Doug Bryant, Antonio Capone, Michelle Coleman, Christina Consolo, Cindy Cook, Candice DuLong, Bruce Garretson, Tracy Grooten, Julie Hammersley, Tarek Hassan, Heather Jessick, Nanette Jones, Crystal Kinsman, Jennifer Krumlauf, Sandy Lewis, Heather Locke, Alan Margherio, Debra Markus, Tanya Marsh, Serena Neal, Amy Noffke, Kean Oh, Clarence Pence, Lisa Preston, Paul Raphaelian, Virginia R. Regan, Peter Roberts, Alan Ruby, Ramin Sarrafizadeh, Marissa Scherf, Sarita Scott, Scott Sneed, Lisa Staples, Brad Terry, Matthew T. Trese, Joan Videtich, George Williams, Mary Zajechowski, Daniel P. Joseph, Kevin Blinder, Lynda Boyd, Sarah Buckley, Meaghan Crow, Amanda Dinatale, Nicholas Engelbrecht, Bridget Forke, Dana Gabel, Gilbert Grand, Jennifer Grillion-Cerone, Nancy Holekamp, Charlotte Kelly, Ginny Nobel, Kelly Pepple, Matt Raeber, P. Kumar Rao, Tammy Ressel, Steven Schremp, Merrilee Sgorlon, Shantia Shears, Matthew Thomas, Cathy Timma, Annette Vaughn, Carolyn Walters, Rhonda Weeks, Jarrod Wehmeier, Tim Wright, Daniel M. Berinstein, Aida Ayyad, Mohammed K. Barazi, Erica Bickhart, Tracey Brady, Lisa Byank, Alysia Cronise, Vanessa Denny, Courtney Dunn, Michael Flory, Robert Frantz, Richard A. Garfinkel, William Gilbert, Michael M. Lai, Alexander Melamud, Janine Newgen, Shamekia Newton, Debbie Oliver, Michael Osman, Reginald Sanders, Manfred von Fricken, Pravin Dugel, Sandra Arenas, Gabe Balea, Dayna Bartoli, John Bucci, Jennifer A. Cornelius, Scheleen Dickens, Don Doherty, Heather Dunlap, David Goldenberg, Karim Jamal, Norma Jimenez, Nicole Kavanagh, Derek Kunimoto, John Martin, Jessica Miner, Sarah Mobley, Donald Park, Edward Quinlan, Jack Sipperley, Carol Slagle, Danielle Smith, Miguelina Yafchak, Rohana Yager, Christina J. Flaxel, Steven Bailey, Peter Francis, Chris Howell, Thomas Hwang, Shirley Ira, Michael Klein, Andreas Lauer, Teresa Liesegang, Ann Lundquist, Sarah Nolte, Susan K. Nolte, Scott Pickell, Susan Pope, Joseph Rossi, Mitchell Schain, Peter Steinkamp, Maureen D. Toomey, Debora Vahrenwald, Kelly West, Baker Hubbard, Stacey Andelman, Chris Bergstrom, Judy Brower, Blaine Cribbs, Linda Curtis, Jannah Dobbs, Lindreth DuBois, Jessica Gaultney, Deborah Gibbs, Debora Jordan, Donna Leef, Daniel F. Martin, Robert Myles, Timothy Olsen, Bryan Schwent, Sunil Srivastava, Rhonda Waldron, Andrew N. Antoszyk, Uma Balasubramaniam, Danielle Brooks, Justin Brown, David Browning, Loraine Clark, Sarah Ennis, Susannah Held, Jennifer V. Helms, Jenna Herby, Angie Karow, Pearl Leotaud, Caterina Massimino, Donna McClain, Michael McOwen, Jennifer Mindel, Candace Pereira, Rachel Pierce, Michele Powers, Angela Price, Jason Rohrer, Jason Sanders, Robert L. Avery, Kelly Avery, Jessica Basefsky, Liz Beckner, Alessandro Castellarin, Stephen Couvillion, Jack Giust, Matthew Giust, Maan Nasir, Dante Pieramici, Melvin Rabena, Sarah Risard, Robert See, Jerry Smith, Lisha Wan, Sophie J. Bakri, Nakhleh Abu-Yaghi, Andrew Barkmeier, Karin Berg, Jean Burrington, Albert Edwards, Shannon Goddard, Shannon Howard, Raymond Iezzi, Denise Lewison, Thomas Link, Colin A. McCannel, Joan Overend, John Pach, Margaret Ruszczyk, Ryan Shultz, Cindy Stephan, Diane Vogen, Reagan H. Bradford, Vanessa Bergman, Russ Burris, Amanda Butt, Beth Daniels, Connie Dwiggins, Stephen Fransen, Tiffany Guerrero, Darin Haivala, Amy Harris, Sonny Icks, Ronald Kingsley, Lena Redden, Rob Richmond, Brittany Ross, Kammerin White, Misty Youngberg, Trexler M. Topping, Steve Bennett, Sandy Chong, Mary Ciotti, Tina Cleary, Emily Corey, Dennis Donovan, Albert Frederick, Lesley Freese, Margaret Graham, Natalya Gud, Taneika Howard, Mike Jones, Michael Morley, Katie Moses, Jen Stone, Robin Ty, Torsten Wiegand, Lindsey Williams, Beth Winder, Carl C. Awh, Michelle Amonette, Everton Arrindell, Dena Beck, Brandon Busbee, Amy Dilback, Sara Downs, Allison Guidry, Gary Gutow, Jackey Hardin, Sarah Hines, Emily Hutchins, Kim LaCivita, Ashley Lester, Larry Malott, MaryAnn McCain, Jayme Miracle, Kenneth Moffat, Lacy Palazzotta, Kelly Robinson, Peter Sonkin, Alecia Travis, Roy Trent Wallace, Kelly J. Winters, Julia Wray, April E. Harris, Mari Bunnell, Katrina Crooks, Rebecca Fitzgerald, Cameron Javid, Corin Kew, Erica Kill, Patricia Kline, Janet Kreienkamp, Maricruz Martinez, Roy Ann Moore, Egbert Saavedra, LuAnne Taylor, Mark Walsh, Larry Wilson, Thomas A. Ciulla, Ellen Coyle, Tonya Harrington, Charlotte Harris, Cindi Hood, Ingrid Kerr, Raj Maturi, Dawn Moore, Stephanie Morrow, Jennifer Savage, Bethany Sink, Tom Steele, Neelam Thukral, Janet Wilburn, Joseph P. Walker, Jennifer Banks, Debbie Ciampaglia, Danielle Dyshanowitz, Jennifer Frederick, A. Tom Ghuman, Richard Grodin, Cheryl Kiesel, Eileen Knips, Jonathan McCue, Maria Ortiz, Crystal Peters, Paul Raskauskas, Etienne Schoeman, Ashish Sharma, Glenn Wing, Rebecca Youngblood, Suresh R. Chandra, Michael Altaweel, Barbara Blodi, Kathryn Burke, Kristine A. Dietzman, Justin Gottlieb, Gene Knutson, Denise Krolnik, T. Michael Nork, Shelly Olson, John Peterson, Sandra Reed, Barbara Soderling, Guy Somers, Thomas Stevens, Angela Wealti, Srilaxmi Bearelly, Brenda Branchaud, Joyce W. Bryant, Sara Crowell, Sharon Fekrat, Merritt Gammage, Cheala Harrison, Sarah Jones, Noreen McClain, Brooks McCuen, Prithvi Mruthyunjaya, Jeanne Queen, Neeru Sarin, Cindy Skalak, Marriner Skelly, Ivan Suner, Ronnie Tomany, Lauren Welch, Susanna S. Park, Allison Cassidy, Karishma Chandra, Idalew Good, Katrina Imson, Sashi Kaur, Helen Metzler, Lawrence Morse, Ellen Redenbo, Marisa Salvador, David Telander, Mark Thomas, Cindy Wallace, Charles C. Barr, Amanda Battcher, Michelle Bottorff, Mary Chasteen, Kelly Clark, Diane Denning, Debra Schoen, Amy Schultz, Evie Tempel, Lisa Wheeler, Greg K. Whittington, Thomas W. Stone, Todd Blevins, Michelle Buck, Lynn Cruz, Wanda Heath, Diana Holcomb, Rick Isernhagen, Terri Kidd, John Kitchens, Cathy Sears, Ed Slade, Jeanne Van Arsdall, Brenda VanHoose, Jenny Wolfe, William Wood, John Zilis, Carol Crooks, Larry Disney, Mimi Liu, Stephen Petty, Sandra Sall, James C. Folk, Tracy Aly, Abby Brotherton, Douglas Critser, Connie J. Hinz, Stefani Karakas, Valerie Kirschner, Cheyanne Lester, Cindy Montague, Stephen Russell, Heather Stockman, Barbara Taylor, Randy Verdick, Jean Walshire, John T. Thompson, Barbara Connell, Maryanth Constantine, John L. Davis, Gwen Holsapple, Lisa Hunter, C. Nicki Lenane, Robin Mitchell, Leslie Russel, Raymond Sjaarda, David M. Brown, Matthew Benz, Llewellyn Burns, JoLene G. Carranza, Richard Fish, Debra Goates, Shayla Hay, Theresa Jeffers, Eric Kegley, Dallas Kubecka, Stacy McGilvra, Beau Richter, Veronica Sneed, Cary Stoever, Isabell Tellez, Tien Wong, Ivana Kim, Christopher Andreoli, Leslie Barresi, Sarah Brett, Charlene Callahan, Karen Capaccioli, William Carli, Matthew Coppola, Nicholas Emmanuel, Claudia Evans, Anna Fagan, Marcia Grillo, John Head, Troy Kieser, Elaine Lee, Ursula Lord, Edward Miretsky, Kate Palitsch, Todd Petrin, Liz Reader, Svetlana Reznichenko, Mary Robertson, Justin Smith, Demetrios Vavvas, John Wells, Cassie Cahill, W. Lloyd Clark, Kayla Henry, David Johnson, Peggy Miller, LaDetrick Oliver, Robbin Spivey, Tiffany Swinford, Mallie Taylor, Michael Lambert, Kris Chase, Debbie Fredrickson, Joseph Khawly, Valerie Lazarte, Donald Lowd, Pam Miller, Arthur Willis, Philip J. Ferrone, Miguel Almonte, Rachel Arnott, Ingrid Aviles, Sheri Carbon, Michael Chitjian, Kristen DAmore, Christin Elliott, David Fastenberg, Barry Golub, Kenneth Graham, AnnMarie Lavorna, Laura Murphy, Amanda Palomo, Christina Puglisi, David Rhee, Juan Romero, Brett Rosenblatt, Glenda Salcedo, Marianne Schlameuss, Eric Shakin, Vasanti Sookhai, Richard Kaiser, Elizabeth Affel, Gary Brown, Christina Centinaro, Deborah Fine, Mitchell Fineman, Michele Formoso, Sunir Garg, Lisa Grande, Carolyn Herbert, Allen Ho, Jason Hsu, Maryann Jay, Lisa Lavetsky, Elaine Liebenbaum, Joseph Maguire, Julia Monsonego, Lucia O'Connor, Lisa Pierce, Carl Regillo, Maria Rosario, Marc Spirn, James Vander, Jennifer Walsh, Frederick H. Davidorf, Amanda Barnett, Susie Chang, John Christoforidis, Joy Elliott, Heather Justice, Alan Letson, Kathryne McKinney, Jeri Perry, Jill A. Salerno, Scott Savage, Stephen Shelley, Lawrence J. Singerman, Joseph Coney, John DuBois, Kimberly DuBois, Gregg Greanoff, Dianne Himmelman, Mary Ilc, Elizabeth Mcnamara, Michael Novak, Scott Pendergast, Susan Rath, Sheila Smith-Brewer, Vivian Tanner, Diane E. Weiss, Hernando Zegarra, Lawrence Halperin, Patricia Aramayo, Mandeep Dhalla, Brian Fernandez, Cindy Fernandez, Jaclyn Lopez, Monica Lopez, Jamie Mariano, Kellie Murphy, Clifford Sherley, Rita Veksler, Firas Rahhal, Razmig Babikian, David Boyer, Sepideh Hami, Jeff Kessinger, Janet Kurokouchi, Saba Mukarram, Sarah Pachman, Eric Protacio, Julio Sierra, Homayoun Tabandeh, Adam Zamboni, Michael Elman, Jennifer Belz, Tammy Butcher, Theresa Cain, Teresa Coffey, Dena Firestone, Nancy Gore, Pamela Singletary, Peter Sotirakos, JoAnn Starr, Travis A. Meredith, Cassandra J. Barnhart, Debra Cantrell, RonaLyn Esquejo-Leon, Odette Houghton, Harpreet Kaur, Fatoumatta NDure, Ronald Glatzer, Leonard Joffe, Reid Schindler, Stuart L. Fine, Marilyn Katz, Mary Brightwell-Arnold, Ruchira Glaser, Judith Hall, Sandra Harkins, Jiayan Huang, Alexander Khvatov, Kathy McWilliams, Ellen Peskin, Maxwell Pistilli, Susan Ryan, Allison Schnader, Gui-Shuang Ying, Glenn Jaffe, Jennifer Afrani-Sakyi, Brannon Balsley, Linda S. Bennett, Adam Brooks, Adrienne Brower-Lingsch, Lori Bruce, Russell Burns, Dee Busian, John Choong, Lindsey Cloaninger, Francis Char DeCroos, Emily DuBois, Mays El-Dairi, Sarah Gach, Katelyn Hall, Terry Hawks, ChengChenh Huang, Cindy Heydary, Alexander Ho, Shashi Kini, Michelle McCall, Daaimah Muhammad, Jayne Nicholson, Pamela Rieves, Kelly Shields, Adam Specker, Sandra Stinnett, Sujatha Subramaniam, Patrick Tenbrink, Cynthia Toth, Aaron Towe, Kimberly Welch, Natasha Williams, Katrina Winter, Ellen Young, Judith Alexander, Elisabeth Flannagan, E. Revell Martin, Candace Parker, Krista Sepielli, Tom Shannon, Claressa Whearry, Maryann Redford, Marcia R. Kopfer, Frederick L. Ferris, Joan DuPont, Lawrence M. Friedman, Susan B. Bressler, David L. DeMets, Martin Friedlander, Mark W. Johnson, Anne Lindblad, Douglas W. Losordo, and Franklin G. Miller

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, Visual acuity, genetic structures, Visual Acuity, Angiogenesis Inhibitors, Retinal Pigment Epithelium, Antibodies, Monoclonal, Humanized, Retina, Article, Cicatrix, Ophthalmology, Geographic Atrophy, Ranibizumab, Medicine, Humans, Prospective Studies, Fluorescein Angiography, External limiting membrane, Prospective cohort study, medicine.diagnostic_test, business.industry, Fundus photography, Macular degeneration, Middle Aged, medicine.disease, Fluorescein angiography, eye diseases, Bevacizumab, Choroidal neovascularization, medicine.anatomical_structure, Intravitreal Injections, Wet Macular Degeneration, sense organs, medicine.symptom, business, Tomography, Optical Coherence, medicine.drug
Abstract

To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Prospective cohort study within a randomized clinical trial.The 1185 CATT participants.Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks.Presence of SHRM, as well as location and size, and associations with VA, scar, and GA.Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P0.05).In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.

Published
2015

30. Multifocal Visual Evoked Potentials in the Anesthetized Non-human Primate

Author

James N. Ver Hoeve, Mark J. Lucarelli, Nathan A. Maertz, Leonard A. Levin, Paul L. Kaufman, Charlene B. Y. Kim, and T Michael Nork

Subjects
Retinal Ganglion Cells, Pentobarbital, genetic structures, Ocular hypertension, Stimulation, Stimulus (physiology), Retina, Cellular and Molecular Neuroscience, Electroretinography, medicine, Animals, Hypnotics and Sedatives, Visual Pathways, Cerebral Cortex, medicine.diagnostic_test, business.industry, Reproducibility of Results, Optic Nerve, Anatomy, medicine.disease, Macaca mulatta, eye diseases, Sensory Systems, Peripheral, Ganglion, Macaca fascicularis, Ophthalmology, medicine.anatomical_structure, Anesthesia, Intravenous, Evoked Potentials, Visual, sense organs, business, Erg, medicine.drug
Abstract

To evaluate monkey multifocal visual evoked cortical potentials (mfVEPs) recorded from central and peripheral fields for reliability and isolation from electroretinographic (ERG) activity.The mfVEP stimulus consisted of a 7-element hexagonal array that subtended 80 degrees of the central visual field. Recordings were made under intravenous pentobarbital sodium (15 mg/kg) anesthesia. Two monkeys with absent optic nerve and ganglion cell function after combined unilateral optic nerve transection and experimental ocular hypertension (ONT/OHT) were followed longitudinally. In a second study, 16 ophthalmologically normal monkeys were tested once.Testing of the non-transected eye in two transected animals revealed robust first- and second-order kernel, first slice (K1 and K2.1) mfVEPs. Stimulation of the transected eye revealed no contamination of the mfVEP from the concurrently recorded multifocal ERGs. There was complete separation of the root-mean-square (RMS) mfVEP amplitudes from the transected and the fellow eyes tested repeatedly across a 4- to 17- month period. The largest amplitude mfVEP was generated by the central element; however, mfVEPs were recorded from outside the central 20 degrees element. The 16 normal animals showed waveforms similar to the normal eyes of the ONT/OHT animals both in shape and distribution throughout the visual field. A scalar-product measure showed both K1 and K2.1 mfVEPs from central and some peripheral elements were statistically distinct from noise.mfVEPs can be reliably recorded from non-human primates anesthetized with pentobarbital. Under the recording conditions described, mfVEPs are not contaminated by ERG activity. mfVEPs may be useful in animal models of diseases that differentially affect macular and peripheral visual field responsiveness.

Published
2006

31. Effects of Reference Electrode Location on Monopolar-derived Multifocal Electroretinograms in Cynomolgus Monkeys

Author

James N. VerHoeve, T Michael Nork, Paul L. Kaufman, and Charlene B. Y. Kim

Subjects
Male, genetic structures, Reference electrode, Retina, Root mean square, Physiology (medical), Electroretinography, medicine, Outer Canthus, Animals, Waveform, Electrodes, Physics, Monocular, medicine.diagnostic_test, Equipment Design, Anatomy, eye diseases, Sensory Systems, Visual field, Macaca fascicularis, Ophthalmology, Amplitude, Female, sense organs, Photic Stimulation
Abstract

The purpose of this study is to determine the effect of reference electrode location on the multifocal electroretinographic waveform. Multifocal electroretinograms (mfERGs) were recorded from 20 ocularly normal cynomolgus monkeys. The corneal electrode was an ERG-jet referenced to an ipsilaterally (outer canthus) situated subdermal needle electrode and to the contralateral corneal electrode. Testing was monocular and recordings from both montages were obtained simultaneously. The stimulus array consisted of 103 equal-sized hexagonal elements, which subtended +/-44 degrees about the central visual axis. Mean luminance of the display was 100 cd/m2. First-order (K1) and second-order (first slice) kernels (K2.1) of the mfERG were grouped in (a) 4 rings, representing the central 56 degrees of visual field and (b) in 15-element quadrants. The mfERG waveform measures included amplitude, implicit time, and root mean square (RMS) of the oscillatory potentials (OP) and response waveform. K1 and K2.1 ring and quadrant amplitudes were larger with the contralateral than with the ipsilateral reference, but more notably signal-to-noise ratios (S:N) of the response waveform were always larger with the ipsilateral reference. Implicit times were longer for the contralateral than ipsilateral reference montage. K1 and K2.1 implicit times in males were longer than in females. Quadrant groupings revealed generally larger K1 and K2.1 amplitudes in nasal than in temporal retina.

Published
2005

32. 88. Safety and Biodistribution Study of rAAV2tYF-PR1.7-hCNGB3 in Nonhuman Primates

Author

Paulette M. Robinson, Chantelle Gaskin, Paul E. Miller, Roberto Calcedo, Tara Arndt, Leia M. Smith, William W. Hauswirth, Ewa Budzynski, Peter Sonnentag, David R. Knop, Jeffrey D. Chulay, T. Michael Nork, Guo-jie Ye, James N. Ver Hoeve, and Alok K. Sharma

Subjects
Pharmacology, Intraocular pressure, medicine.medical_specialty, Achromatopsia, genetic structures, medicine.diagnostic_test, ELISPOT, Retinal, medicine.disease, eye diseases, Posterior segment of eyeball, chemistry.chemical_compound, chemistry, Ophthalmology, Drug Discovery, Toxicity, Immunology, Genetics, medicine, Molecular Medicine, sense organs, Molecular Biology, Erg, Electroretinography
Abstract

Background: AGTC is developing a recombinant AAV vector expressing the human CNGB3 gene for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. Here we report results of a toxicology and biodistribution study of this vector administered by subretinal injection in cynomolgus macaques. Methods: Three groups of animals (n=2 males and 2 females per group) received a subretinal injection in one eye of 300 µL containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 1011 or 4 × 1012 vg/mL) and were evaluated for safety and biodistribution over a 3-month period prior to euthanasia. Toxicity assessment was based on mortality, clinical observations, body weights, ophthalmic examinations, intraocular pressure (IOP) measurements, electroretinography (ERG), visual evoked potentials (VEP), and clinical and anatomic pathology. Vector shedding and biodistribution was assessed by qPCR analyses. Immune responses to AAV and hCNGB3 were measured by ELISA, Elispot, or neutralization antibody assay for AAV2tYF. Results: There was no evidence of local or systemic toxicity and no changes in IOP, VEP responses, or hematology, coagulation or clinical chemistry parameters and no clinically important changes in ERG responses. Aqueous cells, sometimes with aqueous flare, were observed at the Day 3 evaluation in all groups and generally resolved or were at the mild (1+) levels by Week 4 and absent on Week 8 and thereafter except in one high dose animal. Posterior segment findings consisted of varying degrees of dose-related white vitreous cell, vitreous haze, white retinal perivascular sheathing, and white to grey-white subretinal infiltrates within and outside of the injection site. Vitreous haze resolved by Day 8 in eyes given vehicle control, by Week 4 in the low dose group and by Week 13 in the high dose group. Vitreous cells were observed at the mild (trace or 1+) level in the vehicle control group and resolved by Study Weeks 9 or 13 but persisted through Week 13 in a dose-related fashion in the low and high dose groups. Serum neutralizing antibodies against AAV2tYF were detected in all animals given vector. There were no T cell responses to AAV capsid peptides and no antibody or T cell responses to hCNGB3. Mononuclear cell infiltrates in the vitreous body/optic disc, of minimal intensity, in the vector-injected eye of all animals at both dose levels. All other tissues collected for histopathological examination showed no abnormalities. Results of biodistribution studies demonstrated that the vector did not spread widely or consistently outside the injected eye. High levels of vector DNA were found in vector-injected eyes but minimal or no vector DNA was found in any other tissue. Conclusions: Subretinal injection of rAAV2tYF-PR1.7-hCNGB3 at concentrations of 4 × 1011 or 4 × 1012 vg/mL was associated with a dose-related anterior and posterior segment inflammatory response that improved over time. There was no evidence of systemic toxicity and no changes in IOP, VEP responses, or hematology, coagulation or clinical chemistry parameters and no clinically important changes in ERG responses. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia. A Phase 1/2 clinical trial evaluating rAAV2tYF-PR1.7-hCNGB3 in patients with achromatopsia is scheduled to begin in 2016.

Published
2016

33. MASSIVE SPONTANEOUS SUPRACHOROIDAL HEMORRHAGE IN A YOUNG WOMAN WITH CYSTIC FIBROSIS AND DIABETES MELLITUS ON ANTICOAGULANTS

Author

T Michael Nork and Hau N. Nguyen

Subjects
Pediatrics, medicine.medical_specialty, medicine.drug_class, business.industry, Anticoagulant, General Medicine, Diabetic retinopathy, Suprachoroidal hemorrhage, medicine.disease, Cystic fibrosis, Article, Ophthalmology, Diabetes mellitus, medicine, business
Abstract

To report a case of massive spontaneous suprachoroidal hemorrhage in a young woman with cystic fibrosis and proliferative diabetic retinopathy on anticoagulant therapy.Single case report.A 24-year-old woman with cystic fibrosis and diabetes mellitus developed a massive spontaneous suprachoroidal hemorrhage in the left eye after two months of warfarin therapy and recent treatment with heparin. Fundus examination and B-scan ultrasonography of the left eye revealed a hemorrhagic choroidal detachment. Elevated intraocular pressure was controlled with brimonidine, but four months later the left eye ceased to perceive light.Massive spontaneous suprachoroidal hemorrhage (SSCH) is a rare event that occurs almost exclusively in patients of advanced age. To our knowledge, this is the youngest patient with SSCH described in the literature. Regardless of age or other medical conditions, anticoagulant therapy appears to be a strong risk factor. SSCH carries a poor visual prognosis with or without surgical intervention.

Published
2012

34. Effects of Vitrectomy and Lensectomy on Older Rhesus Macaques: Oxygen Distribution, Antioxidant Status, and Aqueous Humor Dynamics

Author

Paul L. Kaufman, Gregg A Heatley, Carla J. Siegfried, Baohe Tian, Ying-Bo Shui, and T Michael Nork

Subjects
Aging, medicine.medical_specialty, Intraocular pressure, Pseudophakia, genetic structures, Open angle glaucoma, medicine.medical_treatment, Glaucoma, Vitrectomy, Intraocular lens, Ascorbic Acid, oxidative damage, medicine.disease_cause, Polymerase Chain Reaction, Antioxidants, Aqueous Humor, 03 medical and health sciences, 0302 clinical medicine, Lens Implantation, Intraocular, Anterior Eye Segment, Ophthalmology, Lens, Crystalline, Animals, Medicine, Intraocular Pressure, business.industry, trabecular meshwork, Deoxyguanosine, Posterior Eye Segment, medicine.disease, Macaca mulatta, eye diseases, Oxygen, medicine.anatomical_structure, 8-Hydroxy-2'-Deoxyguanosine, Lens (anatomy), Anesthesia, 030221 ophthalmology & optometry, sense organs, Trabecular meshwork, business, 030217 neurology & neurosurgery, Oxidative stress
Abstract

Purpose The purpose of this study is to evaluate effects of vitrectomy (PPV) and lens extraction with intraocular lens implantation (PE/IOL) on molecular oxygen (pO2) distribution, aqueous humor antioxidant-oxidant balance, aqueous humor dynamics, and histopathologic changes in the trabecular meshwork (TM) in the older macaque monkey. Methods Six rhesus monkeys underwent PPV followed by PE/IOL. pO2, outflow facility, and intraocular pressure (IOP) were measured. Aqueous and vitreous humor specimens were analyzed for antioxidant status and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage. TM specimens were obtained for immunohistochemical and quantitative PCR analysis. Results pO2 at baseline revealed steep gradients in the anterior chamber and low levels in the posterior chamber (PC) and around the lens. Following PPV and PE/IOL, pO2 significantly increased in the PC, around the IOL, and angle. IOP increased following both surgical interventions, with no change in outflow facility. Histopathologic analysis did not show changes in TM cell quantification, but there was an increase in 8-OHdG. Quantitative PCR did not reveal significant differences in glaucoma-related gene expression. Aqueous and vitreous humor analysis revealed decreased ascorbate and total reactive antioxidant potential and increased 8-OHdG in the aqueous humor only in the surgical eyes. Conclusions Oxygen distribution in the older rhesus monkey is similar to humans at baseline and following surgical interventions. Our findings of histopathologic changes of TM oxidative damage and alterations in the oxidant-antioxidant balance suggest a potential correlation of increased oxygen exposure with oxidative stress/damage and the development of open angle glaucoma.

Published
2017

35. Regional choroidal blood flow and multifocal electroretinography in experimental glaucoma in rhesus macaques

Author

T Michael Nork, Charlene B. Y. Kim, Ryan J. Dashek, Kaitlyn M. Munsey, and James N. Ver Hoeve

Subjects
medicine.medical_specialty, Intraocular pressure, genetic structures, Glaucoma, Cellular and Molecular Neuroscience, Ophthalmology, medicine, Electroretinography, Animals, Axon, Visual Cortex, medicine.diagnostic_test, business.industry, Choroid, Choroidal blood flow, Optic Nerve, Anatomy, Articles, medicine.disease, Macaca mulatta, Sensory Systems, eye diseases, Axons, Disease Models, Animal, medicine.anatomical_structure, Visual cortex, Regional Blood Flow, Optic nerve, Evoked Potentials, Visual, Female, sense organs, business, Glaucoma, Open-Angle
Abstract

To test a hypothesis of regional variation in the effect of experimental glaucoma on choroidal blood flow (ChBF) and retinal function.Five rhesus macaques underwent laser trabecular destruction (LTD) to induce elevated intraocular pressure (IOP). Intraocular pressures were elevated for 56 to 57 weeks. Multifocal electroretinographic (mfERG) and multifocal visual evoked cortical potential (mfVEP) testing were performed at regular intervals before and during the period of IOP elevation. At euthanasia, the IOP was manometrically controlled at 35 (experimentally glaucomatous eye) and 15 (fellow control eye) mm Hg. Fluorescent microspheres were injected into the left ventricle. Regional ChBF was determined.All of the experimentally glaucomatous eyes exhibited supranormal first-order kernel (K1) root mean square (RMS) early portions of the mfERG waveforms and decreased amplitudes of the late waveforms. The supranormality was somewhat greater in the central macula. Second-order kernel, first slice (K2.1) RMS mfVEP response was inversely correlated (R(2) = 0.97) with axonal loss. Total ChBF was reduced in the experimentally glaucomatous eyes. The mean blood flow was 893 ± 123 and 481 ± 37 μL/min in the control and glaucomatous eyes, respectively. The ChBF showed regional variability with the greatest proportional decrement most often found in the central macula.This is the first demonstration of globally reduced ChBF in chronic experimental glaucoma in the nonhuman primate. Both the alteration of mfERG waveform components associated with outer retinal function and the reduction in ChBF were greatest in the macula, suggesting that there may be a spatial colocalization between ChBF and some outer retinal effects in glaucoma.

Published
2014

36. Nuclear Exclusion of Wild-Type p53 in Immortalized Human Retinoblastoma Cells

Author

Gretchen L. Poulsen, T Michael Nork, Robert W. Nickells, and Cassandra L. Schlamp

Subjects
Cancer Research, Transcription, Genetic, Biology, Retinoblastoma-like protein 1, Tumor Cells, Cultured, medicine, Humans, E2F1, RNA, Messenger, Nuclear protein, Child, Fluorescent Antibody Technique, Indirect, Cell Line, Transformed, Cell Nucleus, Retinoblastoma, Eye Neoplasms, Transfection, Genes, p53, medicine.disease, Immunohistochemistry, eye diseases, Cell nucleus, medicine.anatomical_structure, Oncology, Cell culture, Cancer research, Tumor Suppressor Protein p53, Immortalised cell line, Polymorphism, Restriction Fragment Length
Abstract

Background: Retinoblastoma is the most common childhood tumor of the eye, arising from cells that are defective in both copies of the retinoblastoma susceptibility gene (RB1). Most retinoblastoma tumor cells eventually undergo programmed cell death (i.e., apoptosis) ; however, some cells can acquire the ability to metastasize and become immortal. Transfection of immortal retinoblastoma cells with DNA sequences encoding wild-type p53 protein induces cell death, suggesting that the loss of both RB1 and p53 functions may be required for cell immortalization. We have examined this possibility by characterizing the p53 protein and messenger RNA in six independently isolated, immortalized retinoblastoma cell lines. Methods: Western blotting methods were used to assess p53 protein level in each cell line, and Cleavase Fragment-Length Polymorphism analysis of complementary DNAs was used to screen for mutations in p53 messenger RNA. Localization of p53 protein in cells of the immortalized lines and in specimens of retinoblastoma tumors was achieved by means of indirect immunofluorescence and immunocytochemistry, respectively. Results: All six immortalized cell lines expressed wild-type p53 messenger RNA and high levels of p53 protein. Although p53 is normally a nuclear protein, the p53 in four of the six cell lines was located predominately in the cytoplasm; in the remaining two cell lines, p53 was localized in both the nucleus and the cytoplasm. Cytoplasmic localization of p53 in retinoblastoma tumor specimens was rare and usually restricted to cells that had invaded adjacent ocular tissues, indicative of the early stages of metastasis. Conclusions: Some immortalized retinoblastoma cells may exhibit p53 dysfunction through nuclear exclusion of wild-type p53 protein.

Published
1997

37. Response to aflibercept in patients with persistent exudation despite prior treatment with bevacizumab or ranibizumab for age-related macular degeneration

Author

Barbara A Blodi, Ronald P. Danis, Suresh R. Chandra, James A. Eadie, Michael M. Altaweel, T Michael Nork, Michael S. Ip, Brendan S Stern-Hogan, and Justin L. Gottlieb

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Visual acuity, genetic structures, Bevacizumab, Recombinant Fusion Proteins, Visual Acuity, Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized, chemistry.chemical_compound, Ophthalmology, Ranibizumab, medicine, Humans, Aflibercept, Aged, Retrospective Studies, Dose-Response Relationship, Drug, business.industry, Drug Substitution, Retrospective cohort study, Macular degeneration, medicine.disease, eye diseases, Surgery, Clinical trial, Vascular endothelial growth factor, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, chemistry, Intravitreal Injections, Wet Macular Degeneration, Female, sense organs, medicine.symptom, business, Tomography, Optical Coherence, medicine.drug, Follow-Up Studies
Abstract

BACKGROUND AND OBJECTIVE: This study examines the clinical response of patients transitioned to aflibercept, the newest anti-VEGF medication, due to persistent evidence of exudation on optical coherence tomography (OCT) despite regular treatment with bevacizumab and/or ranibizumab. PATIENTS AND METHODS: Aflibercept was administered to 111 patients considered for study inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with at least three injections of ranibizumab or bevacizumab. Retrospective data were collected from medical records. RESULTS: Complete resolution of exudation was seen in 34% of eyes at final follow-up. Clear improvement in exudation amount or severity without complete resolution was seen in 25%. No improvement was seen in 34%, and 6% demonstrated worsening of exudation. Snellen visual acuity at the time of transition versus final follow-up after aflibercept injection did not appreciably change (logMAR 0.494 to 0.505, Snellen equivalent 20/62 to 20/64; P = .84). The mean center point neurosensory retina thickness decreased from 228.6 to 176.9 µm ( P = .001). CONCLUSION: Aflibercept may decrease the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity. [ Ophthalmic Surg Lasers Imaging Retina . 2014;45:394–397.]

Published
2013

38. Quantifying optic nerve axons in a cat glaucoma model by a semi-automated targeted counting method

Author

Leandro B C, Teixeira, Kevin A, Buhr, Owen, Bowie, Felicia D, Duke, T Michael, Nork, Richard R, Dubielzig, and Gillian J, McLellan

Subjects
Automation, Disease Models, Animal, Time Factors, Cats, Animals, Cell Count, Glaucoma, Optic Nerve, Axons, Research Article
Abstract

Purpose To describe and validate a semi-automated targeted sampling (SATS) method for quantifying optic nerve axons in a feline glaucoma model. Methods Optic nerve cross sections were obtained from 15 cats, nine with mild to severe glaucoma and six with normal eyes. Optic nerves were dissected, fixed in paraformaldehyde and glutaraldehyde, and processed for light microscopy by resin embedding, sectioning, and staining of axon myelin sheaths with 1% p-phenylenediamine before axon quantification. Commercially available image analysis software was used as a semi-automated axon counting tool (SCT) and was first validated by comparison with a manual axon count (MAC). This counting tool was then used in a SATS method performed by three masked raters and in a semi-automated full count (SAFC) method performed by a single observer. Correlation was assessed between the SCT and MAC using a linear model and analysis of covariance (ANCOVA). Correlation between the SATS and SAFC methods was calculated and the bias, systematic errors, and variance component assessed. The intraclass correlation coefficient (ICC) was determined to establish inter-rater agreement. In addition, the time required to perform the SATS and SAFC methods was evaluated. Results Correlation between the axon counts obtained by the SCT and MAC was strong (r = 0.9985). There was evidence of an overcounting of axons by the SCT compared to the MAC with a percentage error rate of 13.0% (95% confidence interval [CI] 11.0%, 15.1%). Both the correlation of SATS count (average per rater) to SAFC (r = 0.9891) and inter-rater agreement (ICC = 0.986) were high. The SATS method presented an overall positive counting error (p

Published
2013

39. 299. Safety and Biodistribution Study of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-Deficient Mice

Author

Leslie E McPherson, T. Michael Nork, Jeffrey D. Chulay, Tara Arndt, Roberto Calcedo, Paulette M. Robinson, Guo-jie Ye, James N. Ver Hoeve, Paul E. Miller, Ewa Budzynski, Peter Sonnentag, William W. Hauswirth, Savitri Mandapati, David R. Knop, and Leia M. Smith

Subjects
Pharmacology, medicine.medical_specialty, Biodistribution, Pathology, genetic structures, medicine.diagnostic_test, Clinical pathology, Balanced salt solution, Spleen, Anatomy, Biology, Peripheral blood mononuclear cell, eye diseases, medicine.anatomical_structure, Drug Discovery, Genetics, medicine, Molecular Medicine, Histopathology, sense organs, Molecular Biology, Erg, Electroretinography
Abstract

Background: AGTC is developing a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. Here we report results of a toxicology and biodistribution study of this vector administered by subretinal injection in CNGB3-deficient mice. Methods: Three groups of CNGB3-deficient mice (n= 35 per sex per group) received a subretinal injection in one eye of 1 µL of vehicle (balanced salt solution with 0.014% Tween 20) or rAAV2tYF-PR1.7-hCNGB3 vector at a concentration of 1 × 1012 vg/mL (1 × 109 vg/eye) or 4 × 1012 vg/mL (4 × 109 vg/eye). The other eye was untreated. Ten animals/sex/group were used for toxicology evaluation with ophthalmic examinations and pathological evaluations, 10 animals/sex/group were used for biodistribution evaluation, and 15 animals/sex/group were used for efficacy evaluation. Half the animals in the biodistribution and toxicology groups were euthanized 4 weeks after vector administration and the remaining animals were euthanized 12 weeks after vector administration. For animals in the biodistribution groups, blood for qPCR analysis was obtained on Study Days 3, 8 and at euthanasia. At necropsy, samples of eyes, brain, heart, liver, gall bladder, kidneys, spleen, thymus, lungs, adrenals, ovaries, epididymides and testes were obtained for histopathology (for animals in the toxicology groups) or DNA PCR (for animals in the biodistribution groups). For animals scheduled for efficacy evaluations, electroretinography (ERG) testing included scotopic and photopic tests performed at Week 4, 8, and 12 on each eye and serum was collected at euthanasia for measurement of antibodies to AAV and hCNGB3. Results: There were no test article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated ERG responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group, 31% of animals in the lower dose group, and none of the untreated or vehicle-treated eyes. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia, and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in non-ocular tissue. Conclusions: Subretinal injection of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice was associated with no clinically important toxicology findings, rescue of cone-mediated ERG responses in vector-treated eyes, and vector DNA detection limited primarily to vector-injected eyes. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations. A Phase 1/2 clinical trial evaluating rAAV2tYF-PR1.7-hCNGB3 is scheduled to begin in 2016.

Published
2016

40. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(®), for age-related macular degeneration

Author

James Miskin, Georgina Ferrige, Michelle Kelleher, Katie Binley, Vladimir Bantseev, Paul E. Miller, T Michael Nork, Diana Angell-Manning, Stuart Naylor, Peter Widdowson, Kyriacos A. Mitrophanous, Jackie de Belin, Julie Loader, Marie Carlucci, Margaret Esapa, Scott Ellis, and Daniel Chipchase

Subjects
Pathology, medicine.medical_specialty, Intraocular pressure, Biodistribution, Time Factors, genetic structures, Genetic enhancement, Genetic Vectors, Virus, Equine infectious anemia, Macular Degeneration, Genetics, medicine, Animals, Humans, Molecular Biology, Angiostatins, Angiostatin, biology, business.industry, Genetic Therapy, Macular degeneration, biology.organism_classification, medicine.disease, Macaca mulatta, eye diseases, Endostatins, Vitreous Body, Leukocytes, Mononuclear, Molecular Medicine, sense organs, Rabbits, Endostatin, business, Infectious Anemia Virus, Equine
Abstract

RetinoStat(®) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ∼1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.

Published
2012

41. AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits angiogenesis in models of ocular neovascular diseases

Author

William Fanslow, T. Michael Nork, Linh T. Nguyen, Stephen C. Kaufman, Jonathan D. Oliner, James Pretorius, Hongjin Ma, James Bready, Robert A Leedle, Juan Estrada, Eunju Hurh, and Angela Coxon

Subjects
Male, Pathology, medicine.medical_specialty, genetic structures, Angiogenesis, Recombinant Fusion Proteins, Angiogenesis Inhibitors, Retinal Neovascularization, Eye, Angiopoietin-2, Capillary Permeability, chemistry.chemical_compound, Mice, Ciliary body, Cornea, medicine, Angiopoietin-1, Animals, Humans, Retinopathy of Prematurity, Tissue Distribution, Fluorescein Angiography, In Situ Hybridization, medicine.diagnostic_test, business.industry, Infant, Newborn, Retinal Vessels, Retinopathy of prematurity, Retinal, medicine.disease, Fluorescein angiography, eye diseases, Choroidal Neovascularization, Mice, Inbred C57BL, Disease Models, Animal, Macaca fascicularis, medicine.anatomical_structure, Choroidal neovascularization, chemistry, Animals, Newborn, Autoradiography, Female, sense organs, Choroid, medicine.symptom, business
Abstract

Purpose To determine whether systemic treatment with AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits neovascular processes in animal models of ocular disease. Methods AMG 386 was tested in a laser-induced choroidal neovascularization (CNV) model in monkeys using fluorescein angiography. The biodistribution of (125)I-AMG 386 was determined in cynomolgus monkeys by whole-body autoradiography and radioanalysis of ocular tissues. A murine retinopathy of prematurity (ROP) model was used to examine the effect of AMG 386 on established and newly formed retinal vessels, either as a single agent or when combined with VEGF inhibition.AMG 386 pharmacokinetics were evaluated in each model. Results In the CNV model, AMG 386 significantly decreased fluorescent angiographic leakage and reduced fibroplasia, indicating an impaired healing response consistent with angiogenesis blockade. Radiolabeled AMG 386 was widely distributed across ocular tissues, with highest concentrations in the choroid, cornea, retinal pigmented epithelium, iris/ciliary body, and sclera. In the ROP model, AMG 386 prevented pathologic retinal angiogenesis when administered from P8 to P16 but transiently impeded regression of these abnormal vessels when administered from P17 to P23. Combining AMG 386 with VEGF inhibition led to cooperative prevention of retinal angiogenesis in this model. No AMG 386-related ocular toxicities occurred, and no treatment-related clinical observations were made in any of the studies. Conclusions In this study, AMG 386 inhibited angiogenesis in animal models of CNV and ROP, supporting investigation of AMG 386 for the treatment of ocular neovascular diseases in the clinical setting.

Published
2012

42. Emerging Electrophysiological Technologies for Assessing Ocular Toxicity in Laboratory Animals

Author

Christopher J. Murphy, T Michael Nork, Robert J. Munger, and James N. Ver Hoeve

Subjects
medicine.medical_specialty, Optic nerve hypoplasia, genetic structures, medicine.diagnostic_test, business.industry, Hydroxychloroquine, Pharmacology, Fluorescein angiography, medicine.disease, eye diseases, Ocular toxicity, Electrophysiology, Optical coherence tomography, Ophthalmology, Retinitis pigmentosa, medicine, Multifocal electroretinography, business, medicine.drug
Abstract

The previous chapter on emerging imaging technologies emphasized new or improved devices that, for the most part, provide anatomic information about the living eye. In this chapter, we will review electrophysiological measures of ocular function. Functional assessment can often confirm and strengthen the anatomical findings. For example, in establishing early hydroxychloroquine (Plaquenil®) toxicity in humans, spectral domain optical coherence tomography (sdOCT) and multifocal electroretinography (mfERG) are frequently used together. Sometimes imaging can provide the most sensitive toxicologic test, such as may be the case for vitreous fluorophotometry and fluorescein angiography in detecting subtle breakdown of the blood-retinal barrier. At other times, functional measures may be the most sensitive. An example from clinical medicine is retinitis pigmentosa, which, early on, may produce only vague subjective symptoms in patients with normal appearing fundi but show a markedly reduced full-field ERG (ffERG). Since the animals used in preclinical toxicologic testing cannot communicate their visual symptoms, a combination of anatomic and functional measures is needed to definitively rule out injury to the visual system.

Published
2012

43. Emerging Imaging Technologies for Assessing Ocular Toxicity in Laboratory Animals

Author

Mary Ann Croft, Brian J Christian, Christopher J. Murphy, T Michael Nork, and Carol A. Rasmussen

Subjects
Optical coherence tomography, medicine.diagnostic_test, Computer science, Computer processing, medicine, Optometry, Ocular imaging, eye diseases, Ocular toxicity, Biomedical engineering
Abstract

Recent decades have seen a dramatic increase in ocular imaging technologies—both for the anterior and posterior segments. This has been largely the result of increased computer processing power as applied to hardware control and data analysis. For example, the theoretical basis for ocular coherence tomography (OCT) was developed by Michelson in the nineteenth century, but only recently, thanks to computers, lasers, and electronic control circuitry, has it become a practical tool in the clinical and for toxicological studies.

Published
2012

44. The effects of acetazolamide in albino rabbits, pigmented rabbits, and humans

Author

Barbara M. Schroeder, T. Michael Nork, Sheri A. Cavender, Monique J Leys, J. Vernon Odom, and Steven Van Slycken

Subjects
Adult, Male, medicine.medical_specialty, genetic structures, Color vision, Color discrimination, Photometry, Optics, Ophthalmology, Electroretinography, medicine, Animals, Humans, Lagomorpha, medicine.diagnostic_test, biology, Adaptation, Ocular, business.industry, Chemistry, biology.organism_classification, eye diseases, Sensory Systems, Light-adapted, Anomaloscope, Acetazolamide, Sensory Thresholds, Female, Rabbits, sense organs, business, Erg, Color Perception, medicine.drug
Abstract

In three separate experiments albino rabbits, pigmented rabbits, and humans were tested following administration of acetazolamide and without acetazolamide. In all three experiments, we recorded electroretinograms (ERGs) under dark adapted and light adapted conditions and measured the b -wave amplitudes. Dark adapted ERG b -wave amplitudes were increased following administration of acetazolamide as compared to control conditions, in albino rabbits, pigmented rabbits and humans. Light adapted b -wave amplitudes showed no statistically significant changes as a function of acetazolamide administration although in all three experiments there was a trend toward light adapted b -wave amplitude reduction following administration of acetazolamide. In the human experiments, ERG a -wave amplitudes were also measured. Light adapted a -wave amplitudes were reduced following administration of acetazolamide. In the human experiments, several behavioral tests were performed, including L' Anthony desaturated D-15, Farnsworth-Munseu 100 hue, Cogan-Gunkel chromatograph, Nagel anomaloscope, Goldmann-Weckers dark adaptometry. There were no consistent changes in the human dark adaptation thresholds or color discrimination, although several measures approached significance.

Published
1994

45. Functional and Anatomic Consequences of Subretinal Dosing in the Cynomolgus Macaque

Author

Michael W. Neider, Charlene B Y Kim, Brian J Christian, Christopher J. Murphy, Ryan J. McCulloh, Hugh D. Wabers, Carol A. Rasmussen, Paul E. Miller, Richard R. Dubielzig, T Michael Nork, and James N. Ver Hoeve

Subjects
Opsin, medicine.medical_specialty, Rhodopsin, genetic structures, Acetates, Sodium Chloride, Article, Retina, Ophthalmoscopy, Drug Delivery Systems, Macula Lutea, Ophthalmology, Glial Fibrillary Acidic Protein, medicine, Electroretinography, Animals, Minerals, Glial fibrillary acidic protein, biology, medicine.diagnostic_test, Opsins, Fundus photography, Retinal detachment, Anatomy, medicine.disease, Immunohistochemistry, eye diseases, Drug Combinations, Macaca fascicularis, Microscopy, Electron, medicine.anatomical_structure, Intravitreal Injections, biology.protein, sense organs, Tomography, Optical Coherence
Abstract

Objective To characterize functional and anatomic sequelae of a bleb induced by subretinal injection. Methods Subretinal injections (100 μL) of balanced salt solution were placed in the superotemporal macula of 1 eye in 3 cynomolgus macaques. Fellow eyes received intravitreal injections (100 μL) of balanced salt solution. Fundus photography, ocular coherence tomography, and multifocal electroretinography were performed before and immediately after injection and again at intervals up to 3 months postinjection. Histopathologic analyses included transmission electron microscopy and immunohistochemistry for glial fibrillary acidic protein, rhodopsin, M/L-cone opsin, and S-cone opsin. Results Retinas were reattached by 2 days postinjection (seen by ocular coherence tomography). Multifocal electroretinography waveforms were suppressed post–subretinal injection within the subretinal injection bleb and, surprisingly, also in regions far peripheral to this area. Multifocal electroretinography amplitudes were nearly completely recovered by 90 days. The spectral-domain ocular coherence tomography inner segment–outer segment line had decreased reflectivity at 92 days. Glial fibrillary acidic protein and S-cone opsin staining were unaffected. Rhodopsin and M/L-cone opsins were partially displaced into the inner segments. Transmission electron microscopy revealed disorganization of the outer segment rod (but not cone) discs. At all postinjection intervals, eyes with intravitreal injection were similar to baseline. Conclusions Subretinal injection is a promising route for drug delivery to the eye. Three months post–subretinal injection, retinal function was nearly recovered, although reorganization of the outer segment rod disc remained disrupted. Understanding the functional and anatomic effects of subretinal injection is important for interpretation of the effects of compounds delivered to the subretinal space. Clinical Relevance Subretinal injection is a new potential route for drug delivery to the eye. Separating drug effects from the procedural effects is critical.

Published
2011

46. Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates

Author

Jacqueline M. Miller, Brian J Christian, Jingtai Cao, Edward P. Zimmer, Paul E. Miller, Stanley J. Wiegand, Richard R. Dubielzig, and T Michael Nork

Subjects
Pathology, medicine.medical_specialty, medicine.medical_treatment, Recombinant Fusion Proteins, Vascular permeability, Placebo, Retina, Capillary Permeability, chemistry.chemical_compound, Ophthalmology, medicine, Animals, Fluorescein Angiography, Aflibercept, Laser Coagulation, medicine.diagnostic_test, business.industry, Macular degeneration, medicine.disease, Fluorescein angiography, Choroidal Neovascularization, Vascular endothelial growth factor, Disease Models, Animal, Macaca fascicularis, Choroidal neovascularization, Receptors, Vascular Endothelial Growth Factor, chemistry, Intravitreal Injections, medicine.symptom, business, Laser coagulation, medicine.drug
Abstract

Objective To evaluate the efficacy of systemic and intravitreous administration of VEGF Trap (aflibercept) in a nonhuman primate model of choroidal neovascularization (CNV). Methods VEGF Trap treatment on laser-induced CNV was evaluated in 48 adult cynomolgus monkeys. In the prevention arms of the study, VEGF Trap was administered by intravenous injection (3 or 10 mg/kg weekly) or intravitreous injection (50, 250, or 500 μg/eye every 2 weeks) beginning before laser injury. In the treatment arm, a single intravitreous injection (500 μg) was given 2 weeks following laser injury. Laser-induced lesions were scored from grade 1 (no hyperfluorescence) to grade 4 (clinically relevant leakage). Representative lesions were evaluated histologically. Results Grade 4 leakage developed at 32.4% and 45.4% of the laser sites in animals receiving intravitreous or intravenous administration of placebo at 2 weeks following laser injury, respectively. In contrast, the development of grade 4 lesions was completely or nearly completely prevented in all groups receiving intravenous or intravitreous injections of VEGF Trap. A single intravitreous injection of VEGF Trap (500 μg) administered following the development of CNV reduced the frequency of grade 4 lesions from 44.4% to 0% within 14 days of treatment. Intravitreous VEGF Trap was well tolerated with either no or only mild ocular inflammation. Histological evaluation showed decreased scores for morphologic features of tissue proliferation in the VEGF Trap prevention groups. Conclusions VEGF Trap prevented the development of clinically relevant CNV leakage when administered at the lowest doses tested. Moreover, a single intravitreous injection induced inhibition of active CNV leakage. Clinical Relevance The animal model used in this study has an established track record as a predictor of pharmacologic efficacy of antineovascular drugs in humans having the neovascular, or wet, form of age-related macular degeneration.

Published
2011

47. Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing the efficacy of bevacizumab, adalimumab, and ESBA105

Author

Peter Lichtlen, David Urech, T. T. Lam, Tim Streit, and T Michael Nork

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, genetic structures, Bevacizumab, Anti-Inflammatory Agents, Angiogenesis Inhibitors, Sodium Chloride, Antibodies, Monoclonal, Humanized, Severity of Illness Index, chemistry.chemical_compound, Ophthalmology, medicine, Adalimumab, Animals, medicine.diagnostic_test, business.industry, Tumor Necrosis Factor-alpha, Lasers, Antibodies, Monoclonal, Retinal, Intravitreal administration, Macular degeneration, medicine.disease, Fluorescein angiography, eye diseases, Choroidal Neovascularization, Vitreous Body, Disease Models, Animal, Macaca fascicularis, Choroidal neovascularization, chemistry, Monoclonal, sense organs, medicine.symptom, Injections, Intraocular, business, medicine.drug
Abstract

Purpose To compare the relative contribution of VEGF and TNF-alpha in the development of laser-induced choroidal neovascularization (CNV) in monkeys and to exploit the feasibility of topical use of suitable antibody fragments for the prevention of experimental CNV. Methods To induce experimental CNV, small high-energy laser spots were used to treat several areas of the macula in the retinas of cynomolgus monkeys according to previously published protocols. To prevent abnormalities, bevacizumab (a potent VEGF inhibitor) and adalimumab or ESBA105 (potent TNF-alpha inhibitors) were given by intravitreal injection 1 week before and 1 week and 3 weeks after laser treatment. ESBA105 was also applied topically in a separate group. Control animals were treated with either intravitreal or topical saline. Eyes were monitored by ophthalmic examination, color photography, and fluorescein angiography. Results Inhibition of VEGF by bevacizumab completely blocked the formation of CNV. Both TNF-alpha inhibitors also significantly reduced laser-induced CNV abnormalities after intravitreal administration. Most important, topical use of the anti-TNF-alpha single-chain antibody fragment ESBA105 also reduced the formation of CNV. Conclusions TNF-alpha contributes to laser-induced CNV formation, and its inhibition can be a new therapeutic target for CNV. This study suggests TNF-alpha as another therapeutic target for the prevention and treatment of CNV and adds to the emerging clinical data suggesting the therapeutic value of TNF-alpha inhibitors in age-related macular degeneration (AMD). Further, this study shows that topical therapy with suitable antibody fragments has the potential of being introduced to retinal disease treatment regimens.

Published
2010

48. Photobiomodulation for the Treatment of Retinal Injury and Retinal Degenerative Diseases

Author

Krisztina Valter, Margaret T.T. Wong-Riley, Harry T. Whelan, Kristina D Desmet, James N. Ver Hoeve, Diana K. Kirk, Janis T. Eells, T Michael Nork, and Jonathan Stone

Subjects
Pathology, medicine.medical_specialty, Programmed cell death, Retinal, Disease, Biology, medicine.disease_cause, Pathogenesis, chemistry.chemical_compound, chemistry, medicine, biology.protein, Cancer research, Cytochrome c oxidase, Wound healing, Oxidative stress, Intracellular
Abstract

Retinal injury and retinal degenerative diseases are a leading causes of visual impairment in the developed world. Mitochondrial dysfunction and oxidative stress play key roles in the pathogenesis of retinal injury and disease. The development and testing of strategies designed to improve mitochondrial function and attenuate oxidative stress are essential for combating retinal disease. One strategy involves the use of photobiomodulation. Photobiomodulation, low-energy photon irradiation by light in the far-red to near-infrared (NIR) range using low energy lasers or light-emitting diode (LED) arrays, has been applied clinically in the treatment soft tissue injuries and acceleration of wound healing for more than 30 years. The therapeutic effects of photobiomodulation have been hypothesized to be mediated by intracellular signaling mechanisms triggered by the interaction of farred to NIR photons with the mitochondrial photoacceptor molecule cytochrome oxidase which culminate in improved mitochondrial energy metabolism, increased synthesis of cytoprotective factors and cell survival.

Published
2008

49. IMMUNOCYTOCHEMICAL STUDY OF AN EYE WITH PROLIFERATIVE VITREORETINOPATHY AND RETINAL TACKS

Author

Thomas S. Stevens, T Michael Nork, Guillermo de Venecia, Stephen J. Sramek, and Ingolf H. L. Wallow

Subjects
Pars plana, medicine.medical_specialty, Proliferative vitreoretinopathy, genetic structures, medicine.medical_treatment, Vimentin, Vitrectomy, chemistry.chemical_compound, Ophthalmology, medicine, Retina, Glial fibrillary acidic protein, biology, business.industry, Retinal detachment, Retinal, General Medicine, Anatomy, medicine.disease, eye diseases, medicine.anatomical_structure, chemistry, biology.protein, sense organs, business
Abstract

After an eye-wall resection for a choroidal melanoma, a 32-year-old woman had subsequent retinal detachment with proliferative vitreoretinopathy (PVR), and an unsuccessful attempt at repair with retinal tacks. Gross and light-microscopic examination of the globe revealed a total retinal detachment with extensive preretinal and subretinal membranes. The membranes surrounded the tack heads and extended in taut bands to form a tractional detachment of the pars plana. The membranes contained glial and nonglial cells. The glial cells immunolabeled for glial fibrillary acidic protein (GFAP), carbonic anhydrase-C (CA-C), vimentin, and glutamine synthetase (GS), thus suggesting that they were Muller's cells. While the tacks did not seem to cause PVR, in this case they may have provided an anchoring point from which membranes were able to exert traction on the retina and pars plana.

Published
1990

50. Outcomes of Eyes with Lesions Composed of >50% Blood in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)

Author

Michael M. Altaweel, Ebenezer Daniel, Daniel F. Martin, Robert A. Mittra, Juan E. Grunwald, Michael M. Lai, Alexander Melamud, Lawrence S. Morse, Jiayan Huang, Frederick L. Ferris, Stuart L. Fine, Maureen G. Maguire, David F. Williams, Sara Beardsley, Steven Bennett, Herbert Cantrill, Carmen Chan- Tram, Holly Cheshier, Kathyrn Damato, John Davies, Sundeep Dev, Julianne Enloe, Gennaro Follano, Peggy Gilbert, Jill Johnson, Tori Jones, Lisa Mayleben, Robert Mittra, Martha Moos, Ryan Neist, Neal Oestreich, Polly Quiram, Robert Ramsay, Edwin Ryan, Stephanie Schindeldecker, John Snater, Trenise Steele, Dwight Selders, Jessica Tonsfeldt, Shelly Valardi, Gary Edd Fish, Hank A. Aguado, Sally Arceneaux, Jean Arnwine, Kim Bell, Tina Bell, Bob Boleman, Patricia Bradley, David Callanan, Lori Coors, Jodi Creighton, Timothy Crew, Kimberly Cummings, Christopher Dock, Karen Duignan, Dwain Fuller, Keith Gray, Betsy Hendrix, Nicholas Hesse, Diana Jaramillo, Bradley Jost, Sandy Lash, Laura Lonsdale, Michael Mackens, Karin Mutz, Michael Potts, Brenda Sanchez, William Snyder, Wayne Solley, Carrie Tarter, Robert Wang, Patrick Williams, Stephen L. Perkins, Nicholas Anderson, Ann Arnold, Paul Blais, Joseph Googe, Tina T. Higdon, Cecile Hunt, Mary Johnson, James Miller, Misty Moore, Charity K. Morris, Christopher Morris, Sarah Oelrich, Kristina Oliver, Vicky Seitz, Jerry Whetstone, Bernard H. Doft, Jay Bedel, Robert Bergren, Ann Borthwick, Paul Conrad, Amanda Fec, Christina Fulwylie, Willia Ingram, Shawnique Latham, Gina Lester, Judy Liu, Louis Lobes, Nicole M. Lucko, Holly Mechling, Lori Merlotti, Keith McBroom, Karl Olsen, Danielle Puskas, Pamela Rath, Maria Schmucker, Lynn Schueckler, Christina Schultz, Heather Shultz, David Steinberg, Avni Vyas, Kim Whale, Kimberly Yeckel, David H. Orth, Linda S. Arredondo, Susan Brown, Barbara J. Ciscato, Joseph M. Civantos, Celeste Figliulo, Sohail Hasan, Belinda Kosinski, Dan Muir, Kiersten Nelson, Kirk Packo, John S. Pollack, Kourous Rezaei, Gina Shelton, Shannya Townsend-Patrick, Marian Walsh, H. Richard McDonald, Nina Ansari, Amanda Bye, Arthur D. Fu, Sean Grout, Chad Indermill, Robert N. Johnson, J. Michael Jumper, Silvia Linares, Brandon J. Lujan, Ames Munden, Meredith Persons, Rosa Rodriguez, Jennifer M. Rose, Brandi Teske, Yesmin Urias, Stephen Young, Richard F. Dreyer, Howard Daniel, Michele Connaughton, Irvin Handelman, Stephen Hobbs, Christine Hoerner, Dawn Hudson, Marcia Kopfer, Michael Lee, Craig Lemley, Joe Logan, Colin Ma, Christophe Mallet, Amanda Milliron, Mark Peters, Harry Wohlsein, Joel A. Pearlman, Margo Andrews, Melissa Bartlett, Nanette Carlson, Emily Cox, Robert Equi, Marta Gonzalez, Sophia Griffin, Fran Hogue, Lance Kennedy, Lana Kryuchkov, Carmen Lopez, Danny Lopez, Bertha Luevano, Erin McKenna, Arun Patel, Brian Reed, Nyla Secor, Iris R. Sison, Tony Tsai, Nina Varghis, Brooke Waller, Robert Wendel, Reina Yebra, Daniel B. Roth, Jane Deinzer, Howard Fine, Flory Green, Stuart Green, Bruce Keyser, Steven Leff, Amy Leviton, Amy Martir, Kristin Mosenthine, Starr Muscle, Linda Okoren, Sandy Parker, Jonathan Prenner, Nancy Price, Deana Rogers, Linda Rosas, Alex Schlosser, Loretta Studenko, Thea Tantum, Harold Wheatley, Michael T. Trese, Thomas Aaberg, Denis Bezaire, Craig Bridges, Doug Bryant, Antonio Capone, Michelle Coleman, Christina Consolo, Cindy Cook, Candice DuLong, Bruce Garretson, Tracy Grooten, Julie Hammersley, Tarek Hassan, Heather Jessick, Nanette Jones, Crystal Kinsman, Jennifer Krumlauf, Sandy Lewis, Heather Locke, Alan Margherio, Debra Markus, Tanya Marsh, Serena Neal, Amy Noffke, Kean Oh, Clarence Pence, Lisa Preston, Paul Raphaelian, Virginia R. Regan, Peter Roberts, Alan Ruby, Ramin Sarrafizadeh, Marissa Scherf, Sarita Scott, Scott Sneed, Lisa Staples, Brad Terry, Matthew T. Trese, Joan Videtich, George Williams, Mary Zajechowski, Daniel P. Joseph, Kevin Blinder, Lynda Boyd, Sarah Buckley, Meaghan Crow, Amanda Dinatale, Nicholas Engelbrecht, Bridget Forke, Dana Gabel, Gilbert Grand, Jennifer Grillion-Cerone, Nancy Holekamp, Charlotte Kelly, Ginny Nobel, Kelly Pepple, Matt Raeber, P. Kumar Rao, Tammy Ressel, Steven Schremp, Merrilee Sgorlon, Shantia Shears, Matthew Thomas, Cathy Timma, Annette Vaughn, Carolyn Walters, Rhonda Weeks, Jarrod Wehmeier, Tim Wright, Daniel M. Berinstein, Aida Ayyad, Mohammed K. Barazi, Erica Bickhart, Tracey Brady, Lisa Byank, Alysia Cronise, Vanessa Denny, Courtney Dunn, Michael Flory, Robert Frantz, Richard A. Garfinkel, William Gilbert, Janine Newgen, Shamekia Newton, Debbie Oliver, Michael Osman, Reginald Sanders, Manfred von Fricken, Pravin Dugel, Sandra Arenas, Gabe Balea, Dayna Bartoli, John Bucci, Jennifer A. Cornelius, Scheleen Dickens, Don Doherty, Heather Dunlap, David Goldenberg, Karim Jamal, Norma Jimenez, Nicole Kavanagh, Derek Kunimoto, John Martin, Jessica Miner, Sarah Mobley, Donald Park, Edward Quinlan, Jack Sipperley, Carol Slagle, Danielle Smith, Miguelina Yafchak, Rohana Yager, Christina J. Flaxel, Steven Bailey, Peter Francis, Chris Howell, Thomas Hwang, Shirley Ira, Michael Klein, Andreas Lauer, Teresa Liesegang, Ann Lundquist, Sarah Nolte, Susan K. Nolte, Scott Pickell, Susan Pope, Joseph Rossi, Mitchell Schain, Peter Steinkamp, Maureen D. Toomey, Debora Vahrenwald, Kelly West, Baker Hubbard, Stacey Andelman, Chris Bergstrom, Judy Brower, Blaine Cribbs, Linda Curtis, Jannah Dobbs, Lindreth DuBois, Jessica Gaultney, Deborah Gibbs, Debora Jordan, Donna Leef, Robert Myles, Timothy Olsen, Bryan Schwent, Sunil Srivastava, Rhonda Waldron, Andrew N. Antoszyk, Uma Balasubramaniam, Danielle Brooks, Justin Brown, David Browning, Loraine Clark, Sarah Ennis, Susannah Held, Jennifer V. Helms, Jenna Herby, Angie Karow, Pearl Leotaud, Caterina Massimino, Donna McClain, Michael McOwen, Jennifer Mindel, Candace Pereira, Rachel Pierce, Michele Powers, Angela Price, Jason Rohrer, Jason Sanders, Robert L. Avery, Kelly Avery, Jessica Basefsky, Liz Beckner, Alessandro Castellarin, Stephen Couvillion, Jack Giust, Matthew Giust, Maan Nasir, Dante Pieramici, Melvin Rabena, Sarah Risard, Robert See, Jerry Smith, Lisha Wan, Sophie J. Bakri, Nakhleh Abu-Yaghi, Andrew Barkmeier, Karin Berg, Jean Burrington, Albert Edwards, Shannon Goddard, Shannon Howard, Raymond Iezzi, Denise Lewison, Thomas Link, Colin A. McCannel, Joan Overend, John Pach, Margaret Ruszczyk, Ryan Shultz, Cindy Stephan, Diane Vogen, Reagan H. Bradford, Vanessa Bergman, Russ Burris, Amanda Butt, Beth Daniels, Connie Dwiggins, Stephen Fransen, Tiffany Guerrero, Darin Haivala, Amy Harris, Sonny Icks, Ronald Kingsley, Lena Redden, Rob Richmond, Brittany Ross, Kammerin White, Misty Youngberg, Trexler M. Topping, Steve Bennett, Sandy Chong, Mary Ciotti, Tina Cleary, Emily Corey, Dennis Donovan, Albert Frederick, Lesley Freese, Margaret Graham, Natalya Gud, Taneika Howard, Mike Jones, Michael Morley, Katie Moses, Jen Stone, Robin Ty, Torsten Wiegand, Lindsey Williams, Beth Winder, Carl C. Awh, Michelle Amonette, Everton Arrindell, Dena Beck, Brandon Busbee, Amy Dilback, Sara Downs, Allison Guidry, Gary Gutow, Jackey Hardin, Sarah Hines, Emily Hutchins, Kim LaCivita, Ashley Lester, Larry Malott, MaryAnn McCain, Jayme Miracle, Kenneth Moffat, Lacy Palazzotta, Kelly Robinson, Peter Sonkin, Alecia Travis, Roy Trent Wallace, Kelly J. Winters, Julia Wray, April E. Harris, Mari Bunnell, Katrina Crooks, Rebecca Fitzgerald, Cameron Javid, Corin Kew, Erica Kill, Patricia Kline, Janet Kreienkamp, Maricruz Martinez, Roy Ann Moore, Egbert Saavedra, LuAnne Taylor, Mark Walsh, Larry Wilson, Thomas A. Ciulla, Ellen Coyle, Tonya Harrington, Charlotte Harris, Cindi Hood, Ingrid Kerr, Raj Maturi, Dawn Moore, Stephanie Morrow, Jennifer Savage, Bethany Sink, Tom Steele, Neelam Thukral, Janet Wilburn, Joseph P. Walker, Jennifer Banks, Debbie Ciampaglia, Danielle Dyshanowitz, Jennifer Frederick, A. Tom Ghuman, Richard Grodin, Cheryl Kiesel, Eileen Knips, Jonathan McCue, Maria Ortiz, Crystal Peters, Paul Raskauskas, Etienne Schoeman, Ashish Sharma, Glenn Wing, Rebecca Youngblood, Suresh R. Chandra, Michael Altaweel, Barbara Blodi, Kathryn Burke, Kristine A. Dietzman, Justin Gottlieb, Gene Knutson, Denise Krolnik, T. Michael Nork, Shelly Olson, John Peterson, Sandra Reed, Barbara Soderling, Guy Somers, Thomas Stevens, Angela Wealti, Srilaxmi Bearelly, Brenda Branchaud, Joyce W. Bryant, Sara Crowell, Sharon Fekrat, Merritt Gammage, Cheala Harrison, Sarah Jones, Noreen McClain, Brooks McCuen, Prithvi Mruthyunjaya, Jeanne Queen, Neeru Sarin, Cindy Skalak, Marriner Skelly, Ivan Suner, Ronnie Tomany, Lauren Welch, Susanna S. Park, Allison Cassidy, Karishma Chandra, Idalew Good, Katrina Imson, Sashi Kaur, Helen Metzler, Lawrence Morse, Ellen Redenbo, Marisa Salvador, David Telander, Mark Thomas, Cindy Wallace, Charles C. Barr, Amanda Battcher, Michelle Bottorff, Mary Chasteen, Kelly Clark, Diane Denning, Debra Schoen, Amy Schultz, Evie Tempel, Lisa Wheeler, Greg K. Whittington, Thomas W. Stone, Todd Blevins, Michelle Buck, Lynn Cruz, Wanda Heath, Diana Holcomb, Rick Isernhagen, Terri Kidd, John Kitchens, Cathy Sears, Ed Slade, Jeanne Van Arsdall, Brenda VanHoose, Jenny Wolfe, William Wood, John Zilis, Carol Crooks, Larry Disney, Mimi Liu, Stephen Petty, Sandra Sall, James C. Folk, Tracy Aly, Abby Brotherton, Douglas Critser, Connie J. Hinz, Stefani Karakas, Valerie Kirschner, Cheyanne Lester, Cindy Montague, Stephen Russell, Heather Stockman, Barbara Taylor, Randy Verdick, Jean Walshire, John T. Thompson, Barbara Connell, Maryanth Constantine, John L. Davis, Gwen Holsapple, Lisa Hunter, C. Nicki Lenane, Robin Mitchell, Leslie Russel, Raymond Sjaarda, David M. Brown, Matthew Benz, Llewellyn Burns, JoLene G. Carranza, Richard Fish, Debra Goates, Shayla Hay, Theresa Jeffers, Eric Kegley, Dallas Kubecka, Stacy McGilvra, Beau Richter, Veronica Sneed, Cary Stoever, Isabell Tellez, Tien Wong, Ivana Kim, Christopher Andreoli, Leslie Barresi, Sarah Brett, Charlene Callahan, Karen Capaccioli, William Carli, Matthew Coppola, Nicholas Emmanuel, Claudia Evans, Anna Fagan, Marcia Grillo, John Head, Troy Kieser, Elaine Lee, Ursula Lord, Edward Miretsky, Kate Palitsch, Todd Petrin, Liz Reader, Svetlana Reznichenko, Mary Robertson, Justin Smith, Demetrios Vavvas, John Wells, Cassie Cahill, W. Lloyd Clark, Kayla Henry, David Johnson, Peggy Miller, LaDetrick Oliver, Robbin Spivey, Tiffany Swinford, Mallie Taylor, Michael Lambert, Kris Chase, Debbie Fredrickson, Joseph Khawly, Valerie Lazarte, Donald Lowd, Pam Miller, Arthur Willis, Philip J. Ferrone, Miguel Almonte, Rachel Arnott, Ingrid Aviles, Sheri Carbon, Michael Chitjian, Kristen D’Amore, Christin Elliott, David Fastenberg, Barry Golub, Kenneth Graham, AnnMarie Lavorna, Laura Murphy, Amanda Palomo, Christina Puglisi, David Rhee, Juan Romero, Brett Rosenblatt, Glenda Salcedo, Marianne Schlameuss, Eric Shakin, Vasanti Sookhai, Richard Kaiser, Elizabeth Affel, Gary Brown, Christina Centinaro, Deborah Fine, Mitchell Fineman, Michele Formoso, Sunir Garg, Lisa Grande, Carolyn Herbert, Allen Ho, Jason Hsu, Maryann Jay, Lisa Lavetsky, Elaine Liebenbaum, Joseph Maguire, Julia Monsonego, Lucia O’Connor, Lisa Pierce, Carl Regillo, Maria Rosario, Marc Spirn, James Vander, Jennifer Walsh, Frederick H. Davidorf, Amanda Barnett, Susie Chang, John Christoforidis, Joy Elliott, Heather Justice, Alan Letson, Kathryne McKinney, Jeri Perry, Jill A. Salerno, Scott Savage, Stephen Shelley, Lawrence J. Singerman, Joseph Coney, John DuBois, Kimberly DuBois, Gregg Greanoff, Dianne Himmelman, Mary Ilc, Elizabeth McNamara, Michael Novak, Scott Pendergast, Susan Rath, Sheila Smith-Brewer, Vivian Tanner, Diane E. Weiss, Hernando Zegarra, null Lawrence Halperin, Patricia Aramayo, Mandeep Dhalla, Brian Fernandez, Cindy Fernandez, Jaclyn Lopez, Monica Lopez, Jamie Mariano, Kellie Murphy, Clifford Sherley, Rita Veksler, Firas Rahhal, Razmig Babikian, David Boyer, Sepideh Hami, Jeff Kessinger, Janet Kurokouchi, Saba Mukarram, Sarah Pachman, Eric Protacio, Julio Sierra, Homayoun Tabandeh, Adam Zamboni, Michael Elman, Jennifer Belz, Tammy Butcher, Theresa Cain, Teresa Coffey, Dena Firestone, Nancy Gore, Pamela Singletary, Peter Sotirakos, JoAnn Starr, Travis A. Meredith, Cassandra J. Barnhart, Debra Cantrell, RonaLyn Esquejo-Leon, Odette Houghton, Harpreet Kaur, Fatoumatta N’Dure, Ronald Glatzer, Leonard Joffe, Reid Schindler, Marilyn Katz, Mary Brightwell-Arnold, Ruchira Glaser, Judith Hall, Sandra Harkins, Alexander Khvatov, Kathy McWilliams, Ellen Peskin, Maxwell Pistilli, Susan Ryan, Allison Schnader, Gui-Shuang Ying, Glenn Jaffe, Jennifer Afrani-Sakyi, Brannon Balsley, Linda S. Bennett, Adam Brooks, Adrienne Brower-Lingsch, Lori Bruce, Russell Burns, Dee Busian, John Choong, Lindsey Cloaninger, Francis Char DeCroos, Emily DuBois, Mays El-Dairi, Sarah Gach, Katelyn Hall, Terry Hawks, ChengChenh Huang, Cindy Heydary, Alexander Ho, Shashi Kini, Michelle McCall, Daaimah Muhammad, Jayne Nicholson, Pamela Rieves, Kelly Shields, Adam Specker, Sandra Stinnett, Sujatha Subramaniam, Patrick Tenbrink, Cynthia Toth, Aaron Towe, Kimberly Welch, Natasha Williams, Katrina Winter, Ellen Young, Judith Alexander, Elisabeth Flannagan, E. Revell Martin, Candace Parker, Krista Sepielli, Tom Shannon, Claressa Whearry, Maryann Redford, Marcia R. Kopfer, Joan DuPont, Lawrence M. Friedman, Susan B. Bressler, David L. DeMets, Martin Friedlander, Mark W. Johnson, Anne Lindblad, Douglas W. Losordo, and Franklin G. Miller

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Visual acuity, genetic structures, Visual Acuity, Angiogenesis Inhibitors, Fundus (eye), Antibodies, Monoclonal, Humanized, Article, Cohort Studies, Lesion, Pro re nata, Ranibizumab, Ophthalmology, medicine, Humans, Prospective Studies, Fluorescein Angiography, Prospective cohort study, Aged, Aged, 80 and over, business.industry, Retinal Hemorrhage, Macular degeneration, medicine.disease, Choroidal Neovascularization, eye diseases, Bevacizumab, Treatment Outcome, Choroidal neovascularization, Intravitreal Injections, Wet Macular Degeneration, Female, sense organs, medicine.symptom, business, Tomography, Optical Coherence, Follow-Up Studies, medicine.drug
Abstract

To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Prospective cohort study within a multicenter randomized clinical trial.CATT patients with neovascular age-related macular degeneration (AMD).Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA.Morphologic features and VA at 1 and 2 years.The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P0.001), total lesion size was greater (4.55 vs 2.31 DA; P0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years.In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of50% blood can be managed similarly to those with less or no blood.

Published
2015

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