Skip to main content
SpringerLink
Log in

Standardized Scoring of Ocular Findings in the Context of Drug and Device Development Programs

  • Chapter
  • First Online:
Standards for Ocular Toxicology and Inflammation

Abstract

This chapter presents a comprehensive review of the approaches and methods used to perform clinical ocular scoring of the anterior and posterior segment in laboratory animals in toxicologic and preclinical drug development studies. It represents a distillation and integration of two recent publications from our group with expanded commentary (Eaton et al., J Ocul Pharmacol Ther 33:707–717, 2017; 718–734). The reader is introduced to the indications and features of the most commonly used semi-quantitative scoring systems in laboratory studies, as well as important limitations and considerations for each. The reader is also introduced to the ocular scoring systems employed by the clinical team at Ocular Services On Demand (OSOD), which modify many criteria from previous systems and introduce novel scoring elements to improve the applicability and predictive value of clinical observations made in support of modern preclinical ocular drug and device development programs. Species considerations pertinent to ocular examination and clinical scoring in general toxicology and ocular drug/device development are also discussed.

Endorsed by the American College of Veterinary Ophthalmologists (ACVO).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Eaton JS, Miller PE, Bentley E, Thomasy SM, Murphy CJ. Slit lamp-based ocular scoring systems in toxicology and drug development: a literature survey. J Ocul Pharmacol Ther. 2017;33:707–17.

    Article  CAS  PubMed  Google Scholar 

  2. Eaton JS, Miller PE, Bentley E, Thomasy SM, Murphy CJ. The SPOTS system: an ocular scoring system optimized for use in modern preclinical drug development and toxicology. J Ocul Pharmacol Ther. 2017;33:718–34.

    Article  CAS  PubMed  Google Scholar 

  3. Singer M. Oxford textbook of critical care. New York: Oxford University Press; 2016.

    Google Scholar 

  4. Barbini P, Cevenini G, Furini S, Barbini E. A naive approach for deriving scoring systems to support clinical decision making. J Eval Clin Pract. 2014;20:1–6. https://doi.org/10.1111/jep.12064.

    Article  PubMed  Google Scholar 

  5. Wilkie DA. The ophthalmic examination as it pertains to general ocular toxicology: basic and advanced techniques and species-associated findings. In: Ocular pharmacology and toxicology. Totowa: Humana Press; 2014. p. 143–203.

    Google Scholar 

  6. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–16.

    Article  PubMed  Google Scholar 

  7. BenEzra D, Forrester JV, Nussenblatt RB, Tabbara K, Timonen P. Uveitis scoring system. Berlin: Springer; 1991. p. 1–2.

    Google Scholar 

  8. Deschenes J, Murray PI, Rao NA, Nussenblatt RB. International Uveitis Study Group (IUSG) clinical classification of uveitis. Ocul Immunol Inflamm. 2008;16(1-2):1.

    Article  PubMed  Google Scholar 

  9. Munger RJ. Veterinary ophthalmology in laboratory animal studies. Vet Ophthalmol. 2002;5:167–75.

    Article  PubMed  Google Scholar 

  10. Thomasy SM, et al. Species differences in the geometry of the anterior segment differentially affect anterior chamber cell scoring systems in laboratory animals. J Ocul Pharmacol Ther. 2016;32:28–37. https://doi.org/10.1089/jop.2015.0071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Bito LZ. Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research. Exp Eye Res. 1984;39:807–29.

    Article  CAS  PubMed  Google Scholar 

  12. McDonald TO, Shadduck JA. In: Marzulli FN, Maibach HI, editors. Dermatotoxicology and pharmacology, Advanced in modern toxicology, vol. 4. Washington, DC: Hemisphere; 1977. p. 139–91.

    Google Scholar 

  13. Hackett RB, McDonald TO. Assessing ocular irritation. In: Dermatotoxicology. Washington, DC: Hemisphere; 1996. p. 557–67.

    Google Scholar 

  14. Friedenwald J, Hughes W, Herrmann H. Acid-base tolerance of the cornea. Arch Ophthalmol. 1944;31:279–83.

    Article  CAS  Google Scholar 

  15. Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther. 1944;82:377–90.

    CAS  Google Scholar 

  16. Sasaki H, Yamamura K, Nishida K, Nakamura J, Ichikawa M. Delivery of drugs to the eye by topical application. Prog Retin Eye Res. 1996;15:583–620.

    Article  CAS  Google Scholar 

  17. Salminen L, Urtti A, Periviita L. Effect of ocular pigmentation on pilocarpine pharmacology in the rabbit eye. I. Drag distribution and metabolism. Int J Pharm. 1984;18:17–24.

    Article  CAS  Google Scholar 

  18. Urtti A, Salminen L, Kujari H, Jäntti V. Effect of ocular pigmentation on pilocarpine pharmacology in the rabbit eye. II. Drug response. Int J Pharm. 1984;19:53–61.

    Article  CAS  Google Scholar 

  19. Studer ME, Martin CL, Stiles J. Effects of 0.005% latanoprost solution on intraocular pressure in healthy dogs and cats. Am J Vet Res. 2000;61:1220–4.

    Article  CAS  PubMed  Google Scholar 

  20. Gelatt KN, MacKay EO. Effect of different dose schedules of latanoprost on intraocular pressure and pupil size in the glaucomatous Beagle. Vet Ophthalmol. 2001;4:283–8.

    Article  CAS  PubMed  Google Scholar 

  21. Gelatt KN, MacKay EO. Effect of different dose schedules of bimatoprost on intraocular pressure and pupil size in the glaucomatous Beagle. J Ocul Pharmacol Ther. 2002;18:525–34.

    Article  CAS  PubMed  Google Scholar 

  22. Wilhelmus KR. The Draize eye test. Surv Ophthalmol. 2001;45:493–515. https://doi.org/10.1016/S0039-6257(01)00211-9.

    Article  PubMed  CAS  Google Scholar 

  23. Waring GO, Laibson PR. A systematic method of drawing corneal pathologic conditions. Arch Ophthalmol. 1977;95:1540–2.

    Article  CAS  PubMed  Google Scholar 

  24. Friberg TR, Jenny YY. Chapter 156, Choroidal and retinal folds. In: Albert and Jakobiec’s principles and practice of ophthalmology. 3rd ed. Philadelphia: Elsevier Inc; 2008. p. 2039–48.

    Chapter  Google Scholar 

  25. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002;20:338–46.

    Article  Google Scholar 

  26. Nork TM, Dubielzig RR, Christian BJ, et al. Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates. Arch Ophthalmol. 2001;129:1042–52.

    Article  Google Scholar 

  27. Ryan SJ. Subretinal neovascularization: natural history of an experimental model. Arch Ophthalmol. 1982;100:1804–9.

    Article  CAS  PubMed  Google Scholar 

  28. Ohkuma H, Ryan SJ. Experimental subretinal neovascularization in the monkey: permeability of new vessels. Arch Ophthalmol. 1983;101:1102–10.

    Article  CAS  PubMed  Google Scholar 

  29. Jakobiec FA, Stacy RC, Mendoza PR, Chodosh J. Hyperplastic corneal pannus: an immunohistochemical analysis and review. Surv Ophthalmol. 2014;59:448–53.

    Article  PubMed  Google Scholar 

  30. Williams D. Histological and immunohistochemical evaluation of canine chronic superficial keratitis. Res Vet Sci. 1999;67:191–5.

    Article  CAS  PubMed  Google Scholar 

  31. Gelatt KN, Gilger BC, Kern TJ. Veterinary ophthalmology. Ames: Wiley; 2012.

    Google Scholar 

  32. Dumonde D, et al. Anti-retinal autoimmunity and circulating immune complexes in patients with retinal vasculitis. Lancet. 1982;320:787–92.

    Article  Google Scholar 

  33. Lee EK, Lee S-Y, Yu HG. A clinical grading system based on ultra-wide field retinal imaging for sunset glow fundus in Vogt-Koyanagi-Harada disease. Graefes Arch Clin Exp Ophthalmol. 2015;253:359–68.

    Article  PubMed  Google Scholar 

  34. Seddon JM, Sharma S, Adelman RA. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology. 2006;113:260–6.

    Article  PubMed  Google Scholar 

  35. Nussenblatt RB, Palestine AG, Chan C-C, Roberge F. Standardizatlon of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 1985;92:467–71.

    Article  CAS  PubMed  Google Scholar 

  36. Kimura SJ, Thygeson P, Hogan MJ. Signs and symptoms of uveitis. II. Classification of the posterior manifestations of uveitis. Am J Ophthalmol. 1959;47:171.

    Article  CAS  PubMed  Google Scholar 

  37. Kempen JH, Ganesh SK, Sangwan VS, Rathinam SR. Interobserver agreement in grading activity and site of inflammation in eyes of patients with uveitis. Am J Ophthalmol. 2008;146:813–8.

    Article  PubMed  Google Scholar 

  38. Sen HN, et al. A standardized grading system for scleritis. Ophthalmology. 2011;118:768–71. https://doi.org/10.1016/j.ophtha.2010.08.027.

    Article  PubMed  Google Scholar 

  39. Murphy CJ, Rowland HC. The optics of comparative ophthalmoscopy. Vis Res. 1987;27:599–607.

    Article  CAS  PubMed  Google Scholar 

  40. Agarwal M, Malathi J, Biswas J. Frosted branch angiitis in a patient with typhoid fever. Ocul Immunol Inflamm. 2016:1–3. https://doi.org/10.1080/09273948.2016.1265654.

  41. Wood EH, Wong RW. Bilateral frosted branch angiitis as the presenting sign of antiphospholipid antibody syndrome. J Ophthalmic Inflamm Infect. 2016;6:20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Short BG. Safety evaluation of ocular drug delivery formulations: techniques and practical considerations. Toxicol Pathol. 2008;36:49–62.

    Article  CAS  PubMed  Google Scholar 

  43. Hosseini A, et al. Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model. J Ocul Pharmacol Ther. 2012;28:194–201.

    Article  CAS  PubMed  Google Scholar 

  44. Taradach C, Greaves P, Rubin LF. Spontaneous eye lesions in laboratory animals: incidence in relation to age. CRC Crit Rev Toxicol. 1984;12:121–47.

    Article  CAS  Google Scholar 

  45. Taradach C, Regnier B, Perraud J. Eye lesions in Sprague-Dawley rats: type and incidence in relation to age. Lab Anim. 1981;15:285–7.

    Article  CAS  PubMed  Google Scholar 

  46. Wegener A, Kaegler M, Stinn W. Frequency and nature of spontaneous age-related eye lesions observed in a 2-year inhalation toxicity study in rats. Ophthalmic Res. 2002;34(5):281–7.

    Article  CAS  PubMed  Google Scholar 

  47. Eiben R. Frequency of spontaneous opacities in the cornea and lens observed in chronic toxicity studies in Wistar rats: experience with a standardized terminology glossary (Hattersheimer Kreis). Res Commun Pharmacol Toxicol. 2001;6(3/4):238–51.

    CAS  Google Scholar 

  48. Bruner RH, Keller WF, Stitzel KA, Sauers LJ, Reer PJ, Long PH, Bruce RD, Alden CL. Spontaneous corneal dystrophy and generalized basement membrane changes in Fischer-344 rats. Toxicol Pathol. 2016;20(3–1):357–66.

    Google Scholar 

  49. Van TW, Balk MW. Spontaneous corneal opacities in laboratory mice. Lab Anim Sci. 1986;36(3):248–55.

    Google Scholar 

  50. Koehn D, Meyer KJ, Syed NA, Anderson MG. Ketamine/xylazine-induced corneal damage in mice. PLoS One. 2015;10:e0132804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bawa G, Tkatchenko TV, Avrutsky I, Tkatchenko AV. Variational analysis of the mouse and rat eye optical parameters. Biomed Opt Express. 2013;4:2585–95.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Massof RW, Chang FW. A revision of the rat schematic eye. Vis Res. 1972;12:793–6.

    Article  CAS  PubMed  Google Scholar 

  53. Pe’er J, Muckarem M, Zajicek G. Epithelial cell migration in the normal rat lens. Ann Anat. 1996;178:433–6.

    Article  PubMed  Google Scholar 

  54. Remtulla S, Hallett P. A schematic eye for the mouse, and comparisons with the rat. Vis Res. 1985;25:21–31.

    Article  CAS  PubMed  Google Scholar 

  55. Mailankot M, et al. Indoleamine 2, 3-dioxygenase overexpression causes kynurenine-modification of proteins, fiber cell apoptosis and cataract formation in the mouse lens. Lab Investig. 2009;89:498.

    Article  CAS  PubMed  Google Scholar 

  56. Sharif NA, et al. Preclinical pharmacology of AL-12182, a new ocular hypotensive 11-oxa prostaglandin analog. J Ocul Pharmacol Ther. 2006;22:291–309.

    Article  CAS  PubMed  Google Scholar 

  57. Barabino S, Dana MR. Animal models of dry eye: a critical assessment of opportunities and limitations. Investig Ophthalmol Vis Sci. 2004;45:1641–6.

    Article  Google Scholar 

  58. Burgalassi S, Panichi L, Chetoni P, Saettone MF, Boldrini E. Development of a simple dry eye model in the albino rabbit and evaluation of some tear substitutes. Ophthalmic Res. 1999;31:229–35.

    Article  CAS  PubMed  Google Scholar 

  59. Guo Z, et al. Autologous lacrimal-lymphoid mixed-cell reactions induce dacryoadenitis in rabbits. Exp Eye Res. 2000;71:23–31. https://doi.org/10.1006/exer.2000.0855.

    Article  PubMed  CAS  Google Scholar 

  60. Li N, et al. Establishment of the mild, moderate and severe dry eye models using three methods in rabbits. BMC Ophthalmol. 2013;13:50. https://doi.org/10.1186/1471-2415-13-50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Toshida H, Nguyen DH, Beuerman RW, Murakami A. Neurologic evaluation of acute lacrimomimetic effect of cyclosporine in an experimental rabbit dry eye model. Investig Ophthalmol Vis Sci. 2009;50:2736–41.

    Article  Google Scholar 

  62. Yañez-Soto B, et al. Interfacial phenomena and the ocular surface. Ocul Surf. 2014;12:178–201.

    Article  PubMed  Google Scholar 

  63. Yánez-Soto B, Leonard BC, Raghunathan VK, Abbott NL, Murphy CJ. Effect of stratification on surface properties of corneal epithelial cells. Invest Ophthalmol Vis Sci. 2015;56:8340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Leonard BC, Yañez-Soto B, Raghunathan VK, Abbott NL, Murphy CJ. Species variation and spatial differences in mucin expression from corneal epithelial cells. Exp Eye Res. 2016;152:43–8.

    Article  CAS  PubMed  Google Scholar 

  65. Kikkawa Y. Normal corneal staining with fluorescein. Exp Eye Res. 1972;14:13–20.

    Article  CAS  PubMed  Google Scholar 

  66. Moore C, Dubielzig R, Glaza S. Anterior corneal dystrophy of American Dutch belted rabbits: biomicroscopic and histopathologic findings. Vet Pathol. 1987;24:28–33.

    Article  CAS  PubMed  Google Scholar 

  67. Port C, Dodd D. Two cases of corneal epithelial dystrophy in rabbits. Lab Anim Sci. 1983;33:587–8.

    PubMed  CAS  Google Scholar 

  68. Holmberg ÅS. Schlemm’s canal and the trabecular meshwork. An electron microscopic study of the normal structure in man and monkey (Cercopithecus ethiops). Doc Ophthalmol. 1965;19:339–73.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ocular Services on Demand (OSOD), LLC, Madison, WI, USA

    J. Seth Eaton, Paul E. Miller, Ellison Bentley, Sara M. Thomasy & Christopher J. Murphy

  2. Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, USA

    J. Seth Eaton, Sara M. Thomasy & Christopher J. Murphy

  3. Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin – Madison, Madison, WI, USA

    Paul E. Miller & Ellison Bentley

  4. Department of Ophthalmology and Vision Science, School of Medicine, University of California - Davis, Sacramento, CA, USA

    Christopher J. Murphy

Authors
  1. J. Seth Eaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul E. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ellison Bentley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara M. Thomasy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher J. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to J. Seth Eaton or Christopher J. Murphy .

Editor information

Editors and Affiliations

  1. Department of Clinical Sciences, North Carolina State University, Raleigh, NC, USA

    Brian C. Gilger

  2. Veterinary Vision, San Francisco, CA, USA

    Cynthia S. Cook

  3. Veterinary Ophthalmology Services, Inc., Little Falls, NJ, USA

    Michael H. Brown

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Eaton, J.S., Miller, P.E., Bentley, E., Thomasy, S.M., Murphy, C.J. (2018). Standardized Scoring of Ocular Findings in the Context of Drug and Device Development Programs. In: Gilger, B., Cook, C., Brown, M. (eds) Standards for Ocular Toxicology and Inflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-78364-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation