Introduction

Glaucoma is nowadays considered as a disease of optic nerve where in it is susceptible to damage from many factors. The nerve is susceptible to the existing IOP, or `the damage can be due to IOP independent mechanisms. The damaging IOP can be much lower than the statistical normal range .The seemingly non IOP dependent damage seen in some patients even after control of the IOP factor, made us think about other alternative pathogenesis factors and this concept of Normal Tension Glaucoma has influenced our understanding of glaucoma, resulting in elimination of IOP from the diagnostic criteria of POAG.

Neurodegenerative (NDD) disease was accidentally discovered to have an association with POAG when Chandra et al¹ found an increased incidence of POAG in the death registry record of people with dementia. The association was seen consistently in a few subsequent observational studies. Research also suggests common pathogenesis and terminal cellular events (apoptosis) in both. 

1. Chandra V, Scheonberg BS. Conditions associated with Alzheimer’s diseases at death: case – control study. Neurology 1986; 36:209 -211.
2. Boivin JF, McGregor M, Archer C. Cost effectiveness of screening for primary open angle glaucoma. J Medical Screening 1996; 3: 154–163.
3. Quigley HA. New paradigms in the mechanisms and management of glaucoma. Eye 2005; 19: 1241–1248.
4. Wostyn P, Audenaert K, De Deyn PP. Alzheimer’s Disease and Glaucoma: is there a causal relationship? Br J Ophthalmol 2009; 93: 1557- 1559.
5. FaniTsolaki, Eleni Gogaki, SotiriaTiganita et al .Alzheimer’s disease and primary open-angle glaucoma: is there a connec-tion? Clinical Ophthalmology 2011;5: 887–8909.
6. Quigley HA. The number of persons with glaucoma worldwide.Br J Ophthalmol 1996;80:389–93.
7. Thylefors B, Negrel AD. The global impact of glaucoma. Bull World Health Organ 1994; 72: 323–326.
8. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol2006;90:262–267.
9. Dandona L, Dandona  R, Srinivas  Open-angle glaucoma in an urban population in southern India. Ophthalmology 2000;107:1702–9.
10. Vijaya L, George R, Aravind H et al. Prevalance of angle closure disease in a rural southern Indian population. Arch Ophthalmol 2006;124:403-9.
11. Thomas R, Parikh R, George R et al. Five – year risk of progression of ocular hypertension to primary open angle glaucoma. A population based study. Indian J Ophthalmol 2003;51 :329-33.
12. Ramakrishnan R, Nirmalan KP, Krishnadas R, Thulasiraj RD, Tielsch MJ, Katz J, Friedman DS et al. Glaucoma in a rural population of southern India: The Aravind Comprehensive Eye Survey. Ophthalmology 2003; 110(8): 1484- 1490.
13. Raju, Vijaya L, George R, Baskaran M, Arvind H, Raju P, Ramesh SV et al. Prevalence of primary open angle glaucoma in an urban south Indian population and comparison with a rural population. The Chennai Glaucoma Study. Opthalmology 2008; 115: 648-54.
14. Vijaya L, George R, Paul PG, Baskaran M, Arvind H, Raju P et al. Prevalence of open angle glaucoma in a rural south Indian population. Invest Ophtahl Vis Sci 2005; 46: 4461-7.
15. Raychaudhuri A, Lahiri SK, Bandyopadhyay M, Foster PJ, Reeves BC, Johnson GJ. A population based survey of the prevalence and types of Glaucoma in rural West Bengal: The West Bengal Glaucoma study. Br J Opthalmol 2005; 89:1559-64.
16. Leske MC, MD, Connell AMS et al.Risk Factors for Open-angle Glaucoma. The Barbados Eye Study Arch Ophthalmol.1995;113(7):918-924.
17. Tielsh JM, Sommer A, Katz J, Toyall RM, Quigley HA, Javitt J. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991; 266: 369-74.
18. Kass MA. The Ocular Hypertension Treatment Study. J Glaucoma 1994; 3: 97-100.
19. Lichter PR, Musch DC, Gillespie BW et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing Initial treatment randomized to medications or surgery. Ophthalmology 2001; 108: 1943- 1953.
20. Rudnicka AR, Shahrul Mt- Isa, Owen CG, Cook DG, Ashby D. Variations in primary open- angle glaucoma prevalence by age, gender, and race: a Bayesian meta- analysis. Invest Opthalmol Vis Sci 2006; 47: 4254-61.
21. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbe DE, de Jong PTVM. The prevalence of primary open- angle glaucoma in a population based study in the Netherlands. The Rotterdam Study. Opthalmology 1994; 101:1851-5.
22. Leske MC, Heijl A, Hussein M et al.  Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.  Arch Ophthalmol  2003;  121:48-56.
23. Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). ArchOphthalmol1988; 106:898-900.
24. Kass MA, Heuer DK et al. The Ocular Hypertension Treatment Trial: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open angle glaucoma. Arch Opthalmol 2002;120:701 – 13.
25. Anderson DR. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol 2003; 14: 86–90.
26. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120: 1268–1279.
27. George R, Ramesh S, Viajaya L. Glaucoma in India: Estimated burden of disease. J Glaucoma 2010; 19:391-7.
28. Jacob A, Thomas R, Koshi SP, Braganza A, Muliyil J. Prevalance of primary glaucoma in an urban south Indian population. Indian J Ophthalmol 1998; 46: 81-6.
29. Sommer A. Doyne Lecture. Glaucoma: facts and fancies. Eye1996; 10: 295–301.
30. Mitchell P, Smith W, Attebo K, Healey RR. Prevalence of open- angle glaucoma in Australia. The Blue Mountains Eye Study. Opthalmology 1996; 103:1661-9.
31. Klein BE, Klein R, Sponsel WE, Franke T, Cantor LD, Martone J et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Opthalmology 1992; 1999: 1499-504.
32. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma:a population-based assessment. Arch Ophthalmol1995;113:216–21.
33. Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 1999; 213:76-96.
34. Hayreh SS, Zimmerman MB, Podhajsky P et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994; 117:603-24.
35. Graham SL, Drance SM, Wijsman K, et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnaldip. Ophthalmology 1995; 102:61-9.
36. Mueller HJ. Anatomische Beitragezurop-hthalmologie: Uber Nervean-veranderungenausdereint. rittsstelle des schnerven, Arch ophthalmol 1858; 4:1.
37. Von Jaeger E. UeberGlaukom und seine Heilungdruckiridectomie Z GesAerzte Wein 1858; 14:465.
38. Quigley HA, McKinnon SJ, Zack DJ et al. Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 2000;41:3460–6.
39. Quigley HA, Addicks EM. Regional differences in the structure of" tile lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophlhalmol1981; 99: IS7-143.
40. Radius RL, Bade B. Pressure-induced optic nerve axonal transport interruption in cat eyes. Arch Ophthalmol 1981; 99:2163-216.
41. Miller KN, Quigley HA: The clinical appearance' of the lamina cribrosa as a function of the extent of glaucomatous optic nerve damage. Ophlhalmolo,o' 1988; 95:135-138.
42. Griffin JW, Watson DF. Axonal transport in neurological disease. Ann Neurol1988; 23:3-13.
43. Tielsch JM, Katz J, Sommer A et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol1995;113:216–21.
44. Flammer J, Orgul S, Costa VP et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21:359.
45. Hayreh SS. Inter-individual variation in blood supply of the optic nerve head. Its importance in various ischemic disorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders.  Documenta Ophthalmol1985; 59:217-246.
46. Flammer J. The vascular concept of glaucoma Surv Ophthalmol 1994; 38 (Suppl): S3-S6.
47. Tezel G, Wax MB. Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol 2004;122 :1348 –56.
48. Chauhan BC, LeVatte TL, Jollimore CA et al. Model of endothelin-1-induced chronic optic neuropathy in rat. Invest Ophthalmol Vis Sci 2004;45:144– 52.
49. Orgul S, Cioffi G, Bacon D et al. An endothelin-1-induced model of chronic optic nerve ischemia in rhesus monkeys. J Glaucoma 1996;5: 135 – 8.
50. Wang X, Tay SS, Ng YK. An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res 2000;132: 476– 84.
51. Woldemussie E, Wijono M, Ruiz G. Mu¨ ller cell response to laser-induced increase in intraocular pressure in rats. Glia 2004; 47:109–19.
52. Dreyer EB. A proposed role for excitotoxicity in glaucoma. J Glaucoma 1998;7:62–7.
53. Lipton SA, Nicotera P. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium 1998; 23:165-71.
54. Tezel G, Wax MB. Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci2000;20:8693–700.
55. Tezel G, Li LY, Patil RV et al. TNF-alpha and TNF alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 2001; 42:1787–94.
56. Mozaffarieh M, Flammer J. Pocket Reference to Ocular Blood Flow and Glaucomatous Optic Atrophy. Chapter 7. London: Current Medical Group;2008.
57. Tatton W, Chen D, Chalmers-Redman R, et al.  Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation [Review].  Surv Ophthalmol 2003; 48 (Suppl 1):S25-S37.
58. Tatton WG, Chalmers-Redman RM, Tatton NA. Apoptosis and anti apoptosis signaling in glaucomatous retinopathy. (review) EurOphthalmol 2001; 11(suppl2):S12-22.
59. Tezel G, Yang X. Caspase-independent component of retinal ganglion cell death, in vitro.  Invest Ophthalmol Vis Sci.2004; 45:4049-4059.
60. American Academy of Ophthalmology, Glaucoma Panel. Open Angle Glaucoma: San Francisco, CA: AAO; 2009- 2010: 85-100.
61. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classify-cation of glaucoma in prevalence surveys. Br J Ophthalmol 2002; 86: 238–242.
62. Susanna R Jr, Vessani RM. New findings in the evaluation of the optic disc in glaucoma diagnosis. CurrOpinOphthalmol 2007 Mar;18(2):122-8.
63. Sekhar GC. Optic disc evaluation in glaucoma. Indian J Ophthalmol [serial online] 1996 [cited 2012 Nov 6];44: 235-9.
64. Jonas JB, Gusek GC, Naumann GO. Optic disc, cup and neuroretinal rim size, configuration and correlations in normal eyes.  Invest Ophthalmol Vis Sci. 1988; 29:1151-1158.
65. George L Spaeth, MD, Henderer JD, Connie Liu, BA ,Mugekesen, MD. The Disc Damage Likelihood Scale: Reproducibility Of A New Method Of Estimating The Amount Of Optic Nerve Damage Caused By Glaucoma (98% Intraobserver Of Reproducibility And 85%  Interobserver Reproducibility). Br J Ophthalmol 2006 April; 90(4): 395–396.
66. Bayer A, Harasymowycz P, Henderer JD et al. Validity of a new disc grading scale for estimating glaucomatous damage: correlation with visual field damage Trans Am OphthalmolSoc2002; 100: 181-186.
67. Sumit Choudhury, Suchanda Sar. Evaluation of the Optic Nerve Head. AIOS Guidelines for Glaucoma Investigations. 2012; suppl 24-28.
68. Sommer A, Quigley HA, Robin AL, Miller NR, Katz J, Arkell S. Evaluation of nerve fiber layer assesment. Arch Ophthalmol1984; 102: 1766–71.
69. Sommer A. Retinal nerve fiber layer. Am J Ophthalmol1995;
70. Liang Xu, Yaxing Wang et al.Differences in Parapapillary Atrophy between Glaucomatous and Normal Eyes: The Beijing Eye Study published online 28 June 2007.
71. Quigley HA. Current and future approaches to glaucoma screening. J Glaucoma 1998; 7: 210–219.
72. Drance SM. Some factors in the production of low tension glaucoma. Br J Ophthalmol 1972; 56: 229-42.
73. Anderson DR. Normal-tension glaucoma (Low-tension glaucoma).Indian J Ophthalmol 2011; 59 suppl1:S97-101.
74. Anderson DR. Glaucoma, capillaries, and pericytes: Blood flow regulation. Ophthalmologica 1996; 210:257-62.
75. Thompson LM. “Neurodegeneration : a question of balance”. Nature. 2008 April; 452(7188): 707-8.
76. Bredesen DE, Rao RV, MehlenP.”Cell death in the nervous system”. Nature 443(7113):796-802.
77. Lin MT, Beal MF. Mitochondrial disorders in the nervous system”. Nature 2006 October; 443(7113):787-95.
78. Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC et al. Bradley’s Neurology in Clinical Practice. Ed. 6; Elsevier Saunders 2012.
79. Gupta Neeru ,Yucel, Yeni H .Glaucoma as a neuro degenerative disease. Current opinion in Ophthalmology Mar 2007 ;(18):110-114.
80. Andreas U. Bayer, MD, Othmar N. Keller, MD. Association of Glaucoma With Neurodegenerative Diseases With Apoptotic Cell Death: Alzheimer’s Disease and Parkinson’s Disease. Am J Ophthalmol 2002; 133:135–137.

Dr Padmasree K. M
Assistant Professor, Dept. of Ophthalmology,

Medical College, Kottayam