Glaucoma is a group of eye diseases characterized by a progressive optic neuropathy (with multifactorial risk factors) and recognizable patterns of optic disc and retinal nerve fiber structural and visual field functional damage.1
The disease is caused by a variety of mechanical, vascular and biochemical factors leading to retinal ganglion cell apoptosis, which manifests clinically as optic neuropathy and finally can lead to blindness for a patient if not recognized or treated in time.
MAGNITUDE OF THE PROBLEM
Glaucoma is the leading cause for irreversible blindness worldwide and in India. It is estimated that glaucoma cases worldwide will increase from 60 million in 2010 to 80 million in 2020 due to increased aging population.2, 3 It has been estimated that nearly 12 million Indians currently have glaucoma and this figure will increase to more than 16 million by 2020.2 Population-based studies in India suggest that more than 90% of glaucoma cases in our country remain undiagnosed.4–10 This is in contrast to 40–60% rates of undiagnosed disease in more developed countries. These high rates of undiagnosed glaucoma translate into significant rates of glaucoma blindness.
The World Glaucoma Association has set a goal of reducing the undiagnosed rate of glaucoma from “50% to No more than 20% by 2020.” Since visual loss for glaucoma is totally preventable if detected and treated in time, it is imperative for general ophthalmologists to have an overview of the disease and understand the principles of its medical management.
Since 1622, when Richard Banister first noticed a connection between hard eyeballs and blindness, IOP and primary open-angle glaucoma has been inexorably linked. In this text, we will focus mainly on the management of primary open angle glaucoma (POAG). Primary angle closure disease and glaucoma management in special cases such as in children and pregnant women will be dealt in a separate section. In addition this manual will also look at non-IOP dependant factors which can influence the course of the disease.
The purpose of this manual is to focus the attention of the reader on the patient as a whole and not just treat the intraocular pressure, because we are dealing with a sick eye in a sick body. Therefore, the target is not the “IOP” but the “Patient,” as the final aim of treating any disease is to improve the quality of life of the patient.
Primary open angle glaucoma is a chronic, progressive optic neuropathy causing characteristic morphological changes at the optic nerve head and retinal nerve fiber layer in the absence of other ocular disease or congenital anomalies in eyes with open anterior chamber angles. Progressive retinal ganglion cell loss leads to corresponding visual field defects. The relative risk for primary open angle glaucoma rises continuously with the level of intraocular pressure (IOP) and there is no evidence of a threshold intraocular pressure for the onset of the condition.11 Diagnosis of the disease can be made if there is evidence of progressive structural change in the optic nerve head and/or retinal nerve fiber layer in the absence of functional defects on standard automated white on white perimetry (Preperimetric glaucoma).
Normal Tension Glaucoma (NTG)
The definition is same as POAG except that the central corneal thickness (CCT) corrected IOP is less than 22 mmHg (mean + 2SD) on diurnal variation. It is a diagnosis of exclusion; most cases are managed like POAG.12, 13
Ocular Hypertension (OHT)
It is defined as the CCT corrected IOP above the 97.5 percentile in that population, with open angles on gonioscopy and no disc or field changes.14
PATHOGENESIS OF GLAUCOMA
There are three major theories regarding the pathogenesis of glaucoma:
- Mechanical (IOP related damage),
- Vascular (decrease in blood supply to optic nerve head), and
- Biochemical (decrease in neurotrophic factors/increased levels of neurotoxins).
Therefore, the three possible therapeutic options would be to decrease IOP and/or increase perfusion to the optic nerve head and provide neuroprotection to retinal ganglion cells.15, 16
Elevated IOP often results from alterations in aqueous humor dynamics due to changes in trabecular meshwork leading to impaired drainage of aqueous. The trabecular meshwork has been shown to exhibit cytoskeletal changes in cells, altered cellularity and changes in extracellular matrix (ECM). An increase in IOP leads to interference with axoplasmic flow, which results in decreased delivery of essential growth factors produced by target cells of superior colliculus and lateral geniculate body to the optic nerve head. The axons of RGCs which are subjected to axoplasmic flow obstruction become distended at the nerve head due to membrane bound vesicles. RGC death after exposure to elevated IOP takes place in two phases. The primary mechanism of neuronal loss in the initial phase is apoptosis18 while in the second phase neuronal loss is due to toxic effects of the primary degenerating neurons in addition to continuing exposure to elevated IOP.17–19
Figure 1.1 is a simplified flow diagram of the mechanical theory.
The optic nerve head blood flow is dependent on the following factors:
- Resistance to blood flow
- Blood pressure (BP)
- Blood viscosity
Ocular blood flow is determined by the equation:
Blood flow = Perfusion pressure/ Resistance to flow
Perfusion pressure can be calculated as:
Perfusion pressure = Mean arterial BP– IOP
where, Mean arterial BP = Diastolic BP + 1/3 (Systolic BP- Diastolic BP)
Hence a decrease in blood pressure or an increase in IOP reduces the perfusion pressure to optic nerve head.
In a healthy eye, a constant flow of blood is required in the retina and optic nerve head so as to meet their high metabolic needs. To maintain a constant rate of blood flow an efficient autoregulatory mechanism operates in arteries, arterioles and capillaries over a wide range of day-to-day fluctuations in ocular perfusion pressure that is dependent on both the systemic blood pressure and IOP.
These autoregulatory mechanisms are more robust in young individuals as compared to the elderly. Deficient autoregulatory mechanisms leading to ischemia contribute to the development of glaucomatous neuronal damage with increasing age. POAG and normal tension glaucoma patients have also shown a chronically reduced optic nerve head and retinal blood flow20, 21 especially in people with low systemic blood pressure leading to reduced ocular perfusion pressure.
Several studies point towards an association between vascular insufficiency and glaucoma. A positive association of glaucoma has been observed with migraine22 and peripheral vascular abnormalities23 that involve dysregulation of cerebral and peripheral vasculature respectively. Increased sensitivity to endothelin-1-mediated vasoconstriction is implicated in these vascular abnormalities. The possible role of this vasoconstrictor is also suspected in the pathogenesis of glaucoma as increased levels of endothelin-1 have been detected in the aqueous humor and plasma of glaucoma patients. Figure 1.2 shows the association between primary endothelial dysfunction and neuronal damage.
In a way mechanical and vascular theories are interlinked, because excavation of the optic disc leads to kinking of the blood vessels which in itself can compromise the blood supply.
The term “excitotoxic” describes dual action of specific amino acids like glutamate and aspartate, which leads to neural excitation in their normal state and cell toxicity when they are in excess. Glutamate Mediated toxicity:
Glutamate is a normal neurotransmitter in the retina which can accumulate in excess, resulting in toxic levels. Apoptotic cell death of RGCs has also been attributed to glutamate-mediated toxicity and upon exposure to hypoxic conditions retinal cells are known to release glutamate.24 Glutamate-induced excitotoxicity is primarily mediated by ionotropic NMDA subtype receptors.25–27 NMDA receptor activation leads to opening of associated ion channels and the entry of extracellular Ca++ and Na+ into the neurons, finally leading to apoptosis and cell death. In addition, excess production of nitric oxide (NO) by astrocytes and microglia in optic nerve head may play a crucial role in the development of optic neuropathy associated with glaucoma.28 It is a free radical of moderate reactivity and after entering the cell leads to the production of highly reactive free radicals such as peroxynitrite after combining with superoxide (a product of mitochondrial metabolism). These highly reactive free radicals are capable of causing massive destruction of cell components and macromolecules leading to apoptosis.
Our concepts of the glaucomas are constantly evolving as our understanding of disease processes becomes better, technology advances, and our treatment strategies become more sophisticated.
As of today the only feasible option is to reduce IOP by medical, laser or surgical therapy. In addition, one needs to address non-IOP dependant systemic factors such as blood pressure, diabetes, sleep apnea, lipids, vasospasm and life-style changes which can contribute to a worsening of glaucomatous optic neuropathy (discussed later in detail).
- American Academy of Ophthalmology Glaucoma Panel. Primary open-angle glaucoma preferred practice pattern. CA7 American Academy of Ophthalmology San Francisco, 2005; p. 1–39.
- Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262–7.
- Quigley HA. Proportion of those with open angle glaucoma who become blind. Ophthalmology 1999;106:2039–41.
- Dandona L, Dandona R, Srinivas M, Mandal P, John RK, McCarty CA, et al. Open-angle glaucoma in an urban population in southern India: The Andhra Pradesh eye disease study. Ophthalmology 2000;107:1702–9.
- Ramakrishnan R, Nirmalan PK, Krishnadas R, Thulasiraj RD, Tielsch JM, Katz J, et al. Glaucoma in a rural population of southern India: The Aravind Comprehensive Eye Survey. Ophthalmology 2003;110:1484–90.
- Vijaya L, George R, Arvind H, Baskaran M, Paul PG, Ramesh SV, et al. Prevalence of angle-closure disease in a rural southern Indian population. Arch Ophthalmol 2006;124:403–9.
- 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 Ophthalmol Vis Sci 2005;46:4461–7.
- 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. Ophthalmology 2008 Apr;115(4):648–54.e1.
- Vijaya L, George R, Arvind H, Baskaran M, Ve Ramesh S, Raju P, et al. Prevalence of primary angle-closure disease in an urban south Indian population and comparison with a rural population The Chennai Glaucoma Study. Ophthalmology 2008 Apr;115(4):655–60.e1.
- Wilson MR, Martine JF. Epidemiology of chronic open-angle glaucoma. In Ritch R, Shield MB, Krupin T, editors. The Glaucomas. 2nd ed. Mosby Yearbook Inc: St. Louis 1996.
- Werner EB. Normal tension glaucoma. In: Ritch R, Shield MB, Krupin T, editors. The glaucomas. 2nd ed. Mosby Yearbook Inc: St. Louis 1996; p. 770.
- Mardin CY, Horn FK, Jonas JB, Budde WM. Preperimetric glaucoma diagnosis by confocal scanning laser tomography of the optic disc. Br J Ophthalmol 1999;83:299–304.
- Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86:238–42.
- Garway-Heath DF, Rudnicka AR, Lowe T, et al. Measurement of optic disc size: equivalence of methods to correct for ocular magnification. Br J Ophthalmol 1998;82:643–9.
- Thylefors B, Negrel AD. The global impact of glaucoma. Bull World Health Organ 1994;72:323–6.
- WoldeMussie E, Ruiz G, Wijono M, Wheeler LA. Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci 2001;42:2849–55.
- Agar A, Yip SS, Hill MA, Coroneo MT. Pressure related apoptosis in neuronal cell lines. J Neurosci Res 2000;60:495–503.
- Mittag TW, Danias J, Pohorenec G, Yuan HM, Burakgazi E, Redman RC, et al. Retinal damage after 3 to 4 months of elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci 2000;41:3451–9.
- Chung HS, Harris A, Kagemann L, Martin B. Peripapillary retinal blood flow in normal-tension glaucoma. Br J Ophthalmol 1999;83:466–9.
- Wang JJ, Mitchell P, Smith W. Is there an association between migraine headache and open-angle glaucoma? Findings of the Blue Mountains Study. Ophthalmol 1997;104:1714–9.
- O'Brien C, Butt Z. Blood flow velocity in the peripheral circulation of glaucoma patients. Ophthalmologica 1999;213:150–3.
- Neal MJ, Cunningham JR, Hutson PH, Hogg J. Effects of ischaemia on neurotransmitter release from the isolated retina. J Neurochem 1994;62:1025–33.
- Choi DW. Ionic dependence of glutamate neurotoxicity. J Neurosci 1987;7:369–79.
- Novelli A, Reilly JA, Lysko PG, Henneberry RC. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res 1988;451:205–12.
- Moreno MC, Moreno, Sande P, Aldana H, Marcos, Zavala N de, et al. Effect of glaucoma on the retinal glutamate/glutamine cycle activity. FASEB J 2005;19:1161–2.
- Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Ann Rev Physiol 1995;57:683–706.