Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Box 25.4a  Mechanisms of primary angle closure

Levels of block

•Level I: iris and pupil

•Level II: ciliary body

•Level III: lens-induced glaucoma

•Level IV: malignant glaucoma/retrolenticular

gradually move towards normal values in suspected and unaffected family members. Amongst Chinese twins, additive genetic effects appear to be the major factor in the variation of ACD and relative ACD (defined as ACD/axial length).65

No genetic associations have yet been conclusively proven for PACG. Two studies have reported that PACG subjects may carry a mutation in the myocilin gene (MYOC)66,67; however other analysis has not supported this in Chinese patients with chronic PACG.68 Linkage with a locus at 10q for PACG has been reported,69 as has an association between a single-nucleotide polymorphism in the matrix metalloproteinase 9 (MMP-9) gene and APAC.70

Pathophysiology

Primary angle closure

Ritch and Lowe described the four main mechanisms of angle closure resulting in iris blocking aqueous outflow through the trabecular meshwork. Treatment for each level of the block is necessary71 and each level of the block may have a component of the preceding level (Box 25.4a).

Level I: iris and pupil

Pupil block is the most common mechanism of angle closure.72 There is resistance to aqueous flow through the pupil in the area of iridolenticular contact. This causes a limitation of aqueous flow from the posterior chamber to the anterior chamber, and creates an increased pressure gradient between the anterior and posterior chambers with resultant anterior bowing of the iris (bombé), narrowing of the angle, and iridotrabecular contact. Laser iridotomy or surgical iridectomy relieves the pressure difference between the anterior and posterior chambers caused by pupil block. Consequently, the iris becomes flatter and the iridocorneal angle widens.

Level II: ciliary body

An abnormal ciliary body position leads to anteriorly positioned or rotated ciliary processes, pushing the peripheral iris into the angle. This condition is also known as plateau iris. Gonioscopy will show the iris root angulated forward and centrally, giving the appearance of a “double hump.” Plateau iris syndrome occurs when angle closure with raised IOP develops in an eye with plateau iris configuration despite a patent iridotomy. As laser iridotomy only relieves pupil block, laser iridoplasty has been suggested as the treatment of choice for plateau iris.73 Iridociliary cysts, tumors, or edema may mimic plateau iris configuration.74

Pathophysiology

Figure 25.4  Ultrasound biomicroscopy image of plateau iris causing angle closure.

A study in Singapore using standardized UBM criteria found plateau iris (Figure 25.4) in about a third of PACS eyes after LPI,75 confirming that non pupil block mechanisms are important in angle closure in Asians. However, this may not be pertinent to other populations.76

Level III: lens-induced glaucoma

A large intumescent lens or an anteriorly subluxed lens51 may push the iris and ciliary body forward, triggering acute or chronic ACG (phacomorphic glaucoma) (Figure 25.5). Treatment involves removing the lens.

Level IV: malignant glaucoma/retrolenticular

In this condition, a pressure difference is created between the vitreous and aqueous compartments due to aqueous misdirection into the vitreous. Anterior rotation of the ciliary body with forward rotation of the lens–iris diaphragm causes anterior lens displacement and angle closure by pushing the iris against the trabecular meshwork. A shallow supraciliary detachment may be present and it is this effusion that is thought to cause the anterior rotation of the ciliary body.51

Medical treatment with cycloplegics, hyperosmotic and ocular hypotensive agents helps reverse the abnormal anatomy. Vitrectomy is indicated if Nd:YAG laser anterior hyaloidotomy or posterior capsulotomy (in pseudophakic patients) fails.

Choroidal effusion

Quigley et al77 proposed several contributing risk factors for PACG/APAC: small eye size, choroidal expansion, and poor vitreous conductivity. Choroidal expansion causing anterior rotation of the ciliary body and iridolenticular forward movement is thought to be the mechanism by which scleri-

tis, sulfa drugs, and panretinal photocoagulation cause secondary angle closure. Uveal effusion has been found in untreated PACG/APAC eyes prior to LPI by UBM,78,79 but it is not known if this is a cause or effect of PACG/APAC.80 Alternatively, the accumulation of suprachoroidal fluid could be secondary to rapid changes in IOP, exudation from uveal vessels, a congestion of the choroidal circulation due to high IOP, or the effect of topical pilocarpine and oral acetazolamide.

Causes of secondary angle closure (Box 25.4b)

Secondary angle closure glaucoma with an anterior pulling mechanism without pupil block

This occurs when the trabecular meshwork is obstructed by iris tissue or a membrane. Examples are neovascular glaucoma, where a fibrovascular membrane occludes the trabecular meshwork. Iridocorneal endothelial syndrome (ICE) occurs when a progressive endothelial membrane formation

Box 25.4b  Causes of secondary angle closure

•With an anterior pulling mechanism without pupil block

•With a posterior pushing mechanism without pupil block

occludes the trabecular meshwork. Epithelial ingrowth after intraocular surgery or the formation of inflammatory membranes may also cause this secondary angle closure. Rarer causes are aniridia and endothelial posterior polymorphous dystrophy.

Secondary angle closure with a posterior pushing mechanism without pupil block

Causes are iris and ciliary body cysts, silicone oil, or expansile gas injected in the vitreous cavity, uveal effusions due to inflammation, scleral buckling (by the resultant increased choroidal venous) pressure and retinopathy of prematurity.51

6.Foster PJ, Buhrmann R, Quigley HA,

et al. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86:238–242.

8.Foster PJ, Aung T, Nolan WP, et al. Defining “occludable” angles in population surveys: drainage angle width, peripheral anterior synechiae, and glaucomatous optic neuropathy in east Asian people. Br J Ophthalmol 2004;88: 486–490.

25.Radhakrishnan S, Goldsmith J, Huang D, et al. Comparison of optical coherence tomography and ultrasound biomicroscopy for detection of narrow

anterior chamber angles. Arch Ophthalmol 2005;123:1053–1059.

36.Ritch R, Lowe RF. Angle-closure glaucoma: therapeutic overview. In: Ritch R, Shields MB, Krupin T (eds) The Glaucomas, 2nd edn. St. Louis: Mosby, 1996:1521–1531.

40.Ritch R, Tham CC, Lam DS. Long-term success of argon laser peripheral iridoplasty in the management of plateau iris syndrome. Ophthalmology 2004;111: 104–108.

42.Lai JS, Tham CC, Chan JC. The clinical outcomes of cataract extraction by phacoemulisfication in eyes with primary

angle-closure glaucoma (PACG) and co-existing cataract: a prospective case series. J Glaucoma 2006;15:47–52.

43.Aung T. In: Weinreb RN, Friedman DS, editors. Angle Closure and Angle Closure Glaucoma. Consensus Series 3. The Hague, Netherlands: Kugler Publications, 2006:27–35.

45.Choong YF, Irfan S, Manage MJ. Acute angle closure glaucoma: an evaluation of a protocol for acute treatment. Eye 1999;13:613–616.

65.He M, Wang D, Zheng Y, et al. Heritability of anterior chamber depth as an intermediate phenotype of angle-

closure in Chinese: the Guangzhou Twin Eye Study. Invest Ophthalmol Vis Sci 2008;49:81–86.

71.Ritch R, Lowe RF. Classifications and mechanisms of the glaucomas. In: Ritch R, Shields MB, Krupin T (eds) The Glaucomas, 2nd edn. St. Louis: Mosby, 1996:752.

72.Nolan WP, Foster PJ, Devereux JG, et al. YAG laser iridotomy treatment for

primary angle closure in East Asian eyes. Br J Ophthalmol 2000;84:1255–1259.

74.Foster P, He M, Liebmann J. In: Weinreb RN, Friedman DS (eds) Angle Closure and Angle Closure Glaucoma. Consensus Series 3. The Hague, Netherlands: Kugler Publications; 2006:20.

75.Kumar RS, Baskaran M, Chew PTK, et al. Prevalence of plateau iris in primary angle closure suspects an ultrasound

Key references

biomicroscopy study. Ophthalmology 2008;115:430–434.

76.He M, Foster PJ, Johnson GJ, et al. Angle-closure glaucoma in East Asian and European people. Different diseases? Eye 2006;20:3–12.

79.Sakai H, Morine-Shinjyo S, Shinzato M, et al. Uveal effusion in primary angleclosure glaucoma. Ophthalmology 2005;112:413–419.

Glaucoma is the leading cause of irreversible blindness and is estimated to affect approximately 67 million people worldwide.1 The pathological correlate of disease is the loss of retinal ganglion cells (RGCs)2,3 and their optic nerve axons. Glaucoma is a silent, slowly progressive disease that causes irreversible vision loss. Elevated intraocular pressure (IOP) is a major risk factor. Other risk factors include family history of glaucoma, black race, increasing age, myopia, and abnormal blood pressure.

Key components of the clinical assessment for glaucoma include measurement of IOP, and examination of the optic nerve head. The diagnosis is made based on visualizing characteristic patterns of damage to the optic nerve head. Features of glaucomatous optic neuropathy include evidence of retinal nerve fiber layer loss, excavation and cupping of the nerve head, focal or diffuse loss of the neuroretinal rim, and disc hemorrhage (Box 26.1). These findings correlate with visual field deficits in a retinotopic fashion when vision loss is present. A complete eye assessment that includes the anterior-chamber angle helps to determine whether these changes are secondary to specific etiologies such as angle closure glaucoma, or whether the entity is primary open-angle glaucoma in which no abnormality is detected other than optic nerve head pathology and possibly elevated IOP.

All treatments for glaucoma are based on lowering IOP by pharmacological agents in the form of eye drops or surgical methods. Glaucoma may also occur in patients without evidence of elevated IOP, so-called low-tension glaucoma, where the IOP lies within the range observed in the general population. Large randomized prospective clinical trials have demonstrated that reducing IOP helps protect vision loss compared to untreated patients, including those without obvious elevated IOP.4–7 Many patients, however, continue to lose sight in spite of adequate IOPlowering treatment.4–7 In this context, factors other than IOP that are implicated in RGC injury and death in glaucoma are under active investigation. Understanding how and why glaucoma progresses will propel the development of novel adjunctive treatments to prevent blindness.

The pathologic basis for vision loss in glaucoma appears to be RGC injury and death.2 The RGC injury in glaucoma is typically slow, partial, and progressive, accounting for specific patterns of vision loss that deepen and expand over time. Some evidence suggests that RGC death is apoptotic in nature,2 and primary mechanisms leading to programmed cell death have been reviewed elsewhere.3 Experimental work performed in glaucoma models with elevated IOP has been optimized over the years to study the sequence of pathological events triggered by IOP elevation.8–11

As RGCs die, histological examination of the optic nerve head reveals progressive optic nerve head excavation, with progressive tissue atrophy and gliosis. In the retina, there is reduced density of surviving RGCs and thinning of the inner nerve fiber layer. These changes are likely due to atrophy and/ or loss of the RGC cell body.12,13 Previous morphological studies demonstrated increased susceptibility of larger optic nerve fibers to IOP and this was interpreted as selective injury to magnocellular neurons.14,15 However, it is now accepted that cell atrophy may have accounted for some of these observations, and recent studies show that at least 10 RGC types in nonhuman primates are larger than magnocellular RGCs.16

In addition to inner retinal pathology, photoreceptor pathology in glaucoma has been reported17,18 but remains controversial.19 Horizontal cell abnormality was reported previously in two glaucoma eyes with elevated IOP requiring enucleation.20 A recent report demonstrated abnormal phosphorylation of tau protein involving the horizontal cells of human glaucoma surgical enucleation specimens (Box 26.2).21

Pathological events associated with RGC death include glial cell alteration at the optic nerve head,22,23 disruption of axonal transport mechanisms leading to growth factor deprivation,24 oxidative stress,25 glutamate excitotoxicity,26 immune alterations,27 and vascular pathology23,28 (Figure 26.1).

Etiology

The cause of open-angle glaucoma is not clearly established. The major risk factor, elevated IOP, can be considered as the

Box 26.1  Clinical background

•Glaucomatous optic neuropathy shows characteristic patterns of optic nerve damage

•Elevated intraocular pressure is a major risk factor for the development of glaucoma

•All current therapies for glaucoma aim to lower intraocular pressure

•Many patients continue to lose vision despite treatments to lower pressure

Box 26.2  Retinal pathology in glaucoma

•The major pathologic correlate of vision loss in glaucoma is retinal ganglion cell injury and death

•Excavation of the optic nerve head with tissue atrophy and gliosis may also be observed

•In addition to retinal ganglion cell death, photoreceptor and horizontal cell pathology have been reported in glaucoma

•Multiple mechanisms of cell death are implicated in the pathobiology of glaucomatous optic nerve damage

•Elevated intraocular pressure in experimental primate glaucoma closely reproduces optic nerve and visual field changes of human disease

cause of the glaucomatous injury in many cases. Support for this comes from nonhuman primate studies in which damage from elevated IOP closely mimics human glaucoma. In this model, IOP elevation is caused by laser-induced scarring of trabecular meshwork in the eye.9,29 The IOP elevation is typically induced in one eye, and eye pressure is chronically monitored during experiment (Figure 26.2). The experimental primate model of glaucoma is highly relevant to human disease due to similar anatomy and physiology of central visual pathways,30 characteristic glaucomatous optic nerve changes as observed in human glaucoma,9,31,32 and visual deficits similar to those observed in glaucoma patients.33 In addition to IOP, optic disc changes34,35 and visual electrophysiological changes36–38 can be monitored in vivo. After chronic exposure to elevated IOP there is blocked anterograde transport to the lateral geniculate nucleus (LGN)39 and retrograde transport at the level of the lamina cribrosa,40–43 RGC death,2 and atrophy of surviving cell bodies and dendrites.12,44,45

Anatomy and pathophysiology

The unmyelinated RGC axon inside the eye becomes myelinated as it leaves the eye beyond the lamina cribrosa. The RGC axon is long and forms the intraorbital, intracanalicular, and intracranial components of the optic nerve, optic chiasm, and optic tract (Figure 26.3 and Box 26.3). In primates most RGC axons are retinogeniculate, and target the LGN directly,46 while a remaining 10% target other subcortical structures including the superior colliculus, pretectal nuclei, accessory optic system, and suprachiasmatic nucleus.47

The LGN conveys visual information received from the retina to the primary visual cortex in humans and nonhu-

Anatomy and pathophysiology

Figure 26.1  Multiple cell types and mechanisms implicated in neural degeneration in visual pathways in glaucoma. IOP, intraocular pressure.

Figure 26.2  Laser-induced injury to the right eye induces elevated intraocular pressure (IOP). IOP is monitored in the experimental right and fellow nonglaucoma eyes over time.

man primates. This structure is composed of neuronal cell bodies arranged into six anatomically segregated layers that carry signals from the three major magno-, parvo-, and koniocellular vision pathways. Each LGN layer receives input from one eye only: layers 2, 3, and 5 receive input from the ipsilateral eye, and layers 1, 4, and 6 from the contralateral eye. In the two most ventral layers, magnocellular neurons convey motion information, and in the four remaining dorsal LGN layers, parvocellular neurons convey red–green color information. Koniocellular neurons are found intercalated between principal layers and convey blue–yellow color information.48 Eighty percent of neurons in the LGN are relay neurons that comprise the axons of the optic radiations to the primary visual cortex. Approximately 20% of LGN neurons stay within the LGN: these are GABAergic interneurons.49 Of the total input to the LGN, less than 10% derive from RGCs, with the remaining 90% coming from GABAergic interneurons, cortical, and subcortical synaptic inputs.50

Transsynaptic degeneration of the lateral geniculate nucleus in glaucoma

Transsynaptic degeneration is a phenomenon in which injured neurons spread injury to previously uninjured neurons connected by a synapse. Within the central nervous

6

4

2

1

P M K

Control

Figure 26.5  Cross-sections of the right lateral geniculate nucleus in control (lower panel) and glaucomatous monkeys (top panel) show the laminar arrangement of the neuronal cell bodies. Compared to the control, in glaucoma, overall atrophy is observed. Parvalbumin-positive relay neurons in layers 1, 4, and 6 are decreased in number. (Reproduced with permission from Yücel YH, Zhang Q, Gupta N, et al. Loss of neurons in magno and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol 2000;118:378–384.)

Visual cortex changes in glaucoma

Relay neurons of the LGN project to the primary visual cortex. Here, neurons are arranged into six layers subdivided into sublayers. The M, P, and K geniculate axons terminate in sublayers of layer 4 and superficial layers in eye-specific columns called ocular dominance columns.66 In monkeys with unilateral glaucoma, a relative decrease in metabolic activity has been detected with cytochrome oxidase activity in ocular dominance columns driven by the glaucomatous eye, compared to those driven by the fellow nonglaucoma eye55,56,60,67 (Figure 26.6). Neurochemical changes in the visual cortex involving growth cone-associated protein-43 (GAP-43) and inhibitory neurotransmitter receptor γ-aminobutyric acid (GABA) A receptor subtype are additional evidence of neuroplasticity in the primate visual system.68 Apart from these neurochemical changes, direct evidence of neuron loss in the primary visual cortex in primate glaucoma is lacking. However, relative differences in metabolic activity of ocular dominance columns between the glaucoma and nonglaucoma eye appeared more pronounced with increasing optic nerve fiber loss.60

were noted in the dendrites, with measurable reduced dendrite complexity and field area in the magnoand parvocellular layers of the LGN.61 These findings suggest that not all LGN changes are attributable to deafferentation within the visual system. Transsynaptic degeneration of the LGN in primate glaucoma appears to affect the three major vision channels, namely the magno, parvoand koniocellular pathways (Box 26.4).60 While changes to relay neurons in experimental glaucoma are described above, it is not known whether GABAergic interneurons in the LGN are also altered in glaucoma, as has been observed following enucleation and monocular deprivation.62

Glial cells including astrocytes and NG-2 cells appeared altered in experimental glaucoma in the optic tract and LGN.54,63 Other studies show the involvement of other cell types such as microglia64 and vascular65 cells in the LGN in glaucoma. Mechanisms related to transsynaptic degeneration in glaucoma may be relevant to strategies aimed at preventing the spread of disease to visual centers in the brain and presumably disease progression.

Central visual system changes in human glaucoma

Decreased LGN neuron density was reported in humans, with more pronounced effect in magnocellular layers,69 a subject of considerable controversy.70,71 Recent findings in human glaucoma support observations of central visual pathway neural degeneration in experimental primate glaucoma.72 In an index human glaucoma case, postmortem analysis of the visual system revealed neuropathology in the prechiasmal intracranial optic nerve, LGN, and visual cortex and correlated with visual field defects in a retinotopic fashion.72 Thus, in this case with superior bilateral visual field defects, marked inferior optic nerve atrophy and decreased phosphorylated neurofilament, neuron atrophy in the lateroposterior LGN and marked thinning of the inferior bank of the primary visual cortex was noted. In a study of human primary open-angle glaucoma patients with vision loss, atrophy of the LGN by magnetic resonance imaging has been reported.73 Functional neuroimaging (fMRI) showed

Box 26.7  Clinical implications

•Glaucoma is a neurodegenerative disease affecting visual neurons in the eye and brain

•Early intervention to lower intraocular pressure in glaucoma and prevent the spread of damage to target neurons is an important therapeutic strategy

•Progressive damage in glaucoma despite adequate intraocular pressure control may be explained by ongoing central neural degeneration

•There is a strong need for neuroprotective agents to target neural degeneration in glaucoma

•Functional deficits in glaucoma may be unveiled by a multidisciplinary approach to retinogeniculocortical pathway involvement

•In human primary open glaucoma there is evidence of structural atrophy of the lateral geniculate nucleus and functional change in the visual cortex

In patients with inadequate IOP control and progressive loss of RGCs, degeneration in the visual system might be expected. Thus, treatment to lower IOP prior to significant RGC loss would help to prevent the spread of injury from RGCs to their target neurons in the brain. Furthermore, in patients with well-controlled IOP and progressive glaucomatous damage, transsynaptic central degeneration triggered by RGC injury helps to explain the progressive nature of the disease. Future more comprehensive treatment strategies to treat glaucoma may need to protect neurons in the retina and central visual system (Box 26.7).87 Clinical trials in glaucoma with memantine, an NMDA open channel blocker, have recently failed to show significant effect as detected by primary outcomes. At this time, there is no neuroprotective agent that has proven to help preserve vision in glaucoma patients.

The retinogeniculocortical involvement in glaucoma might be exploited to uncover specific functional neural deficits in patients, including cortical binocular functions such as stereovision88–90 or other pathway-specific functions. Nongeniculocortical pathways involved in eye movements and reflexes and circadian rhythms may also be worth exploring in glaucoma. Multifocal and evoked electrophy­ siological measurements may be relevant to the detection of dysfunction along visual pathways.91

The loss of visual field in moderate to advanced disease is likely a representation of damage to central visual pathways in glaucoma. Increased susceptibility of RGCs to ongoing glaucomatous injury has been described as a determinant in progression of the disease.92 We suggest that degeneration with neuronal loss and atrophy of target neurons in the LGN may alter the normal function of surviving RGCs in glaucoma. In fact, degenerative changes in RGCs are observed following the loss of target cells in the LGN93–95 and lesions of the striate cortex.96,97 Changes in the visual

Acknowledgment

Box 26.8  Conclusions

•Visual field loss in moderate to advanced glaucoma is a reflection of damage throughout the visual pathway

•A better understanding of brain changes in glaucoma may contribute to novel strategies to diagnose, manage, and follow disease

•Intraocular pressure (IOP)-lowering strategies combined with therapies to protect retina and central visual system neurons offer new opportunities to prevent blindness from glaucoma

•In glaucoma, features of progressive loss of visual neurons, transsynaptic degeneration in the visual system, and abnormal protein accumulation make it the most common neurodegenerative disease

stations may deplete growth factor sources to be transported back to the retina, contributing to the susceptibility of surviving RGCs to ongoing glaucomatous injury and progression, and studies are needed to test this hypothesis.

Conclusion

While RGC death is central to the pathology in glaucoma, depending on the severity of disease, injury may extend anywhere from the retina to the visual cortex in the brain. It is likely that by the time visual field deficits are detected, central nervous system pathology is present. Lowering IOP is an important strategy to prevent RGC death in the eye, and may reduce the risk of central nervous system degeneration in glaucoma. In patients with progressive vision loss despite adequate IOP control, secondary pathological changes in the brain are likely. Thus, IOP-lowering strategies combined with therapies to protect retina and central visual system neurons offer new opportunities to prevent blindness from glaucoma (Box 26.8).

Numerous similarities exist between glaucoma and neurodegenerative diseases98: the selective loss of neuron populations; transsynaptic degeneration in which elevated IOP and injury to RGCs can trigger injury in distant connected neurons; common mechanisms of cell injury and death, including abnormal protein accumulation. There is a need to understand factors other than IOP involved in disease progression in patients. Approaching glaucoma as a neurodegenerative disease that considers eye and central visual pathway damage may help to identify future strategies to prevent progressive blindness from glaucoma.

Acknowledgment

This work was supported in part by the Glaucoma Research Society of Canada, Canadian Institutes of Health Research, and The Nicky and Thor Eaton Fund and Dorothy Pitts Fund.

21.Gupta N, Fong J, Ang LC, et al. Retinal tau pathology in human glaucomas. Can J Ophthalmol 2008;43:53–60.

55.Vickers JC, Hof PR, Schumer RA, et al. Magnocellular and parvocellular visual pathways are both affected in

a macaque monkey model of glaucoma. Aust NZ J Ophthalmol 1997;25: 239–243.

56.Crawford ML, Harwerth RS, Smith EL 3rd, et al. Glaucoma in primates: cytochrome oxidase reactivity in parvoand magnocellular pathways. Invest Ophthalmol Vis Sci 2000;41: 1791–1802.

57.Weber AJ, Chen H, Hubbard WC, et al. Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus. Invest Ophthalmol Vis Sci 2000;41:1370– 1379.

58.Yücel YH, Zhang Q, Weinreb RN, et al. Atrophy of relay neurons in magnoand parvocellular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci 2001;42:3216–3222.

59.Yücel YH, Zhang Q, Gupta N, et al. Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol 2000;118:378–384.

60.Yücel YH, Zhang Q, Weinreb RN, et al. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 2003;22:465–481.

61.Gupta N, Ly T, Zhang Q, et al. Chronic ocular hypertension induces dendrite pathology in the lateral geniculate nucleus of the brain. Exp Eye Res 2007;84:176–184.

65.Luthra A, Gupta N, Kaufman PL, et al. Oxidative injury by peroxynitrite in neural and vascular tissue of the lateral geniculate nucleus in experimental glaucoma. Exp Eye Res 2005;80:43–49.

67.Crawford ML, Harwerth RS, Smith EL 3rd, et al. Experimental glaucoma in primates: changes in cytochrome oxidase blobs in V1 cortex. Invest Ophthalmol Vis Sci 2001;42:358–364.

68.Lam DY, Kaufman PL, Gabelt BT, et al. Neurochemical correlates of cortical plasticity after unilateral elevated intraocular pressure in a primate model of glaucoma. Invest Ophthalmol Vis Sci 2003;44:2573–2581.

72.Gupta N, Ang LC, Noel de Tilly L, et al. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol 2006;90:674– 678.

73.Gupta N, Greenberg G, de Tilly LN, et al. Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging. Br J Ophthalmol 2009;93:56–60.

74.Duncan RO, Sample PA, Weinreb RN,

et al. Retinotopic organization of primary visual cortex in glaucoma: Comparing fMRI measurements of cortical function with visual field loss. Prog Retin Eye Res 2007;26:38–56.

98.Gupta N, Yücel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 2007;18:110–114.