Journal of Glaucoma:
Central Nervous System Changes in Glaucoma
Yücel, Yeni MD, PhD, FRCPC
Ophthalmic Pathology Laboratory, University of Toronto, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON, Canada
Disclosure: The author declares no conflict of interest.
Many glaucoma patients continue to lose vision despite treatment to lower intraocular pressure. In addition to the loss of retinal ganglion cells in the eye, there is injury to major visual pathways of the brain along the retino-geniculo-cortical pathway. Evidence for this comes from both glaucoma models and glaucoma patients. Understanding central visual system changes in glaucoma will provide insights into human glaucomatous neural degeneration and disease progression, in addition to potential novel strategies to prevent vision loss in glaucoma.
Elevated intraocular pressure (IOP) in glaucoma is associated with death of retinal ganglion cells (RGC) and their axons. Ninety percent of RGC project to the lateral geniculate nucleus (LGN). Neurons of the LGN send their axons via the optic radiation to the primary visual cortex. Each hemisphere of the brain has a LGN, arranged in 6 distinct layers, corresponding to the cell bodies of 2 inner magnocellular, 4 outer parvocellular layers, and koniocellular neurons sandwiched between them.
Studies of glaucomatous neurodegeneration in the brain have come primarily from the experimental monkey models, which are highly relevant given the similarities of anatomy and physiology of major visual pathways between humans and primates. In this model, trabeculoplasty leads to elevated IOP, typically induced in one eye. Varying degrees of RGC loss can be induced in this model, as measured by histomorphometric techniques, including ocular hypertension, in which elevated IOP in present in the absence of RGC loss, as well as a range from partial to total loss of RGCs.1
In this model, the anatomic layout of the LGN allows us to separate central nervous system (CNS) changes induced by the glaucomatous eye compared to the fellow eye, with unique perspective into the damage occurring in the LGN secondary to elevated IOP. The first evidence of cell death in major central visual pathways came from studies of the LGN in a monkey model.2,3 Loss of both magnocellular and parvocellular relay neurons was observed (Fig. 1).2 Surviving LGN relay neurons showed significant cell body shrinkage.4 Furthermore, the damage in the LGN to these layers increased with increasing IOP and optic nerve damage.4 The koniocellular pathway also showed decreased immunoreactivity of CaMK-II alpha, a selective marker of koniocellular neurons.5 Thus, in this model, glaucoma appears to affect 3 major vision channels, the magno-, parvo-, and koniocellular pathways.5
These changes do not appear to be exclusively attributable to deafferentation, as reduced dendrite complexity and distribution area were detected in monkeys with ocular hypertension without significant optic nerve fiber loss.6 In fact, it is quite possible that the shrinkage of LGN neurons and dendrite changes represent a window of opportunity for strategies to prevent vision loss in glaucoma. Evidence comes from studies in which monkeys treated with memantine—an open channel N-methyl-D-aspartate (NMDA) blocker—demonstrated attenuation of atrophy,7 and increased dendrite complexity in the memantine-treated glaucoma group compared to the vehicle-treated glaucoma group (Fig. 2).8
Neuropathological findings in the monkey model were confirmed in human glaucoma, with evidence of degeneration in the intracranial optic nerve, LGN, and visual cortex, corresponding to visual field defects.9 Using newer neuroimaging modalities, such as magnetic resonance imaging (MRI), to visualize the LGN has revealed significant structural atrophy in glaucoma patients compared to age-matched normal controls.10 Important insights continue to come from non-human models of glaucoma and human neuroimaging studies of glaucoma patients.
In summary, aside from the typically described optic nerve head changes seen in glaucoma, work over the past decade has demonstrated neurodegeneration extending throughout the visual pathway from the retina to the LGN and on to primary visual cortex. Understanding glaucomatous neural degeneration in the brain may help to develop new neuroimaging biomarkers to assess disease progression, and novel treatment strategies to prevent vision loss in glaucoma.
1. Yücel YH, Kalichman MK, Mizisin AP, et al .Histomorphometric analysis of optic nerve changes in experimental glaucoma.J Glaucoma. 1999; 8:38–45.
2. 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.
3. 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.
4. Yücel YH, Zhang Q, Weinreb RN, et al .Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma.Invest Ophthalmol Vis Sci. 2001; 42:3216–3222.
5. 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.
6. 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.
7. Yücel YH, Gupta N, Zhang Q, et al .Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma.Arch Ophthalmol. 2006; 124:217–225.
8. Ly T, Gupta N, Weinreb RN, et al .Dendrite plasticity of the lateral geniculate nucleus in primate glaucoma.Vision Res. 2011; 51:243–250.
9. Gupta N, Ang L-C, Noël 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.
10. Gupta N, Greenberg G, Noël 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.
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