Should we treat the brain in glaucoma? Neeru Gupta,* † MD, PhD, FRCSC; Yeni H. Yücel, †‡ MD, PhD, FRCPC ABSTRACT • RÉSUMÉ The loss of retinal ganglion cells in glaucoma may lead to blindness, and current therapies are directed at reducing pressure within the eye. Most of the retinal ganglion cell axon lies outside the eye, and evidence from experimental primate and human glaucoma suggests that axon injury extends from the optic nerve to visual pathways in the brain. Neurodegenerative changes in the central visual system may contribute to the pathology of glaucomatous progression. Thus, intraocular pressure-lowering strategies combined with neuroprotective therapies to protect visual neurons in the retina and brain may help to preserve vision in patients with glaucoma. La perte des cellules ganglionnaires de la rétine due au glaucome peut entraîner la cécité et les thérapies actuelles ont pour objet de réduire la pression intraoculaire. La majeure partie des axones des cellules ganglionnaires de la rétine est cependant située en dehors du globe oculaire et les données sur le glaucome expérimental primate et chez les humains, semblent indiquer que l’atteinte de l’axone s’étend du nerf optique aux voies optiques du cerveau. La neurodégénérescence du système visuel central peut, en partie, sous-tendre la pathologie de la progression glaucomateuse. Ainsi, les stratégies de réduction de la pression intraoculaire pour protéger les cellules ganglionnaires de la rétine, combinées avec les thérapies neuroprotectrices pour protéger les neurones visuelles de la rétine et du cerveau, pourraient aider à préserver la vue des patients atteints de glaucome. I n glaucoma, retinal ganglion cell (RGC) death 1 and atrophy 2 of surviving RGCs lead to vision loss and visual dysfunction. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, 3 and current treat- ments to lower IOP are helpful in slowing progressive vision loss. 4–6 Many patients, however, continue to lose vision despite adequate IOP control. 4–9 This evidence suggests that mechanisms other than IOP also con- tribute to disease progression. In this context, a discus- sion of pathological events beyond the eye in glaucoma is relevant. FROM THE RETINAL GANGLION CELLS TO THE LATERAL GENICULATE NUCLEUS Most of the RGC axon is extraocular, forming the intraorbital, intracanalicular, and intracranial optic nerve, chiasm, and optic tract. Ninety percent of RGCs are retinogeniculate neurons and convey visual information from the retina to the lateral geniculate nucleus (LGN). The LGN has 3 distinct visual channels, namely the magno-, parvo-, and koniocellular pathways for motion, red–green colour, and blue–yellow modalities, respec- tively. The human and nonhuman primate LGN is organized anatomically into 6 principal layers of neurons with magnocellular neurons located in ventral layers 1 and 2, parvocellular neurons located in dorsal layers 3–6, and koniocellular neurons intercalated between principal LGN layers (Fig. 1). LGN layers are eye-specific, with layers 2, 3, and 5 connected to the ipsilateral eye, and layers 1, 4, and 6 connected to the contralateral eye. CENTRAL VISUAL SYSTEM INJURY IN GLAUCOMA In experimental primate glaucoma, elevated IOP induces RGC death and this leads to characteristic changes in the optic nerve head that closely mimic human glau- coma. 10 RGC atrophy 2 and loss 1 is well described in this primate glaucoma model, and the optic nerve behind the globe also undergoes significant injury. 11 Examination of From *the Glaucoma and Nerve Protection Unit, St. Michael’s Hospital, † the Departments of Ophthalmology & Vision Sciences and Laboratory Medicine & Pathobiology, University of Toronto, the Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, and ‡ the Ophthalmic Pathology Laboratory, University of Toronto Presented in part at the International Ocular Neuroprotection Symposium in Toronto Oct. 14, 2006 Originally received Feb. 18, 2007. Revised Feb. 21, 2007 Accepted for publication Feb. 25, 2007 Correspondence to: Yeni Yücel, MD, PhD, Eye Research & Pathology Laboratory, University of Toronto, St. Michael’s Hospital, 30 Bond St., Toronto ON M5B 1W8; yeni.yucel@utoronto.ca This article has been peer-reviewed. Cet article a été évalué par les pairs. Can J Ophthalmol 2007;42:409–13 doi: 10.3129/can j ophthalmol.i07-051 Treating the brain in glaucoma—Gupta & Yücel 409