Glaucoma neuroprotection

Robert N. Weinreb

Glaucoma is an optic neuropathy in which patients can lose visual field despite intraocular pressure (IOP) lowering. The death of retinal ganglion cells is the hallmark of glaucoma and contributes to the optic neuropathy. Figure 1 summarizes some factors that can contribute to the death of the retinal ganglion cell in glaucoma.¹ The leading risk factor for glaucoma is IOP, which can cause a blockade in axoplasmic flow and interfere with delivery of neurotrophic growth factors from the lateral geniculate nucleus (LGN) to the retinal ganglion cell. Increased IOP can compress and alter the lamina cribosa, and cause a blockade of both retrograde and anterograde axoplasmic flow.

Fig. 1. Factors that contribute to the pathophysiology of glaucomatous neurodegeneration. (Adapted from: Weinreb RN and Khaw PT. Lancet 2004; 363: 1711-1720, with permission.)

Other factors that contribute to retinal ganglion cell death include ischemia and the condition of the mi-crocirculation, changes in the immune system (both in B-cell immunity and cell-mediated immunity), and other factors such as excessive glutamate stimulation, inflammatory cytokines, microglia and astrocytes² (summarized in Fig. 2).

Fig. 2. Mechanisms hypothesized to play a role in causing retinal ganglion cell death in glaucoma. (Adapted from: Weinreb RN and Levin LA. Arch Ophthalmol 1999; 117: 1540-1544, with permission.)

Current management of glaucoma

Glaucoma is a continuum, progressing from undetect-able, to asymptomatic, to functional impairment, and – in some patients – to blindness. Currently, we manage glaucoma by ‘staging’ the disease and by monitoring progression. Staging the disease means placing the patient on the glaucoma continuum, and then following the patient over a period of time by repeatedly assessing visual function, and assessing the structure of the optic disc and retinal nerve fiber layer. Assessing progression is challenging, even for experts, and requires time, numerous visual field tests, and numerous observations of the optic disc. Another approach is to examine various risk factors for progression to determine which patients are at greatest risk and need more careful observation. For example, a patient with mild ocular hypertension and a low risk of progression (i.e., normal standard visual field and normal appearing optic disk) may only need monitoring at intervals of a year or more. In contrast, a patient with marked ocular hypertension and a high risk of progression (e.g., high IOP, thin central corneal thickness, exfoliation, disc hemorrhage) may need to be followed at three- or six-month intervals to monitor progression. IOP lowering is currently the only approved therapy for glaucoma. Although many patients benefit from the widespread use of safe and effective medications to lower IOP, many continue to experience progres-sive visual field loss, progressive loss of optic nerve fibers, and progressive loss of retinal ganglion cells despite IOP lowering.

The need for glaucoma neuroprotection

A number of studies have shown that blindness can result from a lack of treatment as well as ineffective treatment. A study by Wilson et al. examined the natural history of glaucoma in a West Indies population of 205 patients with untreated glaucoma or suspected glaucoma during the period 1986 to 1987. About one-sixth of these patients progressed to blindness in at least one eye over 10 years. About 10% progressed to bilateral blindness. More than half of the eyes that progressed to end-stage glaucoma had no visual field loss or minimal visual field loss at baseline.³ A retrospective study by Hatenhauer et al. showed that the lack of effective treatment can also result in blindness.⁴ In this study of 295 patients with newly diagnosed open-angle glaucoma, the probability of blindness after 20 years was 27% in one eye, and 9% in both eyes. Of the 114 patients initially treated for ocular hypertension, the probability of blindness after 20 years was 14% in one eye, and 4% in both eyes. A large number of clinical trials have examined the effect of lowering IOP to delay glaucoma progres-sion. In the Ocular Hypertension Treatment Study,⁵ lowering IOP was effective in delaying or preventing the onset of primary open angle glaucoma in some, but not all, subjects with elevated IOP. Progression to a glaucoma endpoint occurred even with medi-cal treatment. In the Early Manifest Glaucoma Trial (EMGT),⁶ treatment reduced the number of patients with early glaucoma who appeared to progress. How-ever, even in the treated patients, almost one-half of the patients appeared to progress. As another example, the Collaborative Normotension Glaucoma Study,⁷ showed that treatment reduced the number of patients that progressed. But even in the treated eyes, 12% of patients progressed. Each of these studies showed that although lowering IOP reduces the number of patients who progress and lowers the rate of progression, glaucoma continues to progress despite treatment.

Challenges in developing a neuroprotective drug in glaucoma

Neuroprotection offers the potential for preventing retinal ganglion cell death independent of the particular factors that are contributing to the optic nerve damage in individual patients. Regulatory agencies throughout the world have approved drugs to lower IOP, but have not approved drugs for preventing retinal ganglion cell death in glaucoma. Most regulatory agencies, includ-ing the FDA in the United States, equate glaucoma progression with standard visual field loss, and do not allow a primary endpoint to be structural alteration in the appearance of the optic disc or retinal nerve fiber layer. Detection of progressive glaucomatous injury and the definition of study endpoints, continues to be problematic. As glaucoma is a slowly progressive disease, the duration of clinical trials of neuroprotection are nec-essarily much longer than the duration required for determining IOP-lowering effects. Large numbers of patients are needed for clinical trials. To date, very few neuroprotection trials have been initiated with an adequate size of patient sample and adequate power to show a result.

References

1. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004; 363: 1711-1720.
2. Weinreb RN, Levin LA. Is neuroprotection a viable therapy for glau-coma? Arch Ophthalmol 1999; 117: 1540-1544.
3. Wilson MR. Progression of visual field loss in untreated glaucoma patients and suspects in St Lucia, West Indies. Trans Am Ophthalmol Soc 2002; 100: 365-410.
4. Hattenhauer MG, Johnson DH, Ing HH, et al. The probability of blindness from open-angle glaucoma. Ophthalmology 1998; 105: 2099-2104.
5. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 701-713; discussion 829-730.
6. Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120: 1268-1279.
7. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma.
   Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 1998; 126: 498-505.