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New algorithms for assessing Humphrey visual fields have been developed. FDT is created by a low spatial frequency sinusoidal grating undergoing high temporal frequency counterphase flicker producing the appearance of twice as many light and dark bars than are actually present. This doubling of the special frequency of the bars is thought to be mediated by magnocellular (M-cell) retinal ganglion cells and, therefore, has high sensitivity and specificity for detection of glaucomatous visual field loss (Johnson and Samuels, 1997; Casson et al., 2001). Importantly, the sensitivity and specificity of FDT for detection of moderate and advanced glaucomatous visual field loss were greater than 97% in one study, suggesting that it may be especially useful for detecting the progression of the disease (Cello et al., 2000). SWAP may also be able to detect functional deficits not seen with standard visual field testing (Klistorner and Graham, 2000; Hutchings et al., 2001). Furthermore, both SWAP and FDT testing have found deficits that were not picked up with standard automated perimetry, and the SWAP and FDT abnormalities were highly correlated (Landers et al., 2000).

Increasingly, there is an interest in assessing the effect of new therapies on quality of life. Questionnaires are often employed to determine quality of life; however, it is important to make sure that the questionnaires are validated for the disease of interest. The visual function questionnaire is one such quality-of-life measure that has been validated in a number of diseases including diabetes mellitus, macular degeneration, glaucoma, and cytomegalovirus retinitis (Mangione et al., 2001).

Neuroprotection and glaucoma

A number of scientists are trying to develop neuroprotective therapies for glaucoma. However, data suggest that lowering IOP can decrease visual loss, and, in a sense, provide neuroprotection (Collaborative Normal-Tension Glaucoma Study Group, 1998; The AGIS Investigators, 2000; Lichter et al., 2001; Heijl et al., 2002; Kass et al., 2002; Miglior et al., 2005). Therefore, in studying neuroprotection in glaucoma, it will be important

to assess preservation of vision while controlling for IOP. For example, laboratory studies of glaucoma medications demonstrate neuroprotection in animal models of optic nerve disease. It is important to compare these drugs to control medications that similarly lower IOP but reportedly have no neuroprotective effects. For example, in an animal model of ocular hypertension, systemic administration of brimonidine or timolol had equivalent effect on IOP (WoldeMussie et al., 2001). Nevertheless, brimonidine significantly reduced the progressive loss of retinal ganglion cells by greater than 50%, whereas timolol had no effect. These considerations should also apply to human clinical trials. Two phase 3 randomized, double-masked clinical trials assessing the neuroprotective effects of memantine, a drug that blocks the NMDA receptor, were recently completed. In these trials, the neuroprotective effects of the drug on visual function in glaucoma patients will be assessed apart from effects on IOP.

Although definitive proof of a neuroprotective medication in ophthalmology will probably require data from a randomized, clinical trial, there are some instances where an open-label trial of a medication could lead to believable evidence. In diseases where the clinical outcome is well documented with little or no variability, an openlabel trial could provide convincing data, using historical controls. Unfortunately, there are few such conditions. One potential disorder is central retinal artery occlusion in patients lacking a cilioretinal artery. If a treatment were studied that preserved 20/20 vision in even a relatively small number of patients, the data could be fairly convincing, since the visual outcome of this condition is usually catastrophic. However, there is still the opportunity for bias, and one should be very careful about misinterpreting data from trials without a concurrent control group and random assignment of treatment.

Conclusions

In conclusion, neuroprotection offers an exciting therapeutic approach to a number of diseases.

Clearly, patients with disorders affecting the retina or optic nerve may benefit from neuroprotective medications. One must be careful in interpreting data from small, uncontrolled studies. Welldesigned clinical trials with validated endpoints will provide the best insight on the neuroprotective effects of medications, and provide new treatment options that hopefully will save vision.

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