Martin_edit_Cardiology_book_temp 21/01/2010 11:58 Page 28
Glaucoma
which is an active cell death programme that involves a cascade of essential to the management of glaucoma patients, and is also crucial
events that lead to the orderly demise of a cell. In transgenic mice in the quest to develop new therapies for the disease. However,
with hereditary glaucoma that also lack Bax, a major component of existing methods to measure progression have significant limitations.
the apoptotic pathway, RGC loss from the retina is greatly reduced, Visual field analysis is widely used and is arguably the most clinically
but axonal degeneration continues.
10
Thus, blocking apoptosis is relevant measure of glaucoma change as visual function is measured
insufficient to prevent RGC axonal degeneration in glaucoma, and directly. However, most visual field analysis relies on psychophysical
therapeutic strategies to protect axons are potentially worth exploring testing and as a result variability is a major difficulty. Variability in visual
for their ability to alleviate glaucoma progression. field testing means that multiple tests are often required to confirm
progression; therefore, it can take a considerable period of time to
Axoprotection confirm whether a patient is deteriorating. This has implications not
In order to protect axons it is necessary to understand the just for the treatment of individual patients, but also for clinical studies
mechanisms by which they degenerate. Axonal degeneration of new potentially neuroprotective treatments where the ‘noisiness’ of
can occur by several mechanisms, but Wallerian degeneration visual field end-points contributes to the need for long, and therefore
frequently occurs, especially following major axonal injury. Wallerian expensive, clinical trials with large numbers of patients.
degeneration is an active process that leads to the orderly
breakdown of axons in response to injury, and mutations that block In addition, visual field changes tend to lag behind RGC loss, with
this process can enhance axonal survival. The best characterised defects developing only after 25–35% of RGCs have been lost at a
example mutation that reduces Wallerian degeneration is the slow given retinal location.
16
Testing strategies can be modified to improve
Wallerian degeneration mutation (
S
Wld ).
S
Wld arose spontaneously in progression detection using visual field testing, for example by
mice, where it delayed injury-induced degeneration of distal axon optimising the inter-test interval
17
and establishing a rate of
stumps by several weeks in both the peripheral and central nervous progression.
18
However, visual fields remain a relatively insensitive
system.
11
No other mutation is known to protect axons so robustly measure of glaucoma progression, at least in early disease.
from Wallerian degeneration, and several studies have demonstrated
that WldS protein expression delays axonal degeneration in Other approaches to the measurement of progression in current
experimental glaucoma.
2,12
We found that WldS delayed axonal clinical use include assessment of the nerve fibre layer and the 3D
degeneration in experimental rat glaucoma for at least two weeks. structure of the optic nerve head using scanning laser
The duration of axonal protection was similar to that after optic nerve ophthalmoscopy, ocular coherence tomography and polarimetry.
19
transection and crush, providing further evidence that axonal These techniques can provide evidence of structural changes
degeneration in glaucoma follows a Wallerian-like mechanism.
12
associated with glaucoma progression, but are relatively insensitive
Axonal degeneration must be prevented to maintain RGC function; to small changes. Thus, new techniques with the ability to rapidly
therefore, pharmacologically mimicking and enhancing the determine with precision the exact rate of glaucomatous progression
protective mechanism of WldS could offer an important route would be a major advance.
towards therapy. However, WldS did not protect RGC bodies in
glaucoma or after other types of optic nerve injury, suggesting that Using Basic Science to Improve
combined treatments to protect both axons and cell bodies may Detection of Progression
offer the best therapeutic prospects. Detailed understanding of the mechanisms of RGC loss in glaucoma
has the potential to suggest new approaches to the assessment of
Although Wallerian degeneration is the end result of severe axonal progression. As an example, the observation that RGC death in
injury, lesser insults can also have an effect on axonal function. As glaucoma occurs by apoptosis means that existing techniques to
an example, axonal transport blockade occurs soon after elevation visualise apoptosing cells may be applied to the glaucomatous eye.
of intraocular pressure in glaucoma models.
13,14
Axonal transport is Technology to image individual RGCs in the living eye and to trace
essential for normal RGC function and is mediated by motor the fate of individual labelled retinal cells over time has advanced
proteins, such as dynein and kinesin, which convey cargo along the rapidly over the last few years.
20–22
Cordeiro et al. used annexin V
microtubules of the axonal cytoskeleton. RGC retrograde transport labelling and carefully refined imaging techniques to identify
of brain-derived neurotrophic factor (BDNF) is interrupted by apoptosing retinal cells in the living eye.
23
Annexin V specifically
elevated eye pressure, leading to the accumulation of BDNF and its labels cells with surface membrane changes characteristic of
receptor, trkB, at the optic nerve head.
14
Impaired delivery of BDNF apoptosis. This technology has also been applied to glaucoma
to the RGC bodies is likely to adversely affect RGC survival, and models,
24
and a clinical trial in glaucoma patients is also planned.
supplementation of BDNF to the retina, for example by gene Such techniques represent a potentially important breakthrough in
therapy, has been shown to mitigate the effect of glaucomatous the assessment of glaucomatous progression by allowing individual
transport blockade in animal models.
15
Other approaches to reduce dying RGCs to be visualised. However, the ability of apoptosis
the effects of axonal transport dysfunction in glaucoma are worth imaging to separate normal RGC attrition due to ageing from
further exploration. glaucomatous progression remains to be established. Given that
apoptosing cells can only be detected by annexin V for four to six
Problems with Detecting hours, it is likely that the eye of a slowly progressing glaucoma
Progression in Glaucoma patient will have a relatively small number of apoptosing cells
In addition to helping us understand the mechanisms underlying detectable at a given point in time.
degeneration of RGC in glaucoma, basic science research is playing an
important role in the search for new ways to measure progression. Additional challenges will be introduced if the apoptosis rate in
Accurate determination of the presence and rate of progression is glaucoma subjects and controls is not uniform, with cell death
28 EUROPEAN OPHTHALMIC REVIEW
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