This editorial article is based on information presented at a glaucoma symposium entitled “How Does Age Increase Risk in Glaucoma?” held at the ARVO 2008 meeting. The moderators were Claude Burgoyne and David Garway-Heath. Editorial comments in italics follow each section.
Overview of age and IOP in normal population
This presentation was given by Paul Mitchell from the University of Sydney, Australia, and presented some observations from large cross sectional eye studies. The Blue Mountain Eye Study and the Singapore Eye Study showed that increases in blood pressure and IOP accompany aging in a population. However, after the fifth decade of life, IOP undergoes only minor population changes. This may be affected by thinning central corneal thickness, which may cause a decrease in measured IOP by applanation tonometry. Other confounding factors that must be taken into consideration are environmental such as diet, smoking and exercise and these effects on cardiovascular health and blood pressure.
Age as a risk factor in glaucoma: is it duration or deterioration?
Harry Quigley from Johns Hopkins Wilmer Eye Institute, Baltimore, noted that the world population is aging as a whole. With this, there is an increase in glaucoma prevalence with increasing age across all races. While open angle glaucoma prevalence increases with age in blacks, whites, Latinos and Chinese, the prevalence curves are race dependent. Angle closure glaucoma also increases with age, and differs ethnically. One caveat to this data is that it is derived from prevalence data, not a direct measure. For example, a population is measured cross-sectionally at one point in time to determine the prevalence as a function of age, which is an indirect measure of the risk attributable to age. A direct measurement can only be obtained by following one age cohort through many decades of life to obtain incidence data, something that is not practical.
Retinal ganglion cell death occurs at a rate of 5000 axons per year, or 0.5% per year as a function of normal aging. Data from Jonas confirms this, but there is a large amount of variability, or scatter in this rate. After 50 years of age, the rate increases to approximately 7000 per year. With this background rate of ganglion cell loss occurs a loss of retinal sensitivity as measured by visual fields. However, this is incorporated into perimeters with an age matched normative data base.
Data from several cross sectional studies were analyzed to determine the effect of age on glaucoma across several ethnic groups. The average duration of disease of open angle glaucoma is 13.1 years in whites, 15.4 in blacks, 13.0 in Latinos, and 10.5 in Chinese populations. How fast open angle glaucoma worsens was calculated using visual fields as loss of dB per year. The slowest rate of loss is in Europeans, at -1.1 dB per year, with Africans and Latinos at -1.3 and Chinese at -1.6. It seems also that the rate of loss is different with age in Europeans and Africans; in Europeans the rate worsens in older populations, and in Africans this is reversed. In Latinos and Chinese populations, however, the rate does not seem to be age dependent.
He concluded that age has also been identified by clinical trials such as the Early Manifest Glaucoma Trial as an independent risk factor for progression of glaucoma. While age may be an independent risk factor, it can also affect other risk factors such as blood pressure and vascular supply to the optic nerve and retina.
I think that treating physicians have to understand that there is a background loss of retinal ganglion cells, and hence visual field in normals, and that the goal for glaucoma treatment is to reduce the rate of RGC loss to this basal rate. Some visual deterioration is inevitable, so stability of visual function in glaucoma patients is only based on an age matched measure. It is also worth noting that the risk of rate of progression varies with ethnicity. One observation that surprised me is that the Chinese population showed the greatest rate of visual field loss over time.
The aging TM – Why doesn’t IOP go up with age?
Elke Lutjen-Drecoll from University of Erlangen Nurnberg, Germany, noted that with increasing age, there is an increase in outflow resistance, but also a decrease in aqueous production that helps to balance this. She went on to discuss changes in ocular anatomy with age and how this can affect IOP.
Anatomic analysis of the trabecular meshwork (TM) shows that this elastic fiber network ends in a cribriform region and is connected to the inner wall of Schlemm’s canal endothelium. Contraction of the ciliary muscle opens the cribriform pathways and thus opens Schlemm’s canal. The cribriform elastic network is composed of elastic fibers that become sheathed with age, and thereby stiffen and lose compliance. The ciliary muscle also undergoes aging changes. The posterior elastic tendons lose elasticity, and the anterior elastic tendons stiffen. This results in a decreasing ability to pull back the ciliary muscle fibers. Within the TM, there is an increase of extracellular matrix causing an increase in aqueous outflow resistance. There is also a decrease in the washout of extracellular matrix contributing to this.
Uveoscleral outflow also decreases with age. The trabeculum ciliare muscle shows a decrease in the entrance of aqueous due to thickening. The spaces between the muscle fibers are reduced, and connective tissue within the muscle becomes hyalinized.
Aqueous production is affected by aging changes in the ciliary processes. These show hyalinization of the stroma, and increase distance between the capillaries and the ciliary epithelium, thus reducing ultrafiltration. The ciliary epithelium becomes smaller, with decreases in mitochondria and active secretion.
I thought this was an interesting look at the way anatomical changes in the aqueous outflow and production change with age. While most are aware that aging is associated with an increase in trabecular outflow resistance, it is noteworthy that changes also occur in uveoscleral outflow and aqueous production. This has several clinically significant ramifications. The first is that glaucoma may become more difficult to treat in an individual as they age. Therefore, if IOP rises, it may not be loss of effect of medications or other treatment, but a change in the balance between aqueous production and outflow. It is important to explain to patients that glaucoma is never cured, and requires constant monitoring and adjustment of therapy. Some medications may be more effective in older individuals. For example, since aqueous production decreases naturally and uveoscleral outflow resistance increases with age, aqueous suppressants may be less effective than uveoscleral outflow drugs with age. This assumes, however, that the effect of the drugs on their respective pathways does not also change with age.
The aging optic nerve: is it more susceptible?
M. Rosario Hernandez of Northwestern University in Chicago presented views on aging changes of the optic nerve that may affect susceptibility to glaucomatous damage. With age, there is an activation of glia within the optic nerve head, an increase in extracellular matrix (ECM), and a decrease in retinal ganglion cells (RGC). But is the age related loss of RGCs the same as loss related to glaucoma?
Other aging changes include an increase in astrocytes and connective tissue and increase in glial reactivity. The ECM undergoes increase in synthesis and cross linking, as well as decreased degradation and the accumulation of advanced glycation end products (AGE). There is an increase in elastin in the lamina cribrosa and thickness of elastic fibers in the optic nerve head. This is accompanied by changes in the types of collagen, with an increase in the stiffer Type I collagen and a decrease in the more flexible Type III collagen. The net effect is a stiffer lamina cribrosa. This hardening of the support structure for retinal ganglion cells may lead to a greater susceptibility to mechanical stress due to elevated IOP.
Normal aging changes in the optic nerve head and especially the support for RGCs increases susceptibility to IOP related damage. Therefore, a glaucoma patient may require a lower target IOP as they age.
Age related alterations in systemic and ocular blood flow
Alon Harris from Indiana University, Indianapolis, presented research from his group and others on blood flow and aging and its possible effect on open angle glaucoma. With age, there are functional and structural changes in the cerebral vasculature. Thickening of the cerebral arteriolar basement membrane, decreased elastin, among other things, cause decreasing cerebral blood flow, increased resistance to flow and decreased nitric oxide activity.
Ocular blood flow can be divided into choroidal, retrobulbar, and retinal blood flow. Choroidal blood vessels show a decreased density, lumen diameter and blood volume with age. Combined with an increase in scleral rigidity and systemic blood pressure, this leads to a decrease in ocular blood supply. The retrobulbar circulation undergoes a decrease in flow velocity and increase in resistivity. Retinal blood flow shows a similar decrease in volume and velocity, leading to a decrease in optic nerve head circulation.
All of these vascular changes can lead to increase oxidative stress on retinal ganglion cells and hasten their demise. However, he cautions that there are no longitudinal studies of vascular changes over time in the same cohort. It is not known if the effect is linear, or if the effect of aging is homogenous or heterogenous. It also remains to be seen what the effect of ocular and systemic medications is on ocular blood flow.
Certainly blood flow to the brain and eye changes with age. The problem is that this is very difficult to measure even in a research setting (let alone a clinical setting), and currently relies on assumptions between blood velocity and volumetric flow. It is not currently possible to measure blood flow in specific small arteries supplying the optic nerve, and therefore not possible to direct therapy at improving blood flow. However, the volume of evidence supports maintaining a healthy vascular system to reduce glaucoma risk, and also has the benefit of reducing the risk of morbidity and mortality from systemic disease. This remains a very interesting area of glaucoma research as well as other ocular diseases (such as diabetic retinopathy).
Does the aging immune system contribute?
Gülgün Tezel of the University of Louisville, Kentucky, discussed the effects of aging on the immune system and glaucoma risk. Glial cells are resident immune regulatory cells and responsible for glial immune regulatory activity. The immune system changes with aging, showing a dysfunction of immunoregulation. Aging neurons may be more susceptible, and aging glia provides a less effective support structure.
Oxidative stress occurs in glaucoma, and also with increasing age. There can be direct oxidative damage to neurons. There can also be an oxidative stress dysfunction of immune regulatory systems leading to an immune injury to retinal ganglion cells. When tissues are chemically stressed, they show an increase in antigenicity and may be more susceptible to immune attack.
Future research in this area will likely include the evaluation of antioxidants for glaucoma treatment. In addition, targeting glia for protection and immunomodulation are possibilities.
There is increasing evidence that immune related injury can contribute to glaucomatous optic neuropathy. It will be very interesting to see if antioxidant therapy for glaucoma is incorporated into any clinical trials as it was in the AREDS trial. Immunomodulation therapy is another candidate, but likely further in the future.
Are there clinical differences in the neuropathy with age?
Balwantray Chauhan from Dalhousie University, Halifax, Canada, next discussed the changes seen in the optic nerve with aging versus those seen in open angle glaucoma. As mentioned in previous talks, one thing to keep in mind is that all age related loss data is cross sectional and not longitudinal.
With age, the optic nerve undergoes a decrease in rim area and increase in peripapillary atrophy, accompanied by a decrease in visual field sensitivity. However, the standard deviation of mean deviation loss with age exceeds the expected loss over a 60 year span, so this may not be significant or easily measured.
The measured loss of neuroretinal rim area with age occurs mostly in the inferotemporal region, which is quite similar to glaucomatous loss over time. The inferotemporal region showed the greatest change over time, then temporal, followed by superior and then nasal.
In their study, glaucomatous optic nerves were categorized into four groups: diffuse, focal, myopic and senile sclerotic. The diffuse group showed a generalized enlargement of the cup to disc ratio and was associated with younger age. The focal group showed localized notching of the rim and was associated with older age. The myopic group exhibited tilting of the nerve, peripapillary atrophy and focal loss and was associated with younger age. The senile sclerotic group was characterized by attenuated vessels, moth-eaten appearance of the rim, and a saucerized and pale nerve. Not surprisingly, this group was associated with older age, but showed less progression with increasing age.
The most interesting point of this talk was that the optic nerve changes over time with age alone, and that some of these changes are similar to glaucoma progression. The categories of glaucomatous optic disc damage are also classic and should be recognizable to any clinician. In the future, therapy may be directed towards which pattern of optic nerve damage is seen.
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