Glaucoma

Risk factors for open-angle glaucoma

Harry A. Quigley

Glaucoma Service and Dana Center for Preventive Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Risk factors are attributes of a person at risk or of their environment that make disease more likely to occur. Some risk factors are immutable (such as chromosomal gender), while others are variable, and even amenable to change through therapy or behavior modification. The understanding of risk factors provides clues to causation, but the complexity of most disorders typically frustrates direct, simple cause and effect linkage. The causes of disease in each individual who share a common phenotype may be different or may share some risk factors but not others. The sequence of events that cause a disease is not simple and linear, though some factors are present prior to others, and the entry of the last risk factor into the picture is followed by a period before disease appears known as the induction period. So, the cause of open-angle glaucoma (OAG) is not simply ‘mechanical’ or ‘vascular’, but deserves a more sophisticated analysis. Risk factors for open-angle glaucoma will be considered here in a brief format, as a more definitive report on this subject is presently in preparation for publication.

Age is a consistent risk factor for OAG, the older the person, the more likely the disease. Prevalence of OAG rises more than linearly with age. This may be a combination of a number of features related to age. The relevant body tissues age, and older retinal ganglion cells (RGC) may die faster than younger ones. Age expresses the length of time that the person is exposed to other risk factors, increasing the chance that they will lead to disease. The longer the sufficient component risk factors are present for a person, the more likely that disease will be present. Age modifies the strength of association of other risk factors, for example, hypertension.

Gender shows only modest association with aspects of OAG. Some studies show that men are somewhat more likely to develop OAG or to undergo progression, while others suggest that women are at greater risk for worsening. We must keep in mind that men and women differ only in 60 or so genes on the Y-chro- mosome, and that the gender-related differences in OAG may relate as much to culturally determined behaviors that are gender-specific as they do to hormonal

Address for correspondence: Glaucoma Service, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA

Eye on the Bayou, New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology, pp. 61–64 Transactions of the 54th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 18-20, 2005

edited by Jonathan D. Nussdorf

© 2006 Kugler Publications, The Hague, The Netherlands

influences that are biochemical. Men may be less likely to seek preventive care, or doctors may behave differently toward female patients.

Ethnicity plays an important role in the literature of OAG, but many experts now question whether we can actually distinguish humans on the basis of an artificial construct called race. With particular reference to black or African-de- rived persons, there is cultural and historical baggage associated with designating persons differently. We speak of these categories as if they are genetic, yet there are no consistent DNA markers that distinguish us, and some of the risk associated with physical appearance may be socio-economic or cultural in origin.1

Having expressed those reservations, we have found that African-derived persons in East Baltimore, Maryland, and African villagers in Tanzania, East Africa share a prevalence of OAG that is four times higher than that of European-de- rived persons.2 Across an ocean of differences in diet, education, environment and attitudes, this similarity speaks to a genetic component to this shared risk. East Indian, Chinese, and Europeans seem to have similar OAG prevalence. The differences for African-derived persons may relate to having larger diameter optic discs with smaller numbers of RGC, thinner corneas, poorer response to topical drugs, or poorer access to care.

Those who have family members affected by OAG are ten times more likely to develop the disease.3 To say that this is a genetic effect is appropriate, though one must leave open the possibility that families share more than genes, and the environmental impact on a common genetic endowment may magnify the association within family units. The linkage is significant for siblings and parents, but more distant relationships are not so well studied. The likelihood that a patient who gives a ‘positive’ family history is actually correct that the family member has OAG is far from reliable. But, family members are known to share similar disc parameters, IOP levels, and refractive errors. And, we now know that at least two genes, optineurin and myocilin,4 when mutated in particular ways, are associated with a small number of cases of OAG.

The IOP, both its level and its fluctuation range are consistent risk factors for OAG, though it is incorrect to equate this with ‘elevated’ IOP, as was commonly done in the past. POAG can occur at all levels of IOP. The higher the IOP, the more likely POAG is to occur, the more severe it is, and the more likely it is to progressively worsen, even when IOP is consistently in the range considered normal.5 The association between IOP level and risk of development of POAG is a shallowly increasing exponential relation, with no ‘break-point’. The transition from the normal IOP in a population to the level considered elevated does not distinguish those below and above this zone from each other. The past use of the terms normal tension glaucoma is an anachronism. It is now recognized that a substantial minority of POAG occurs at normal levels of IOP and the definition of POAG now does not include an IOP criterion. A causative linkage between IOP and POAG has been firmly established by the additional facts that lowering of IOP decreases onset or progression, and by the production by increasing IOP in animal models of a disease identical to human glaucoma.

Other ocular anatomic features are risk factors for OAG. These include exfoliation syndrome and pigment dispersion syndrome. Myopia, even at relatively lower refractive errors also confers increased risk. The thinner cornea has recently been recognized as an important factor, at least because it causes artificially lower IOP

measurements by applanation tonometry, but also perhaps as an indication of poorer responsiveness to the stresses on the eyewall that associate with OAG. The larger the optic disc diameter, the more likely OAG is to occur,6 probably as a biomechanical disadvantage of a larger weak spot in the posterior globe where axons exit. It seems that peripapillary crescents of non-junction between disc margin and Bruch’s membrane may also increase risk, though they are very common in the general population.

There has been considerable study of whether personal behaviors affect OAG risk. Interestingly, nearly all of them seem unrelated. This includes no association with caffeine, alcohol, or cigarette consumption, and no consistent relationship with body mass index. The failure to have an association with cigarettes, which are highly related to two other major eye diseases, cataract and macular degeneration, is interesting. We frequently do not pay attention to ‘negative’ risk factors. But here, one must wonder why the definitive effect of smoking (presumed to act through generation of excess free radicals) has no effect on OAG. Does this suggest that free radicals are rarely of import in OAG pathogenesis? Some things may matter, for example, exercise lowers IOP, so couch potatoes should be urged to start a program. But, it should not include hanging upside down or any other behavior that raises episcleral venous pressure – such as playing a wind musical instrument.7 The latter raise IOP and may be associated with OAG.

Some non-glaucoma medications are OAG risk factors. On the good side, therapies that lower cholesterol were recently linked to lower OAG risk.8 It is wellknown that oral and topical corticosteroids raise IOP. The steroid nasal sprays and inhaled steroid products must also be treated as risk factors as well.9

Other clinical diseases and states are also risk factors for OAG, though none of the relationships are strong or simple. Thyroid disease, migraine, and sleep apnea are all reported associations, as are both late menarche and early menopause in women. The story with hypertension used to be simple, it was a risk factor. Most studies now agree that it is not a global risk factor, but only when considered together with age and IOP. Younger persons with hypertension are less likely to have POAG, while older hypertensives were at greater risk.10 This suggests that the duration of hypertension is an important modifier of the effect of blood pressure on POAG. Furthermore, low blood pressure is also highly associated with presence of POAG when it is near enough to the level of IOP that their difference (blood pressure minus IOP = perfusion pressure) falls below a certain level (below 50 mmHG and particularly below 30 mmHg).

Diabetes was also formerly considered an OAG risk factor, but most studies now show that it is not. Furthermore, there is the intriguing fact that diabetics have higher mean IOP than non-diabetics. Hence, they should have more OAG, unless there’s some protective aspect of diabetes for OAG. This sounded farfetched until the Ocular Hypertension Treatment Study found that diabetes (nonretinopathy, early disease) was protective for development of initial damage.11 One speculation is that early diabetes causes leakage of serum proteins into the retina that are actually neuroprotective.

Now that we have listed factors that are linked to OAG in some way, we should be more sophisticated and realize that some things would make initial OAG more likely, some would make progression more likely, and some would relate to response to therapy. The list might not be the same for each. In fact, some

64 Harry A. Quigley

might be detrimental for incidence but be beneficial factors in response to treatment (e.g., pigment dispersion). We will need to dissect the roles of risk factors in greater detail.

The future holds the use of risk factors in calculations that predict the most likely future course of patients as they enter the care system. We will use the available information on the patient and risk associations for them based on past data to generate the level of concern for treatment, i.e., the target pressure and whether we wish to add neuroprotective treatments that are developed independent of IOP-lowering. This risk assessment will be continuously updated as examination information is accumulated on the patient to maximize the chance that we do the least harm.

References

1.Wilson MR: The use of “race” for classification in medicine: is it valid? J Glaucoma 12:293294, 2003

2.Buhrmann RR, Quigley HA, Barron Y, West SK, Oliva MS, Mmbaga BBO: The prevalence of glaucoma in a rural east African population. Invest Ophthalmol Vis Sci 41:40-48, 2000

3.Wolfs RCW, Klaver CCW, Ramrattan RS, van Duijn CM et al: Genetic risk of primary openangle glaucoma. Population-based familial aggregation study. Arch Ophthalmol 116:16401645, 1998

4.Stone EM, Fingert JH, Alward WL, Nguyen TD et al: Identification of a gene that causes primary open angle glaucoma. Science 275:668-70, 1997

5.Cartwright MJ, Anderson DR: Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol 106:898900, 1988

6.Healey PR, Mitchell P: Optic disc size in open-angle glaucoma: The Blue Mountains Eye Study. Am J Ophthalmol 128:515-517, 1999

7.Schuman JS, Massicotte EC, Connolly S, Hertzmark E, Mukherji B, Kunen MZ: Increased intraocular pressure and visual field defects in high resistance wind instrument players. Ophthalmology 107:127-133, 2000

8.McGwin G Jr, McNeal S, Owsley C, Girkin C, Epstein D, Lee PP: Statins and other choles- terol-lowering medications and the presence of glaucoma. Arch Ophthalmol 122:822-826, 2004

9.Mitchell P, Cumming RG, Mackey DA: Inhaled corticosteroids, family history, and risk of glaucoma. Ophthalmology 106:2301-2306, 1999

10.Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC: Hypertension, perfusion pressure and primary open-angle glaucoma: a population-based assessment. Arch Ophthalmol 113:216221, 1995

11.Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Kass MA: The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120:714-720, 2002