Glaucoma risk increases with age.20–22 As a consequence, glaucoma can be expected to be associated with other age-related diseases such as macular degeneration,20 vascular diseases,23 and obstructive sleep apnea24 for example. However this is not a direct link for most age-related diseases. The concept of frailty is a non-specific state of vulnerability which results in a higher risk for accelerated physical and cognitive decline, disability and death.25 Assessment of frailty depends on the accumulation of health deficits26 such as hypertension, hypotension, diabetes, migraine, obstructive sleep apnea syndrome, cataracts, glaucoma and the need for medications.27 As is the case for glaucoma, the prevalence of many other health problems tends to increase with frailty and may be an important reason for their concurrence in some patients. A frail patient at a younger age may have greater risk for developing glaucoma.

In the Ocular Hypertension Treatment (OHT) study, male gender was found by univariate analysis to be a useful predictor for the onset of primary open angle glaucoma (POAG).28 A Bayesian meta-analysis found that men were more likely to have OAG with the reservation that gender influence depends on the definition of glaucoma.29 For example, a review of the literature concluded that women are at higher risk for angle-closure glaucoma (ACG) but that there is no clear gender predilection for OAG.30 These findings may only be relevant to the groups studied. That women usually live longer than men increases their risk for glaucoma and glaucoma blindness.29

Evidence of the significance of Myocilin mutations in advanced primary open angle glaucoma (POAG)31 and copy number variations of TBK1 in normal tension glaucoma (NTG)32 illustrate the diagnostic potential for genetic testing. However, the contribution of genetics in glaucoma risk prediction has usually been limited to knowledge of family history33 although, too often, patients are unaware of family members who have been diagnosed with glaucoma.34 That more than 50% of glaucoma cases can be undiagnosed3 adds to the unreliability of family history. A family history of glaucoma was found to carry a relative risk of 2.1 times for being associated with at least possible OAG20 However, the relative importance of family history may vary according to the closeness of relationship of a patient to an affected family member (first. second or even third degree).35 Around half of all primary OAG patients have a positive family history, and their first degree relatives (parents, siblings or children) have an approximately 9-fold increased risk of developing glaucoma.32 Wolfs and co-authors found that the first degree relatives of glaucoma patients were found to have a 22% lifetime risk of glaucoma themselves in comparison to 2.3% in relatives of normal controls.36 The prevalence of glaucoma was 10.4% in the siblings of glaucoma patients compared to 0.7% in the siblings of normal controls.36 In addition, the risk of inheriting glaucoma may increase with the number of relatives diagnosed with the disease. Approximately 60% of a glaucoma patient sample was found to belong to families in which other members have the disease.7

A review of the findings from 11 population-based studies found a wide range in the prevalence of POAG among populations of the “same race”.37 Variable prevalence reported in different studies may have been due to different methods of examination as well as being a consequence of differences in exposure to geographic, social, behavioural and environmental factors.37 For certain age groups Racette and co-authors estimated the prevalence of POAG in a black American population, to be six times higher compared to whites.38 Although black populations have the highest prevalence of OAG, white populations showed the steepest increase in OAG prevalence with age.29 A higher glaucoma prevalence has been found in Asian populations including a higher incidence of primary angle-closure glaucoma (ACG) compared to white patients.39

Myopia has been found to be a significant risk factor for glaucoma.21,39–44 That myopia is a risk factor for glaucoma and that it is also more prevalent among Asian patients may help explain increased prevalence.39 In addition, that high myopia42 and increased axial length in certain age groups have both been identified as risk factors43,44 suggests that the risk of glaucoma development and progression increases with the degree of myopia.44

The significance of history items may vary with the type of glaucoma. For example, risk factors for acute ACG include hyperopia45 and myopia is a significant history item for progression of ocular hypertension (OHT) and POAG.40

Systemic hypertension, vasospasm, and acute hypotension have been proposed as potential risk factors for glaucoma in clinic-based studies.46–48 Several studies have reported associations between low diastolic pressure, lower ocular perfusion pressure (OPP) and higher prevalence and/or incidence of glaucoma.46–49 Low systemic blood pressure (BP), especially when combined with an elevated IOP, will lower OPP and risk a reduction in the volume of blood flow to the ONH in eyes with an impaired auto-regulatory system,50 leading to ischaemic and reperfusion oxidative stress damage to the axons and associated atrophy of the RGCs. A history of antihypertensive treatment and associated lower BP could increase the risk of glaucoma by this mechanism.51 The Blue Mountains population study found that mean IOP increased linearly from 14.3mmHg for systolic BP <110mmHg to 17.7mmHg for systolic BP >200mmHg.52 A study of 4297 subjects over 40 years of age in a defined predominantly white population found a positive correlation between systemic BP and IOP and an association between POAG and systemic hypertension.47 However, a cross-sectional population study concluded that the association between hypertension and POAG was most likely due to the correlation between age and hypertension.21

Vasospasm represents vascular dysregulation associated with inappropriate constriction or insufficient dilatation in the microcirculation.53 The eye is frequently involved in a vasospastic syndrome with vasospasm associated with anterior ischaemic optic neuropathy and glaucoma.53 Vasospasm is often falsely equated with Raynaud's phenomenon.53 Vasospasm patients often present with cold hand symptoms but they usually do not have the pale fingers which are characteristic of Raynaud's disease.53 Vasospasm patients frequently have low BP53 which, as discussed, may also be associated with reduced OPP and glaucoma risk.

An association between NTG and migraine has been suggested, with a potential common vascular aetiology for both diseases.54 However, an association between OAG and migraine was found to only be significant for subjects aged 70–79 years.55

Pigmentary glaucoma characteristically develops in young myopic patients with pigmentary dispersion syndrome.56 Male gender, black race, severe myopia, and Krukenberg spindles were identified as possible risk factors for the development and severity of glaucoma in the pigment dispersion syndrome.57

Pseudoexfoliation syndrome is a common age-related generalised fibrotic matrix process58 with significance because it increases the risk of developing glaucoma.20,22

Compared to normal patients, obstructive sleep apnea syndrome patients were found to have 1.67 times greater likelihood of developing glaucoma over a 5 year follow-up period.24

A meta-analysis by Zhou and co-authors found that six case-control studies indicated diabetes as a risk factor for POAG with a mean odds ratio greater than one, while a seventh study found an odds ratio of 0.61.59 Of six population-based cohort studies five indicated a significant association between diabetes mellitus and POAG.52 It appears that diabetes may increase the risk of POAG, especially as hyperglycaemia results in heightened sensitivity to IOP and risk of neuronal injury.53 When 80 NTG and 4015 control patients were compared in a Korean population, a higher proportion of fasting capillary glucose ≥200mg/dL was identified as a risk factor for OAG in both univariate and multivariate analyses.35 Nevertheless, the association between diabetes and glaucoma remains controversial.60

The concomitant use of glaucoma and systemic medications for co-existing systemic disorders creates the potential for drug interactions, as well as side effects from both groups of drugs.61 For example, ACG due to pupillary block, can be caused by local or systemic administration of adrenergic agents, as well as by sulfa-based drugs62 Corticosteroid-induced glaucoma and OHT is a response to increased resistance to aqueous outflow.63 Treatment for systemic hypertension or Raynaud's disease could increase the risk of glaucoma.51 For example, a five year follow-up of 3271 subjects found the risk factors associated with the incidence of POAG development included having ever taken calcium-channel or alpha-blocker medication.20 However, whether alpha-blocking medications have any haemodynamic influence on the ONH remains to be elucidated.20

Studies of the association between glaucoma and smoking have been contradictory.60 It has been hypothesised that, in the presence of genetic risk factors, exposure to environmental stresses such as smoking, corticosteroid medication and diabetes, results in an earlier age of onset of glaucoma.60 The risk of glaucoma in smokers may be higher in men.60

IOP is the only known modifiable factor in OAG.12 One of the factors associated with progression of glaucoma is fluctuation in IOP either over the 24h diurnal period or across visits.64–67 For example, in NTG patient's progression of VF losses was found to be associated with a higher 24h peak IOP and greater IOP fluctuation over 24h.68 Exposure to IOP elevations and fluctuations which occur during a variety of regular or occasional activities may increase the risk for the development or progression of glaucoma.69–71 For example activities involving sleep-related postures,71 lid squeezing/squinting, eye wiping, massaging or rubbing, inverted body positions (such as in the practice of Yoga), wearing swimming goggles, muscular effort, increased expiratory effort such as during physical exercise or when playing high wind resistant musical instruments, and wearing a shirt or tie which are tight around the neck are all known to elevate IOP,67 sometimes in conjunction with intracranial pressure elevation.72 Reducing participation in activities which elevate either or both IOP and intracranial pressure will decrease exposure to higher levels of lamina cribrosa displacement and/or lamina cribrosa compression with the associated possibility of risk of damage to RNFL axons passing through the lamina cribrosa.72 Although a single short-term fluctuation is likely to be of negligible significance, the cumulative effect of constant or frequent fluctuation could be significant in contributing to glaucoma pathogenesis.73 Any risk associated with a single short-term fluctuation may increase with the degree of elevation involved. IOP measured with the patient sitting with neck in a neutral position (no flexion or extension) is probably the lowest of any body position.74 Estimation of the degree of exposure to IOP elevation and fluctuation episodes, sometimes to levels many times the sitting-position level, can be aided by questionnaire responses.67 (Copies of the questionnaire can be obtained from c.mcmonnies@unsw.edu.au.)

Glaucoma progression carries a burden of both nonvisual and visual symptoms which are a considerable concern to patients in more advanced cases.75 However, at the time of diagnosis, most patients are relatively free of glaucoma-induced impairments.76 The absence of symptoms which are specific to early glaucoma appears likely to contribute to the high number of undiagnosed subjects found in population studies.75,76 The Glaucoma Symptom Scale provides a valid and reliable estimate of symptoms associated with glaucoma and its treatments.75 However, for the early stages of glaucoma, sensitivity may be high and specificity correspondingly low with this instrument because many of the Glaucoma Scale symptoms such as burning, smarting, stinging, tearing, dryness, itching, soreness and tiredness75 can occur in many diseases such as any of the dry eye syndromes, and even in otherwise healthy eyes during exposure to adverse environmental conditions. However, these types of symptoms may occur as a consequence of glaucoma treatment. In both clinical and research settings this scale should prove to be a valuable patient-centred tool for the assessment and comparison of symptoms experienced by patients with glaucoma especially perhaps for those who present with new symptoms while undergoing treatment.75

Comprehensive history findings may make an important contribution to the identification of glaucoma suspects prior to any evidence of glaucomatous changes. The findings of a thorough history may aid decisions about the range of objective testing required during a clinical examination. The potential value for a comprehensive history in decision making may be greater when objective testing indicates borderline or conflicting diagnostic findings. For example, OCT using guided progression analysis software, perimetry and stereophotography examinations were repeated during follow-up to examine for glaucomatous progression in 246 eyes.13 Notwithstanding some agreement between the three methods, most cases with detectable changes were identified by only one of these methods of examination. These findings suggest that reference to history information may assist decision making when glaucoma monitoring examination findings obtained with different instruments are not in agreement or are at a borderline level in regard to recommended diagnostic cut-offs for particular instruments. It is important to stress that a predictive instrument such as a comprehensive history15 as well as an instrument-based objective predictive risk model should always be supplemented by clinical judgement.12 The need for clinical judgement may be reduced if it was possible to appropriately weight the significance of individual history items in relation to glaucoma diagnosis in order that the combined predictive performance of a history could be maximised. Combining multiple-screening strategies together with family history can be a very powerful diagnostic method for glaucoma.15 No evidence of a family history can be an appropriate finding whereas a finding of no family history cannot be made confidently. However, given its potential for unreliability, rather than considering only the presence of a family history of glaucoma, the combination of a comprehensive history and clinical assessment20 may be more successful, especially in marginal/suspect diagnoses. Genetic variations related to OAG may provide additional indication of risk.77 Apart from diagnostic potential, treatment and the appropriateness of follow-up schedules may be improved by reference to history findings. For example, a patient's history may also contribute to difficult management decisions in cases of ocular hypertension. Screening of higher-risk groups may be the most cost-effective method of reducing the volume of undiagnosed glaucoma78 and patient history appears to be a practical means of helping to identify patients with higher risk for developing glaucoma. As a possible consequence of the importance placed on objective findings in recent literature, the potential usefulness of history findings may sometimes be ignored or under-emphasised.

There are no funding, proprietary or financial interests to declare in relation to this paper.