Graefe's Arch Clin Exp Ophthalmol (1999) 237:554557 Springer-Verlag 1999 CLINICAL INVESTIGATION Wido M. Budde Jost B.

Jonas

Family history of glaucoma in the primary and secondary open-angle glaucomas

Received: 6 July 1998 Revised version received: 7 October 1998 Accepted: 28 October 1998 W. M. Budde ()) J. B. Jonas Department of Ophthalmology, Friedrich-Alexander University ErlangenNrnberg, Schwabachanlage 6, D-91054 Erlangen, Germany e-mail: Wido.Budde@augen.med.unierlangen.de Tel. +49-9131-8533001 Fax: +49-9131-8534436 Abstract l Background: A study was carried out to evaluate the frequency of a positive family history in the primary and secondary open-angle glaucoma. Patients and methods: The study included 1176 patients with chronic open-angle glaucoma who were differentiated into secondary open-angle glaucoma [pseudoexfoliative glaucoma (n=144) and pigmentary glaucoma (n=61)], and primary open-angle glaucoma (POAG; n=971). The POAG group was divided into non-highly-myopic patients without (non-highly-myopic POAG; n=662) or with circular para papillary atrophy (age-related atrophic POAG; n=168), highly myopic POAG (n=35), and focal normal-pressure glaucoma (n=106). All patients were asked whether family members had glaucoma. Results: In the POAG group, frequency of a positive family history of glaucoma (overall frequency 24.5%) decreased significantly with age from 35.8% in patients (n=240) younger than 50 years, to 25% in patients (n=501) aged between 51 and 70 years and to 11.7% in patients (n=230) older than 70 years. The overall frequencies of a positive family history of glaucoma did not vary significantly between agerelated atrophic POAG, focal normal- pressure glaucoma, pseudo-exfoliative glaucoma, and pigmentary glaucoma, compared with age-matched groups of non-highly-myopic POAG. Highly myopic POAG had a lower, but not significantly lower, frequency of a positive family history of glaucoma (17.1% vs 26.9%). Conclusions: In POAG, frequency of a known positive family history of glaucoma decreases with increasing age. Apart from juvenile-onset POAG with a relatively high, and highly myopic POAG with a relatively low frequency of known heredity, other primary and secondary open-angle glaucoma do not show pronounced differences in this variable when adjusted for age.

Introduction The open-angle glaucoma are a spectrum of entities that can be differentiated from one another by a variety of variables such as the morphology of the anterior chamber angle, predisposing risk factors, cause for the elevation of intraocular pressure, the average age at onset, pre - ponderance of males or females, and the level of the intraocular pressure [22, 23]. Recent studies have shown that, parallel to this variability of characteristics, the morphology of the optic disc also differs among the glaucomas [3, 4, 6, 14, 20, 26]. Family history of glaucoma is considered to be a risk factor for the development of a glaucomatous disease [30]. The purpose of the present study was to evaluate whether various types of primary and secondary open-angle glaucoma differ in prevalence of family history of glaucoma. Methods The study group consisted of 1176 patients with chronic open-angle glaucoma. Criteria for the diagnosis of open-angle glaucoma, each of which had to be fulfilled, were an open anterior chamber angle, typical glaucomatous changes of the optic nerve, and visual field loss. An open chamber angle was defined by visibility of the scleral spur on gonioscopy. Optic discs with (a) an unusually small neuroretinal rim area in relation to the optic disc size, (b) an unusual disc shape [13, 15], and (c) localized or diffuse retinal nerve fiber layer defects on 15- optic disc photographs and 60- red-free fundus photographs respectively were considered as glaucomatous. A glaucomatous visual field defect was defined as a Octopus G1 field with (a) at least three adjacent test points having a deviation equal to or greater than 5 dB and with one test point with a deviation greater than 10 dB, (b) at least two adjacent test points with a deviation equal to or greater than 10 dB, (c) at least three adjacent test points with a deviation equal to or greater than 5 dB abutting the nasal horizontal meridian, and (d) a mean visual field defect of more than 2 dB. The whole study group was differentiated into patients with secondary open-angle glaucoma due to pseudoexfoliation of the lens (pseudoexfoliative glaucoma) or primary melanin dispersion syndrome (pigmentary glaucoma) and those with primary open-angle glaucoma (Table 1). The patients had consecutively attended the eye hospital for diagnosis and treatment of glaucoma. The primary open-angle glaucoma group was further divided in- to patients with focal normal-pressure glaucoma [17, 18, 25, 26], highly myopic patients (highly myopic primary open-angle glaucoma [10]), non-highlymyopic patients with parapapillary atrophy at all four quadrants of the optic disc (age-related atrophic type [8, 11, 16, 27]), and non-highly-myopic patients without parapapillary atrophy or with parapapillary atrophy not in all quadrants (non- highly-myopic primary open-angle glaucoma) (Table 1). For the diagnosis of the focal type of normal-pressure glaucoma, the maximal intraocular pressure readings had to be equal to or less than 21 mm Hg in at least two 24-h pressure profiles containing measurements at 5.00 p.m., 9.00 p.m., midnight, 7.00 a.m. and noon without any glaucoma medications. Other reasons for optic nerve atrophy had been ruled out by additional medical and neuroradiologic examinations. Refractive error ranged between 8.0 diopters and +5.0 diopters. The optic disc and retinal nerve fiber layer showed signs of focal optic nerve damage such as neuroretinal rim notches, disc hemorrhages, and localized retinal nerve fiber layer defects. The patients in the highly myopic glaucoma group had a myopic refractive error exceeding 8.0 diopters. The remaining patients with pri- mary open-angle glaucoma in whom no obvious reason for elevated intraocular pressure could be detected were differentiated into those in whom parapapillary atrophy was present in all four optic

disc quadrants (age-related atrophic type of primary open-angle glaucoma) and those with no parapapillary atrophy or with parapapillary atrophy not present at all four disc quadrants. (non-highly myopic primary open-angle glaucoma). Parapapillary atrophy was defined as a zone located directly at the border of the optic disc and showing visible sclera and visible large choroidal vessels [16]. The latter two groups did not differ in refractive error (mean SD 0.181.92 vs. 0.321.48; P=0.35, MannWhitney UWilcoxon test). The eyes with secondary open-angle glaucoma due to pseudoex- foliation syndrome had to show, additionally to the criteria for open- angle glaucoma, a dandruff-like material on the lens zonules and the lens surface, especially in its center and its periphery, often separated by an intermediate clear zone. Other frequent features were secondary melanin dispersion with translucent defects in the parapupillary region of the iris pigment epithelium, hyperpigmentation of the anterior chamber angle, and decreased pupil dilation facility. Additionally to the above-mentioned criteria for open-angle glaucoma, pigmentary glaucoma was characterized by radial trans- lucent defects in the periphery of the iris pigment epithelium and hy- perpigmentation in the posterior and anterior chamber, e. g. pigmentation of the hyaloideocapsular ligament, Krukenberg's spindle, melanin granules on the iris surface, pronounced hyperpigmentation of the anterior chamber angle, and pigment dispersion upon mydriasis. Other reasons for pigment dispersion, such as intraocular su gery or herpetic iritis, had been excluded. All patients included in the study were prospectively asked at every visit whether family members had glaucoma. Only the answers obtained at the second or later visit were taken for statistical analysis, to make sure that the patients had had the opportunity to inform themselves about their disease and about the occurrence of the dis- ease in their families. A family history of glaucoma was positive if any first- or second-degree relative was reported to suffer from glau- coma. This interrogation had been established as part of the routine work-up of glaucoma patients. The various glaucoma groups differed in age. To compare the groups with each other, age-matched control groups were formed from the non-highly-myopic primary open-angle glaucoma group (Table 1). The percentage of patients per life decade in each control group was equal (1%) to the percentage of patients per life decade in the respective study group. Results In the group with primary open-angle glaucoma, the over- all frequency of a positive family history of glaucoma was 24.5% (Table 1). It decreased significantly with increasing age (P<0.0001, Mann-Whitney UWilcoxon test), from 35.8% in patients younger than 50 years to 25.0% in patients aged between 51 and 70 years and 11.7% in patients older than 70 years. In all age groups, frequency of a positive family history was independent (P>0.05) of gender (chi-square test, Fisher's exact test), refractive error (MannWhitney UWilcoxon test), optic disc size, neuroretinal rim area, size of parapapillary atrophy [16], and mean visual field defect. As compared with the aged-matched control groups formed from the patients in the non-highly-myopic prima- ry open-angle glaucoma group, frequencies of a positive family history of glaucoma did not vary significantly among focal normal-pressure glaucoma, highly myopic primary open-angle glaucoma, age-related atrophic primary open-angle glaucoma, pseudoexfoliative glaucoma, and pigmentary glaucoma (chi-square test, Fisher's exact test P>0.45, for the highly myopic type of primary open- angle glaucoma group P=0.14) (Table 1).

Discussion The results of the present study suggest that the frequency of a positive family history of glaucoma decreases with increasing age of the patients (Table 1). One may infer that a relatively high degree of heredity should be added to the panoply of features characterizing the juvenile- onset type of primary open-angle glaucoma, including deep and steep disc cupping, normal-sized and normal- shaped optic discs, low frequency of disc hemorrhages, rim notches and localized retinal nerve fiber layer defects, only slightly enlarged parapapillary atrophy, high minimal and maximal intraocular pressure values, normal arterial blood pressure, and no vasospastic syndromes [4, 12]. The age dependence found in the present study may also partially be due to the cross-sectional design of the study. Young patients know more about the presence of glaucoma in their grandparents than old patients know about the disease in their grandparents several decades ago, when the medical infrastructure was less well developed. This may lead to a statistical artifact with a misleadingly low frequency of a positive family history of glaucoma in the old patient group. Independent of the reasons for this finding, it implies that in studies on the frequency of a positive family history of glaucoma the age distribution in the study populations must be taken into account. The present study found a tendency towards a lower frequency of positive family history of glaucoma in glaucoma patients with high myopia than in the age-matched control group of open-angle glaucoma. The lack of statistical significance may be due to the small number of patients with this special entity. If further studies with larger groups of patients substantiate the observation of a relatively low frequency of a positive family history in this glaucoma group, it might suggest that a positive family history may not be as important a risk factor in this type of glaucoma as in the non-highly-myopic primary open- angle glaucoma [5, 19, 30]. Other factors besides heredity may have relatively high importance in the highly myopic type of primary open-angle glaucoma, such as the myopic stretching of the lamina cribrosa which may possibly re- duce the pressure tolerance of the optic nerve head [18]. The results of the present study further suggest that the other types of primary and secondary open-angle glaucoma, including focal normal-pressure glaucoma, have a similar frequency of a positive family history if the groups are adjusted for age. The overall frequency of a positive family history of glaucoma found in the present study is in agreement with previous reports in the literature. Becker, Francois, Shin and others found a positive family history of glaucoma in 13%25% of patients with primary open-angle glaucoma [2, 7, 24, 32]. In these studies, however, the different types of open-angle glaucoma, such as age-related atrophic primary open-angle glaucoma, focal normal-pressure glaucoma, and highly myopic primary open-angle glaucoma were not separately investigated. In pseudoexfoliation syndrome, an increased prevalence of the disease in relatives of affected individuals and pedigrees is described [1, 9, 28, 29, 31]. Pohjanpelta and Hurskainen found glaucoma or `suspect glaucoma' in 33% of the relatives of patients with pseudoexfoliative glaucoma [21]. There are factors limiting the present study. A statistical artifact may have been introduced by the selection of patients referred to a university hospital. In the Baltimore Eye Survey, frequency of positive family history was high- er in those patients who were aware of their glaucoma diagnosis before the enrollment in the study than in the glaucoma patients, whose disease was discovered during the study examination [30]. Therefore frequencies of positive family history in glaucoma patients may be higher in clinic-based studies than in epidemiological studies [19, 30]. In

epidemiological studies, however, it is rather difficult to collect sufficiently large numbers of patients who are affected by special types of the open-angle glaucoma, such as the highly myopic-type of primary open-angle glaucoma. Another factor limiting the present study is the lack of differentiation into first-degree relatives, siblings, and other relatives, which would have helped to assess differences in the genetic background of the various types of chronic open-angle glaucoma. Another factor influencing the results of studies such as the present one is the patient's awareness of his glaucomatous disease and the patient's knowledge of diseases occurring in his family. Most of the subjects investigated in the present study live in a rural setting in the north of Bavaria, Germany, with much lower mobility than in a metropolitan area. A rela- tively high proportion of each patient's relatives may live in the vicinity, so that family members know of each oth- er's health problems. On the other hand, the awareness of a family history of glaucoma might differ in different forms of glaucoma. Independent of these limiting factors, the results of the present study indicate that the frequency of a positive family history of glaucoma in patients with primary open-angle glaucoma decreases with increasing age in cross-sectional studies, that this finding has to be taken in- to account when various glaucoma and control groups are compared with each other, and that the observation of a relatively low frequency of a positive family history in patients with highly myopic primary open-angle glaucoma warrants further investigation.

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