- Email: [email protected]
Optic disc hemorrhages in a population with and without signs of glaucoma
Optic Disc Hemorrhages in a Population with and without Signs of Glaucoma Paul R. Healey, BMedSc, MBBS, I Paul Mitchell, M D , FRCOphth, ~ Wayne Smith, BMed, MPH, 2 Jie Jin Wang, MMed (Clin Epi) ~ Objective: This study aimed to determine the prevalence and associations of optic disc hemorrhage in a welldefined older Australian population. Design: The study design was a population-based, cross-sectional study. Participants: A total of 3654 persons 49 years of age or older, representing 88% of permanent residents from an area west of Sydney, participated in the study. Main Outcome Measures: Participants underwent a detailed eye examination. The diagnosis of optic disc hemorrhage was made from masked photographic grading; disc hemorrhages were subclassified as flame or blot in shape. Open-angle glaucoma was diagnosed from matching visual field loss and optic disc rim thinning. Results: . The overall prevalence of disc hemorrhage in either or both eyes was 1.4%. Disc hemorrhage prevalence was higher in women (odds radios [OR], 1.9; confidence interval [CI], 1.0-3.5) and increased with age (OR, 2.2 per decade; CI, 1.7-2.8 per decade). The overall prevalence in subjects with open-angle glaucoma was 13.8% (8% in high-pressure glaucoma and 25% in low-pressure glaucoma) and 1.5% in subjects with ocular hypertension. Disc hemorrhages were associated with increasing intraocular pressure (OR, 1.7 per 5 mmHg; GI, 1.3-2.3 per 5 mmHg), pseudoexfoliation (OR, 3.5; CI, 1.1-11.8), diabetes (OR, 2.9; CI, 1.4-6.3), and increasing systolic blood pressure (OR, 1.1 per 10 mmHg; CI, 1.0-1.3) after adjusting for age and gender. Among subjects without openangle glaucoma, disc hemorrhages were more frequent in eyes with larger vertical cup-disc ratios and in subjects with a history of typical migraine headache (OR, 2.2; CI, 1.1 -4.6). No associations were found among subjects with a history of vascular events, smoking, regular aspirin use, or myopia. Conclusions: Disc hemorrhage prevalence in this population is higher than that in the two previous populationbased reports. Although the strong association of disc hemorrhage with open-angle glaucoma was confirmed (particularly low-pressure glaucoma), most disc hemorrhages (70%) were found in participants without definite signs of glaucoma. Ophthalmology 1998; 105:216-223
Small hemorrhages on or crossing the optic disc have been reported to precede both retinal nerve fiber layer damage and visual field loss in subjects with glaucoma or ocular hypertension. These observations have led to the hypothesis that optic disc hemorrhages are markers of imminent deterioration in glaucoma or an early sign of glaucomatous damage in glaucoma suspects. ~-5 Their presence also lends weight to vascular theories of glaucoma etiology. 6-8 However, the relatively rare occurrence and transient nature of disc hemorrhages 9 make them difficult to study. Consequently, most research has been limited to case series and case-control studies. Understand-
ably, most studies have focused on subjects with glaucoma or ocular hypertension. In contrast, only two population-based studies have reported any data on disc hemorrhages, m.~t The first aim of this report is to provide precise prevalence estimates o f disc hemorrhage in a well-defined older population. The second aim is to examine disc hemorrhage associations with age, gender, glaucoma, and systemic vascular factors such as diabetes, migraine, systemic hypertension, and vascular disease history.
Methods Originally received: January 17, 1997. Revision accepted: August 26, 1997. Department of Ophthalmology,University of Sydney, Sydney, Australia. 2 Department of Community Medicine, University of Sydney, Sydney, Australia. Supported by the Ophthalmic Research Institute of Australia and the Australian Department of Health and Family Services. Reprint requests to Paul Mitchell, MD, FRCOphth, University of Sydney, Department of Ophthalmology, Westmead Hospital Hawkesbury Road, Westmead, NSW, Australia, 2145.
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Population The Blue Mountains Eye Study was a population-based survey of eye disease and visual impairment in individuals 49 years of age or older living in the Blue Mountains, west of Sydney, Australia, that was conducted during 1992-1993.t2 Of the 4433 eligible persons, identified by a door-to-door census, 3654 (82.4%) participated in the eye study. A total of 501 persons (11.3%) refused to participate. After those who died or left the area during the study were excluded, the response rate was
H e a l e y et al •
Optic Disc Hemorrhages and Glaucoma 4.74
87.9%. Participants mostly were of northern European descent. The project was approved by the Western Sydney Area Health Service, and informed consent was obtained from all participants.
Procedures All participants underwent a detailed eye examination, which included a single applanation intraocular pressure (IOP) measurement, blood pressure measurement, and subjective refraction, using a logarithm of the minimum angle of resolution (IogMAR) chart. After pupil dilatation, nonsimuitaneous stereoscopic 30 ° color retinal photographs were taken, centered on the optic disc (Diabetic Retinopathy Study field 1), macula (field 2), temporal, and peripheral retina. A Zeiss FF3 fundus camera (Carl Zeiss, Oberkochen, Germany) and Kodachrome 25 slide film (Eastman Kodak, Rochester, NY) were used. Participants were asked to return for a fasting pathology test, which included venous blood glucose. Photographs were assessed by one of two trained graders who followed a modification of the protocol developed for the Wisconsin Epidemiologic Study of Diabetic Retinopathy. t3 The slides were mounted in clear plastic sheets and viewed with a Donaldson stereo-viewer on a translucent light box. Photographs were considered gradable if field 1 was gradable or the disc was clearly visible from field 2. A disc hemorrhage was defined as a hemorrhage on or crossing the optic disc. Retinal hemorrhages outside the disc margin were excluded, as were hemorrhages associated with other retinal hemorrhages in Diabetic Retinopathy Study field 1 (for example, those due to retinal vein occlusion or diabetic retinopathy) or with optic disc edema. The longest diameter in a range between clock-hours 11:00 to 1:00 and 5:00 to 7:00 was used to measure both the optic disc and cup, with high intraobserver and interobserver reliability.L4 The cup margin was determined by its contour rather than by its pallor. Optic disc and cup measurements were corrected for magnification using the spherical equivalent refraction for each eye.~S The glaucoma examination has been described previously.~6 In brief, it was conducted in two phases. In the first phase, a screening Humphrey 76-point suprathreshold visual field test. was performed in 3241 subjects (89%), applanation tonometry in 3641 participants (99.6%), and stereo optic disc photography in 3568 participants (98%). In the second phase, 336 participants (9.2%) with glaucomatous field defects on the screening field or a glaucomatous optic disc appearance returned for a Humphrey 3 0 - 2 full-threshold visual field test, gonioscopy, and repeat tonometry. All 3 0 - 2 fields were assessed by the study ophthalmologist (PM) in a masked fashion for typical glaucomatous features. The minimum diagnostic criteria were an abnormal Humphrey 3 0 - 2 Glaucoma Hemifield Test, plus one or more of the following field defects, not explained by ocular or neurologic causes: (1) arcuate or paracentral scotoma, at least four contiguous points on the pattern deviation plot depressed at P < 0.5% level; (2) nasal step at least two horizontal points in width on the pattern deviation plot depressed at P < 0.5% level; or (3) advanced glaucomatous field loss. Open-angle glaucoma was diagnosed when typical glaucomatous visual field loss on the Humphrey 3 0 - 2 test was present, combined with matching optic disc rim thinnin~ and an enlarged cup-disc ratio (~-0.7) or cup-disc asymmetry between the two eyes of 0.0.3 or greater. Gonioscopy excluded angle closure, rubeosis or secondary glaucoma, other than pseudoexfoliation.
3
% 2
0 <60
60-69
70-79
80+
age group (years) Figure 1. Prevalence of optic disc hemorrhages in 3582 participants by age and gender. Bar numbers indicate percent of subjects.
In this study, low-pressure glaucoma was defined as open-angle glaucoma with IOP in each eye of more than 21 mmHg, both at screening and on a subsequent visit. These subjects were not receiving ocular hypotensive treatment and had no history of glaucoma surgery. Other open-angle glaucoma cases were defined as high-pressure glaucoma. Assessment and diagnosis of typical migraine were made by a clinician after directed questioning about specific symptoms, consistent with the International Headache Society criteria. ~7 A typical migraine history included recurrent severe headache that was unilateral and associated with nausea, vomiting, photophobia, or visual disturbance. Diabetes was diagnosed from history or an elevated fasting venous blood glucose of 7.8 mmol/l or greater (140 mg%). Statistical Methods Statistical Analysis System (SAS Institute, Cary, NC) was used for tabulations, Student's t test, and logistic regression analyses. All continuous variables were used as such in the logistic regressions. Odds ratios (OR) and 95% confidence intervals (CI) are presented.
Results Prevalence and Characteristics of Optic Disc Hemorrhage On initial grading, disc hemorrhages were found in 60 eyes of 55 subjects. Three cases had features suggesting previous retinal vein occlusion and one case had marked premacular fibrosis. All four cases were excluded, leaving disc hemorrhages in 56 eyes of 51 subjects, a prevalence of 1.4% (CI, 1.0%-1.8%) among subjects or 0.8% (CI, 0.6%- 1.0%) of eyes. Disc hemorrhages were bilateral in five subjects, and in one subject, two disc hemorrhages were found in the same eye. Overall, 34 left eyes and 22 right eyes were affected. Figure 1 shows the age and gender distribution of disc hemorrhages. The prevalence was 0.2% in persons younger than 60 years of age, 0.4% id persons 60 to 69 years of age, 1.4% in persons 70 to 79 years
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73 T 15~1
"
1NT1
2
1 N
2
1
flame-shaped
3
Normal Subjects
blot-shaped
5 3 :,, 5 T
N T 2
2 2-'"~ 2 glaucoma
3 2 N
31 no glaucoma
Figure 2. Circumferential distribution of optic disc hemorrhages reproduced as if all were in the right eye, with temporal (T) and nasal disc margins indicated.
of age, and 1.9% in persons 80 years of age or older. Disc hemorrhage prevalence was higher in women than in men (OR, 1.9; CI, 1.0-3.5) after adjusting for age and glaucoma. Most disc hemorrhages (71%) were flame shaped, appearing to lie on the surface of the disc and retinal nerve fiber layer. The remaining hemorrhages (29%) were blot shaped. In 48% of cases, the hemorrhages were dense, obscuring underlying structures. Disc hemorrhages occupied less than a half clockhour of the disc circumference (approximately 15°) in 71% of cases, were between a half and 1-clock-hour width in 20%, and were wider than 1 clock-hour in 9% of cases. The distribution of disc hemorrhages around the optic disc is shown in Figure 2. Flame hemorrhages were more frequent on the temporal side of the optic disc, with the largest proportion seen in the superior-temporal quadrant. Blot hemorrhages were distributed more evenly. In persons with open-angle glaucoma, disc hemorrhages mainly involved the upper and lower poles of the disc, whereas in persons without open-angle glaucoma, some disc hemorrhages also were present at either the temporal or nasal disc margins. Open-Angle Glaucoma Disc hemorrhages were found in 15 of the 108 subjects with open-angle glaucoma, a prevalence of 13.8% (CI, 7.3%20.3%). Three examples are shown in Figure 3 (A-C). Glaucoma previously was undiagnosed in 55 persons (51%). Agespecific prevalence rates were 0% in open-angle glaucoma subjects younger than 60 years of age, 17.6% in subjects 60 to 69 years of age, 8.9% in subjects 70 to 79 years of age, and 19% in subjects 80 years of age or older. Table 1 lists age-specific prevalence by type of hemorrhage. Flame hemorrhages proportionally were more frequent than blot hemorrhages. Disc hemorrhages were associated strongly with open-angle glaucoma after age and gender adjustment (OR, 9.0; CI, 4.8-17.0), as listed in Table 2. Of the 108 subjects with open-angle glaucoma, 36
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were assessed as having low-pressure glaucoma. The prevalence of disc hemorrhages in this group (25%) was higher than in the 72 high-pressure glaucoma cases (8%) (OR, 2.9; CI, 1.1-8.1) after adjusting for age and gender. In all, 17 glaucomatous eyes had disc hemorrhages, representing 30% of all disc hemorrhages.
Although the finding of disc hemorrhage was associated strongly with open-angle glaucoma, most disc hemorrhages (70%) were found in subjects with no evidence of open-angle glaucoma (39 disc hemorrhages in 36 subjects), a prevalence of 1.0% (CI, 0.7%- 1.3%). Seven examples of disc hemorrhage in subjects without glaucomatous cupping or visual field loss are shown in Figure 3 (D-J). Age-specific prevalence rates were 0.30% in subjects younger than 60 years of age, 0.47% in persons 60 to 69 years of age, 2.44% in persons 70 to 79 years of age, and 1.60% in persons 80 years of age or older. Blot hemorrhages were relatively more frequent in normal subjects compared to open-angle glaucoma subjects, although flame hemorrhages still predominated. Associations with Optic Disc Hemorrhage Cup-Disc Ratio. Disc hemorrhages were more prevalent in eyes with larger vertical cup-disc ratios after adjusting for age and gender (/~ = 5.17, P < 0.0001). This association was not significant in subjects with open-angle glaucoma (,8 = 0.98, P = 0.96), but was statistically significant in persons without open-angle glaucoma (/~ = 4.75, P < 0.0001), as shown in Figure 4. Intraocular Pressure. Disc hemorrhage prevalence was positively associated with increasing lOP (OR, 1.7 per 5 mmHg; CI, 1.3-2.3) after adjusting for age and gender, as listed in Table 2. No statistically significant associations were found in normal subjects nor in subjects with high-pressure glaucoma. In subjects with low-pressure glaucoma, there was a borderline significant positive association between disc hemorrhage and IOP (OR, 12.2; CI, 1.0-155). In this group, the mean IOP was 17.7 mmHg for eyes with disc hemorrhage and 16.7 mmHg for eyes without disc hemorrhage. The association between disc hemorrhage and lOP changed little after adjusting for vertical cup-disc ratio (OR, 15.4; CI, 1.1-218). Among 135 participants with ocular hypertension (IOP > 21 mmHg, but not assessed as having open-angle glaucoma), 2 persons had a disc hemorrhage, a prevalence of 1.5% (CI, 0%-3.5%). However, the association between disc hemorrhage and ocular hypertension was not statistically significant (Table 2). Pseudoexfoliation and Myopia. Disc hemorrhages were found in 3-of 82 subjects with pseudoexfoliation in 1 or both eyes, a prevalence of 3.7%. These consisted of one flame and two blot hemorrhages. None of the three subjects had openangle glaucoma. The association of disc hemorrhage with pseudoexfoliation was significant in all subjects (OR, 3.5; CI, 1.1-11.8) as well as in subjects without glaucoma (OR, 6.0; CI, 1.8-20.2) after adjusting for age and gender. The magnitude of the association between pseudoexfoliation and disc hemorrhage was similar after adjusting for IOP (OR, 5.6; CI, 1.719). No significant association was found between disc hemorrhage and myopia in any group after adjusting for age and gender. Diabetes. Disc hemorrhages were found in 6 of 256 persons with a history or biochemical evidence of diabetes, a prevalence
H e a l e y et al •
Optic Disc Hemorrhagesand Glaucoma
Figure 3. Ten examples of optic disc hemorrhages (flame and blot) seen in the Blue Mountains Eye Study. A - C , eyes of subjects with open-angle glaucoma diagnosed from matching visual field loss and optic disc rim thinning. D - J , eyes of subjects without visual field loss or optic disc rim thinning.
G
H
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Ophthalmology Volume I05, Number 2, February 1998 Table 1. Prevalence of Optic Disc Hemorrhages in 3582 Participants in the Blue Mountains Eye Study by Age Group and Optic Disc Hemorrhage Type* Age Group (yrs)
% of Subjects (no. of Subjects) with OAG F/ame
Blot
2
% of Subjects (no. of Subjects) without OAG F/ame
49-59 60-69 70-79 >80
0 (0) 17.6% (3) 6.6% (3) 16.6% (7)
0 (0) 0 (0) 2.2% (l) 2.4% (1)
0.2% 0.30% 1.6% 1.0%
(2) (4) (14) (3)
Total
12.0% (13)
1.9% (2)
0.6% (23)
1.5
Blot 0.1% 0.2% 0.9% 0.6%
2.38
2.5
1.01
% 1
(1) (3) (7) (2)
0.5
I
o
0.4% (13)
0.32
0.27
OAG = open-angle glaucoma. * Flame and blot are optic disc hemorrhage types.
I
I
0.03-0.29
I,
0.3-0.49
I
0.5-0.69
0.7-0.84
Vertical cup-disc ratio (group) Figure 4. Prevalence of optic disc hemorrhages in participants without open-angle glaucoma by vertical cup-disc ratio (grouped to improve clarity). Bar numbers indicate percent of subjects.
of 2.3%, including 6 flame and 2 blot hemorrhages. None of these eyes had. any other hemorrhages in field 1, although four had evidence of nonproliferative diabetic retinopathy elsewhere. Two of these subjects with diabetes also had open-angle glaucoma. Diabetes was associated significantly with disc hemorrhage overall (OR, 2.9; CI, 1.4-6.3). The disc hemorrhage prevalence in subjects with diabetes and open-angle glaucoma was 14.3% (4 disc hemorrhages in 2 of 14 subjects with diabetes and open-angle glaucoma). Hypertension and Other Vascular Factors. Increased systolic blood pressure was associated significantly with disc hemorrhage (OR, 1.1; CI, 1.0-1.3) for each 10-mmHg increase in systolic blood pressure after adjusting for age and gender. The association was stronger in subjects with open-angle glaucoma. Although increased odds for disc hemorrhage also were found in subjects with a history of hypertension requiring medication, this was not statistically significant (Table 2). No significant associations were found between disc hemorrhage and a history of vascular events (e.g., angina, myocardial infarct, or stroke), smoking (current or past), or regular use of aspirin after adjusting for age and gender (Table 2). Migraine. Disc hemorrhages were found in 11 of 608 sub-
jects who had a history of typical migraine headaches, including 2 with bilateral disc hemorrhages, a prevalence of 1.8%. Twelve of the 13 disc hemorrhages in this group were flame shaped, and only 1 subject with disc hemorrhage had both migraine and open-angle glaucoma. Increased, but nonsignificant, odds were found for the association between disc hemorrhage and a history of typical migraine (OR, 1.7; CI, 0.9-3.3) in all subjects, and there was no association in subjects with open-angle glaucoma. However, typical migraine history was associated significantly with disc hemorrhage in subjects without open-angle glaucoma (OR, 2.2; CI, 1.1-4.6). This association was not altered by adjusting for c u p - d i s c ratio (OR, 2.1; CI, 1.0-4.4).
Disc Hemorrhage as a Test for Open-angle Glaucoma Table 3 lists the frequency of disc hemorrhage per person for subjects with and without open-angle glaucoma. As a diagnostic test for open-angle glaucoma, the sensitivity of disc hemorrhage
Table 2. Associations of Optic Disc Hemorrhages with Selected Characteristics, after Adjusting for Age and Sex* Characteristic
All Subjects
Normals
Age (per decade) Open-angle glaucomat Ocular hypertension Intraocular pressure (per 5 mmHg) Pseudoexfoliation Diabetes$ Migraine history Systolic blood pressure (per 10 mmHg) Hypertension§ Vascular disease historyl[
2.2 (1.7-2.8) 9.0 (4.8-17.0) 0.9 (0.2-3.8) 1.7 (1.3-2.3) 3.5 ( 1.1-11.8) 2.9 (1.4-6.3) 1.7 (0.9-3.3) 1.1 (1.0-1.3) 1.3 (0.8-2.3) 0.6 (0.3-1.2 )
2.2 (1.6-3.0) . 1.3 (0.3-5.3) 1.4 (0.9-2.3) 6.0 (1.8-20.2) 2.0 (0.7-5.7) 2.2 (1.1-4.6) 1.0 (0.9-1.2) 1.0 (5.1-1.9) 0.7 (0.3-1.6)
All OAG .
0.9 (0.5-1.5) . -- 1.2 (0.8-1.9) -4.4 (1.2-15.8) 0.6 (0.1-2.6) 1.3 (1.1-1.5) 2.0 (0.6-6.3) 0.3 (0.1- 1.4)
LPG
HPG
0.5 (0.2-1,2) . -12.2 (1.0-155) -7.7 (0.8-79) 1.0 (0.1-9.3) 1.3 (1.0-1.6) 5.2 (0.5-50) 0.3 (0.0- 2.5 )
1.5 (0.6-3,7) -1.4 (0.8-2.5) -3.1 (0.8-31) 0.7 (0.1-7.0) 1.4 (1.1-1.8) 1.0 (0.2-4.6) 0.4 (0.0-3.0)
* Odd ratios (95% confidence intervals) are shown for normal subjects and those with open-angle glaucoma (OAG), low-pressureglaucoma (LPG), and high-pressure glaucoma (HPG). t Defined as congruent, typical glaucomatous optic disc and visual field changes, after excluding cases of rubeotic or secondary glaucoma. ;~Defined as diabetes history or fasting glucose >7.8 mmol/l. § Defined as history of hypertension requiring medication or systolic blood pressure > 160 mmHg or diastolic blood pressure >95 mmHg. IIDefined as history of angina, myocardial infarct, or stroke.
220
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Optic Disc Hemorrhages and Glaucoma
Table 3. Freqt,ency of Optic Disc Hemorrhage in Participants with and without Open-angle Glaucoma* OAG Present
OAG Absent
Total
DH present DH absent
14 94
37 3509
51 3603
Total
108
3546
3654
OAG = open-angleglaucoma;DH = disc hemorrhage. *Sensitivity: 12.9%; specificity: 98.96%; positive predictive value: 27.45%; negativepredictivevah,e: 97.4%.
was 13%, specificity was 99%, positive predictive value was 27%, and negative predictive value was 97%.
Discussion There are few published data on the prevalence of optic disc hemorrhage, with most reports presenting data by eye. Only two population-based studies m'~ have reported prevalence estimates. In comparing our results with published estimates, we have presented data by subject rather than by eye. The Beaver Dam Eye Study, the methodology of which was similar to ours, reported an overall disc hemorrhage prevalence of 0.9%. ~j In the first Dalby survey, the disc hemorrhage prevalence was 0.8%) 0 Both these rates are lower than our prevalence of 1.4%. However, the Dalby survey did find a higher prevalence in women as well as an age-related increase, and the combined Dalby survey findings are close to our rates for younger age groups ( < 7 0 years). All other reports of disc hemorrhage prevalence have focused on subjects with diagnosed or suspected glaucoma in clinic populations, the results of which may be subject to considerable selection bias. Disc hemorrhage prevalence estimates in subjects with open-angle glaucoma 3's'9'm'18 range from 4.7% 5 to 58.3%. t° Our disc hemorrhage prevalence estimate (13.8%) for open-angle glaucoma cases is in the middle of this range. Our age-specific open-angle glaucoma prevalence rates also are comparable with those of other similar population-based studies) 6 Kitazawa et al 9 reported a higher prevalence of disc hemorrhage in subjects with low-pressure glaucoma (20.5%) compared to high-pressure glaucoma (4.2%). 9 Our findings are similar, with higher disc hemorrhage prevalence in low-pressure glaucoma cases (25%) compared to high-pressure glaucoma (8%), a threefold difference, after age-gender adjustment (OR, 2.9; CI, 1.18.1). Although low-pressure glaucoma was defined on the basis of only two lOP measurements, ~6we found a similar proportion of low-pressure glaucoma to that of other population studies. The small differences found in the site,distribution of disc hemorrhages between subjects with and without open-angle glaucoma may indicate different etiologies or reflect small numbers. In subjects with open-angle glau-
coma, disc hemorrhages tended to concentrate at the temporal upper and lower poles, sites of early glaucomatous rim loss. In subjects without open-angle glaucoma, the site distribution tended to be more generalized. There are few published estimates of disc hemorrhage prevalence in normal subjects (i.e., those who neither have open-angle glaucoma nor are suspected of having glaucoma). Bengtsson et al m reported 5 disc hemorrhages in 1496 subjects without open-angle glaucoma, a 0.3% prevalence. Kitazawa et al 9 reported fi 0.4% prevalence (2 disc hemorrhages in 473 normal subjects), whereas two other case-control studies found no disc hemorrhages in control subjects. 5'19Our 1.0% disc hemorrhage prevalence in subjects without signs of open-angle glaucoma is higher even though our age-specific disc hemorrhage prevalence rates were similar to those of the Bengtsson report, m Our data support the reported increased disc hemorrhage prevalence in low-pressure glaucoma. 9'2°m However, the relationship between disc hemorrhage and lOP appears complex. Intraocular pressure may be an important determinant of disc hemorrhage in eyes with lowpressure glaucoma, whereas it may be less important in high-pressure glaucoma. Alternatively, the association between IOP and disc hemorrhage in the low-pressure glaucoma group may have been a chance finding. An association between disc hemorrhages and larger vertical cup-disc ratios has not been described previously in normal subjects, but has been reported in those suspected of having glaucoma. 5 This finding could suggest that some apparently normal eyes with disc hemorrhages actually had early open-angle glaucoma, implying an underestimate of glaucoma prevalence. However, our agespecific open-angle glaucoma prevalence rates already are at the upper end of comparable population-based studies. 16 Large vertical cup-disc ratio and pseudoexfoliation, a form of elastosis, may be independent risk factors for disc hemorrhage. Elastotic changes in the lamina cribrosa have been reported in eyes with the exfoliation syndrome. = Both the association with cup-disc ratio and pseudoexfoliation suggest a structural etiology for disc hemorrhage, which already has been proposed. 23Wide IOP fluctuations are typical of pseudoexfoliation, and it is possible that lOP measurements in our study did not reflect this. The positive association found between open-angle glaucoma and diabetes 24 is well reported 25-27 though questioned recentlyfl8 The disc hemorrhage prevalence in diabetes was 2.3%, significantly higher than in subjects without diabetes. Although retinal hemorrhages near or crossing the disc could represent diabetic retinopathy, no subjects with diabetic disc hemorrhage had retinopathy in the disc field. The two open-angle glaucoma subjects who had bilateral disc hemorrhages also had diabetes. The significant association found between diabetes and glaucoma suggests that the finding of an isolated disc hemorrhage in a subject with diabetes should not necessarily be dismissed as a sign of diabetic retinopathy. ' A predictor of disc hemorrhage in normal subjects was
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Volume 105, Number 2, February 1998
a history of typical migraine. Although an association between migraine and low-pressure glaucoma has been reported, 29 some studies have failed to confirm this association. 3°'3~ The association between disc hemorrhage and migraine in normal subjects is not explained by larger c u p - d i s c ratios, as adjusting for vertical cup-disc ratio had little effect on the estimate. Migraine is associated with changes in cerebral arterial blood flow and vessel diameter. 32 Both retinal and optic nerve ischemia have been reported in association with acute migraine. 33'34Disc hemorrhages may be an ophthalmic manifestation of a vasospastic tendency associated with migraine. Our data support a previous report that in open-angle glaucoma, subjects with disc hemorrhages have a higher frequency of systemic hypertension? S Posterior vitreous detachment also has been reported as a possible cause of disc hemorrhage. 36"37 Although this could provide an explanation for some disc hemorrhages found in normal subjects in our study, it seems unlikely to explain the large number found, ss The use of disc hemorrhage as a screening tool for open-angle glaucoma is debated. 5'9 Our data suggest that only approximately one in four persons older than 50 years of age observed with a disc hemorrhage has concurrent matching disc and field signs suggesting open-angle glaucoma (Table 3). Although the finding of a disc hemorrhage increases the suspicion for open-angle glaucoma above the background glaucoma prevalence of 3%, the sensitivity of disc hemorrhage as a test for open-angle glaucoma is low. In summary, the Blue Mountains Eye Study has provided precise prevalence estimates of optic disc hemorrhage for an older general population. The well-known association between disc hemorrhage and open-angle glaucoma was confirmed with a threefold increased prevalence of disc hemorrhage in subjects with open-angle glaucoma with low screening IOP measurements. Nevertheless, most disc hemorrhages were seen in persons without signs of open-angle glaucoma. In this apparently normal group, however, we showed an association between disc hemorrhage and larger vertical cup-disc ratio as well as a history of typical migraine. It is likely that in some subjects with disc hemorrhages who we have assessed as not having open-angle glaucoma, open-angle glaucoma will develop with time. It also is probable that the cumulative incidence of disc hemorrhage in our population, particularly among persons with open-angle glaucoma, will be higher than the prevalence estimates reported here. These questions may be answered in the follow-up examination currently underway.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17.
18.
19. 20. 21. 22.
References 1. Drance SM, Begg IS. Sector haemorrhage--a probable acute ischaemic disc change in chronic simple glaucoma. Can J Ophthalmol 1970;5:137-41. 2. Drance SM, Fairclough M, Butler DM, Kottler MS. The
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24.
importance of disc hemorrhage in the prognosis of chronic open angle glaucoma. Arch Ophthalmol 1977;95:226-8. Airaksinen PJ, Mustonen E, Alanko HI. Optic disc haemorrhages precede retinal nerve fibre layer defects in ocular hypertension. Acta Ophthalmol (Copenh) 1981 ; 59:627-41. Bengtsson B. Optic disc haemorrhages preceding manifest glaucoma. Acta Ophthalmol (Copenh) 1990;68:450-4. Diehl DL, Quigley HA, Miller NR, et al. Prevalence and significance of optic disc hemorrhage in a longitudinal study of glaucoma. Arch Ophthalmol 1990; 108:545-50. Sonnsjo B, Krakau CE. Arguments for a vascular glaucoma etiology. Acta Ophthalmol (Copenh) 1993;71:433-44. Flammer J. The vascular concept of glaucoma. Surv Ophthalmol 1994; 38(Suppl):S3-6. Jay JU The vascular factor in low tension glaucoma: alchemists' gold? [editorial] Br J Ophthalmol 1992;76:1. Kitazawa Y, Shirato S, Yamamoto T. Optic disc hemorrhage in low-tension glaucoma. Ophthalmology 1986; 93:853-7. Bengtsson B, Holmin C, Krakau CE. Disc haemorrhage and glaucoma. Acta Ophthalmol (Copenh) 1981; 59:1 - 14. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992; 99:1499-504. Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology 1996; 103:357-64. Klein BE, Magli YL, Richie KA, et al. Quantitation of optic disc cupping. Ophthalmology 1985;92:1654-6. Healey PR, Mitchell P, Wang JJ, Smith W. The relationship between cup-disc ratio and optic disc diameter: the Blue Mountains Eye Study. Aust N Z J Ophthalmol 1997; 25(Suppl):S99-101. Bengtsson B, Krakau CE. Correction of optic disc measurements on fundus photographs. Graefes Arch Clin Exp Ophthalmol 1992; 230:24-8. Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996; 103:1661-9. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1-96. Susanna R, Drance SM, Douglas GR. Disc hemorrhages in patients with elevated intraocular pressure. Occurrence with and without field changes. Arch Ophthalmol 1979;97:2845. Jonas JB, Xu L. Optic disk hemorrhages in glaucoma. Am J Ophthalmol 1994; 118:1-8. Gloster J. Incidence of optic disc haemorrhages in chronic simple-glaucoma and ocular hypertension. Br J Ophthalmol 1981;65:452-6. Siegner SW, Netland PA. Optic disc hemorrhages and progression of glaucoma. Ophthalmology 1996; 103:1014-24. Netland PA, Ye H, Streeten BW, Hernandez MR. Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma. Ophthalmology 1995; 102:878-86. Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve damage in human glaucoma. II: The site of injury and susceptibility to damage. Arch Ophthalmol 1981 ;99:635 -49. Mitchell P, Smith W, Chey T, Healey PR. Open-angle glaucoma and diabetes: the Blue Mountains Eye Study. Ophthalmology 1997; 104:712-8.
Healey et al •
Optic Disc Hemorrhages and Glaucoma
25. Becker B. Diabetes mellitus and primary open-angle glaucoma. The XXVII Edward Jackson Memorial Lecture. Am J Ophthalmol 1971;71:1-16. 26. Kahn HA, Milton RC. Alternative definitions of open-angle glaucoma. Effect on prevalence and associations in the Framingham Eye Study. Arch Ophthalmol 1980;98:2172-7. 27. Klein BE, Klein R, Jensen SC. Open-angle glaucoma and older-onset diabetes. The Beaver Dam Eye Study. Ophthalmology 1994; 101:1173-7. 28. Tielsch JM, Katz J, Quigley HA, et al. Diabetes, intraocular pressure, and primary open-angle glaucoma in the Baltimore Eye Survey. Ophthalmology 1995; 102:48-53. 29. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci 1985; 26:1105- 8. 30. Usui T, Iwata K, Shirakashi M, Abe H. Prevalence of migraine in low-tension glaucoma and primary open-angle glaucoma in Japanese. Br J Ophthalmol 1991;75:224-6. 31. Klein BE, Klein R, Meuer SM, Goetz LA. Migraine head-
32. 33. 34. 35. 36. 37. 38.
ache and its association with open-angle glaucoma: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 1993; 34:3024-7. Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet 1991; 338:13-7. O'Hara M, O'Connor PS. Migrainous optic neuropathy. J Clin Neuroophthalmol 1984;4:85-90. Katz B. Migrainous central retinal artery occlusion. J Clin Neuroophthalmol 1986;6:69-75. Kottler MS, Drance SM. Studies of.hemorrhage on the optic disc. Can J Ophthalmol 1976; 11:102-5. Wise GN. Relationship of idiopathic preretinal macular fibrosis to posterior vitreous detachment. Am J Ophthalmol 1975; 79:358-62. Roberts TV, Gregory-Roberts JC. Optic disc haemorrhages in posterior vitreous detachment. Aust N Z J Ophthalmol 1991; 19:61-3. Bengtsson B. Chronic glaucoma and symptomatic vitreous detachment. Acta Ophthalmol (Copenh) 1986;64:152-6.
Historical Image Eye surgery before anesthesia. Taken from Desmarres, LA. Trait6 Th6orique et Pratique des Maladies des Yeux, volume III, Paris, 1858.*
* Courtesy of the Museum of Ophthalmology, Foundation of the American Academy of Ophthalmology, San Francisco, California.
223
Small hemorrhages on or crossing the optic disc have been reported to precede both retinal nerve fiber layer damage and visual field loss in subjects with glaucoma or ocular hypertension. These observations have led to the hypothesis that optic disc hemorrhages are markers of imminent deterioration in glaucoma or an early sign of glaucomatous damage in glaucoma suspects. ~-5 Their presence also lends weight to vascular theories of glaucoma etiology. 6-8 However, the relatively rare occurrence and transient nature of disc hemorrhages 9 make them difficult to study. Consequently, most research has been limited to case series and case-control studies. Understand-
ably, most studies have focused on subjects with glaucoma or ocular hypertension. In contrast, only two population-based studies have reported any data on disc hemorrhages, m.~t The first aim of this report is to provide precise prevalence estimates o f disc hemorrhage in a well-defined older population. The second aim is to examine disc hemorrhage associations with age, gender, glaucoma, and systemic vascular factors such as diabetes, migraine, systemic hypertension, and vascular disease history.
Methods Originally received: January 17, 1997. Revision accepted: August 26, 1997. Department of Ophthalmology,University of Sydney, Sydney, Australia. 2 Department of Community Medicine, University of Sydney, Sydney, Australia. Supported by the Ophthalmic Research Institute of Australia and the Australian Department of Health and Family Services. Reprint requests to Paul Mitchell, MD, FRCOphth, University of Sydney, Department of Ophthalmology, Westmead Hospital Hawkesbury Road, Westmead, NSW, Australia, 2145.
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Population The Blue Mountains Eye Study was a population-based survey of eye disease and visual impairment in individuals 49 years of age or older living in the Blue Mountains, west of Sydney, Australia, that was conducted during 1992-1993.t2 Of the 4433 eligible persons, identified by a door-to-door census, 3654 (82.4%) participated in the eye study. A total of 501 persons (11.3%) refused to participate. After those who died or left the area during the study were excluded, the response rate was
H e a l e y et al •
Optic Disc Hemorrhages and Glaucoma 4.74
87.9%. Participants mostly were of northern European descent. The project was approved by the Western Sydney Area Health Service, and informed consent was obtained from all participants.
Procedures All participants underwent a detailed eye examination, which included a single applanation intraocular pressure (IOP) measurement, blood pressure measurement, and subjective refraction, using a logarithm of the minimum angle of resolution (IogMAR) chart. After pupil dilatation, nonsimuitaneous stereoscopic 30 ° color retinal photographs were taken, centered on the optic disc (Diabetic Retinopathy Study field 1), macula (field 2), temporal, and peripheral retina. A Zeiss FF3 fundus camera (Carl Zeiss, Oberkochen, Germany) and Kodachrome 25 slide film (Eastman Kodak, Rochester, NY) were used. Participants were asked to return for a fasting pathology test, which included venous blood glucose. Photographs were assessed by one of two trained graders who followed a modification of the protocol developed for the Wisconsin Epidemiologic Study of Diabetic Retinopathy. t3 The slides were mounted in clear plastic sheets and viewed with a Donaldson stereo-viewer on a translucent light box. Photographs were considered gradable if field 1 was gradable or the disc was clearly visible from field 2. A disc hemorrhage was defined as a hemorrhage on or crossing the optic disc. Retinal hemorrhages outside the disc margin were excluded, as were hemorrhages associated with other retinal hemorrhages in Diabetic Retinopathy Study field 1 (for example, those due to retinal vein occlusion or diabetic retinopathy) or with optic disc edema. The longest diameter in a range between clock-hours 11:00 to 1:00 and 5:00 to 7:00 was used to measure both the optic disc and cup, with high intraobserver and interobserver reliability.L4 The cup margin was determined by its contour rather than by its pallor. Optic disc and cup measurements were corrected for magnification using the spherical equivalent refraction for each eye.~S The glaucoma examination has been described previously.~6 In brief, it was conducted in two phases. In the first phase, a screening Humphrey 76-point suprathreshold visual field test. was performed in 3241 subjects (89%), applanation tonometry in 3641 participants (99.6%), and stereo optic disc photography in 3568 participants (98%). In the second phase, 336 participants (9.2%) with glaucomatous field defects on the screening field or a glaucomatous optic disc appearance returned for a Humphrey 3 0 - 2 full-threshold visual field test, gonioscopy, and repeat tonometry. All 3 0 - 2 fields were assessed by the study ophthalmologist (PM) in a masked fashion for typical glaucomatous features. The minimum diagnostic criteria were an abnormal Humphrey 3 0 - 2 Glaucoma Hemifield Test, plus one or more of the following field defects, not explained by ocular or neurologic causes: (1) arcuate or paracentral scotoma, at least four contiguous points on the pattern deviation plot depressed at P < 0.5% level; (2) nasal step at least two horizontal points in width on the pattern deviation plot depressed at P < 0.5% level; or (3) advanced glaucomatous field loss. Open-angle glaucoma was diagnosed when typical glaucomatous visual field loss on the Humphrey 3 0 - 2 test was present, combined with matching optic disc rim thinnin~ and an enlarged cup-disc ratio (~-0.7) or cup-disc asymmetry between the two eyes of 0.0.3 or greater. Gonioscopy excluded angle closure, rubeosis or secondary glaucoma, other than pseudoexfoliation.
3
% 2
0 <60
60-69
70-79
80+
age group (years) Figure 1. Prevalence of optic disc hemorrhages in 3582 participants by age and gender. Bar numbers indicate percent of subjects.
In this study, low-pressure glaucoma was defined as open-angle glaucoma with IOP in each eye of more than 21 mmHg, both at screening and on a subsequent visit. These subjects were not receiving ocular hypotensive treatment and had no history of glaucoma surgery. Other open-angle glaucoma cases were defined as high-pressure glaucoma. Assessment and diagnosis of typical migraine were made by a clinician after directed questioning about specific symptoms, consistent with the International Headache Society criteria. ~7 A typical migraine history included recurrent severe headache that was unilateral and associated with nausea, vomiting, photophobia, or visual disturbance. Diabetes was diagnosed from history or an elevated fasting venous blood glucose of 7.8 mmol/l or greater (140 mg%). Statistical Methods Statistical Analysis System (SAS Institute, Cary, NC) was used for tabulations, Student's t test, and logistic regression analyses. All continuous variables were used as such in the logistic regressions. Odds ratios (OR) and 95% confidence intervals (CI) are presented.
Results Prevalence and Characteristics of Optic Disc Hemorrhage On initial grading, disc hemorrhages were found in 60 eyes of 55 subjects. Three cases had features suggesting previous retinal vein occlusion and one case had marked premacular fibrosis. All four cases were excluded, leaving disc hemorrhages in 56 eyes of 51 subjects, a prevalence of 1.4% (CI, 1.0%-1.8%) among subjects or 0.8% (CI, 0.6%- 1.0%) of eyes. Disc hemorrhages were bilateral in five subjects, and in one subject, two disc hemorrhages were found in the same eye. Overall, 34 left eyes and 22 right eyes were affected. Figure 1 shows the age and gender distribution of disc hemorrhages. The prevalence was 0.2% in persons younger than 60 years of age, 0.4% id persons 60 to 69 years of age, 1.4% in persons 70 to 79 years
217
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Volume 105, Number 2, February 1998
73 T 15~1
"
1NT1
2
1 N
2
1
flame-shaped
3
Normal Subjects
blot-shaped
5 3 :,, 5 T
N T 2
2 2-'"~ 2 glaucoma
3 2 N
31 no glaucoma
Figure 2. Circumferential distribution of optic disc hemorrhages reproduced as if all were in the right eye, with temporal (T) and nasal disc margins indicated.
of age, and 1.9% in persons 80 years of age or older. Disc hemorrhage prevalence was higher in women than in men (OR, 1.9; CI, 1.0-3.5) after adjusting for age and glaucoma. Most disc hemorrhages (71%) were flame shaped, appearing to lie on the surface of the disc and retinal nerve fiber layer. The remaining hemorrhages (29%) were blot shaped. In 48% of cases, the hemorrhages were dense, obscuring underlying structures. Disc hemorrhages occupied less than a half clockhour of the disc circumference (approximately 15°) in 71% of cases, were between a half and 1-clock-hour width in 20%, and were wider than 1 clock-hour in 9% of cases. The distribution of disc hemorrhages around the optic disc is shown in Figure 2. Flame hemorrhages were more frequent on the temporal side of the optic disc, with the largest proportion seen in the superior-temporal quadrant. Blot hemorrhages were distributed more evenly. In persons with open-angle glaucoma, disc hemorrhages mainly involved the upper and lower poles of the disc, whereas in persons without open-angle glaucoma, some disc hemorrhages also were present at either the temporal or nasal disc margins. Open-Angle Glaucoma Disc hemorrhages were found in 15 of the 108 subjects with open-angle glaucoma, a prevalence of 13.8% (CI, 7.3%20.3%). Three examples are shown in Figure 3 (A-C). Glaucoma previously was undiagnosed in 55 persons (51%). Agespecific prevalence rates were 0% in open-angle glaucoma subjects younger than 60 years of age, 17.6% in subjects 60 to 69 years of age, 8.9% in subjects 70 to 79 years of age, and 19% in subjects 80 years of age or older. Table 1 lists age-specific prevalence by type of hemorrhage. Flame hemorrhages proportionally were more frequent than blot hemorrhages. Disc hemorrhages were associated strongly with open-angle glaucoma after age and gender adjustment (OR, 9.0; CI, 4.8-17.0), as listed in Table 2. Of the 108 subjects with open-angle glaucoma, 36
218
were assessed as having low-pressure glaucoma. The prevalence of disc hemorrhages in this group (25%) was higher than in the 72 high-pressure glaucoma cases (8%) (OR, 2.9; CI, 1.1-8.1) after adjusting for age and gender. In all, 17 glaucomatous eyes had disc hemorrhages, representing 30% of all disc hemorrhages.
Although the finding of disc hemorrhage was associated strongly with open-angle glaucoma, most disc hemorrhages (70%) were found in subjects with no evidence of open-angle glaucoma (39 disc hemorrhages in 36 subjects), a prevalence of 1.0% (CI, 0.7%- 1.3%). Seven examples of disc hemorrhage in subjects without glaucomatous cupping or visual field loss are shown in Figure 3 (D-J). Age-specific prevalence rates were 0.30% in subjects younger than 60 years of age, 0.47% in persons 60 to 69 years of age, 2.44% in persons 70 to 79 years of age, and 1.60% in persons 80 years of age or older. Blot hemorrhages were relatively more frequent in normal subjects compared to open-angle glaucoma subjects, although flame hemorrhages still predominated. Associations with Optic Disc Hemorrhage Cup-Disc Ratio. Disc hemorrhages were more prevalent in eyes with larger vertical cup-disc ratios after adjusting for age and gender (/~ = 5.17, P < 0.0001). This association was not significant in subjects with open-angle glaucoma (,8 = 0.98, P = 0.96), but was statistically significant in persons without open-angle glaucoma (/~ = 4.75, P < 0.0001), as shown in Figure 4. Intraocular Pressure. Disc hemorrhage prevalence was positively associated with increasing lOP (OR, 1.7 per 5 mmHg; CI, 1.3-2.3) after adjusting for age and gender, as listed in Table 2. No statistically significant associations were found in normal subjects nor in subjects with high-pressure glaucoma. In subjects with low-pressure glaucoma, there was a borderline significant positive association between disc hemorrhage and IOP (OR, 12.2; CI, 1.0-155). In this group, the mean IOP was 17.7 mmHg for eyes with disc hemorrhage and 16.7 mmHg for eyes without disc hemorrhage. The association between disc hemorrhage and lOP changed little after adjusting for vertical cup-disc ratio (OR, 15.4; CI, 1.1-218). Among 135 participants with ocular hypertension (IOP > 21 mmHg, but not assessed as having open-angle glaucoma), 2 persons had a disc hemorrhage, a prevalence of 1.5% (CI, 0%-3.5%). However, the association between disc hemorrhage and ocular hypertension was not statistically significant (Table 2). Pseudoexfoliation and Myopia. Disc hemorrhages were found in 3-of 82 subjects with pseudoexfoliation in 1 or both eyes, a prevalence of 3.7%. These consisted of one flame and two blot hemorrhages. None of the three subjects had openangle glaucoma. The association of disc hemorrhage with pseudoexfoliation was significant in all subjects (OR, 3.5; CI, 1.1-11.8) as well as in subjects without glaucoma (OR, 6.0; CI, 1.8-20.2) after adjusting for age and gender. The magnitude of the association between pseudoexfoliation and disc hemorrhage was similar after adjusting for IOP (OR, 5.6; CI, 1.719). No significant association was found between disc hemorrhage and myopia in any group after adjusting for age and gender. Diabetes. Disc hemorrhages were found in 6 of 256 persons with a history or biochemical evidence of diabetes, a prevalence
H e a l e y et al •
Optic Disc Hemorrhagesand Glaucoma
Figure 3. Ten examples of optic disc hemorrhages (flame and blot) seen in the Blue Mountains Eye Study. A - C , eyes of subjects with open-angle glaucoma diagnosed from matching visual field loss and optic disc rim thinning. D - J , eyes of subjects without visual field loss or optic disc rim thinning.
G
H
219
Ophthalmology Volume I05, Number 2, February 1998 Table 1. Prevalence of Optic Disc Hemorrhages in 3582 Participants in the Blue Mountains Eye Study by Age Group and Optic Disc Hemorrhage Type* Age Group (yrs)
% of Subjects (no. of Subjects) with OAG F/ame
Blot
2
% of Subjects (no. of Subjects) without OAG F/ame
49-59 60-69 70-79 >80
0 (0) 17.6% (3) 6.6% (3) 16.6% (7)
0 (0) 0 (0) 2.2% (l) 2.4% (1)
0.2% 0.30% 1.6% 1.0%
(2) (4) (14) (3)
Total
12.0% (13)
1.9% (2)
0.6% (23)
1.5
Blot 0.1% 0.2% 0.9% 0.6%
2.38
2.5
1.01
% 1
(1) (3) (7) (2)
0.5
I
o
0.4% (13)
0.32
0.27
OAG = open-angle glaucoma. * Flame and blot are optic disc hemorrhage types.
I
I
0.03-0.29
I,
0.3-0.49
I
0.5-0.69
0.7-0.84
Vertical cup-disc ratio (group) Figure 4. Prevalence of optic disc hemorrhages in participants without open-angle glaucoma by vertical cup-disc ratio (grouped to improve clarity). Bar numbers indicate percent of subjects.
of 2.3%, including 6 flame and 2 blot hemorrhages. None of these eyes had. any other hemorrhages in field 1, although four had evidence of nonproliferative diabetic retinopathy elsewhere. Two of these subjects with diabetes also had open-angle glaucoma. Diabetes was associated significantly with disc hemorrhage overall (OR, 2.9; CI, 1.4-6.3). The disc hemorrhage prevalence in subjects with diabetes and open-angle glaucoma was 14.3% (4 disc hemorrhages in 2 of 14 subjects with diabetes and open-angle glaucoma). Hypertension and Other Vascular Factors. Increased systolic blood pressure was associated significantly with disc hemorrhage (OR, 1.1; CI, 1.0-1.3) for each 10-mmHg increase in systolic blood pressure after adjusting for age and gender. The association was stronger in subjects with open-angle glaucoma. Although increased odds for disc hemorrhage also were found in subjects with a history of hypertension requiring medication, this was not statistically significant (Table 2). No significant associations were found between disc hemorrhage and a history of vascular events (e.g., angina, myocardial infarct, or stroke), smoking (current or past), or regular use of aspirin after adjusting for age and gender (Table 2). Migraine. Disc hemorrhages were found in 11 of 608 sub-
jects who had a history of typical migraine headaches, including 2 with bilateral disc hemorrhages, a prevalence of 1.8%. Twelve of the 13 disc hemorrhages in this group were flame shaped, and only 1 subject with disc hemorrhage had both migraine and open-angle glaucoma. Increased, but nonsignificant, odds were found for the association between disc hemorrhage and a history of typical migraine (OR, 1.7; CI, 0.9-3.3) in all subjects, and there was no association in subjects with open-angle glaucoma. However, typical migraine history was associated significantly with disc hemorrhage in subjects without open-angle glaucoma (OR, 2.2; CI, 1.1-4.6). This association was not altered by adjusting for c u p - d i s c ratio (OR, 2.1; CI, 1.0-4.4).
Disc Hemorrhage as a Test for Open-angle Glaucoma Table 3 lists the frequency of disc hemorrhage per person for subjects with and without open-angle glaucoma. As a diagnostic test for open-angle glaucoma, the sensitivity of disc hemorrhage
Table 2. Associations of Optic Disc Hemorrhages with Selected Characteristics, after Adjusting for Age and Sex* Characteristic
All Subjects
Normals
Age (per decade) Open-angle glaucomat Ocular hypertension Intraocular pressure (per 5 mmHg) Pseudoexfoliation Diabetes$ Migraine history Systolic blood pressure (per 10 mmHg) Hypertension§ Vascular disease historyl[
2.2 (1.7-2.8) 9.0 (4.8-17.0) 0.9 (0.2-3.8) 1.7 (1.3-2.3) 3.5 ( 1.1-11.8) 2.9 (1.4-6.3) 1.7 (0.9-3.3) 1.1 (1.0-1.3) 1.3 (0.8-2.3) 0.6 (0.3-1.2 )
2.2 (1.6-3.0) . 1.3 (0.3-5.3) 1.4 (0.9-2.3) 6.0 (1.8-20.2) 2.0 (0.7-5.7) 2.2 (1.1-4.6) 1.0 (0.9-1.2) 1.0 (5.1-1.9) 0.7 (0.3-1.6)
All OAG .
0.9 (0.5-1.5) . -- 1.2 (0.8-1.9) -4.4 (1.2-15.8) 0.6 (0.1-2.6) 1.3 (1.1-1.5) 2.0 (0.6-6.3) 0.3 (0.1- 1.4)
LPG
HPG
0.5 (0.2-1,2) . -12.2 (1.0-155) -7.7 (0.8-79) 1.0 (0.1-9.3) 1.3 (1.0-1.6) 5.2 (0.5-50) 0.3 (0.0- 2.5 )
1.5 (0.6-3,7) -1.4 (0.8-2.5) -3.1 (0.8-31) 0.7 (0.1-7.0) 1.4 (1.1-1.8) 1.0 (0.2-4.6) 0.4 (0.0-3.0)
* Odd ratios (95% confidence intervals) are shown for normal subjects and those with open-angle glaucoma (OAG), low-pressureglaucoma (LPG), and high-pressure glaucoma (HPG). t Defined as congruent, typical glaucomatous optic disc and visual field changes, after excluding cases of rubeotic or secondary glaucoma. ;~Defined as diabetes history or fasting glucose >7.8 mmol/l. § Defined as history of hypertension requiring medication or systolic blood pressure > 160 mmHg or diastolic blood pressure >95 mmHg. IIDefined as history of angina, myocardial infarct, or stroke.
220
H e a l e y et al •
Optic Disc Hemorrhages and Glaucoma
Table 3. Freqt,ency of Optic Disc Hemorrhage in Participants with and without Open-angle Glaucoma* OAG Present
OAG Absent
Total
DH present DH absent
14 94
37 3509
51 3603
Total
108
3546
3654
OAG = open-angleglaucoma;DH = disc hemorrhage. *Sensitivity: 12.9%; specificity: 98.96%; positive predictive value: 27.45%; negativepredictivevah,e: 97.4%.
was 13%, specificity was 99%, positive predictive value was 27%, and negative predictive value was 97%.
Discussion There are few published data on the prevalence of optic disc hemorrhage, with most reports presenting data by eye. Only two population-based studies m'~ have reported prevalence estimates. In comparing our results with published estimates, we have presented data by subject rather than by eye. The Beaver Dam Eye Study, the methodology of which was similar to ours, reported an overall disc hemorrhage prevalence of 0.9%. ~j In the first Dalby survey, the disc hemorrhage prevalence was 0.8%) 0 Both these rates are lower than our prevalence of 1.4%. However, the Dalby survey did find a higher prevalence in women as well as an age-related increase, and the combined Dalby survey findings are close to our rates for younger age groups ( < 7 0 years). All other reports of disc hemorrhage prevalence have focused on subjects with diagnosed or suspected glaucoma in clinic populations, the results of which may be subject to considerable selection bias. Disc hemorrhage prevalence estimates in subjects with open-angle glaucoma 3's'9'm'18 range from 4.7% 5 to 58.3%. t° Our disc hemorrhage prevalence estimate (13.8%) for open-angle glaucoma cases is in the middle of this range. Our age-specific open-angle glaucoma prevalence rates also are comparable with those of other similar population-based studies) 6 Kitazawa et al 9 reported a higher prevalence of disc hemorrhage in subjects with low-pressure glaucoma (20.5%) compared to high-pressure glaucoma (4.2%). 9 Our findings are similar, with higher disc hemorrhage prevalence in low-pressure glaucoma cases (25%) compared to high-pressure glaucoma (8%), a threefold difference, after age-gender adjustment (OR, 2.9; CI, 1.18.1). Although low-pressure glaucoma was defined on the basis of only two lOP measurements, ~6we found a similar proportion of low-pressure glaucoma to that of other population studies. The small differences found in the site,distribution of disc hemorrhages between subjects with and without open-angle glaucoma may indicate different etiologies or reflect small numbers. In subjects with open-angle glau-
coma, disc hemorrhages tended to concentrate at the temporal upper and lower poles, sites of early glaucomatous rim loss. In subjects without open-angle glaucoma, the site distribution tended to be more generalized. There are few published estimates of disc hemorrhage prevalence in normal subjects (i.e., those who neither have open-angle glaucoma nor are suspected of having glaucoma). Bengtsson et al m reported 5 disc hemorrhages in 1496 subjects without open-angle glaucoma, a 0.3% prevalence. Kitazawa et al 9 reported fi 0.4% prevalence (2 disc hemorrhages in 473 normal subjects), whereas two other case-control studies found no disc hemorrhages in control subjects. 5'19Our 1.0% disc hemorrhage prevalence in subjects without signs of open-angle glaucoma is higher even though our age-specific disc hemorrhage prevalence rates were similar to those of the Bengtsson report, m Our data support the reported increased disc hemorrhage prevalence in low-pressure glaucoma. 9'2°m However, the relationship between disc hemorrhage and lOP appears complex. Intraocular pressure may be an important determinant of disc hemorrhage in eyes with lowpressure glaucoma, whereas it may be less important in high-pressure glaucoma. Alternatively, the association between IOP and disc hemorrhage in the low-pressure glaucoma group may have been a chance finding. An association between disc hemorrhages and larger vertical cup-disc ratios has not been described previously in normal subjects, but has been reported in those suspected of having glaucoma. 5 This finding could suggest that some apparently normal eyes with disc hemorrhages actually had early open-angle glaucoma, implying an underestimate of glaucoma prevalence. However, our agespecific open-angle glaucoma prevalence rates already are at the upper end of comparable population-based studies. 16 Large vertical cup-disc ratio and pseudoexfoliation, a form of elastosis, may be independent risk factors for disc hemorrhage. Elastotic changes in the lamina cribrosa have been reported in eyes with the exfoliation syndrome. = Both the association with cup-disc ratio and pseudoexfoliation suggest a structural etiology for disc hemorrhage, which already has been proposed. 23Wide IOP fluctuations are typical of pseudoexfoliation, and it is possible that lOP measurements in our study did not reflect this. The positive association found between open-angle glaucoma and diabetes 24 is well reported 25-27 though questioned recentlyfl8 The disc hemorrhage prevalence in diabetes was 2.3%, significantly higher than in subjects without diabetes. Although retinal hemorrhages near or crossing the disc could represent diabetic retinopathy, no subjects with diabetic disc hemorrhage had retinopathy in the disc field. The two open-angle glaucoma subjects who had bilateral disc hemorrhages also had diabetes. The significant association found between diabetes and glaucoma suggests that the finding of an isolated disc hemorrhage in a subject with diabetes should not necessarily be dismissed as a sign of diabetic retinopathy. ' A predictor of disc hemorrhage in normal subjects was
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Volume 105, Number 2, February 1998
a history of typical migraine. Although an association between migraine and low-pressure glaucoma has been reported, 29 some studies have failed to confirm this association. 3°'3~ The association between disc hemorrhage and migraine in normal subjects is not explained by larger c u p - d i s c ratios, as adjusting for vertical cup-disc ratio had little effect on the estimate. Migraine is associated with changes in cerebral arterial blood flow and vessel diameter. 32 Both retinal and optic nerve ischemia have been reported in association with acute migraine. 33'34Disc hemorrhages may be an ophthalmic manifestation of a vasospastic tendency associated with migraine. Our data support a previous report that in open-angle glaucoma, subjects with disc hemorrhages have a higher frequency of systemic hypertension? S Posterior vitreous detachment also has been reported as a possible cause of disc hemorrhage. 36"37 Although this could provide an explanation for some disc hemorrhages found in normal subjects in our study, it seems unlikely to explain the large number found, ss The use of disc hemorrhage as a screening tool for open-angle glaucoma is debated. 5'9 Our data suggest that only approximately one in four persons older than 50 years of age observed with a disc hemorrhage has concurrent matching disc and field signs suggesting open-angle glaucoma (Table 3). Although the finding of a disc hemorrhage increases the suspicion for open-angle glaucoma above the background glaucoma prevalence of 3%, the sensitivity of disc hemorrhage as a test for open-angle glaucoma is low. In summary, the Blue Mountains Eye Study has provided precise prevalence estimates of optic disc hemorrhage for an older general population. The well-known association between disc hemorrhage and open-angle glaucoma was confirmed with a threefold increased prevalence of disc hemorrhage in subjects with open-angle glaucoma with low screening IOP measurements. Nevertheless, most disc hemorrhages were seen in persons without signs of open-angle glaucoma. In this apparently normal group, however, we showed an association between disc hemorrhage and larger vertical cup-disc ratio as well as a history of typical migraine. It is likely that in some subjects with disc hemorrhages who we have assessed as not having open-angle glaucoma, open-angle glaucoma will develop with time. It also is probable that the cumulative incidence of disc hemorrhage in our population, particularly among persons with open-angle glaucoma, will be higher than the prevalence estimates reported here. These questions may be answered in the follow-up examination currently underway.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17.
18.
19. 20. 21. 22.
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Historical Image Eye surgery before anesthesia. Taken from Desmarres, LA. Trait6 Th6orique et Pratique des Maladies des Yeux, volume III, Paris, 1858.*
* Courtesy of the Museum of Ophthalmology, Foundation of the American Academy of Ophthalmology, San Francisco, California.
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