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Nonarteritic Anterior Ischemic Optic Neuropathy: Time of Onset of Visual Loss
Nonarteritic Anterior Ischemic Optic Neuropathy: Time of Onset of Visual Loss I'lnl
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SOHAN SINGH HAYREH, MD, PHD, DSC, PATRICIA A. PODHAJSKY, BSN, AND BRIDGET ZIMMERMAN, PHD
• PURPOSE: TO study time of day and seasonal variation of onset of visual loss in nonarteritic anterior ischemic optic neuropathy (AION). • METHODS: From 1975 to 1995, we prospectively investigated the time of discovery of visual loss in 635 patients (871 eyes) with AION—a total of 925 episodes. Data were analyzed for two varia bles: time of day of discovery of visual loss for 544 episodes and seasonal variation of the onset of AION for 839 episodes. • RESULTS: Of 544 episodes, time of day for discovery of visual loss was upon awakening from sleep in the morning or a nap in 282 (51.8%), during the first opportunity to use vision critically early in the morning in 117 (21.5%), and later in the day in 145 (26.7%). AION was significantly (P = .0030) more frequent in summer than winter. Estimated monthly onset rates were 82.7 episodes (95% confidence interval [CI], 71.3 to 95.8) in summer, 58.3 (95% CI, 48.9 to 69.6) in winter, 66.0 (95% CI, 55.9 to 77.9) in spring, and 72.7 (95% CI, 62.1 to 85.1) in fall. Onset significantly
Accepted for publication April 7, 1997. From the Departments of Ophthalmology (Dr Hayreh and Ms Podhajsky) and Preventive Medicine and Environmental Health (Division of Biostatistics) (Dr Zimmerman), College of Medicine, University of Iowa, Iowa City, Iowa. Supported by grants EY-1151 and RR-59 from the National Institutes of Health, Bethesda, Maryland, and in part by unrestricted grants from Research to Prevent Blindness, Inc, New York, New York. Dr Hayreh is a Research to Prevent Blindness Senior Scientific Investigator. Reprint requests to Sohan Singh Hayreh, MD, PhD, DSc, Department of Ophthalmology, University Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242-1091; fax: (319) 353-7996; e-mail: [email protected]
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(P < .0001) occurred more during hot than cold months, with the estimated monthly rate of onset in hot months of 82.2 episodes (95% CI, 73.7 to 91.8) compared with 59.8 (95% CI, 53.3 to 67.1) in cold months. • CONCLUSIONS: In at least 399 (73.3%) of 544 episodes of AION, patients discovered visual loss upon first awakening or at first opportunity to use vision critically after sleeping, suggesting that nocturnal arterial hypotension may play an impor tant role. Also, AION developed more often in summer than in winter.
H
AYREH,1 IN HIS EARLY STUDIES ON NONARTERI-
tic anterior ischemic optic neuropathy (AION), reported that these patients usually discovered their visual loss upon awakening or early in the morning. In his discussion of the pathogenesis of AION, he postulated that nocturnal arterial hypo tension may be an important precipitating factor in an optic nerve head already vulnerable to ischemia. In 1975, when we were designing a long-term system atic prospective planned study of the clinical features of AION at the Ocular Vascular Clinic of the University of Iowa Hospitals and Clinics, this infor mation prompted us to make a point of asking, with extra care, every patient about the timing of his or her visual loss. More recently, many of these AION patients have also been included in a study2 of nocturnal arterial hypotension by means of 24-hour ambulatory blood pressure monitoring. This paper deals with our findings on the time of day and year when patients with AION discovered their visual loss and the importance of this factor in our understand ing of the pathogenesis of AION.
© AMERICAN JOURNAL OF OPHTHALMOLOGY 1997;124:641-647
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PATIENTS AND METHODS THE PRESENT STUDY IS BASED ON THE DATA OF 635
patients (871 eyes) who had a definite diagnosis of AION and were seen in the Ocular Vascular Clinic of the University of Iowa Hospitals and Clinics from 1975 to 1995. The diagnosis of AION was estab lished using the criteria listed below. Each patient underwent a detailed history and ophthalmic evalua tion by one of us (S.S.H.). Of the 871 eyes with AION, 48 eyes had had more than one episode (up to four) of AION. Thus, there was a total of 925 episodes of AION in the entire group. We included only those patients in whom a definite diagnosis of AION could be made based on the following inclusion criteria: history of sudden visual loss; presence of optic disk edema initially and pallor later on, within 2 to 3 months; optic disk-related visual field defect; and no evidence of neurologic, systemic, or ocular disease (including giant cell arteritis) that could be responsible for the visual loss or optic disk changes. Because the time of onset of visual loss was a major consideration in this study, every effort was made to establish the information as accurately as possible by detailed questioning by one of us (S.S.H.), who asked neutral questions so as not to bias answers. We included only those patients from whom this infor mation was available. The data for onset of AION were analyzed for two variables, time of day of the discovery of visual loss and seasonal variation in the onset of AION. • TIME OF DAY FOR THE DISCOVERY OF VISUAL LOSS
Of the 871 eyes in this study, in 330 eyes (353 episodes), the patients could not give information about the exact time of day when they became aware of onset of visual disturbance. This was attributable to a variety of reasons or because the history was ambiguous (for example, patients discovered visual loss accidentally or during an ophthalmic evaluation, or simply had no exact memory of the event apart from sudden loss of vision). We therefore excluded these eyes from the data analysis. It is possible that the missing information from these 330 eyes may be a limitation of this study. In another 28 eyes (28 episodes), AION developed after a variety of known
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conditions, for example, cataract extraction (13), massive gastrointestinal bleeding (three), preeclampsia (two), coronary artery bypass surgery (two), ortho pedic surgery (two), surgery for frontal meningioma (one), hypotensive episode (one), strenuous exercise (one), Nd:YAG laser capsulotomy (one), massive hyphema (one), and going up a ski lift at an altitude of 11,000 to 13,000 feet (one). These eyes were also excluded. For 13 eyes that had had two or more episodes of AION, patients could report the time of day that visual loss was discovered for only one episode. Because the data analysis deals with episodes of AION, these 13 eyes had to be included in both the known and unknown categories of visual loss discov ery time for data analysis. This overlap of 13 eyes in both groups results in having 526 eyes (instead of 513 eyes) in the inclusion group and 358 eyes in the exclusion group. Thus, a total of 544 episodes in 526 eyes constituted the study group for evaluation of the time of day of the onset of AION. •
SEASONAL VARIATION IN THE ONSET OF AION
This was also based on the date or approximate date of discovery of visual loss by the patient. In those patients who had discovered the visual loss acciden tally or who had been nonsymptomatic so that their disease was discovered during ophthalmologic exami nation, the duration of the disease was assessed at the first examination from the fundus findings. We based this decision on our experience of the natural history of optic disk changes in AION noted during the first 2 to 3 months in a large series over 25 years. Because we were interested mainly in knowing the calendar month, this assessment of onset of AION was consid ered reasonable. For 58 episodes of AION, it was not possible to obtain any information, and in another 28 episodes, AION developed after a variety of known conditions (all unrelated to the time of the year; see above). All were deleted from data analysis, leaving a total of 839 episodes with available information. Seasonal variation in the onset of AION was examined in three different ways: by calendar month; by seasons of the year (winter—December through February; spring—March through May; summer— June through August; and fall—September through November); and by temperature of the season in Iowa
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TABLE 1. Time of Day of Discovery of Visual Loss in AION Time of Day of Discovery of Visual Loss (No [%]) Total No. of AION Episodes
Very Early in
Later
Group*
Total No. of Eyes
On Awakening
the Morning
During the Day
A B C
526 490 36
544 490 54
282(51.8) 254(51.8) 28(51.9)
117(21.5) 106(21.6) 11 (20.4)
145(26.7) 130(26.5) 15(27.8)
AION = anterior ischemic optic neuropathy. = patients who had two or more episodes •Group A = entire study group; B = patients who had only one episode of AION in an eye; c = of AION in an eye.
(cold: November to March—average: high, —1 to + 8 C, and low, - 1 to - 1 1 C; mild: April, May, and October—average: high, 16 to 22 C, and low, 4 to 11 C; and hot: June to September—-average: high, 24 to 30 C, and low, 13 to 18 C). For statistical data analysis, the 839 AION epi sodes were categorized by month of onset, resulting in 12 observations. These were additionally identified by calendar and by the temperature of the seasons because, in the literature, temperature has been reported to be closely correlated with both myocardial infarction and cerebrovascular accident; both are more common in winter than in other seasons.3'6 The SAS GENMOD procedure was used to fit Poisson generalized linear models to the 12 observations. The first such model included calendar season as the classifying variable, and the second model included temperature season as the classifying variable.
RESULTS • TIME OF DAY FOR THE DISCOVERY OF VISUAL LOSS
The time of discovery of visual loss by patients with AION was categorized under three types. Upon awakening: in this group, the patient noticed the visual loss immediately upon awakening in the morn ing or sometimes awakening from a nap during the day. Very early in the morning: the patient discovered visual loss during the first opportunity to use vision critically early in the morning, for example, while washing and dressing, shaving, putting on makeup, reading a newspaper at breakfast, or starting to drive
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to work. Later during the day: these patients became aware of the visual loss some time later in the day, although most could not say definitely whether the loss had been there earlier on. For example, these patients first noticed the visual loss while reading their mail or newspaper or watching television during the day; the loss of vision could have been there since awakening, but they did not notice it. The data for the discovery times of AION were further categorized and analyzed under the following three groups: the entire study group (544 episodes of AION in 526 eyes); the group that had had only one episode of AION in an eye (490 episodes in 490 eyes); and the group that had had two or more episodes of AION in an eye (54 episodes in 36 eyes). Table 1 presents the data about the three groups for the three times of visual loss discovery. We feel that the categories of discovery of visual loss upon awaken ing and very early in the morning represent the same group; the combined incidence of these two times was 73.3%, 73.4%, and 72.3%, respectively, for the three groups. These percentages are basically the same in the three groups. • SEASONAL VARIATION IN THE ONSET OF AION
The data for the onset of AION for calendar months, and for the seasons and the seasonal temperatures of the year, are given in Table 2. The data were analyzed using two models: one with the calendar season and the second with the temperature of the season as the classifying variable. With calendar season as the classifying variable, the data suggested varying onset rates of AION
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TABLE 2. Seasonal Incidence of Development of AION Variable
No (%) of Episodes*
Calendar month January February March April May June July August September October November December Season of the year Winter Spring Summer Fall Temperature of the season Cold (5 mos) Mild (3 mos) Hot (4 mos)
60 (7.2) 49 (5.8) 51 (6.1) 79 (9.4) 68(8.1) 83 (9.9) 88(10.5) 77 (9.2) 81 (9.7) 64 (7.6) 73 (8.7) 66 (7.9) 175 (20.9) 198(23.6) 248 (29.6) 218(26.0) 299 (35.6) 211 (25.1) 329 (39.2)
AION = anterior ischemic optic neuropathy 'Total episodes, 839.
among the four seasons (P = .0822). Given the potential importance of the winter months in vascu lar accidents,3'6 the season factor was partitioned into three simultaneous comparisons to winter. The sum mer months had a significantly (P = .0030) higher AION frequency than the winter months did, with estimated monthly onset rates of AION of 82.7 episodes (95% confidence interval [CI], 71.3 to 95.8) in summer months compared with 58.3 episodes (95% CI, 48.9 to 69.6) in winter months. Frequency of AION during the fall (72.7 episodes per month [95% CI, 62.1 to 85.1]) was also higher than in the winter months, but this was not statistically signifi cant (P = .0686). No significant difference (P = .3167) was observed between spring (66.0 episodes per month [95% CI, 55.9 to 77.9]) and winter months. With temperature of the season as the classifying variable, onset rate differed significantly (P = .0111) among cold, mild, and hot months. We also parti tioned the temperature factor into simultaneous com parisons with the cold months. The hot months had a 644
significantly (P < .0001) higher incidence of AION than the cold months did, with estimated monthly onset rates of AION during the hot months of 82.2 episodes (95% CI, 73.7 to 91.8) compared with 59.8 episodes (95% CI, 53.3 to 67.1) during the cold months. Mild months also had a higher incidence of AION (70.3 episodes per month; 95% CI, 61.3 to 80.7) than the cold months did, but this was not statistically significant (P = .0756).
DISCUSSION THE PRESENT STUDY SHOWS THAT IN AION, IN AT LEAST
73.3% (399/544) of episodes, visual loss was discov ered upon awakening (from sleep during the night or a nap during the day) or soon after, when the patient had the first opportunity to use vision critically. In the remaining 26.7% episodes of AION, although the patients became aware of the visual loss later during the day, they could not say definitely when it occurred or could not rule out the possibility that it had not been there since awakening. Becoming aware of visual loss is extremely variable, depending upon the location, severity, and type of visual field defect, the occupation of the patient, and above all, perceptiveness of the patient in detecting a visual problem. For example, one of our patients with superior visual field lossfirstnoticed the visualfielddefect during the day while hunting, when he tried to shoot a flying duck, but he was sure that his vision had been normal the previous day. Another patient, a physician, was not aware of any visual loss, in spite of fairly marked visual loss in the inferior nasal sector of one eye, until it was discovered during our examination. Thus, in view of these limitations, the time of discovery of visual loss by a patient has to be placed in its true perspective. The time offirstdiscovery of visual loss in AION is critical information because it provides important knowledge about the time of development of AION and also, indirectly, about its pathogenesis. The present study indicates that AION develops in the vast majority of persons during sleep and suggests that something must be happening during sleep to precipi tate the development of AION. Our 24-hour ambula tory blood pressure-monitoring studies in patients
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with AION have disclosed a marked interindividual variation in the amount of fall of blood pressure during sleep. We have discussed elsewhere the role of nocturnal arterial hypotension in the pathogenesis of AION.2'7'8 Very briefly, our studies show that AION is a multifactorial disease, with many risk factors acting in various combinations, some acting as predisposing factors, making an optic nerve head susceptible to ischemia, and others acting as precipitating factors, inflicting the final insult and resulting in the develop ment of AION. With such a multifactorial scenario in AION, a particular factor or combination of factors may be present in one case and not in another, or a factor may play a major role in one case and only a subsidiary role in another. The predisposing factors may be systemic or local in the optic nerve head.7,8 When an optic nerve head has been rendered vulnerable to ischemia by these conditions (in disparate combinations in different individuals), nocturnal hy potension may act as the precipitating factor to produce ischemia and AION.2 A similar or even more marked degree of nocturnal arterial hypotension in a healthier optic nerve head would have no effect at all. Thus, nocturnal hypotension is one of the variables in the production of AION, and its role must be placed in the overall context of the disease process and not taken in isolation. Our ambulatory blood pressure-monitoring studies also showed that patients with arterial hypertension who take oral hypotensive medication showed a significant association between progressive visual field deterioration and nocturnal arterial hypotension in AION.2 We have also found that this progression is often discovered by the patient upon awakening in the morning. Some patients develop AION during the daytime, not in association with a nap. This may be because of a variety of causes, including embolism into the posterior ciliary artery circulation or vasospasm in the posterior ciliary artery. Embolism into the posterior ciliary artery circulation (the main source of blood supply to the optic nerve head1,9) can produce AION that can develop at any time of the day. Eyes with the usual type of AION generally have no optic disk cup,10 but eyes of an embolic nature generally have the normal cup size. On fluorescein fundus angiography, in these cases, we have seen complete occlusion of a posterior ciliary artery (with negative temporal artery VOL. 124, NO. 5
biopsy).9 The source of the embolus may be the carotid arteries, the aorta, or the heart. Our recent experimental studies in atherosclerotic monkeys have shown that serotonin in atherosclerosis can produce vasospasm of the posterior ciliary artery, resulting in its occlusion and the development of AION.11 We speculate that the vasospasm is pro duced by the release of serotonin by platelet aggrega tion on atherosclerotic plaques. In the AION Decompression Trial Study,12 it was reported that 42% of patients (174/418) recalled that the onset of visual loss occurred within 2 hours of awakening. The difference in the incidences between this and our study may be because of the differences in examiners and in how specifically the patients were questioned to obtain this information. In our study, one of us (S.S.H.) personally saw all patients and questioned them specifically and in detail about the time of the day when they became aware of visual loss. In the Decompression Study,12 the data were collected from 25 different centers, and many more persons were involved (including technicians). There must therefore have been variability in the nature and manner of questioning about the time of onset. A recently published study by Landau and associ ates,13 based on a study of only 24 patients (13 from Switzerland and 11 from New York) with AION, claimed that a "patient with AION typically notices blurred vision in the affected eye within 1 or 2 hours of arising in the morning" (that is, in a manner similar to the onset of many of the myocardial infarctions), not first thing in the morning, and that nocturnal arterial hypotension does not play any role in the development AION. The authors stressed that the pathogeneses of myocardial infarction and AION are similar and added that this "helps to explain why patients with AION have a high incidence of myocar dial infarction."13 Our reasons for suggesting that the study is flawed, and the various flaws in it, are discussed elsewhere.14 They include, however, flawed data collection, analysis, and interpretation of the ambulatory blood pressure-monitoring data and the fact that no information was given on the short-term fluctuations of blood pressure, which are critical in AION, as well as the fact that our study7 in 406 patients with AION showed no evidence of an increased incidence of myocardial infarction in AION patients on follow-up compared with the age-
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and sex-matched general population. We believe that these and other faults in their study invalidate the conclusions of Landau and associates.13 We investigated the relation between seasonal variation and development of AION because season al variation has been reported in the incidence of vascular accidents, such as myocardial infarction and cerebrovascular accident. For example, temperature has been reported to be closely correlated with both myocardial infarction and cerebrovascular accident, with both of the latter more common in winter than in other seasons.3'5 Bull and Morton5 found a nearly linear fall in death rate as the minimum temperature rises between —10 C and +20 C, but above 20 C, deaths rise steeply as the temperature rises, and below — IOC, deaths again rise steeply as the temperature falls, especially in the elderly; this was also reported by Rogot and Padgett.6 Bull and Morton5 found a stronger association of death rates with temperature in the old than in the young, probably because of failure by the aged to adapt physiologically to temper ature change. Fersini and associates,15 in patients with transient ischemic attacks, showed a seasonal pattern of disease onset in early spring, with a peak in March through April and isolated peaks in January and October. To explain the seasonal variation of myocardial infarction, cerebrovascular accidents, and possibly other vascular accidents, a number of studies have been conducted to find out the effects of temperature variations on hematologic changes and other vascular changes in the body that could contribute to the development of vascular accidents. For example, Bull and associates16 noted a positive correlation between temperature and factor VII, antithrombin III, and cholesterol, and negatively with flbrinolytic activity. Keatinge and associates17 reported that exposure to cold increases packed cell volume, platelet count, mean platelet volume, both whole blood and plasma viscosity, arterial blood pressure, and cholesterol. They speculated that the larger-than-normal platelets seen in these patients may be because of either cold-induced activity of sympathetic nerves releasing sequestered large platelets or production of large, new platelets. Large platelets aggregate and adhere more readily to blood vessels than small platelets do.18,19 Several other changes produced by cold exposure will tend to induce thrombosis; for example, an increase 646
in the number of red blood cells promotes platelet adhesion,20'22 and increased blood viscosity facilitates clotting of blood after formation of a platelet throm bus.17 Stout and Crawford,23 in subjects aged 75 years and older, found significant seasonal effects for fibrinogen, plasma viscosity, and high-density lipoprotein cholesterol. Plasma fibrinogen concentrations were 23% higher in the coldest 6 months compared with the summer months. Fibrinogen significantly and negatively related to core body temperature and all measures of environmental temperature, and Stout and Crawford23 felt that this variation was large enough to increase the risk of myocardial infarction and cerebrovascular accident during winter. Buchan an and Riglar24 reported a high titer of anticentromere antibodies in Raynaud phenomenon and that pa tients with high titers of anticentromere antibodies had a higher risk of developing thrombotic vascular disease. Reilly and associates25 reported in the elderly a notable circannual variation in a large number of hematologic factors. Exton-Smith26 reported that ex posure to low environmental temperature more readi ly produced orthostatic hypotension or hypothermia in old than in younger persons as a consequence of impaired physiologic thermoregulatory mechanisms in the elderly. Brennan and associates27 and Keatinge and associates17 reported an increase in blood pressure with cold. In contrast to seasonal variations associated with myocardial infarction and cerebrovascular accidents (higher during winter than other seasons) and the various possible hematologic and other factors that may be responsible for the seasonal variation, our study shows that AION onset is significantly more frequent in summer (or the hot months) than in winter (or the cold months), with spring and fall, or the mild months, showing intermediate frequency of onset. Our study suggests that factors other than hematologic abnormalities may be play an important role in the development of AION. Moreover, in our study, there was no evidence that patients with AION are at increased risk of developing subsequent cerebrovascular disease, myocardial infarction, or mortality.7 In conclusion, our study shows that in at least 73.3% (399/544) of episodes of AION, patients discovered visual loss upon awakening in the morn ing or from a nap or early in the morning, and that
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most of the remaining patients could not say definitely whether visual loss had been present earlier. This is an important feature that helps in the diagnosis of AION. It also provides important information about the time of development of AION and also indirectly about its pathogenesis. Development of AION during sleep suggests that nocturnal arterial hypotension plays an important role; this is also suggested by our 24-hour ambulatory blood pressure-monitoring stud ies.2 Our study also shows that AION onset is significantly more frequent in summer (or the hot months) than in winter (or the cold months).
REFERENCES 1. Hayreh SS. Anterior ischaemic optic neuropathy, I: terminol ogy and pathogenesis. Br J Ophthalmol 1974;58:955-963. 2. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117:603-624. 3. Bull GM. Meteorological correlates with myocardial and cerebral infarction and respiratory disease. Br J Prevent Soc Med 1973;27:108-113. 4. Clark CV. Seasonal variation in incidence of brachial and femoral emboli. Br Med J 1983;287:1109. 5. Bull GM, Morton J. Environment, temperature and death rates. Age Ageing 1978;7:210-224. 6. Rogot E, Padgett SJ. Associations of coronary and stroke mortality with temperature and snowfall in selected areas of the United States, 1962-1966. Am ] Epidemiol 1976;103: 565-575. 7. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemic diseases associated with non-arteritic anterior ischemic optic neuropathy. Am ] Ophthalmol 1994;118:766-780. 8. Hayreh SS. Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations and management. Ophthalmologic Clinics of North America 1996;9:407-442. 9. Hayreh SS. Inter-individual variation in blood supply of the optic nerve head: its importance in various ischemic disor ders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders. Doc Ophthalmol 1985;59: 217-246. 10. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy, IX: cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503-1508. 11. Hayreh SS, Piegors DJ, Heistad DD. Serotonin-induced constriction of ocular arteries in atherosclerotic monkeys: implications for ischemic disorders of the retina and optic nerve head. Arch Ophthalmol 1997;115:220-228.
12. Ischemic Optic Neuropathy Decompression Trial Study Group. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 1996; 114:1366-1374. 13. Landau K, Winterkorn JMS, Mailloux LU, Vetter W, Naporlitano B. 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol 1996; 114:570-575. 14. Hayreh SS. Nonarteritic anterior ischemic optic neuropathy, role of nocturnal arterial hypotension [letter]. Arch Ophthal mol 1997;115:942-943. 15. Fersini C, Manfredini R, Manfredini F, et al. Chronobiologic aspects of recurrent transient ischemic attack. In: Pauly JE, Scheving LE, editors. Advances in chronobiology. Part B. New York: Alan R Liss, 1987:167-171. 16. Bull GM, Brozovic M, Chakrabarti R, et al. Relationship of air temperature to various chemical, haematological, and haemostatic variables. J Clin Pathol 1979;32:16-20. 17. Keatinge WR, Coleshaw SRK, Cotter F, Mattock M, Murphy M, Chelliah R. Increases in platelet and red cell counts, blood viscosity, and arterial pressure during mild surface cooling: factors in mortality from coronary and cerebral thrombosis in winter. Br Med J 1984;289:1405-1408. 18. Blajchman MA, Senyi AF, Hirsh ], Genton E, George JN. Hemostatic function, survival and membrane glycoprotein changes in young versus old platelets. J Clin Invest 1981;68: 1289-1294. 19. Thompson CB, Jakubowski JA, Quinn PG, Deykin D, Valeri CR. Platelet size as a determinant of platelet function. J Lab Clin Med 1983;101:205-213. 20. Aarts PAMM, Bolhuis PA, Sakariassen KS, Heethaar RM, Sixma JJ. Red blood cell size is important for adherence of blood platelets to artery subendothelium. Blood 1983;62: 214-217. 21. Bouhoutsos ], Morris T, Chavatsas D, Martin P. The influence of haemoglobin and platelet levels on the results of arterial surgery. Br J Surg 1974;61:984-986. 22. Turitto VT, Baumgartner HR. Platelet interaction with subendothelium in a perfusion system: physical role of red blood cells. Microvasc Res 1975;9:335-34423. Stout RW, Crawford V. Seasonal variations in fibrinogen concentrations among elderly people. Lancet 1991;2:9-13. 24. Buchanan RR, Riglar AG. The titre of anti-centromere antibodies: its relationship to Raynaud's phenomenon and vascular occlusion. Br J Rheumatol 1989;3:221-226. 25. Reilly C, Nicolau GY, Lakatua DJ, et al. Circannual rhythms of laboratory measurements in serum of elderly subjects. In: Pauly JE, Scheving LE, editors. Advances in chronobiology. Part B. New York: Alan R Liss, 1987:51-72. 26. Exton-Smith AN. Disturbances of autonomic regulation. In: Issacs B, editor. Recent advances in geriatric medicine. Edinburgh: Churchill Livingstone, 1978:85-100. 27. Brennan PJ, Greenberg G, Miall WE, Thompson SG. Seasonal variation in arterial blood pressure. Br Med J 1982;285:919-923.
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VOL.124, No. 5
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SOHAN SINGH HAYREH, MD, PHD, DSC, PATRICIA A. PODHAJSKY, BSN, AND BRIDGET ZIMMERMAN, PHD
• PURPOSE: TO study time of day and seasonal variation of onset of visual loss in nonarteritic anterior ischemic optic neuropathy (AION). • METHODS: From 1975 to 1995, we prospectively investigated the time of discovery of visual loss in 635 patients (871 eyes) with AION—a total of 925 episodes. Data were analyzed for two varia bles: time of day of discovery of visual loss for 544 episodes and seasonal variation of the onset of AION for 839 episodes. • RESULTS: Of 544 episodes, time of day for discovery of visual loss was upon awakening from sleep in the morning or a nap in 282 (51.8%), during the first opportunity to use vision critically early in the morning in 117 (21.5%), and later in the day in 145 (26.7%). AION was significantly (P = .0030) more frequent in summer than winter. Estimated monthly onset rates were 82.7 episodes (95% confidence interval [CI], 71.3 to 95.8) in summer, 58.3 (95% CI, 48.9 to 69.6) in winter, 66.0 (95% CI, 55.9 to 77.9) in spring, and 72.7 (95% CI, 62.1 to 85.1) in fall. Onset significantly
Accepted for publication April 7, 1997. From the Departments of Ophthalmology (Dr Hayreh and Ms Podhajsky) and Preventive Medicine and Environmental Health (Division of Biostatistics) (Dr Zimmerman), College of Medicine, University of Iowa, Iowa City, Iowa. Supported by grants EY-1151 and RR-59 from the National Institutes of Health, Bethesda, Maryland, and in part by unrestricted grants from Research to Prevent Blindness, Inc, New York, New York. Dr Hayreh is a Research to Prevent Blindness Senior Scientific Investigator. Reprint requests to Sohan Singh Hayreh, MD, PhD, DSc, Department of Ophthalmology, University Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242-1091; fax: (319) 353-7996; e-mail: [email protected]
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(P < .0001) occurred more during hot than cold months, with the estimated monthly rate of onset in hot months of 82.2 episodes (95% CI, 73.7 to 91.8) compared with 59.8 (95% CI, 53.3 to 67.1) in cold months. • CONCLUSIONS: In at least 399 (73.3%) of 544 episodes of AION, patients discovered visual loss upon first awakening or at first opportunity to use vision critically after sleeping, suggesting that nocturnal arterial hypotension may play an impor tant role. Also, AION developed more often in summer than in winter.
H
AYREH,1 IN HIS EARLY STUDIES ON NONARTERI-
tic anterior ischemic optic neuropathy (AION), reported that these patients usually discovered their visual loss upon awakening or early in the morning. In his discussion of the pathogenesis of AION, he postulated that nocturnal arterial hypo tension may be an important precipitating factor in an optic nerve head already vulnerable to ischemia. In 1975, when we were designing a long-term system atic prospective planned study of the clinical features of AION at the Ocular Vascular Clinic of the University of Iowa Hospitals and Clinics, this infor mation prompted us to make a point of asking, with extra care, every patient about the timing of his or her visual loss. More recently, many of these AION patients have also been included in a study2 of nocturnal arterial hypotension by means of 24-hour ambulatory blood pressure monitoring. This paper deals with our findings on the time of day and year when patients with AION discovered their visual loss and the importance of this factor in our understand ing of the pathogenesis of AION.
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PATIENTS AND METHODS THE PRESENT STUDY IS BASED ON THE DATA OF 635
patients (871 eyes) who had a definite diagnosis of AION and were seen in the Ocular Vascular Clinic of the University of Iowa Hospitals and Clinics from 1975 to 1995. The diagnosis of AION was estab lished using the criteria listed below. Each patient underwent a detailed history and ophthalmic evalua tion by one of us (S.S.H.). Of the 871 eyes with AION, 48 eyes had had more than one episode (up to four) of AION. Thus, there was a total of 925 episodes of AION in the entire group. We included only those patients in whom a definite diagnosis of AION could be made based on the following inclusion criteria: history of sudden visual loss; presence of optic disk edema initially and pallor later on, within 2 to 3 months; optic disk-related visual field defect; and no evidence of neurologic, systemic, or ocular disease (including giant cell arteritis) that could be responsible for the visual loss or optic disk changes. Because the time of onset of visual loss was a major consideration in this study, every effort was made to establish the information as accurately as possible by detailed questioning by one of us (S.S.H.), who asked neutral questions so as not to bias answers. We included only those patients from whom this infor mation was available. The data for onset of AION were analyzed for two variables, time of day of the discovery of visual loss and seasonal variation in the onset of AION. • TIME OF DAY FOR THE DISCOVERY OF VISUAL LOSS
Of the 871 eyes in this study, in 330 eyes (353 episodes), the patients could not give information about the exact time of day when they became aware of onset of visual disturbance. This was attributable to a variety of reasons or because the history was ambiguous (for example, patients discovered visual loss accidentally or during an ophthalmic evaluation, or simply had no exact memory of the event apart from sudden loss of vision). We therefore excluded these eyes from the data analysis. It is possible that the missing information from these 330 eyes may be a limitation of this study. In another 28 eyes (28 episodes), AION developed after a variety of known
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conditions, for example, cataract extraction (13), massive gastrointestinal bleeding (three), preeclampsia (two), coronary artery bypass surgery (two), ortho pedic surgery (two), surgery for frontal meningioma (one), hypotensive episode (one), strenuous exercise (one), Nd:YAG laser capsulotomy (one), massive hyphema (one), and going up a ski lift at an altitude of 11,000 to 13,000 feet (one). These eyes were also excluded. For 13 eyes that had had two or more episodes of AION, patients could report the time of day that visual loss was discovered for only one episode. Because the data analysis deals with episodes of AION, these 13 eyes had to be included in both the known and unknown categories of visual loss discov ery time for data analysis. This overlap of 13 eyes in both groups results in having 526 eyes (instead of 513 eyes) in the inclusion group and 358 eyes in the exclusion group. Thus, a total of 544 episodes in 526 eyes constituted the study group for evaluation of the time of day of the onset of AION. •
SEASONAL VARIATION IN THE ONSET OF AION
This was also based on the date or approximate date of discovery of visual loss by the patient. In those patients who had discovered the visual loss acciden tally or who had been nonsymptomatic so that their disease was discovered during ophthalmologic exami nation, the duration of the disease was assessed at the first examination from the fundus findings. We based this decision on our experience of the natural history of optic disk changes in AION noted during the first 2 to 3 months in a large series over 25 years. Because we were interested mainly in knowing the calendar month, this assessment of onset of AION was consid ered reasonable. For 58 episodes of AION, it was not possible to obtain any information, and in another 28 episodes, AION developed after a variety of known conditions (all unrelated to the time of the year; see above). All were deleted from data analysis, leaving a total of 839 episodes with available information. Seasonal variation in the onset of AION was examined in three different ways: by calendar month; by seasons of the year (winter—December through February; spring—March through May; summer— June through August; and fall—September through November); and by temperature of the season in Iowa
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TABLE 1. Time of Day of Discovery of Visual Loss in AION Time of Day of Discovery of Visual Loss (No [%]) Total No. of AION Episodes
Very Early in
Later
Group*
Total No. of Eyes
On Awakening
the Morning
During the Day
A B C
526 490 36
544 490 54
282(51.8) 254(51.8) 28(51.9)
117(21.5) 106(21.6) 11 (20.4)
145(26.7) 130(26.5) 15(27.8)
AION = anterior ischemic optic neuropathy. = patients who had two or more episodes •Group A = entire study group; B = patients who had only one episode of AION in an eye; c = of AION in an eye.
(cold: November to March—average: high, —1 to + 8 C, and low, - 1 to - 1 1 C; mild: April, May, and October—average: high, 16 to 22 C, and low, 4 to 11 C; and hot: June to September—-average: high, 24 to 30 C, and low, 13 to 18 C). For statistical data analysis, the 839 AION epi sodes were categorized by month of onset, resulting in 12 observations. These were additionally identified by calendar and by the temperature of the seasons because, in the literature, temperature has been reported to be closely correlated with both myocardial infarction and cerebrovascular accident; both are more common in winter than in other seasons.3'6 The SAS GENMOD procedure was used to fit Poisson generalized linear models to the 12 observations. The first such model included calendar season as the classifying variable, and the second model included temperature season as the classifying variable.
RESULTS • TIME OF DAY FOR THE DISCOVERY OF VISUAL LOSS
The time of discovery of visual loss by patients with AION was categorized under three types. Upon awakening: in this group, the patient noticed the visual loss immediately upon awakening in the morn ing or sometimes awakening from a nap during the day. Very early in the morning: the patient discovered visual loss during the first opportunity to use vision critically early in the morning, for example, while washing and dressing, shaving, putting on makeup, reading a newspaper at breakfast, or starting to drive
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to work. Later during the day: these patients became aware of the visual loss some time later in the day, although most could not say definitely whether the loss had been there earlier on. For example, these patients first noticed the visual loss while reading their mail or newspaper or watching television during the day; the loss of vision could have been there since awakening, but they did not notice it. The data for the discovery times of AION were further categorized and analyzed under the following three groups: the entire study group (544 episodes of AION in 526 eyes); the group that had had only one episode of AION in an eye (490 episodes in 490 eyes); and the group that had had two or more episodes of AION in an eye (54 episodes in 36 eyes). Table 1 presents the data about the three groups for the three times of visual loss discovery. We feel that the categories of discovery of visual loss upon awaken ing and very early in the morning represent the same group; the combined incidence of these two times was 73.3%, 73.4%, and 72.3%, respectively, for the three groups. These percentages are basically the same in the three groups. • SEASONAL VARIATION IN THE ONSET OF AION
The data for the onset of AION for calendar months, and for the seasons and the seasonal temperatures of the year, are given in Table 2. The data were analyzed using two models: one with the calendar season and the second with the temperature of the season as the classifying variable. With calendar season as the classifying variable, the data suggested varying onset rates of AION
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TABLE 2. Seasonal Incidence of Development of AION Variable
No (%) of Episodes*
Calendar month January February March April May June July August September October November December Season of the year Winter Spring Summer Fall Temperature of the season Cold (5 mos) Mild (3 mos) Hot (4 mos)
60 (7.2) 49 (5.8) 51 (6.1) 79 (9.4) 68(8.1) 83 (9.9) 88(10.5) 77 (9.2) 81 (9.7) 64 (7.6) 73 (8.7) 66 (7.9) 175 (20.9) 198(23.6) 248 (29.6) 218(26.0) 299 (35.6) 211 (25.1) 329 (39.2)
AION = anterior ischemic optic neuropathy 'Total episodes, 839.
among the four seasons (P = .0822). Given the potential importance of the winter months in vascu lar accidents,3'6 the season factor was partitioned into three simultaneous comparisons to winter. The sum mer months had a significantly (P = .0030) higher AION frequency than the winter months did, with estimated monthly onset rates of AION of 82.7 episodes (95% confidence interval [CI], 71.3 to 95.8) in summer months compared with 58.3 episodes (95% CI, 48.9 to 69.6) in winter months. Frequency of AION during the fall (72.7 episodes per month [95% CI, 62.1 to 85.1]) was also higher than in the winter months, but this was not statistically signifi cant (P = .0686). No significant difference (P = .3167) was observed between spring (66.0 episodes per month [95% CI, 55.9 to 77.9]) and winter months. With temperature of the season as the classifying variable, onset rate differed significantly (P = .0111) among cold, mild, and hot months. We also parti tioned the temperature factor into simultaneous com parisons with the cold months. The hot months had a 644
significantly (P < .0001) higher incidence of AION than the cold months did, with estimated monthly onset rates of AION during the hot months of 82.2 episodes (95% CI, 73.7 to 91.8) compared with 59.8 episodes (95% CI, 53.3 to 67.1) during the cold months. Mild months also had a higher incidence of AION (70.3 episodes per month; 95% CI, 61.3 to 80.7) than the cold months did, but this was not statistically significant (P = .0756).
DISCUSSION THE PRESENT STUDY SHOWS THAT IN AION, IN AT LEAST
73.3% (399/544) of episodes, visual loss was discov ered upon awakening (from sleep during the night or a nap during the day) or soon after, when the patient had the first opportunity to use vision critically. In the remaining 26.7% episodes of AION, although the patients became aware of the visual loss later during the day, they could not say definitely when it occurred or could not rule out the possibility that it had not been there since awakening. Becoming aware of visual loss is extremely variable, depending upon the location, severity, and type of visual field defect, the occupation of the patient, and above all, perceptiveness of the patient in detecting a visual problem. For example, one of our patients with superior visual field lossfirstnoticed the visualfielddefect during the day while hunting, when he tried to shoot a flying duck, but he was sure that his vision had been normal the previous day. Another patient, a physician, was not aware of any visual loss, in spite of fairly marked visual loss in the inferior nasal sector of one eye, until it was discovered during our examination. Thus, in view of these limitations, the time of discovery of visual loss by a patient has to be placed in its true perspective. The time offirstdiscovery of visual loss in AION is critical information because it provides important knowledge about the time of development of AION and also, indirectly, about its pathogenesis. The present study indicates that AION develops in the vast majority of persons during sleep and suggests that something must be happening during sleep to precipi tate the development of AION. Our 24-hour ambula tory blood pressure-monitoring studies in patients
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with AION have disclosed a marked interindividual variation in the amount of fall of blood pressure during sleep. We have discussed elsewhere the role of nocturnal arterial hypotension in the pathogenesis of AION.2'7'8 Very briefly, our studies show that AION is a multifactorial disease, with many risk factors acting in various combinations, some acting as predisposing factors, making an optic nerve head susceptible to ischemia, and others acting as precipitating factors, inflicting the final insult and resulting in the develop ment of AION. With such a multifactorial scenario in AION, a particular factor or combination of factors may be present in one case and not in another, or a factor may play a major role in one case and only a subsidiary role in another. The predisposing factors may be systemic or local in the optic nerve head.7,8 When an optic nerve head has been rendered vulnerable to ischemia by these conditions (in disparate combinations in different individuals), nocturnal hy potension may act as the precipitating factor to produce ischemia and AION.2 A similar or even more marked degree of nocturnal arterial hypotension in a healthier optic nerve head would have no effect at all. Thus, nocturnal hypotension is one of the variables in the production of AION, and its role must be placed in the overall context of the disease process and not taken in isolation. Our ambulatory blood pressure-monitoring studies also showed that patients with arterial hypertension who take oral hypotensive medication showed a significant association between progressive visual field deterioration and nocturnal arterial hypotension in AION.2 We have also found that this progression is often discovered by the patient upon awakening in the morning. Some patients develop AION during the daytime, not in association with a nap. This may be because of a variety of causes, including embolism into the posterior ciliary artery circulation or vasospasm in the posterior ciliary artery. Embolism into the posterior ciliary artery circulation (the main source of blood supply to the optic nerve head1,9) can produce AION that can develop at any time of the day. Eyes with the usual type of AION generally have no optic disk cup,10 but eyes of an embolic nature generally have the normal cup size. On fluorescein fundus angiography, in these cases, we have seen complete occlusion of a posterior ciliary artery (with negative temporal artery VOL. 124, NO. 5
biopsy).9 The source of the embolus may be the carotid arteries, the aorta, or the heart. Our recent experimental studies in atherosclerotic monkeys have shown that serotonin in atherosclerosis can produce vasospasm of the posterior ciliary artery, resulting in its occlusion and the development of AION.11 We speculate that the vasospasm is pro duced by the release of serotonin by platelet aggrega tion on atherosclerotic plaques. In the AION Decompression Trial Study,12 it was reported that 42% of patients (174/418) recalled that the onset of visual loss occurred within 2 hours of awakening. The difference in the incidences between this and our study may be because of the differences in examiners and in how specifically the patients were questioned to obtain this information. In our study, one of us (S.S.H.) personally saw all patients and questioned them specifically and in detail about the time of the day when they became aware of visual loss. In the Decompression Study,12 the data were collected from 25 different centers, and many more persons were involved (including technicians). There must therefore have been variability in the nature and manner of questioning about the time of onset. A recently published study by Landau and associ ates,13 based on a study of only 24 patients (13 from Switzerland and 11 from New York) with AION, claimed that a "patient with AION typically notices blurred vision in the affected eye within 1 or 2 hours of arising in the morning" (that is, in a manner similar to the onset of many of the myocardial infarctions), not first thing in the morning, and that nocturnal arterial hypotension does not play any role in the development AION. The authors stressed that the pathogeneses of myocardial infarction and AION are similar and added that this "helps to explain why patients with AION have a high incidence of myocar dial infarction."13 Our reasons for suggesting that the study is flawed, and the various flaws in it, are discussed elsewhere.14 They include, however, flawed data collection, analysis, and interpretation of the ambulatory blood pressure-monitoring data and the fact that no information was given on the short-term fluctuations of blood pressure, which are critical in AION, as well as the fact that our study7 in 406 patients with AION showed no evidence of an increased incidence of myocardial infarction in AION patients on follow-up compared with the age-
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and sex-matched general population. We believe that these and other faults in their study invalidate the conclusions of Landau and associates.13 We investigated the relation between seasonal variation and development of AION because season al variation has been reported in the incidence of vascular accidents, such as myocardial infarction and cerebrovascular accident. For example, temperature has been reported to be closely correlated with both myocardial infarction and cerebrovascular accident, with both of the latter more common in winter than in other seasons.3'5 Bull and Morton5 found a nearly linear fall in death rate as the minimum temperature rises between —10 C and +20 C, but above 20 C, deaths rise steeply as the temperature rises, and below — IOC, deaths again rise steeply as the temperature falls, especially in the elderly; this was also reported by Rogot and Padgett.6 Bull and Morton5 found a stronger association of death rates with temperature in the old than in the young, probably because of failure by the aged to adapt physiologically to temper ature change. Fersini and associates,15 in patients with transient ischemic attacks, showed a seasonal pattern of disease onset in early spring, with a peak in March through April and isolated peaks in January and October. To explain the seasonal variation of myocardial infarction, cerebrovascular accidents, and possibly other vascular accidents, a number of studies have been conducted to find out the effects of temperature variations on hematologic changes and other vascular changes in the body that could contribute to the development of vascular accidents. For example, Bull and associates16 noted a positive correlation between temperature and factor VII, antithrombin III, and cholesterol, and negatively with flbrinolytic activity. Keatinge and associates17 reported that exposure to cold increases packed cell volume, platelet count, mean platelet volume, both whole blood and plasma viscosity, arterial blood pressure, and cholesterol. They speculated that the larger-than-normal platelets seen in these patients may be because of either cold-induced activity of sympathetic nerves releasing sequestered large platelets or production of large, new platelets. Large platelets aggregate and adhere more readily to blood vessels than small platelets do.18,19 Several other changes produced by cold exposure will tend to induce thrombosis; for example, an increase 646
in the number of red blood cells promotes platelet adhesion,20'22 and increased blood viscosity facilitates clotting of blood after formation of a platelet throm bus.17 Stout and Crawford,23 in subjects aged 75 years and older, found significant seasonal effects for fibrinogen, plasma viscosity, and high-density lipoprotein cholesterol. Plasma fibrinogen concentrations were 23% higher in the coldest 6 months compared with the summer months. Fibrinogen significantly and negatively related to core body temperature and all measures of environmental temperature, and Stout and Crawford23 felt that this variation was large enough to increase the risk of myocardial infarction and cerebrovascular accident during winter. Buchan an and Riglar24 reported a high titer of anticentromere antibodies in Raynaud phenomenon and that pa tients with high titers of anticentromere antibodies had a higher risk of developing thrombotic vascular disease. Reilly and associates25 reported in the elderly a notable circannual variation in a large number of hematologic factors. Exton-Smith26 reported that ex posure to low environmental temperature more readi ly produced orthostatic hypotension or hypothermia in old than in younger persons as a consequence of impaired physiologic thermoregulatory mechanisms in the elderly. Brennan and associates27 and Keatinge and associates17 reported an increase in blood pressure with cold. In contrast to seasonal variations associated with myocardial infarction and cerebrovascular accidents (higher during winter than other seasons) and the various possible hematologic and other factors that may be responsible for the seasonal variation, our study shows that AION onset is significantly more frequent in summer (or the hot months) than in winter (or the cold months), with spring and fall, or the mild months, showing intermediate frequency of onset. Our study suggests that factors other than hematologic abnormalities may be play an important role in the development of AION. Moreover, in our study, there was no evidence that patients with AION are at increased risk of developing subsequent cerebrovascular disease, myocardial infarction, or mortality.7 In conclusion, our study shows that in at least 73.3% (399/544) of episodes of AION, patients discovered visual loss upon awakening in the morn ing or from a nap or early in the morning, and that
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most of the remaining patients could not say definitely whether visual loss had been present earlier. This is an important feature that helps in the diagnosis of AION. It also provides important information about the time of development of AION and also indirectly about its pathogenesis. Development of AION during sleep suggests that nocturnal arterial hypotension plays an important role; this is also suggested by our 24-hour ambulatory blood pressure-monitoring stud ies.2 Our study also shows that AION onset is significantly more frequent in summer (or the hot months) than in winter (or the cold months).
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12. Ischemic Optic Neuropathy Decompression Trial Study Group. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 1996; 114:1366-1374. 13. Landau K, Winterkorn JMS, Mailloux LU, Vetter W, Naporlitano B. 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol 1996; 114:570-575. 14. Hayreh SS. Nonarteritic anterior ischemic optic neuropathy, role of nocturnal arterial hypotension [letter]. Arch Ophthal mol 1997;115:942-943. 15. Fersini C, Manfredini R, Manfredini F, et al. Chronobiologic aspects of recurrent transient ischemic attack. In: Pauly JE, Scheving LE, editors. Advances in chronobiology. Part B. New York: Alan R Liss, 1987:167-171. 16. Bull GM, Brozovic M, Chakrabarti R, et al. Relationship of air temperature to various chemical, haematological, and haemostatic variables. J Clin Pathol 1979;32:16-20. 17. Keatinge WR, Coleshaw SRK, Cotter F, Mattock M, Murphy M, Chelliah R. Increases in platelet and red cell counts, blood viscosity, and arterial pressure during mild surface cooling: factors in mortality from coronary and cerebral thrombosis in winter. Br Med J 1984;289:1405-1408. 18. Blajchman MA, Senyi AF, Hirsh ], Genton E, George JN. Hemostatic function, survival and membrane glycoprotein changes in young versus old platelets. J Clin Invest 1981;68: 1289-1294. 19. Thompson CB, Jakubowski JA, Quinn PG, Deykin D, Valeri CR. Platelet size as a determinant of platelet function. J Lab Clin Med 1983;101:205-213. 20. Aarts PAMM, Bolhuis PA, Sakariassen KS, Heethaar RM, Sixma JJ. Red blood cell size is important for adherence of blood platelets to artery subendothelium. Blood 1983;62: 214-217. 21. Bouhoutsos ], Morris T, Chavatsas D, Martin P. The influence of haemoglobin and platelet levels on the results of arterial surgery. Br J Surg 1974;61:984-986. 22. Turitto VT, Baumgartner HR. Platelet interaction with subendothelium in a perfusion system: physical role of red blood cells. Microvasc Res 1975;9:335-34423. Stout RW, Crawford V. Seasonal variations in fibrinogen concentrations among elderly people. Lancet 1991;2:9-13. 24. Buchanan RR, Riglar AG. The titre of anti-centromere antibodies: its relationship to Raynaud's phenomenon and vascular occlusion. Br J Rheumatol 1989;3:221-226. 25. Reilly C, Nicolau GY, Lakatua DJ, et al. Circannual rhythms of laboratory measurements in serum of elderly subjects. In: Pauly JE, Scheving LE, editors. Advances in chronobiology. Part B. New York: Alan R Liss, 1987:51-72. 26. Exton-Smith AN. Disturbances of autonomic regulation. In: Issacs B, editor. Recent advances in geriatric medicine. Edinburgh: Churchill Livingstone, 1978:85-100. 27. Brennan PJ, Greenberg G, Miall WE, Thompson SG. Seasonal variation in arterial blood pressure. Br Med J 1982;285:919-923.
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