- Email: [email protected]
Color Doppler Imaging of the Ophthalmic Artery Blood Flow Spectra of Patients Who Have Had a Transient Ischemic Attack
Color Doppler Imaging of the Ophthalmic Artery Blood Flow Spectra of Patients Who Have Had a Transient Ischemic Attack Correlations with Generalized Iris Transluminance and Pseudoexfoliation Syndrome Leo P. Repo, MD,l Matti T. Suhonen, MD, 2 Markku E. T erasvirta, MD,l Keijo ]. Koivisto, MD3 Purpose: To study the interrelations among pseudoexfoliation syndrome (PXS), abnormal iris transluminance, and ophthalmic artery blood flow in a controlled study. Methods: Ultrasonographic examination using color Doppler imaging (CDI) was performed on the ophthalmic arteries of 46 un selected patients (92 eyes) who have had at least one transient ischemic attack (TIA) and on 32 healthy subjects (64 eyes). The authors recorded the peak systolic and end diastolic velocities and determined the resistivity indices. Iris transillumination photographs were evaluated by two ophthalmologists in a blind trial to show the presence of abnormal iris transluminance of these eyes. Biomicroscopic examination was performed to show the presence of PXS. Results: The frequency of abnormal iris transluminance in the whole group of patients who had had a TIA and in control subjects was 63% and 28%, respectively (P < 0.05). Pseudoexfoliation syndrome was found in 41 % of the right eyes and in 43% of the left eyes in the group of patients who had had a TIA. The difference between the resistivity indices for the ophthalmic arteries of patients who had had a TIA with positive iris transluminance and healthy subjects without transluminance was statistically significant (P < 0.05, Student's t test). Pseudoexfoliation syndrome was detectable in 55.6% of the right eyes and in 61.5% of the left eyes of patients who had had a TIA with abnormal iris transluminance. Conclusion: The exceptionally high frequency of PXS in the eyes of patients who had had a TIA with positive iris transluminance suggests pathologic changes in the blood supply of PXS eyes. High values of reSistivity indices for the ophthalmic arteries of these eyes suggest that disturbances in the ciliary circulation may be the possible cause of these changes. Ophthalmology 1995; 102: 11 99-1205
Originally received: December 7, 1994. Revision accepted: April 14, 1995. 1 Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. 2 Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland.
In the pseudoexfoliation syndrome (PXS), the anterior segment of the eye is involved by dandruff-like material, Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Reprint requests to Leo P. Repo, MD, Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777,70211 Kuopio, Finland.
3
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which is biomicroscopically detectable on the lens, the iris, on the anterior surface of the vitreous, the corneal endothelium, and in the angle of the anterior chamber. 1,2 Based on recent light and electron microscopic studies, pseudoexfoliative material appears within the walls of the central retinal artery, the vorticose veins and within the ocular muscles, the connective tissue of the orbit, and in the cutaneous tissue. 3- 10 Aggregates consistent with pseudoexfoliative material also have been found in the lung, heart, liver, and gallbladder. 11 Clinically, PXS is important because of its association with glaucoma (capsular glaucoma).12 Iris translucency, which may be detected peripupillary or in generalized form, is one of the cardinal clinical features of pXS.l,13 The same phenomenon is common in the eyes of patients who have had transient ischemic attacks (TIAs). In addition, the frequency ofPXS is higher in the eyes of patients who have had a TIA compared with the eyes of healthy subjects of the same age, suggesting that hypoxia may have a contributory role in the development of PXS. 14 This theory is supported by the fluorescein angiographic appearance of the iris in PXS. 15 ,16 Color Doppler imaging (CDI) is a method of ultrasonography, which allows simultaneous two-dimensional imaging of anatomic structures and blood flow. The Doppler information regarding blood flow is superimposed in color onto a conventional gray-scale ultrasound picture. The color image is used as a guide to detect the blood vessels, and the Doppler spectral analysis allows quantitative assessment of the blood flow velocities within the blood vessels. This method generally is used widely in vascular imaging and diagnostics. 17-24 In recent years, CDI has been used extensively for the diagnostic evaluation of ophthalmic and orbital disorders. 25 - 3o The aims of this study are to evaluate, by means of CDI, the ophthalmic artery blood flow spectra of patients who had had a TIA and healthy subjects of the same age and to study the interrelation among the changes in the blood flow, generalized iris transluminance, and PXS.
Subjects and Methods Subjects The study group comprised 46 patients who had had a TIA (92 eyes) and who were treated at the Department of Neurology, Kuopio University Hospital. The criteria for the diagnosis of TIA were transient monocular blindness (amaurosis fugax) or transient hemisphere attack(s) lasting less than 24 hours. The control group consisted of 32 persons (64 eyes) without any systemic or ocular disease participating in two public health studies performed in the Department of Public Health Science of Kuopio University and in Kuopio Research Institute of Exercise Medicine (Table 1). The average time interval between the diagnosis ofTIA and ophthalmologic examination was 1.6 years (range, 0.4-9 years). According to ultrasound examinations, stenosis of 50% or more of the carotid bifurcation was found
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Table 1. Study Group and Control Group by Age and Sex
Age (yrs) Mean ± standard deviation No, of women No. of men No, of eyes
Study Group
Control Group
65.5 ± 7.4
63.4 ± 4.5*
30 16
14
92
18
64
• Nonsignificant (Student's t test),
to be present in five (10.9%) patients in both carotid trunks. Right carotid bifurcation was involved in six (13.0%) patients and left carotid in five (10.9%) patients. Twelve of the patients (26.1 %) had coronary heart disease, 13 (28.3%) had hypertension, 4 (8.7%) had cardiac insufficiency, and 6 (13.0%) had cardiac arrhythmia (Table 2). Five of the six patients with cardiac arrhythmia had stenosis over 50% in their right or left carotid bifurcation. Nine of the patients had had amaurosis fugax in their right eye, three of whom had stenosis over 50% in their right carotid bifurcation. One of the three patients with amaurosis fugax in the left eye had stenoses over 50% in the left carotid bifurcation. Patients with diabetes or ocular disease other than PXS as well as patients in whom carotid endarterectomy had been performed were excluded from the study. All irides were blue to bluish-gray in color. Informed consent was obtained from all subjects participating in the study.
Methods Color Doppler ultrasound was performed on all patients who had had a TIA and on control subjects at the time of ophthalmologic examination by one of us (MTS). All examinations were performed using a color Doppler unit (ATL Ultramark 9, Advanced Technology Laboratories, Bothell, Washington) with a 5-MHz linear transducer. During the ultrasonographic study, patients were in supine position. They were asked to close their eyes and to hold their eyes steady. The ultrasound transducer was applied to the closed eyelids using a small amount of coupling gel, and care was taken not to apply pressure to the eye to avoid iatrogenic errors in the flow measurements. Both eyes were studied and coded separately. Scanning was begun with a horizontal scan through the eye and orbit at the level of the optic nerve with the transducer tilted 10° to 20° medially toward the apex of the orbit. Rotational adjustment of the scanning plane was used to obtain the best view of the ophthalmic artery. Initially, the colorcoded image was obtained in each eye to assess the retrobulbar vascular anatomy. Color setup was selected so that flow toward the transducer appeared in red and flow away from the transducer appeared in blue. Color threshold levels were adjusted to minimize artifacts resulting
Repo et al . CDI of the Ophthalmic Artery Blood Flow Spectra in TIA Table 2. Clinical Characteristics of Patients Who Have Had Transient Ischemic Attacks Characteristics
No. of Patients (%)
Stenosis > 50% in both carotid bifurcations Stenosis > 50% in right carotid bifurcation Stenosis > 50% in left carotid bifurcation Stenosis < 50% in both carotid bifurcations Coronary heart disease Hypertension Cardiac insufficiency Cardiac arrhythmia
5 (10.9) 6 (13.0) 5 (10.9) 30 (65.2) 12 (26.1) 13 (28.3) 4 (8.7) 6 (13.0) Figure 2. Physiologic iris transluminance in the lower part of the iris.
from involuntary lid or eye movements. Pulsed Doppler measurements were performed with the same probe using Doppler spectral analysis. Great effort was made to select the ophthalmic artery measurement site at approximately the same distance from the bulb for all patients. The majority of the measurements could be obtained at the point where ophthalmic artery crosses the optic nerve and runs medially before dividing into smaller peripheral branches. The Doppler angle was carefully determined for all measurements. Two or more recordings were made for each eye to obtain the best possible visual shape of curve. From the spectral curve, the peak systolic velocity and end diastolic velocity were determined in centimeters per second. Pourcelot's resistive index ([peak systolic velocity-end diastolic velocity]/peak systolic velocity) was determined in each measurement by using the unit's own software 30 (Fig 1). The ophthalmologic examinations were done by the first author (LPR), including the (1) determination of visual acuity; (2) measurement of intraocular pressure (lOP); (3) photography of the iris using transcleral technique, described earlier, for recording iris translucency on black
Results
Figure 1. Left, color Doppler scan of the right ophthalmic artery. The artery crosses over the optic nerve. Right, Doppler spectrum (velocity time curve) of the ophthalmic artery.
The mean lOP in the patients who had had a TIA was 14.9 mmHg (range, 9-20 mmHg) in the right eyes and 15.0 mmHg (range, 9-21 mmHg) in the left eyes. In the control group, the lOPs were 14.8 mmHg (range, 10-21 mmHg) in the right eyes and 14.4 mmHg (range, 9-21 mmHg) in the left eyes. No statistical difference between the groups was found. Atrophic or exudative macular degeneration or glaucomatous optic disc cupping was not observed in either group using direct ophthalmoscopy. The frequency of transluminance-positive eyes in patients who had had a TIA and in control subjects was 63% and 28% for both eyes, respectively (P < 0.05; Table 3). The frequency ofPXS-positive eyes in the study group was 41% (19/46) for the right eyes and 43% (20/46) for the left eyes. In PXS-positive right and left eyes, iris transluminance was positive in 84% (16/19) and 85% (17/20), respectively. Two patients in the study group had collateral circulation with reversed blood flow in both ophthalmic arteries measured by ultrasound. One of them had stenosis of 100% in the right carotid bifurcation and stenosis of
and white film (ASA-400)31; (4) assessment of the lens by microscopy; and (5) examination of the retina using direct ophthalmoscopy after the pupil was dilated with drops containing a combination of 0.8% tropicamide and 5% phenylephrine. A diffuse layer of grayish material on the anterior lens capsule with a focal defect or the typical pattern consisting of a central disc, an intermediate clear zone, and a peripheral band of pseudoexfoliative material were the criteria for PXS.32 Two of us (LPR and MET) evaluated the photographs in a blind trial using the method described in a previous study.14 Abnormal iris translucency was considered to be present when generalized translucency was found or when several, often confluent, transluminating spots were found along the circumference of the iris (Figs 2 and 3). The statistical methods used were Student's t test, chi-square test, and kappa coefficient.
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Volume 102, Number 8, August 1995 with the eyes of the control group without transluminance, the resistivity indices of the ophthalmic arteries were significantly higher in the study group for both right and left eyes. Although the peak systolic velocities and end diastolic velocities of the ophthalmic arteries did not differ significantly, the slight tendency to lower values in the study group except the peak systolic velocity of the right ophthalmic artery was detectable (Table 5). Evaluation of the iris photographs by one of us (LPR) showed the presence of iris transilluminance to be identical in 93% of the right eyes and in 95% of the left eyes. Another investigator (MET) interpreted the presence in 91 % of the right eyes and in 92% of the left eyes. For interpretation of iris transluminance, the agreement between the authors, measured by kappa coefficient, was 0.92 for the right eyes and 0.93 for the left eyes (P < 0.001).
Figure 3. Generalized iris transluminance in the eye of patient who had had a transient ischemic attack.
Discussion Capsular glaucoma is common in Finland and other Scandinavian countries. According to statistics from studies done in Finland, 24% to 66% of all patients with open-angle glaucoma have this disease. 33 To date, the only parameter that has been treated is the lOP, due to our limited understanding of the mechanism that causes deterioration of the visual fields in these patients. There is mounting evidence that vascular abnormalities probably lie behind the pathologic changes that take place in eyes with different forms of glaucoma. 34 In PXS, microneovascularization of the iris due to hypoperfusion has been reported. 15.16 In addition, iris transillumination defects are a common finding in eyes with PXS, reflecting the possible hypoxic changes of these eyes. In the current study, the difference in iris transluminance between patients who had had a TIA and healthy subjects of the same age was statistically significant, the figures being higher for both groups than in our previous report. 14 Thus, the frequency of PXS among patients who had had a TIA (41 % for the right eyes and 43% for the left eyes) was twice as high as in our earlier publication and approximately four times more common than in unselected samples of Finnish population studies. 35 ,36 Although the differences in results between the studies may be due in part to the size of study populations and normal variation, the striking disparity
75% in the left carotid bifurcation. Pseudoexfoliation syndrome was found in both eyes of this patient. The other patient had stenosis of 95% to 99% in both carotid bifurcations. One patient in the study group had reversed blood flow in the left ophthalmic artery. The stenosis of carotid bifurcation was approximately 40%, suggesting a more severe stenosis in the distal part of the internal carotid artery. All eyes with collateral circulation (its retrograde blood flow) were excluded from statistical analysis concerning the velocity measurements. When the study group and the control group were compared regarding the peak systolic velocity, the end diastolic velocity, and the resistivity index, no statistical differences except the end diastolic velocity in the left ophthalmic artery were found between the groups (Table 4). The study population was examined in more detail by dividing it into subgroups according to positive iris transluminance. In the study group, there were 29 right eyes and 29 left eyes with positive iris transluminance, and in 25 subjects positive transluminance was binocular. The frequency ofPXS in these eyes was high: 55.6% (n = 15) for the right eyes and 61.5% (n = 16) for the left eyes. When the eyes with positive iris transluminance (excluding the eyes with retrograde blood flow) were compared
Table 3. Abnormal Iris Transluminance in the Study Group and in the Control Group and the Frequency of the Pseudoexfoliation Syndrome in the Study Group Study Group (n
=
Right Eye Positive iris transluminance PXS+ PXS •p
=
=
No.
(%)
No.
(%)
No.
29 19
(63) (41)
29 20
(63) (43)
9
pseudoexfoliation syndrome .
=
Right Eye
Left Eye
0.02 between study and control groups (chi-square test).
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Control Group (n
46)
o
32)
Left Eye (%)
No.
(28)
9
(%)
o
(28)*
Repo et al . CDI of the Ophthalmic Artery Blood Flow Spectra in TIA Table 4. Peak Systolic and End Diastolic Velocities and Resistivity Indices for the Ophthalmic Artery in the Study Population Study Group
Control Group
Mean ± SD
Mean ± SD
Right Ophthalmic Artery
PSV (em/sec) EDV (cm/sec) RI
40.3 ± 14.4 9.7 ± 4.3 0.75 ±
om
39.8 ± 15.7 10.6 ± 4.6 0.73 ± 0.06
Left Ophthalmic Artery
PSV (em/sec) EDV (cm/sec) RI
38.6 ± 13.3 9.9 ± 4.7 0.74 ± 0.06
43.9 ± 16.6 12.3 ± 4.8* 0.72 ± 0.05
SD = standard deviation; PSV = peak systolic velocity; EDV = end diastolic velocity; RI = resistivity index. •p
=
0.04 (Student's t test).
in the frequency of iris transluminance between patients who had had a TIA and healthy persons and the increased frequency of PXS among patients who had had a TIA in the both studies reflect the strong association between iris transluminance and PXS. In addition, one patient in this series with collateral blood flow in the both ophthalmic arteries had also PXS in both eyes. Two other patients with monolateral or bilateral reversed blood flow of the ophthalmic artery had positive iris transluminance of the corresponding eye. Results ofthe ultrasound examinations of carotid bifurcation suggested severe atherosclerotic disease of all these patients. Of the PXS-positive eyes, only three right eyes and three left eyes in the study group were transluminance-negative. However, of the transluminance-positive eyes, 12 right eyes and 10 left eyes were PXS negative. Thus, the high frequency of iris transluminance in PXS eyes together with the lower frequency of PXS in transluminance positive eyes suggest that iris transluminance may precede the appearance of PXS, although one is not an absolute prerequisite for the other. Color Doppler imaging allows reproducible noninvasive imaging and selective Doppler information of orbital vessels. Currently, it is not likely that COl will allow blood volume measurements, because diameters of the vessels cannot be assessed accurately, but the method does allow accurate measurements of flow velocities in the orbit. Inaccuracies in quantitative measurements can arise from errors in interpreting Doppler-shifted frequency spectrum and in measuring the Doppler angle. 26 In the current study, all ultrasound examinations were performed by the same author and two or more recordings were made for each eye. Measurements were made at the level at which the ophthalmic artery crosses the optic nerve, because at this level the artery was recognizable most easily with color Doppler scanning. At this level, the ophthalmic artery runs obliquely in relation to the optic nerve and is fairly
straight, which makes setting the Doppler angle at this point easier compared with more curved or tortuous segments distally. Especially in elderly patients, the ophthalmic artery and its side branches seem to be elongated, which makes the Doppler angle settings and measurements more vulnerable to errors. This level was selected as the site of the measurements to make the measurements more standardized and comparable among patients. In most cases, the central retinal artery and the posterior ciliary arteries also were recognizable with color Doppler scanning. However, the Doppler measurements of these arteries were uncertain and difficult to perform, because the lumens of these particular arteries are very small in diameter. It is difficult to keep the position steady while obtaining the time, and the patients become uncomfortable. Velocity values, except the end diastolic velocity for the left ophthalmic artery, suggest that blood supply of study group patients at the level of the ophthalmic artery is normal but the figures do not exclude the possibility that disturbances may occur in the more distal circulation . A statistically significant lower value of the end diastolic velocity for the left ophthalmic artery in the study group may reflect these changes. The current values are slightly higher than those reported by Guthoff and co-workers37 regarding the average of peak systolic and end diastolic velocities for ophthalmic artery (31.6 ± 9 cm/second and Table 5. Peak Systolic and End Diastolic Velocities and Resistivity Indexes for the Ophthalmic Artery in Patients Who Have Had a Transient Ischemic Attack and Positive Iris Transluminance/ Healthy Persons Study Group
Control Group
Right Ophthalmic Artery No. of eyes
PXS+
PSV (cm/sec) EDV (cm/sec) RI
23 0
27 15
Mean ± SD
Mean ± SD
40.0 ± 15.1 9.1 ± 4.0 0.77 ± 0.1
36.3 ± 14.1 9.6 ± 4.1 0.73 ± 0.05*
Left Ophthalmic Artery No. of eyes
PXS+
PSV (cm/sec) EDV (cm/sec) RI
26 16
23 0
Mean ± SD
Mean ± SD
38.7 ± 14.5 9.5 ± 4.6 0.75 ± 0.06
41.4 ± 11.2 11.5 ± 4.1 0.72 ± 0.01t
PXS = pseudoexfoliation syndrome; SD = standard deviation; PSV = peak systolic velocity; EDV = end diastolic velocity; RI = resistivity index. • p = 0.042 (Student's t test). t p = 0.025 (Student's t test).
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8.2 ± 3.7 cm/second) for the eyes with normal ophthalmic examination results, using an identical color Doppler unit as was used in the current study. Guthoff et aI's findings agree with another study using Doppler ultrasonography but the values are lower than those reported by Rojanapongpun and Drance,38 who used transcranial Doppler probe through the upper eye lid. Rojanapongpun and Drance also found that, when measured from more posterior locations, the peak systolic flow velocity increased significantly but the end diastolic flow velocity did not. It therefore is obvious that several factors, including the method of ultrasound, the segment ofthe ophthalmic artery studied, and different study populations, may affect the variability of blood velocity measurements, making the comparison between different studies difficult. Impedance is the total resistance to flow by several factors. Most of the peripheral resistance resides in the arterioles. Pourcelot's resistive index used in the current study is one of the pulsatility indices used to quantitate the total resistance to blood flow. Velocity measurements are dependent on and may vary with the angle of Doppler insonation, whereas pulsatility is angle independent. 39 The difference regarding the resistivity indices for the ophthalmic arteries between the eyes in the study group with positive iris transluminance and the healthy eyes without transluminance was statistically significant. The peripheral resistance of the ophthalmic artery resides in the ciliary and retinal circulations, implying that the eyes of patients who had had a TIA with positive iris transluminance have defective ocular circulation. The retinal vessels account for only 3% to 5% of overall blood supply to the eye compared with 95% to 97% for the ciliary vessels. 4o The hypoxic changes of retina are well documented. 41 Results of ophthalmoscopic examination did not disclose changes compatible with retinal hypoperfusion in the eyes of the study population. This suggests, although it is not indisputable because of the lack of retinal electrophysiologic measurements, that the ciliary circulation is responsible for the difference between the groups. The frequency of PXS in the eyes of patients who had had a TIA with positive iris transluminance is strikingly high which favors, together with high resistivity indices for the ophthalmic arteries of these eyes, the hypothesis that hypoxia has an important contributory role in the development of PXS.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
15.
16. 17. 18. 19. 20.
21.
References 1. Prince AM, Ritch R. Clinical signs of the pseudoexfoliation syndrome. Ophthalmology 1986;93:803-7. 2. Schlotzer-Schrehardt U, DodIer S, Naumann GOH. Corneal endothelial involvement in pseudoexfoliation syndrome. Arch Ophthalmol 1993;111:666-74. 3. Ringvoid A. Electron microscopy of the limbal conjunctiva in eyes with pseudoexfoliation syndrome (PE syndrome). Yirchows Arch A Pathol Anat 1972;355:275-83. 4. Ringvoid A. On the occurrence of pseudo-exfoliation material in extrabulbar tissue from patients with pseudo-ex-
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22. 23.
24. 25.
foliation syndrome of the eye. Acta Ophthalmol 1973;51: 411-18. Layden WE, Shaffer RN. Exfoliation syndrome. Am 1 Ophthalmol 1974;78:835-41. Speakman lS, Ghosh M. The conjunctiva in senile lens exfoliation. Arch Ophthalmol 1976:94: 1757-59. Roh VB, Ishibashi T, Ito N, Inomata H. Alteration of microfibrils in the conjunctiva of patients with exfoliation syndrome. Arch Ophthalmol 1987;105:978-82. Streeten BW, Bookman L, Ritch R, et al. Pseudoexfoliative fibrillopathy in the conjunctiva. A relation to elastic fibers and elastosis. Ophthalmology 1987;94:1439-49. Schlotzer-Schrehardt U, Kiichle M, Naumann GOH. Electron-microscopic identification of pseudoexfoliation material in extrabulbar tissue. Arch Ophthalmol 1991; 109:56570. Streeten BW, Dark AJ, Wallace RN, et al. Pseudoexfoliative fibrillopathy in the skin of patients with ocular pseudoexfoliation. Am 1 Ophthalmol 1990;110:490-9. Streeten BW, Li Z-Y, Wallace RN, et al. Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992; 110: 1757-62. Tarkkanen A. Pseudoexfoliation of the lens capsule. Acta Ophthalmol Suppl 1962;71. Repo LP, Terasvirta ME, Tuovinen El. Generalized peripheral iris transluminance in the pseudoexfoliation syndrome. Ophthalmology 1990;97: 1027-9. Repo LP, Terasvirta ME, Koivisto KJ. Generalized transluminance of the iris and the frequency of the pseudoexfoliation syndrome in the eyes of transient ischemic attack patients. Ophthalmology 1993; 100:352-5. Yannas A. Fluorescein angiography of the vessels of the iris in pseudoexfoliation of the lens capsule, capsular glaucoma and some other forms of glaucoma. Acta Ophthalmol Suppl 1969;105. Brooks AMY, Gillies WE. The development of micron eovascular changes in the iris in pseudoexfoliation of the lens capsule. Ophthalmology 1987 ;94: 1090-7. Duncan Wl. Color Doppler in Clinical Cardiology. Philadelphia: WB Saunders Co, 1988;1-5. Middleton WD, Thorne DA, Melson GL. Color Doppler ultrasound of the normal testis. A1R Am 1 Roentgenol 1989;152:293-7. Middleton WD, Melson GL. Testicular ischemia: color Doppler sonographic findings in five patients. A1R Am 1 RoentgenoI1989;152:1237-9. Erickson Sl, Mewissen MW, Foley WD, et al. Stenosis of the internal carotid artery: assessments using color Doppler imaging compared with angiography. AJR Am 1 Roentgeno1 1989;152: 1299-305. Erickson Sl, Merwissen MW, Foley WD, et al. Color Doppler evaluation of arterial stenoses and occlusions involving the neck and thoracic inlet. Radiographics 1989;9:389-406. Mitchell DG, Merton D, Needleman L, et aI. Neonatal brain: color Doppler imaging. Part I. Technique and vascular anatomy. Radiology 1988;167:303-6. Mitchell DG, Merton D, Desai H, et al. Neonatal brain: color Doppler imaging. Part II. Altered flow patterns from extracorporeal membrane oxygenation. Radiology 1988;167:307-10. Mitchell DG, Merton D, Mirsky Pl, Needleman L. Circle of Willis in newborns: color Doppler imaging of 53 healthy full-term infants. Radiology 1989; 172:20 1-5. Lieb WE, Flaharty PM, Sergott RC, et al. Color Doppler imaging provides accurate assessment of orbital blood flow
Repo et al . CD! of the Ophthalmic Artery Blood Flow Spectra in TIA
26. 27. 28. 29. 30. 31. 32.
33.
in occlusive carotid artery disease. Ophthalmology 1991 : 98:548-552. Lieb WE, Cohen SM, Merton DA, et al. Color Doppler imaging of the eye and orbit. Technique and normal vascular anatomy. Arch Ophthalmol 1991;109:527-31. Ho AC, Lieb WE, Flaharty PM, et al. Color Doppler imaging of the ocular ischemic syndrome. Ophthalmology 1992;99: 1453-62. Lieb WE, Flaharty PM, Ho A, Sergott RC. Color Doppler imaging of the eye and orbit. A synopsis of a 400 case experience. Acta Ophthalmol Suppl 1992;204:50-54. Williamson TH, Baxter GM, Dutton GN. Color Doppler velocimetry of the optic nerve head in arterial occlusion. Ophthalmology 1993;100:312-17. Sergott RC, Aburn NS, Trible JR, et al. Color Doppler imaging: methodology and preliminary results in glaucoma. Surv Ophthalmol 1994:38(Suppl); S65-S71. Donaldson DD. Stereophotographic systems. Int Ophthalmol Clin 1976; 16(2): 109-31. Tetsumoto K, SchIi:itzer-Schrehardt U, Kiichle M, et aI. Precapsular layer of the anterior lens capsule in early pseudoexfoliaton syndrome. Graefes Arch C1in Exp Ophthalmol 1992;230:252-7. Forsius H. Exfoliation syndrome in various ethnic populations. Acta Ophthalmol Suppl 1988; 184:71-85.
34. Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol 1994;39:23-42. 35. Krause U, Helve J, Forsius H . Pseudoexfoliation of the lens capsule and liberation of iris pigment. Acta Ophthalmol 1973;51 :39-46. 36. Rouhiainen H, Teriisvirta M. Pigmentation of the anterior chamber angle in normal and pseudoexfoliative eyes. Acta Ophthalmol 1990;68:700-2 . 37. Guthoff RF, Berger RW, Winkler P, et al. Doppler ultrasonography of the ophthalmic and central retinal vessels. Arch Ophthalmol 1991; 109:532-6. 38. Rojanapongpun P, Drance SM. Velocity of ophthalmic arterial flow recorded by Doppler ultrasound in normal subjects. Am J Ophthalmol 1993;115:174-80. 39. Taylor KJ, Holland S. Doppler US. Part I. Basic principles, instrumentation, and pitfalls. Radiology 1990; 174:297307. 40. Gasser P. Ocular vasospasm, a risk factor in the pathogenesis of low-tension glaucoma. Int Ophthalmol 1989; 13:28190. 41. Sanborn GE, Magargal LE. Arterial obstructive disease of the eye. In: Tasman W, Jaeger EA, eds. Duane's Clinical Ophthalmology, rev ed. Philadelphia: JB Lippincott, 1994; vol. 3, chap. 14.
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Originally received: December 7, 1994. Revision accepted: April 14, 1995. 1 Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. 2 Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland.
In the pseudoexfoliation syndrome (PXS), the anterior segment of the eye is involved by dandruff-like material, Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Reprint requests to Leo P. Repo, MD, Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777,70211 Kuopio, Finland.
3
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Volume 102, Number 8, August 1995
which is biomicroscopically detectable on the lens, the iris, on the anterior surface of the vitreous, the corneal endothelium, and in the angle of the anterior chamber. 1,2 Based on recent light and electron microscopic studies, pseudoexfoliative material appears within the walls of the central retinal artery, the vorticose veins and within the ocular muscles, the connective tissue of the orbit, and in the cutaneous tissue. 3- 10 Aggregates consistent with pseudoexfoliative material also have been found in the lung, heart, liver, and gallbladder. 11 Clinically, PXS is important because of its association with glaucoma (capsular glaucoma).12 Iris translucency, which may be detected peripupillary or in generalized form, is one of the cardinal clinical features of pXS.l,13 The same phenomenon is common in the eyes of patients who have had transient ischemic attacks (TIAs). In addition, the frequency ofPXS is higher in the eyes of patients who have had a TIA compared with the eyes of healthy subjects of the same age, suggesting that hypoxia may have a contributory role in the development of PXS. 14 This theory is supported by the fluorescein angiographic appearance of the iris in PXS. 15 ,16 Color Doppler imaging (CDI) is a method of ultrasonography, which allows simultaneous two-dimensional imaging of anatomic structures and blood flow. The Doppler information regarding blood flow is superimposed in color onto a conventional gray-scale ultrasound picture. The color image is used as a guide to detect the blood vessels, and the Doppler spectral analysis allows quantitative assessment of the blood flow velocities within the blood vessels. This method generally is used widely in vascular imaging and diagnostics. 17-24 In recent years, CDI has been used extensively for the diagnostic evaluation of ophthalmic and orbital disorders. 25 - 3o The aims of this study are to evaluate, by means of CDI, the ophthalmic artery blood flow spectra of patients who had had a TIA and healthy subjects of the same age and to study the interrelation among the changes in the blood flow, generalized iris transluminance, and PXS.
Subjects and Methods Subjects The study group comprised 46 patients who had had a TIA (92 eyes) and who were treated at the Department of Neurology, Kuopio University Hospital. The criteria for the diagnosis of TIA were transient monocular blindness (amaurosis fugax) or transient hemisphere attack(s) lasting less than 24 hours. The control group consisted of 32 persons (64 eyes) without any systemic or ocular disease participating in two public health studies performed in the Department of Public Health Science of Kuopio University and in Kuopio Research Institute of Exercise Medicine (Table 1). The average time interval between the diagnosis ofTIA and ophthalmologic examination was 1.6 years (range, 0.4-9 years). According to ultrasound examinations, stenosis of 50% or more of the carotid bifurcation was found
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Table 1. Study Group and Control Group by Age and Sex
Age (yrs) Mean ± standard deviation No, of women No. of men No, of eyes
Study Group
Control Group
65.5 ± 7.4
63.4 ± 4.5*
30 16
14
92
18
64
• Nonsignificant (Student's t test),
to be present in five (10.9%) patients in both carotid trunks. Right carotid bifurcation was involved in six (13.0%) patients and left carotid in five (10.9%) patients. Twelve of the patients (26.1 %) had coronary heart disease, 13 (28.3%) had hypertension, 4 (8.7%) had cardiac insufficiency, and 6 (13.0%) had cardiac arrhythmia (Table 2). Five of the six patients with cardiac arrhythmia had stenosis over 50% in their right or left carotid bifurcation. Nine of the patients had had amaurosis fugax in their right eye, three of whom had stenosis over 50% in their right carotid bifurcation. One of the three patients with amaurosis fugax in the left eye had stenoses over 50% in the left carotid bifurcation. Patients with diabetes or ocular disease other than PXS as well as patients in whom carotid endarterectomy had been performed were excluded from the study. All irides were blue to bluish-gray in color. Informed consent was obtained from all subjects participating in the study.
Methods Color Doppler ultrasound was performed on all patients who had had a TIA and on control subjects at the time of ophthalmologic examination by one of us (MTS). All examinations were performed using a color Doppler unit (ATL Ultramark 9, Advanced Technology Laboratories, Bothell, Washington) with a 5-MHz linear transducer. During the ultrasonographic study, patients were in supine position. They were asked to close their eyes and to hold their eyes steady. The ultrasound transducer was applied to the closed eyelids using a small amount of coupling gel, and care was taken not to apply pressure to the eye to avoid iatrogenic errors in the flow measurements. Both eyes were studied and coded separately. Scanning was begun with a horizontal scan through the eye and orbit at the level of the optic nerve with the transducer tilted 10° to 20° medially toward the apex of the orbit. Rotational adjustment of the scanning plane was used to obtain the best view of the ophthalmic artery. Initially, the colorcoded image was obtained in each eye to assess the retrobulbar vascular anatomy. Color setup was selected so that flow toward the transducer appeared in red and flow away from the transducer appeared in blue. Color threshold levels were adjusted to minimize artifacts resulting
Repo et al . CDI of the Ophthalmic Artery Blood Flow Spectra in TIA Table 2. Clinical Characteristics of Patients Who Have Had Transient Ischemic Attacks Characteristics
No. of Patients (%)
Stenosis > 50% in both carotid bifurcations Stenosis > 50% in right carotid bifurcation Stenosis > 50% in left carotid bifurcation Stenosis < 50% in both carotid bifurcations Coronary heart disease Hypertension Cardiac insufficiency Cardiac arrhythmia
5 (10.9) 6 (13.0) 5 (10.9) 30 (65.2) 12 (26.1) 13 (28.3) 4 (8.7) 6 (13.0) Figure 2. Physiologic iris transluminance in the lower part of the iris.
from involuntary lid or eye movements. Pulsed Doppler measurements were performed with the same probe using Doppler spectral analysis. Great effort was made to select the ophthalmic artery measurement site at approximately the same distance from the bulb for all patients. The majority of the measurements could be obtained at the point where ophthalmic artery crosses the optic nerve and runs medially before dividing into smaller peripheral branches. The Doppler angle was carefully determined for all measurements. Two or more recordings were made for each eye to obtain the best possible visual shape of curve. From the spectral curve, the peak systolic velocity and end diastolic velocity were determined in centimeters per second. Pourcelot's resistive index ([peak systolic velocity-end diastolic velocity]/peak systolic velocity) was determined in each measurement by using the unit's own software 30 (Fig 1). The ophthalmologic examinations were done by the first author (LPR), including the (1) determination of visual acuity; (2) measurement of intraocular pressure (lOP); (3) photography of the iris using transcleral technique, described earlier, for recording iris translucency on black
Results
Figure 1. Left, color Doppler scan of the right ophthalmic artery. The artery crosses over the optic nerve. Right, Doppler spectrum (velocity time curve) of the ophthalmic artery.
The mean lOP in the patients who had had a TIA was 14.9 mmHg (range, 9-20 mmHg) in the right eyes and 15.0 mmHg (range, 9-21 mmHg) in the left eyes. In the control group, the lOPs were 14.8 mmHg (range, 10-21 mmHg) in the right eyes and 14.4 mmHg (range, 9-21 mmHg) in the left eyes. No statistical difference between the groups was found. Atrophic or exudative macular degeneration or glaucomatous optic disc cupping was not observed in either group using direct ophthalmoscopy. The frequency of transluminance-positive eyes in patients who had had a TIA and in control subjects was 63% and 28% for both eyes, respectively (P < 0.05; Table 3). The frequency ofPXS-positive eyes in the study group was 41% (19/46) for the right eyes and 43% (20/46) for the left eyes. In PXS-positive right and left eyes, iris transluminance was positive in 84% (16/19) and 85% (17/20), respectively. Two patients in the study group had collateral circulation with reversed blood flow in both ophthalmic arteries measured by ultrasound. One of them had stenosis of 100% in the right carotid bifurcation and stenosis of
and white film (ASA-400)31; (4) assessment of the lens by microscopy; and (5) examination of the retina using direct ophthalmoscopy after the pupil was dilated with drops containing a combination of 0.8% tropicamide and 5% phenylephrine. A diffuse layer of grayish material on the anterior lens capsule with a focal defect or the typical pattern consisting of a central disc, an intermediate clear zone, and a peripheral band of pseudoexfoliative material were the criteria for PXS.32 Two of us (LPR and MET) evaluated the photographs in a blind trial using the method described in a previous study.14 Abnormal iris translucency was considered to be present when generalized translucency was found or when several, often confluent, transluminating spots were found along the circumference of the iris (Figs 2 and 3). The statistical methods used were Student's t test, chi-square test, and kappa coefficient.
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Volume 102, Number 8, August 1995 with the eyes of the control group without transluminance, the resistivity indices of the ophthalmic arteries were significantly higher in the study group for both right and left eyes. Although the peak systolic velocities and end diastolic velocities of the ophthalmic arteries did not differ significantly, the slight tendency to lower values in the study group except the peak systolic velocity of the right ophthalmic artery was detectable (Table 5). Evaluation of the iris photographs by one of us (LPR) showed the presence of iris transilluminance to be identical in 93% of the right eyes and in 95% of the left eyes. Another investigator (MET) interpreted the presence in 91 % of the right eyes and in 92% of the left eyes. For interpretation of iris transluminance, the agreement between the authors, measured by kappa coefficient, was 0.92 for the right eyes and 0.93 for the left eyes (P < 0.001).
Figure 3. Generalized iris transluminance in the eye of patient who had had a transient ischemic attack.
Discussion Capsular glaucoma is common in Finland and other Scandinavian countries. According to statistics from studies done in Finland, 24% to 66% of all patients with open-angle glaucoma have this disease. 33 To date, the only parameter that has been treated is the lOP, due to our limited understanding of the mechanism that causes deterioration of the visual fields in these patients. There is mounting evidence that vascular abnormalities probably lie behind the pathologic changes that take place in eyes with different forms of glaucoma. 34 In PXS, microneovascularization of the iris due to hypoperfusion has been reported. 15.16 In addition, iris transillumination defects are a common finding in eyes with PXS, reflecting the possible hypoxic changes of these eyes. In the current study, the difference in iris transluminance between patients who had had a TIA and healthy subjects of the same age was statistically significant, the figures being higher for both groups than in our previous report. 14 Thus, the frequency of PXS among patients who had had a TIA (41 % for the right eyes and 43% for the left eyes) was twice as high as in our earlier publication and approximately four times more common than in unselected samples of Finnish population studies. 35 ,36 Although the differences in results between the studies may be due in part to the size of study populations and normal variation, the striking disparity
75% in the left carotid bifurcation. Pseudoexfoliation syndrome was found in both eyes of this patient. The other patient had stenosis of 95% to 99% in both carotid bifurcations. One patient in the study group had reversed blood flow in the left ophthalmic artery. The stenosis of carotid bifurcation was approximately 40%, suggesting a more severe stenosis in the distal part of the internal carotid artery. All eyes with collateral circulation (its retrograde blood flow) were excluded from statistical analysis concerning the velocity measurements. When the study group and the control group were compared regarding the peak systolic velocity, the end diastolic velocity, and the resistivity index, no statistical differences except the end diastolic velocity in the left ophthalmic artery were found between the groups (Table 4). The study population was examined in more detail by dividing it into subgroups according to positive iris transluminance. In the study group, there were 29 right eyes and 29 left eyes with positive iris transluminance, and in 25 subjects positive transluminance was binocular. The frequency ofPXS in these eyes was high: 55.6% (n = 15) for the right eyes and 61.5% (n = 16) for the left eyes. When the eyes with positive iris transluminance (excluding the eyes with retrograde blood flow) were compared
Table 3. Abnormal Iris Transluminance in the Study Group and in the Control Group and the Frequency of the Pseudoexfoliation Syndrome in the Study Group Study Group (n
=
Right Eye Positive iris transluminance PXS+ PXS •p
=
=
No.
(%)
No.
(%)
No.
29 19
(63) (41)
29 20
(63) (43)
9
pseudoexfoliation syndrome .
=
Right Eye
Left Eye
0.02 between study and control groups (chi-square test).
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Control Group (n
46)
o
32)
Left Eye (%)
No.
(28)
9
(%)
o
(28)*
Repo et al . CDI of the Ophthalmic Artery Blood Flow Spectra in TIA Table 4. Peak Systolic and End Diastolic Velocities and Resistivity Indices for the Ophthalmic Artery in the Study Population Study Group
Control Group
Mean ± SD
Mean ± SD
Right Ophthalmic Artery
PSV (em/sec) EDV (cm/sec) RI
40.3 ± 14.4 9.7 ± 4.3 0.75 ±
om
39.8 ± 15.7 10.6 ± 4.6 0.73 ± 0.06
Left Ophthalmic Artery
PSV (em/sec) EDV (cm/sec) RI
38.6 ± 13.3 9.9 ± 4.7 0.74 ± 0.06
43.9 ± 16.6 12.3 ± 4.8* 0.72 ± 0.05
SD = standard deviation; PSV = peak systolic velocity; EDV = end diastolic velocity; RI = resistivity index. •p
=
0.04 (Student's t test).
in the frequency of iris transluminance between patients who had had a TIA and healthy persons and the increased frequency of PXS among patients who had had a TIA in the both studies reflect the strong association between iris transluminance and PXS. In addition, one patient in this series with collateral blood flow in the both ophthalmic arteries had also PXS in both eyes. Two other patients with monolateral or bilateral reversed blood flow of the ophthalmic artery had positive iris transluminance of the corresponding eye. Results ofthe ultrasound examinations of carotid bifurcation suggested severe atherosclerotic disease of all these patients. Of the PXS-positive eyes, only three right eyes and three left eyes in the study group were transluminance-negative. However, of the transluminance-positive eyes, 12 right eyes and 10 left eyes were PXS negative. Thus, the high frequency of iris transluminance in PXS eyes together with the lower frequency of PXS in transluminance positive eyes suggest that iris transluminance may precede the appearance of PXS, although one is not an absolute prerequisite for the other. Color Doppler imaging allows reproducible noninvasive imaging and selective Doppler information of orbital vessels. Currently, it is not likely that COl will allow blood volume measurements, because diameters of the vessels cannot be assessed accurately, but the method does allow accurate measurements of flow velocities in the orbit. Inaccuracies in quantitative measurements can arise from errors in interpreting Doppler-shifted frequency spectrum and in measuring the Doppler angle. 26 In the current study, all ultrasound examinations were performed by the same author and two or more recordings were made for each eye. Measurements were made at the level at which the ophthalmic artery crosses the optic nerve, because at this level the artery was recognizable most easily with color Doppler scanning. At this level, the ophthalmic artery runs obliquely in relation to the optic nerve and is fairly
straight, which makes setting the Doppler angle at this point easier compared with more curved or tortuous segments distally. Especially in elderly patients, the ophthalmic artery and its side branches seem to be elongated, which makes the Doppler angle settings and measurements more vulnerable to errors. This level was selected as the site of the measurements to make the measurements more standardized and comparable among patients. In most cases, the central retinal artery and the posterior ciliary arteries also were recognizable with color Doppler scanning. However, the Doppler measurements of these arteries were uncertain and difficult to perform, because the lumens of these particular arteries are very small in diameter. It is difficult to keep the position steady while obtaining the time, and the patients become uncomfortable. Velocity values, except the end diastolic velocity for the left ophthalmic artery, suggest that blood supply of study group patients at the level of the ophthalmic artery is normal but the figures do not exclude the possibility that disturbances may occur in the more distal circulation . A statistically significant lower value of the end diastolic velocity for the left ophthalmic artery in the study group may reflect these changes. The current values are slightly higher than those reported by Guthoff and co-workers37 regarding the average of peak systolic and end diastolic velocities for ophthalmic artery (31.6 ± 9 cm/second and Table 5. Peak Systolic and End Diastolic Velocities and Resistivity Indexes for the Ophthalmic Artery in Patients Who Have Had a Transient Ischemic Attack and Positive Iris Transluminance/ Healthy Persons Study Group
Control Group
Right Ophthalmic Artery No. of eyes
PXS+
PSV (cm/sec) EDV (cm/sec) RI
23 0
27 15
Mean ± SD
Mean ± SD
40.0 ± 15.1 9.1 ± 4.0 0.77 ± 0.1
36.3 ± 14.1 9.6 ± 4.1 0.73 ± 0.05*
Left Ophthalmic Artery No. of eyes
PXS+
PSV (cm/sec) EDV (cm/sec) RI
26 16
23 0
Mean ± SD
Mean ± SD
38.7 ± 14.5 9.5 ± 4.6 0.75 ± 0.06
41.4 ± 11.2 11.5 ± 4.1 0.72 ± 0.01t
PXS = pseudoexfoliation syndrome; SD = standard deviation; PSV = peak systolic velocity; EDV = end diastolic velocity; RI = resistivity index. • p = 0.042 (Student's t test). t p = 0.025 (Student's t test).
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Volume 102, Number 8, August 1995
8.2 ± 3.7 cm/second) for the eyes with normal ophthalmic examination results, using an identical color Doppler unit as was used in the current study. Guthoff et aI's findings agree with another study using Doppler ultrasonography but the values are lower than those reported by Rojanapongpun and Drance,38 who used transcranial Doppler probe through the upper eye lid. Rojanapongpun and Drance also found that, when measured from more posterior locations, the peak systolic flow velocity increased significantly but the end diastolic flow velocity did not. It therefore is obvious that several factors, including the method of ultrasound, the segment ofthe ophthalmic artery studied, and different study populations, may affect the variability of blood velocity measurements, making the comparison between different studies difficult. Impedance is the total resistance to flow by several factors. Most of the peripheral resistance resides in the arterioles. Pourcelot's resistive index used in the current study is one of the pulsatility indices used to quantitate the total resistance to blood flow. Velocity measurements are dependent on and may vary with the angle of Doppler insonation, whereas pulsatility is angle independent. 39 The difference regarding the resistivity indices for the ophthalmic arteries between the eyes in the study group with positive iris transluminance and the healthy eyes without transluminance was statistically significant. The peripheral resistance of the ophthalmic artery resides in the ciliary and retinal circulations, implying that the eyes of patients who had had a TIA with positive iris transluminance have defective ocular circulation. The retinal vessels account for only 3% to 5% of overall blood supply to the eye compared with 95% to 97% for the ciliary vessels. 4o The hypoxic changes of retina are well documented. 41 Results of ophthalmoscopic examination did not disclose changes compatible with retinal hypoperfusion in the eyes of the study population. This suggests, although it is not indisputable because of the lack of retinal electrophysiologic measurements, that the ciliary circulation is responsible for the difference between the groups. The frequency of PXS in the eyes of patients who had had a TIA with positive iris transluminance is strikingly high which favors, together with high resistivity indices for the ophthalmic arteries of these eyes, the hypothesis that hypoxia has an important contributory role in the development of PXS.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
15.
16. 17. 18. 19. 20.
21.
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