- Email: [email protected]
Visual Field Responses to a Hand Vibration Stimulus
SURVEY OF OPHTHALMOLOGY VOLUME 43 • SUPPLEMENT 1 • JUNE 1999
Visual Field Responses to a Hand Vibration Stimulus ERIC CHAI, MB BS, IVAN GOLDBERG, MB BS, FRACO, FRACS, AUDREY CHIA, MB BS, AND JACK CHEN, MB BS
Sydney and Sydney Eye Hospitals, Sydney, NSW, Australia Abstract. Two short visual field tests were performed on 106 subjects approximately 5 minutes apart with or without a hand vibration stimulus between the field tests. There were 31 eyes in the control group (10 without glaucoma, eight glaucoma suspects, 10 with primary open-angle glaucoma, and three with secondary open-angle glaucoma). There were 75 eyes in the hand vibration group (16 without glaucoma, 20 glaucoma suspects, 25 with primary open-angle glaucoma, eight with secondary open-angle glaucoma, three with normal-tension glaucoma, and three with other forms of glaucoma). Average visual field sensitivities were significantly reduced in the arcuate zones after a hand vibration stimulus (20.42 dB; SD, 1.26 dB) when compared with sensitivities in the arcuate zones in subjects without the hand vibration stimulus (10.38 dB; SD, 1.53 dB; P 5 0.01). Multivariate analysis demonstrated a significant reduction in this response in the arcuate zone associated with use of betaxolol (P 5 0.021) and timolol (P 5 0.047). Betaxolol was associated with significantly smaller reductions in visual field sensitivities in the paracentral zone (P 5 0.01). Reductions in visual field sensitivities that may be related to ocular vasospasm occurred after a hand vibration stimulus. This response may be able to be modified pharmacologically with topical b-blockers, particularly betaxolol. (Surv Ophthalmol 43 [Suppl. 1]:S79– S86, 1999. © 1999 by Elsevier Science Inc. All rights reserved.) Key words. b-blockers • glaucoma • ocular vasospasm • visual field
spasm.28 Transient ischemia of the optic nerve fibers caused by the vasospastic response of the microvasculature supplying the optic nerve may account for this finding. Similarly, reductions in visual field sensitivity have been demonstrated at high altitudes, where there is a lower oxygen tension.33 Hand vibration may induce a sympathetic autonomic system release of catecholamines, resulting in a systemic vasospastic response.25,34 Previously, we have used the Hettinger hand vibration test (HHVT) to identify a subgroup with a high systemic vasospastic tendency.15 In this study, we investigated the effects of a hand vibration stimulus and ocular vasospasm on the function of the optic nerve fibers, as measured by visual field sensitivities before and after the hand vibration stimulus.
Visual destruction from glaucoma may result at least partially from ischemic damage to the optic nerve fibers.5,7,10 This may be from a disturbance of autoregulation of the microcirculation in and/or around the optic nerve head.5,10,13 Vasospasm in the ocular microvasculature may result from normal or abnormal physiologic systemic factors, such as surges in circulating catecholamines11 or other endogenous substances.20,30 A subgroup of the population may have a higher tendency for ocular and/or systemic vasospasm that may, in combination with other factors, including ocular hypertension, genetic susceptibility, and structural abnormalities of the cribiform plate, predispose them to glaucoma. If this group can be identified, this trait may be able to be inhibited pharmacologically, thereby assisting in preventing progression of glaucoma. Gasser and Flammer,12 Drance et al,8 and Usui and Iwata38 found that a cold hand stimulus provoked greater and more prolonged nailbed capillary vasospasm in some patients with glaucoma. This systemic stimulus was also found to provoke reductions in visual field sensitivities, suggesting ocular vaso-
Methods Subjects were selected from the patient pool attending our clinic. Inclusion criteria included visual acuity of 6/9 or better in the tested eye and patient age between 15 and 85 years. The eye with better visual acuity was selected for testing. If both eyes had S79
© 1999 by Elsevier Science Inc. All rights reserved.
0039-6257/99/$19.00 PII S0039-6257(99)00051-X
S80
Surv Ophthalmol 43 (Suppl 1) June 1999
equal visual acuity, the test eye was chosen randomly. Exclusion criteria included failure to comply with pretest instructions (Table 1), poor reliability during visual field testing, and failure of hand temperatures to stabilize.4,41 Informed consent was obtained before testing. A brief medical history from each subject included questions regarding concurrent systemic medical and ocular conditions, and systemic and/or topical medications. Compliance with pretest instructions was ascertained. Two visual field tests were performed on each subject. Subjects in the hand vibration group underwent a visual field test, the HHVT after stabilization of hand temperatures, and a second visual field test immediately after the hand vibration. The minimum time between field tests in the hand vibration group was 5 minutes. Subjects in the control group had two visual field tests with a 5-minute break between the tests. Average changes in visual field sensitivities between the two tests were calculated for each subject. Static perimetry was carried out with the Medmont M600 automated perimeter (MAP). The MAP uses a pale green (565 nm) rear projection light-emitting diode as the stimulus, with a size of 0.438 (Goldmann size III) and exposure duration of 200 ms. The stimulus is presented within a 350-mm-radius hemispherical bowl with a background illumination of 10 apostilbs. All tests were conducted in a completely darkened environment. A specially programmed threshold eight test-point strategy was used. Four points, 68 from fixation (paracentral zone) and four points, 158 from fixation (arcuate zone) were tested in addition to four calibration points and the blind spot (Fig. 1). Test durations ranged from 1.5 to 2.5 minutes. The HHVT has been described previously.4,22,23,36,41 In summary, the subjects grasped a 65-mm-diameter knob that vibrated at a frequency of 50 Hz with a vertical amplitude of 2 mm for 30 seconds. After vibration, with the hand resting on the knob, the temperature of the skin on the dorsum of the hand was recorded at 30 seconds, 1 minute, and then every minute for a total of 5 minutes. The Hettinger score
CHAI ET AL
(HS) was derived from hand temperatures recorded after vibration with the following formula: ( 1 + Tmin ) t HS = ------------------------------ × 1 + --- ( 1 + Tmax ) 4 where Tmin 5 difference between the baseline temperature and the lowest temperature recorded below baseline in degrees Celsius; Tmax 5 difference between the highest temperature recorded above baseline and the baseline temperature in degrees Celsius; and t 5 time taken in minutes for the hand temperature to return to baseline after an initial fall. If the temperature did not fall, t 5 0. Demographic variables of the control and hand vibration groups were compared with the chi-square test or t-test to determine any significant differences between the two groups. The change in mean visual field sensitivities in the paracentral and arcuate zones were compared with the Mann-Whitney U test, as the data were not distributed normally and there was inequality of variances. Mean HSs were compared with the Mann-Whitney U test. A multiple linear regression model was used to explore the relationship between the paracentral and arcuate zone sensitivities and a group of predicting variables. Hand vibration, diagnostic categories, age, migraine, and medications were used as predicting variables. The forced-entry method was used to control simultaneously for all these variables in the model. Only the main effects of the predicting vari-
TABLE 1
Pretest Instructions For 2 hours before testing: • No hand washing, bathing, or showering • Avoid cigarette smoking For 12 hours before testing: • Avoid coffee, tea, and other beverages containing caffeine. • Avoid alcohol • Avoid heavy exercise
Fig. 1. Visual field test showing points tested in the left eye. BS 5 blind spot (158 eccentricity); C 5 calibration points (108 eccentricity); p 5 paracentral zones (68 eccentricity); a 5 arcuate zones (158 eccentricity).
S81
VISUAL FIELD CHANGES AND HAND VIBRATION TABLE 2
Demographic Data Group Controls (N 5 31)
Hand Vibration (N 5 75)
P Value
Age (years) 61.4 6 16.8 59.2 6 15.4 0.51 Sex (no.) 0.66 Male 13 28 Female 18 47 Eye (no.) , 0.001 Right 9 59 Left 22 16 Topical b-blockers (no.) Timolol 8 21 0.85 Betaxolol 4 12 0.69 Systemic medications (no.) SBB 4 7 0.58 CCB 1 7 0.28 SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers.
ables were included in the model. Instead of a conventional ordinary least-square estimation method, the robust-variance method (Huber-White-Sandwich method) was used, as it can provide estimates that are robust against departure from the assumptions of normality and homogeneity of variance. Multicollinearity was examined with the variance-inflation factor and was not found to be a significant problem in the model.
Results The control group consisted of 31 eyes of 31 subjects: 10 without glaucoma, eight glaucoma suspects, 10 with primary open-angle glaucoma, and three with secondary open-angle glaucoma. The hand vibration group consisted of 75 eyes of 75 subjects: 16 without glaucoma, 20 glaucoma suspects, 25 with primary open-angle glaucoma, eight with secondary open-angle glaucoma, three with normal-tension glaucoma, two with congenital glaucoma, and one
with chronic angle-closure glaucoma. The control and hand vibration groups were not significantly different with regard to the distribution of diagnoses within the groups (P 5 0.64). The age, sex, and medications were not significantly different between the two groups (Table 2). The laterality of test eyes was significantly different, with a higher percentage of right eyes tested in the hand vibration group compared with the control group. Changes in average visual field sensitivities were compared between the control and hand vibration groups (Table 3). These were significantly reduced in the arcuate zone after a hand vibration stimulus (20.42 dB; SD, 1.26 dB) when compared with sensitivities in the arcuate zone in subjects without the hand vibration stimulus (10.38 dB; SD, 1.53; P 5 0.01). There was a reduction in average visual field sensitivities in the paracentral zone after hand vibration (20.24 dB; SD, 1.39 dB) when compared with the control group (20.06 dB; SD, 1.05 dB), but this difference was not statistically significant (P 5 0.49). Subjects in the hand vibration group who were not taking systemic medications were considered in three groups: subjects using no topical b-blockers and patients using either timolol or betaxolol (Table 4). When compared with subjects not using topical b-blockers (20.81 dB; SD, 1.10 dB), the timolol group (20.09 dB; SD, 1.22 dB) was found to have smaller reductions in visual field sensitivity whereas the betaxolol group (10.52 dB; SD, 1.34 dB) demonstrated increased visual field sensitivities in the arcuate zone. In the paracentral zone, the betaxolol group (10.56 dB; SD, 1.07 dB) had increased visual field sensitivities compared with the timolol group (20.33 dB; SD, 1.34 dB) and with the no-medication group (20.43 dB; SD, 1.26 dB), both of which experienced reductions in visual field sensitivity after hand vibration. The mean HS of the no-medication group was 1.66 (SD, 1.11). Subjects taking timolol had a higher mean HS (1.73; SD, 0.95) and the betaxolol group had a lower means HS (1.41; SD, 0.95). These differences were not statistically significant (P 5 0.71).
TABLE 3
Visual Field Findings in Controls Versus Hand Vibration Group Group
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) VF 5 visual field. *Derived from Mann-Whitney U test.
Controls (N 5 31)
Hand Vibration (N 5 75)
P Value*
20.06 6 1.05 10.38 6 1.53
20.24 6 1.39 20.42 6 1.26
0.49 0.01
S82
Surv Ophthalmol 43 (Suppl 1) June 1999
CHAI ET AL TABLE 4
Effects of Topical b-Blockers
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) Mean HS
Betaxolol (N 5 12)
Timolol (N 5 16)
No Topical b-Blockers (N 5 35)
10.56 6 1.07 10.52 6 1.34 1.41 6 0.95
20.33 6 1.34 20.09 6 1.22 1.73 6 0.95
20.43 6 1.26 20.81 6 1.10 1.66 6 1.11
VF 5 visual field; HS 5 Hettinger score.
Changes in visual field sensitivities after hand vibration varied with different ocular diagnoses (Table 5). In general, subjects with primary open-angle glaucoma had smaller mean reductions in visual field sensitivities after hand vibration than the control group. Glaucoma suspects had reductions in sensitivities intermediate between those of the control and primary open-angle glaucoma groups. The proportion of subjects in each of these diagnostic categories taking topical beta-blockers was highest in the primary open-angle glaucoma group, with 67% of the group instilling a b-blocker (timolol, 41%; betaxolol, 26%) (Fig. 2). No patients in the normal group and 22% of the suspect group were taking topical betablockers (timolol, 11%; betaxolol, 11%). The differences in distribution of beta-blockers among the disease categories were statistically significant (P , 0.001). Patient numbers in other diagnostic categories were too small for meaningful analysis. The mean reductions in visual field sensitivities in the hand vibration group were found to be greater in subjects less than 55 years of age in both the paracentral and arcuate zone (Table 6). Subjects less than 55 years of age had a mean reduction in visual field sensitivities of 20.49 dB (SD, 1.24 dB) and 20.69 dB (SD, 1.31 dB) in the paracentral and arcuate zones, respectively, compared with 20.11 dB (SD, 1.46 dB) and 20.27 dB (SD, 1.22 dB) in subjects aged 55 years and over. Mean HS was slightly higher in the group less than 55 years of age (1.64; SD, 1.01) in comparison with subjects aged 55 years or more (1.56; SD, 1.02), but this too was not statistically significant.
With multiple linear regression analysis, three factors were found to influence significantly the change in sensitivity in the arcuate zones (Table 7). Hand vibration was associated with significant reductions in arcuate visual field sensitivities (P 5 0.005). Betaxolol (P 5 0.021) and timolol (P 5 0.047) were associated with significant improvement or less reduction in arcuate visual field sensitivities. Younger age was of borderline significance as a factor associated with greater sensitivity loss in the arcuate zones (P 5 0.085). Systemic b-blockers, Ca21 channel antagonists, and diagnostic categories were found not to influence changes in visual field sensitivities significantly. In the paracentral zones (Table 8), betaxolol was the only factor that was associated with a significantly smaller reduction in visual field sensitivity (P 5 0.01). Hand vibration, timolol, systemic b-blockers, Ca21 channel antagonists, and diagnostic categories were not found to influence changes in paracentral visual field sensitivities significantly. There was a significant correlation between changes in visual field sensitivities in the arcuate and paracentral zones (r 5 0.29, P 5 0.003) (Fig. 3). Correlation between HS and changes in visual field sensitivities after hand vibration was poor in both the paracentral zone (r 5 0.14, P 5 0.13) and the arcuate zone (r 5 20.11, P 5 0.25).
Discussion Chronic ocular vasospasm may contribute to optic nerve destruction in glaucoma.5,7,10,11,14 A subpopulation with a high systemic vasospastic tendency may be identified with hand temperature measurements
TABLE 5
Effects of Diagnostic Categories Diagnostic Category
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) Number (%) of subjects taking timolol Number (%) of subjects taking betaxolol
Normal (N 5 13)
Glaucoma Suspects (N 5 18)
POAG (N 5 27)
20.92 6 1.37 20.81 6 0.99 0 (0) 0 (0)
20.33 6 0.82 20.40 6 1.20 2 (11) 2 (11)
10.33 6 1.45 20.28 6 1.49 11 (41) 7 (26)
POAG 5 primary open-angle glaucoma; VF 5 visual field.
VISUAL FIELD CHANGES AND HAND VIBRATION
Fig. 2. Ocular diagnosis, topical b-blocker use, and visual field response after hand vibration. The percentage of beta-blocker use in each diagnostic category is shown by the bar graph with the scale on the left axis. The visual field sensitivity changes in the arcuate and paracentral zones are shown by the line graphs and the scale on the right axis.
after a hand vibration stimulus.4,22–24 Although the mechanism is unclear, there is evidence that hand vibration causes a local1,2,42 and systemic9,25,34 sympathetic vasoconstrictive response through the stimulation of Pacinian corpuscles in the skin.25 The vasculature of the eye may be affected by this systemic response. The duration of the response is unclear, and the response is probably maximal within the first 5 minutes after hand vibration. Direct quantification of vasospasm in the retinal and choroidal microvasculature supplying the nerve fiber layer and the optic nerve head is currently not possible. The resistive index calculated from ocular Doppler ultrasound,19,21,31 laser Doppler flow velocimetry,18,32 and measurement of blue field entoptic phenomenon16 are indicators of blood velocity in the ocular vasculature. Pulsatile ocular blood flow3,35,37 is an approximation of blood volume in the choroiTABLE 6
Effects of Age Age (y) , 55 (N 5 26) Paracentral zone VF sensitivity change (dB) 20.496 1.24 Arcuate zone VF sensitivity change (dB) 20.69 6 1.31 Mean HS 1.64 6 1.01 VF 5 visual field; HS, Hettinger score.
$ 55 (N 5 49) 20.11 6 1.46 20.27 6 1.22 1.56 6 1.02
S83
dal circulation. These measurements are, at best, approximations of vascular reactivity or blood flow in the eye. Indirectly, we can observe the effects of reduction of perfusion and relative ischemia through a reduction of visual function in visual field testing. As the time course of the reactive vasospasm is short, we have limited the visual field test to approximately 2 minutes in duration. Longer testing durations are more likely to record visual field sensitivities during the recovery phase reflected by rising hand temperatures beyond baseline, indicating reactive hyperemia. If reactive hyperemia occurs in the ocular microvasculature after a period of ischemia, visual field sensitivities recorded several minutes after hand vibration may reflect increased perfusion of the eye. We have chosen the MAP to perform threshold visual field testing because it offers several advantages. Customized testing strategies are easy to program on the MAP. The “staircasing” procedure of the MAP threshold programs uses 6-dB increases or decreases in stimulus intensities to achieve initial reversal and 3-dB steps to define the threshold. Other perimeters employ a 4-dB/2-dB strategy that may be slower and increase the duration of an eight-point test. Previous studies have demonstrated reliable detection of visual field defects by the MAP when compared with the full threshold strategy on the Humphrey Field Analyzer, with shorter test durations.39 In this study, there was a significant reduction in the mean visual field sensitivity after a hand vibration stimulus in the arcuate zone, suggestive of an ocular vasospastic response. Other studies have demonstrated a similar response after a cold hand stimulus to induce vasospasm.28 A smaller mean reduction was observed in the paracentral zone, but this was not statistically significant. This difference in ocular vasospastic response to the hand vibration stimulus may reflect a greater tendency in some individuals to develop ischemia in the arcuate zone and may contribute to the classic patterns of glaucomatous visual field loss. However, the significant, although weak, correlation between visual field sensitivity changes in the arcuate and paracentral zones suggests that there may be relative ischemia in both zones. With topical b-blockers there was attenuation of this reduction in visual field sensitivity. Topical b-blockers may be protective against this ocular vasospastic response. After hand vibration, subjects taking topical b-blockers had significantly less visual field sensitivity loss in the arcuate zone. This may reflect a local reduction in the systemic sympathetic response to hand vibration by the topical b-blockers. The protective effect was more significant with the b1-selective blocker, betaxolol, than with the nonselective topical b-blocker, timolol, and may explain
S84
Surv Ophthalmol 43 (Suppl 1) June 1999
CHAI ET AL TABLE 7
Multiple Linear Regression Analysis for Factors Influencing Arcuate Zone Visual Field Sensitivities Hand vibration Age Timolol Betaxolol BBS CCB Normal Suspect POAG
b
SE
95% Confidence Interval
P.|t|
20.926 20.015 0.657 0.979 20.143 20.218 20.297 0.236 0.136
0.323 0.009 0.326 0.418 0.550 0.454 0.286 0.333 0.388
21.568 to 20.284 20.033 to 0.002 0.010 to 1.304 0.149 to 1.809 21.236 to 0.949 21.119 to 0.683 20.866 to 0.271 20.426 to 0.897 20.634 to 0.906
0.005 0.085 0.047 0.021 0.795 0.632 0.302 0.481 0.727
SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers; POAG 5 primary open-angle glaucoma. The b coefficients, standard error, 95% confidence interval, and P values for the b coefficients are from the final multiple linear regression model for predicting Hettinger score. R2 for model 5 20%.
the apparently better preservation of visual function on visual field testing with betaxolol than timolol despite poorer intraocular pressure control.6,26,27 This finding may be related to the nonselective blockade of vascular b2-receptors responsible for vascular wall relaxation by nonselective b-blockers17,29 and/or to betaxolol’s calcium channel blocking properties.43 The trend in the paracentral zone was identical to the findings in the arcuate zone, but the differences were too small to be statistically significant in the sample size tested. The protective effect of topical beta-blockers is further illustrated in the visual field sensitivity changes in different diagnostic categories. Subjects with primary open-angle glaucoma had the lowest reductions in visual field sensitivity after hand vibration and the highest percentage of topical betablocker usage. Conversely, the control group had no subjects instilling topical b-blockers but the greatest reduction in visual field sensitivity. Glaucoma suspects were intermediate in their responses and level of b-blocker usage. As the distribution of topical b-blocker usage was significantly different among the
different diagnostic categories, these observations probably reflect the effects of pharmacologic b-blockade and the proportion of subjects within each diagnostic category taking topical b-blockers. Other demographic variables may also affect ocular vasospastic tendency in response to hand vibration. Subjects less than 55 years of age exhibited a greater mean reduction in visual field sensitivity in the arcuate and paracentral zones than subjects 55 years of age or older. This finding was of borderline significance and may reflect a higher prevalence and degree of degenerative vascular conditions in the older population that may reduce the compliance and reactivity of ocular blood vessels. In our previous study, we found a similar pattern in the vasospastic response of peripheral blood vessels in response to hand vibration.15 Thus, the younger population may be more susceptible to vasospasm and chronic or intermittent ocular ischemia, which may contribute to subsequent nerve fiber loss. The HS reflects vasospasm of the vessels in the hand and is indicative of systemic vasospasm, whereas changes in the visual field sensitivity possi-
TABLE 8
Multiple Linear Regression Analysis for Factors Influencing Paracentral Zone Visual Field Sensitivities Hand vibration Age Timolol Betaxolol BBS CCB Normal Suspect POAG
b
SE
95% Confidence Interval
P.|t|
1.377 0.005 0.189 0.897 20.882 0.328 22.001 21.733 21.087
1.460 0.010 0.264 0.341 0.696 0.408 1.502 1.458 1.469
21.523 to 4.277 20.014 to 0.024 20.335 to 0.713 0.220 to 1.574 22.265 to 0.501 20.483 to 1.139 24.984 to 0.982 24.437 to 1.354 24.005 to 1.831
0.348 0.603 0.475 0.010 0.209 0.424 0.186 0.293 0.461
SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers; POAG 5 primary open-angle glaucoma. The b coefficients, standard error, 95% confidence interval, and P values for the b coefficients are from the final multiple linear regression model for predicting Hettinger scores. R2 for model 5 24%.
S85
VISUAL FIELD CHANGES AND HAND VIBRATION
and “beta-blocker,” and “Hettinger.” Several articles that were not found by our MEDLINE search were taken from the references of other articles. Physiology, pharmacology, and ophthalmology texts were consulted. All available articles and abstracts were reviewed. The Medmont M600W manual and Medmont Australia were consulted regarding technical data for the M600W and comparative trials. Articles written by Hettinger were translated from German to English. English abstracts from articles not written in English were used where a translated version was not available. Fig. 3. Relationship between changes in visual field (VF) sensitivity in the paracentral and arcuate zones (r 5 0.29, P 5 0.003).
bly reflect ischemia of the ocular nervous tissues. The relationship between systemic and ocular vasospasm is unclear and may contribute to the poor correlation between mean HS and changes in visual field sensitivities after hand vibration. Variability in systemic beta-receptor binding between betaxolol and timolol,40 and between individuals, makes it difficult to determine the magnitude of the systemic effects of the topical medications. This factor further confounds any comparison of ocular and systemic vasospasm.
Conclusion Long-term, intermittent ocular vasospasm and resultant ocular ischemia may contribute to optic nerve damage in glaucoma. The measurement of changes in visual field sensitivities after a hand vibration stimulus with 2-minute visual field tests before and after the hand vibration stimulus may be useful in identifying patients with a susceptibility to ocular vasospasm. If patients with an ocular vasospastic tendency can be identified, this trait may be able to be modified pharmacologically. That visual field sensitivities are significantly reduced in the arcuate zones after a hand vibration stimulus indicates intraocular neural ischemia and reduction of visual function. Subjects instilling topical b-blockers demonstrated smaller reductions in visual field sensitivity, and these agents may be protective against intermittent ocular vasospasm. The b1-selective blocker, betaxolol, may provide greater protection than the nonselective beta-blocker, timolol.
Method of Literature Search The MEDLINE database (1966–1998) was employed with the key words “hand vibration,” “ocular vasospasm,” “vasospasm” and “hand,” “vasospasm”
References 1. Azuma T, Ohhashi T, Sakaguchi M: Vibration-induced hyperresponsiveness of arterial smooth muscle to noradrenaline with special reference to Raynaud’s phenomenon in vibration disease. Cardiovasc Res 12:758–764, 1978 2. Azuma T, Ohhashi T, Sakaguchi M: An approach to the pathogenesis of “white finger” induced by vibratory stimulation: acute but sustained changes in vascular responsiveness of canine hindlimb to noradrenaline. Cardiovasc Res 14: 725–730, 1980 3. Boles Carenini AB, Sibour G, Boles Carenini B: Differences in longterm effect of timolol and betaxolol on the pulsatile ocular blood flow. Surv Ophthalmol 38:S118–S124, 1994 4. Brown DA, Coyle IR, Beaumont PK: The automated Hettinger test in the diagnosis and prevention of repetition strain injuries. Appl Ergonomics 16:113–118, 1985 5. Carter CJ, Brooks DE, Doyle L, Drance SM: Investigations into a vascular etiology for low-tension glaucoma. Ophthalmology 97:49–55, 1990 6. Collignon-Brach J: Longterm effect of topical beta-blockers on intraocular pressure and visual field sensitivity in ocular hypertension and chronic open-angle glaucoma. Surv Ophthalmol 38:S149–S155, 1994 7. Drance SM: Glaucoma—changing concepts: Bowman Lecture. Eye 6:337–345, 1992 8. Drance SM, Douglas GR, Wijsman K, Schulzer M, Britton RJ: Response of blood flow to warm and cold in normal and lowtension glaucoma patients. Am J Ophthalmol 105:35–39, 1988 9. Farkilla M, Pyykko I: Blood flow in the contralateral hand during vibration and hand grip contractions of lumberjacks. Scand J Work Environ Health 5:368–374, 1979 10. Flammer J: The vascular concept of glaucoma. Surv Ophthalmol 38:S3–S6, 1994 11. Gasser P: Ocular vasospasm: A risk factor in the pathogenesis of low tension glaucoma. Int Ophthalmol 13:281–290, 1989 12. Gasser P, Flammer J: Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol 111:585–588, 1991 13. Gasser P, Flammer J: Influence of vasospasm on visual function. Doc Ophthalmol 66:3–18, 1987 14. Gasser P, Flammer J, Guthauser U, Mahler F: Do vasospasms provoke ocular diseases? Angiology 41:213–220, 1990 15. Goldberg I, Chai E, Chia A, Benscher C, Bauman A, Chen J: The Hettinger hand vibration test, vasospasm and glaucoma. Surv Ophthalmol 43(Suppl 1):S66–S78, 1999 16. Grunwald JE, Riva CE, Stone RA, Keates EU, Petrig BL: Retinal autoregulation in open-angle glaucoma. Ophthalmology 91:1690–1694, 1984 17. Guyton AC: The autonomic nervous system: the adrenal medulla, in Guyton AC (ed): Textbook of Medical Physiology. Philadelphia, WB Saunders, 1986, pp 686–697 18. Hamard P, Hamard H, DuFaux J: Blood flow rate in the microvasculature of the optic nerve head in primary open angle glaucoma: A new approach. Surv Ophthalmol 38:S87– S94, 1994 19. Harris A, Sergott RC, Spaeth GL, Katz JL, Shoemaker JA,
S86
20. 21. 22. 23.
24.
25. 26. 27. 28. 29. 30.
31.
32.
Surv Ophthalmol 43 (Suppl 1) June 1999 Martin BJ: Color Doppler analysis of ocular blood velocity in normal-tension glaucoma. Am J Ophthalmol 118:642–649, 1994 Hayreh SS, Piegers DJ, Heistud DD: Serotonin-induced constriction of ocular arteries in atherosclerotic monkeys. Arch Ophthalmol 115:220–228, 1997 Hesse RJ: Color Doppler ultrasound measurement of betablocker response in normal tension glaucoma. Neuroophthalmol 15:259–263, 1995 Hettinger T: A test for recognition of disposition to inflammations of the tendon sheaths. Int Z Angew Physiol Einschl Arbeitsphysiol 16:472–479, 1957 Hettinger T: Eine Modifikation des Hauttemperaturtestes zur Erkennung der Disposition zu Sehnenscheidenentzundungen. Int Z Angew Physiol Einschl Arbeitsphysiol 17:271– 275, 1958 Hettinger T, Beck W: The reaction capacity of the peripheral vessels as a dispositional factor of the occurrence of diseases of the joints. Int Z Angew Physiol Einschl Arbeitsphysiol 16:250–264, 1956 Hyvarinen J, Pyykko I: Vibration frequencies and amplitudes in the aetiology of traumatic vasospastic disease. Lancet 1: 791–794, 1973 Kaiser HJ, Flammer J, Messmer C, et al: Thirty-month visual field follow-up of glaucoma patients treated with beta-blockers. J Glaucoma 1:153–155, 1992 Kaiser JH, Flammer J, Stumpfig D, Hendrickson P: Longterm visual field follow-up of glaucoma patients treated with beta-blockers. Surv Ophthalmol 38:S156–S159, 1994 Kitazawa Y, Shirai H, Go FU: The effect of Ca21-antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 227:408–412, 1989 Martin XD, Rabineau PA: Vasoconstrictive effects of topical timolol on human retinal arteries. Graefes Arch Clin Exp Ophthalmol 227:526–530, 1989 Meyer P, Flammer J, Luscher TF: Endothelium-dependent regulation of the ophthalmic microcirculation in the perfused porcine eye: role of nitric oxide and endothelins. Invest Ophthalmol Vis Sci 34:3614–3621, 1993 Michelson G, Groh MJM, Groh MEM, Gründler A: Advanced primary open-angle glaucoma is associated with decreased ophthalmic artery blood flow velocity. Ger J Ophthalmol 4:21–24, 1995 Michelson G, Scmaub B, Langhans MJ, et al: Principle, valid-
CHAI ET AL
33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.
ity, and reliability of scanning laser Doppler flowmetry. J Glaucoma 5:99–105, 1996 Nordmann J, Roncin J, Denis P, et al: Contrast sensitivity as an early indicator of acute mountain sickness. Am J Ophthalmol 111:651–653, 1991 Olsen N, Petring OU: Vibration elicited vasoconstrictor reflex in Raynaud’s phenomenon. Br J Industr Med 45:415– 419, 1988 Ravalico G, Pastori G, Toffoli G, Crocé M: Visual and blood flow responses in low-tension glaucoma. Surv Ophthalmol 38:S173–S176, 1994 Schroter G: Zur Eingung des Hettinger-testes dur die Erkennung der Disposition zu Uberlastungsschaden. Int Arch Gewerbepathol Gewerbehyg 23:99–105, 1967 Trew DR, Smith SE: Postural studies in pulsatile ocular blood flow: II. Chronic open angle glaucoma. Br J Ophthalmol 75:71–75, 1991 Usui T, Iwata K: Finger blood flow in patients with low tension glaucoma and primary open-angle glaucoma. Br J Ophthalmol 76:2–4, 1992 Vingrys AJ, Helfrich KA: The Opticom M-600™: A new LED automated perimeter. Clin Exp Optom 73:3–17, 1990 Vuori ML, Ali-Melkkilä T, Kaila T, et al: b1- and b2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation. Acta Ophthalmol 71:682–685, 1993 Welch R: The measurement of physiological predisposition to tenosynovitis. Ergonomics 16:665–668, 1973 Welsh CL: The effect of vibration on digital blood flow. Br J Surg 67:708–710, 1980 Yu DY, Su EN, Crinjle SJ, et al: Systemic and ocular vascular roles of the antiglaucomoa agents b-adrenergic antagonists and calcium entry blockers. Surv Ophthalmol 43(Suppl 1): S219–S222, 1999
We thank David Brown for his invaluable assistance with the operation and maintenance of the equipment. This study was supported by research grants from Eye Associates, Sydney, Australia and Alcon Australia. The authors did not indicate any proprietary or commercial interest in any product or concept discussed in this article. Reprint address: Ivan Goldberg, MB BS, FRACO, FRACS, Park House, Floor 4, Suite 2, 187 Macquarie St., Sydney, NSW, Australia 2000.
Visual Field Responses to a Hand Vibration Stimulus ERIC CHAI, MB BS, IVAN GOLDBERG, MB BS, FRACO, FRACS, AUDREY CHIA, MB BS, AND JACK CHEN, MB BS
Sydney and Sydney Eye Hospitals, Sydney, NSW, Australia Abstract. Two short visual field tests were performed on 106 subjects approximately 5 minutes apart with or without a hand vibration stimulus between the field tests. There were 31 eyes in the control group (10 without glaucoma, eight glaucoma suspects, 10 with primary open-angle glaucoma, and three with secondary open-angle glaucoma). There were 75 eyes in the hand vibration group (16 without glaucoma, 20 glaucoma suspects, 25 with primary open-angle glaucoma, eight with secondary open-angle glaucoma, three with normal-tension glaucoma, and three with other forms of glaucoma). Average visual field sensitivities were significantly reduced in the arcuate zones after a hand vibration stimulus (20.42 dB; SD, 1.26 dB) when compared with sensitivities in the arcuate zones in subjects without the hand vibration stimulus (10.38 dB; SD, 1.53 dB; P 5 0.01). Multivariate analysis demonstrated a significant reduction in this response in the arcuate zone associated with use of betaxolol (P 5 0.021) and timolol (P 5 0.047). Betaxolol was associated with significantly smaller reductions in visual field sensitivities in the paracentral zone (P 5 0.01). Reductions in visual field sensitivities that may be related to ocular vasospasm occurred after a hand vibration stimulus. This response may be able to be modified pharmacologically with topical b-blockers, particularly betaxolol. (Surv Ophthalmol 43 [Suppl. 1]:S79– S86, 1999. © 1999 by Elsevier Science Inc. All rights reserved.) Key words. b-blockers • glaucoma • ocular vasospasm • visual field
spasm.28 Transient ischemia of the optic nerve fibers caused by the vasospastic response of the microvasculature supplying the optic nerve may account for this finding. Similarly, reductions in visual field sensitivity have been demonstrated at high altitudes, where there is a lower oxygen tension.33 Hand vibration may induce a sympathetic autonomic system release of catecholamines, resulting in a systemic vasospastic response.25,34 Previously, we have used the Hettinger hand vibration test (HHVT) to identify a subgroup with a high systemic vasospastic tendency.15 In this study, we investigated the effects of a hand vibration stimulus and ocular vasospasm on the function of the optic nerve fibers, as measured by visual field sensitivities before and after the hand vibration stimulus.
Visual destruction from glaucoma may result at least partially from ischemic damage to the optic nerve fibers.5,7,10 This may be from a disturbance of autoregulation of the microcirculation in and/or around the optic nerve head.5,10,13 Vasospasm in the ocular microvasculature may result from normal or abnormal physiologic systemic factors, such as surges in circulating catecholamines11 or other endogenous substances.20,30 A subgroup of the population may have a higher tendency for ocular and/or systemic vasospasm that may, in combination with other factors, including ocular hypertension, genetic susceptibility, and structural abnormalities of the cribiform plate, predispose them to glaucoma. If this group can be identified, this trait may be able to be inhibited pharmacologically, thereby assisting in preventing progression of glaucoma. Gasser and Flammer,12 Drance et al,8 and Usui and Iwata38 found that a cold hand stimulus provoked greater and more prolonged nailbed capillary vasospasm in some patients with glaucoma. This systemic stimulus was also found to provoke reductions in visual field sensitivities, suggesting ocular vaso-
Methods Subjects were selected from the patient pool attending our clinic. Inclusion criteria included visual acuity of 6/9 or better in the tested eye and patient age between 15 and 85 years. The eye with better visual acuity was selected for testing. If both eyes had S79
© 1999 by Elsevier Science Inc. All rights reserved.
0039-6257/99/$19.00 PII S0039-6257(99)00051-X
S80
Surv Ophthalmol 43 (Suppl 1) June 1999
equal visual acuity, the test eye was chosen randomly. Exclusion criteria included failure to comply with pretest instructions (Table 1), poor reliability during visual field testing, and failure of hand temperatures to stabilize.4,41 Informed consent was obtained before testing. A brief medical history from each subject included questions regarding concurrent systemic medical and ocular conditions, and systemic and/or topical medications. Compliance with pretest instructions was ascertained. Two visual field tests were performed on each subject. Subjects in the hand vibration group underwent a visual field test, the HHVT after stabilization of hand temperatures, and a second visual field test immediately after the hand vibration. The minimum time between field tests in the hand vibration group was 5 minutes. Subjects in the control group had two visual field tests with a 5-minute break between the tests. Average changes in visual field sensitivities between the two tests were calculated for each subject. Static perimetry was carried out with the Medmont M600 automated perimeter (MAP). The MAP uses a pale green (565 nm) rear projection light-emitting diode as the stimulus, with a size of 0.438 (Goldmann size III) and exposure duration of 200 ms. The stimulus is presented within a 350-mm-radius hemispherical bowl with a background illumination of 10 apostilbs. All tests were conducted in a completely darkened environment. A specially programmed threshold eight test-point strategy was used. Four points, 68 from fixation (paracentral zone) and four points, 158 from fixation (arcuate zone) were tested in addition to four calibration points and the blind spot (Fig. 1). Test durations ranged from 1.5 to 2.5 minutes. The HHVT has been described previously.4,22,23,36,41 In summary, the subjects grasped a 65-mm-diameter knob that vibrated at a frequency of 50 Hz with a vertical amplitude of 2 mm for 30 seconds. After vibration, with the hand resting on the knob, the temperature of the skin on the dorsum of the hand was recorded at 30 seconds, 1 minute, and then every minute for a total of 5 minutes. The Hettinger score
CHAI ET AL
(HS) was derived from hand temperatures recorded after vibration with the following formula: ( 1 + Tmin ) t HS = ------------------------------ × 1 + --- ( 1 + Tmax ) 4 where Tmin 5 difference between the baseline temperature and the lowest temperature recorded below baseline in degrees Celsius; Tmax 5 difference between the highest temperature recorded above baseline and the baseline temperature in degrees Celsius; and t 5 time taken in minutes for the hand temperature to return to baseline after an initial fall. If the temperature did not fall, t 5 0. Demographic variables of the control and hand vibration groups were compared with the chi-square test or t-test to determine any significant differences between the two groups. The change in mean visual field sensitivities in the paracentral and arcuate zones were compared with the Mann-Whitney U test, as the data were not distributed normally and there was inequality of variances. Mean HSs were compared with the Mann-Whitney U test. A multiple linear regression model was used to explore the relationship between the paracentral and arcuate zone sensitivities and a group of predicting variables. Hand vibration, diagnostic categories, age, migraine, and medications were used as predicting variables. The forced-entry method was used to control simultaneously for all these variables in the model. Only the main effects of the predicting vari-
TABLE 1
Pretest Instructions For 2 hours before testing: • No hand washing, bathing, or showering • Avoid cigarette smoking For 12 hours before testing: • Avoid coffee, tea, and other beverages containing caffeine. • Avoid alcohol • Avoid heavy exercise
Fig. 1. Visual field test showing points tested in the left eye. BS 5 blind spot (158 eccentricity); C 5 calibration points (108 eccentricity); p 5 paracentral zones (68 eccentricity); a 5 arcuate zones (158 eccentricity).
S81
VISUAL FIELD CHANGES AND HAND VIBRATION TABLE 2
Demographic Data Group Controls (N 5 31)
Hand Vibration (N 5 75)
P Value
Age (years) 61.4 6 16.8 59.2 6 15.4 0.51 Sex (no.) 0.66 Male 13 28 Female 18 47 Eye (no.) , 0.001 Right 9 59 Left 22 16 Topical b-blockers (no.) Timolol 8 21 0.85 Betaxolol 4 12 0.69 Systemic medications (no.) SBB 4 7 0.58 CCB 1 7 0.28 SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers.
ables were included in the model. Instead of a conventional ordinary least-square estimation method, the robust-variance method (Huber-White-Sandwich method) was used, as it can provide estimates that are robust against departure from the assumptions of normality and homogeneity of variance. Multicollinearity was examined with the variance-inflation factor and was not found to be a significant problem in the model.
Results The control group consisted of 31 eyes of 31 subjects: 10 without glaucoma, eight glaucoma suspects, 10 with primary open-angle glaucoma, and three with secondary open-angle glaucoma. The hand vibration group consisted of 75 eyes of 75 subjects: 16 without glaucoma, 20 glaucoma suspects, 25 with primary open-angle glaucoma, eight with secondary open-angle glaucoma, three with normal-tension glaucoma, two with congenital glaucoma, and one
with chronic angle-closure glaucoma. The control and hand vibration groups were not significantly different with regard to the distribution of diagnoses within the groups (P 5 0.64). The age, sex, and medications were not significantly different between the two groups (Table 2). The laterality of test eyes was significantly different, with a higher percentage of right eyes tested in the hand vibration group compared with the control group. Changes in average visual field sensitivities were compared between the control and hand vibration groups (Table 3). These were significantly reduced in the arcuate zone after a hand vibration stimulus (20.42 dB; SD, 1.26 dB) when compared with sensitivities in the arcuate zone in subjects without the hand vibration stimulus (10.38 dB; SD, 1.53; P 5 0.01). There was a reduction in average visual field sensitivities in the paracentral zone after hand vibration (20.24 dB; SD, 1.39 dB) when compared with the control group (20.06 dB; SD, 1.05 dB), but this difference was not statistically significant (P 5 0.49). Subjects in the hand vibration group who were not taking systemic medications were considered in three groups: subjects using no topical b-blockers and patients using either timolol or betaxolol (Table 4). When compared with subjects not using topical b-blockers (20.81 dB; SD, 1.10 dB), the timolol group (20.09 dB; SD, 1.22 dB) was found to have smaller reductions in visual field sensitivity whereas the betaxolol group (10.52 dB; SD, 1.34 dB) demonstrated increased visual field sensitivities in the arcuate zone. In the paracentral zone, the betaxolol group (10.56 dB; SD, 1.07 dB) had increased visual field sensitivities compared with the timolol group (20.33 dB; SD, 1.34 dB) and with the no-medication group (20.43 dB; SD, 1.26 dB), both of which experienced reductions in visual field sensitivity after hand vibration. The mean HS of the no-medication group was 1.66 (SD, 1.11). Subjects taking timolol had a higher mean HS (1.73; SD, 0.95) and the betaxolol group had a lower means HS (1.41; SD, 0.95). These differences were not statistically significant (P 5 0.71).
TABLE 3
Visual Field Findings in Controls Versus Hand Vibration Group Group
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) VF 5 visual field. *Derived from Mann-Whitney U test.
Controls (N 5 31)
Hand Vibration (N 5 75)
P Value*
20.06 6 1.05 10.38 6 1.53
20.24 6 1.39 20.42 6 1.26
0.49 0.01
S82
Surv Ophthalmol 43 (Suppl 1) June 1999
CHAI ET AL TABLE 4
Effects of Topical b-Blockers
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) Mean HS
Betaxolol (N 5 12)
Timolol (N 5 16)
No Topical b-Blockers (N 5 35)
10.56 6 1.07 10.52 6 1.34 1.41 6 0.95
20.33 6 1.34 20.09 6 1.22 1.73 6 0.95
20.43 6 1.26 20.81 6 1.10 1.66 6 1.11
VF 5 visual field; HS 5 Hettinger score.
Changes in visual field sensitivities after hand vibration varied with different ocular diagnoses (Table 5). In general, subjects with primary open-angle glaucoma had smaller mean reductions in visual field sensitivities after hand vibration than the control group. Glaucoma suspects had reductions in sensitivities intermediate between those of the control and primary open-angle glaucoma groups. The proportion of subjects in each of these diagnostic categories taking topical beta-blockers was highest in the primary open-angle glaucoma group, with 67% of the group instilling a b-blocker (timolol, 41%; betaxolol, 26%) (Fig. 2). No patients in the normal group and 22% of the suspect group were taking topical betablockers (timolol, 11%; betaxolol, 11%). The differences in distribution of beta-blockers among the disease categories were statistically significant (P , 0.001). Patient numbers in other diagnostic categories were too small for meaningful analysis. The mean reductions in visual field sensitivities in the hand vibration group were found to be greater in subjects less than 55 years of age in both the paracentral and arcuate zone (Table 6). Subjects less than 55 years of age had a mean reduction in visual field sensitivities of 20.49 dB (SD, 1.24 dB) and 20.69 dB (SD, 1.31 dB) in the paracentral and arcuate zones, respectively, compared with 20.11 dB (SD, 1.46 dB) and 20.27 dB (SD, 1.22 dB) in subjects aged 55 years and over. Mean HS was slightly higher in the group less than 55 years of age (1.64; SD, 1.01) in comparison with subjects aged 55 years or more (1.56; SD, 1.02), but this too was not statistically significant.
With multiple linear regression analysis, three factors were found to influence significantly the change in sensitivity in the arcuate zones (Table 7). Hand vibration was associated with significant reductions in arcuate visual field sensitivities (P 5 0.005). Betaxolol (P 5 0.021) and timolol (P 5 0.047) were associated with significant improvement or less reduction in arcuate visual field sensitivities. Younger age was of borderline significance as a factor associated with greater sensitivity loss in the arcuate zones (P 5 0.085). Systemic b-blockers, Ca21 channel antagonists, and diagnostic categories were found not to influence changes in visual field sensitivities significantly. In the paracentral zones (Table 8), betaxolol was the only factor that was associated with a significantly smaller reduction in visual field sensitivity (P 5 0.01). Hand vibration, timolol, systemic b-blockers, Ca21 channel antagonists, and diagnostic categories were not found to influence changes in paracentral visual field sensitivities significantly. There was a significant correlation between changes in visual field sensitivities in the arcuate and paracentral zones (r 5 0.29, P 5 0.003) (Fig. 3). Correlation between HS and changes in visual field sensitivities after hand vibration was poor in both the paracentral zone (r 5 0.14, P 5 0.13) and the arcuate zone (r 5 20.11, P 5 0.25).
Discussion Chronic ocular vasospasm may contribute to optic nerve destruction in glaucoma.5,7,10,11,14 A subpopulation with a high systemic vasospastic tendency may be identified with hand temperature measurements
TABLE 5
Effects of Diagnostic Categories Diagnostic Category
Paracentral zone VF sensitivity change (dB) Arcuate zone VF sensitivity change (dB) Number (%) of subjects taking timolol Number (%) of subjects taking betaxolol
Normal (N 5 13)
Glaucoma Suspects (N 5 18)
POAG (N 5 27)
20.92 6 1.37 20.81 6 0.99 0 (0) 0 (0)
20.33 6 0.82 20.40 6 1.20 2 (11) 2 (11)
10.33 6 1.45 20.28 6 1.49 11 (41) 7 (26)
POAG 5 primary open-angle glaucoma; VF 5 visual field.
VISUAL FIELD CHANGES AND HAND VIBRATION
Fig. 2. Ocular diagnosis, topical b-blocker use, and visual field response after hand vibration. The percentage of beta-blocker use in each diagnostic category is shown by the bar graph with the scale on the left axis. The visual field sensitivity changes in the arcuate and paracentral zones are shown by the line graphs and the scale on the right axis.
after a hand vibration stimulus.4,22–24 Although the mechanism is unclear, there is evidence that hand vibration causes a local1,2,42 and systemic9,25,34 sympathetic vasoconstrictive response through the stimulation of Pacinian corpuscles in the skin.25 The vasculature of the eye may be affected by this systemic response. The duration of the response is unclear, and the response is probably maximal within the first 5 minutes after hand vibration. Direct quantification of vasospasm in the retinal and choroidal microvasculature supplying the nerve fiber layer and the optic nerve head is currently not possible. The resistive index calculated from ocular Doppler ultrasound,19,21,31 laser Doppler flow velocimetry,18,32 and measurement of blue field entoptic phenomenon16 are indicators of blood velocity in the ocular vasculature. Pulsatile ocular blood flow3,35,37 is an approximation of blood volume in the choroiTABLE 6
Effects of Age Age (y) , 55 (N 5 26) Paracentral zone VF sensitivity change (dB) 20.496 1.24 Arcuate zone VF sensitivity change (dB) 20.69 6 1.31 Mean HS 1.64 6 1.01 VF 5 visual field; HS, Hettinger score.
$ 55 (N 5 49) 20.11 6 1.46 20.27 6 1.22 1.56 6 1.02
S83
dal circulation. These measurements are, at best, approximations of vascular reactivity or blood flow in the eye. Indirectly, we can observe the effects of reduction of perfusion and relative ischemia through a reduction of visual function in visual field testing. As the time course of the reactive vasospasm is short, we have limited the visual field test to approximately 2 minutes in duration. Longer testing durations are more likely to record visual field sensitivities during the recovery phase reflected by rising hand temperatures beyond baseline, indicating reactive hyperemia. If reactive hyperemia occurs in the ocular microvasculature after a period of ischemia, visual field sensitivities recorded several minutes after hand vibration may reflect increased perfusion of the eye. We have chosen the MAP to perform threshold visual field testing because it offers several advantages. Customized testing strategies are easy to program on the MAP. The “staircasing” procedure of the MAP threshold programs uses 6-dB increases or decreases in stimulus intensities to achieve initial reversal and 3-dB steps to define the threshold. Other perimeters employ a 4-dB/2-dB strategy that may be slower and increase the duration of an eight-point test. Previous studies have demonstrated reliable detection of visual field defects by the MAP when compared with the full threshold strategy on the Humphrey Field Analyzer, with shorter test durations.39 In this study, there was a significant reduction in the mean visual field sensitivity after a hand vibration stimulus in the arcuate zone, suggestive of an ocular vasospastic response. Other studies have demonstrated a similar response after a cold hand stimulus to induce vasospasm.28 A smaller mean reduction was observed in the paracentral zone, but this was not statistically significant. This difference in ocular vasospastic response to the hand vibration stimulus may reflect a greater tendency in some individuals to develop ischemia in the arcuate zone and may contribute to the classic patterns of glaucomatous visual field loss. However, the significant, although weak, correlation between visual field sensitivity changes in the arcuate and paracentral zones suggests that there may be relative ischemia in both zones. With topical b-blockers there was attenuation of this reduction in visual field sensitivity. Topical b-blockers may be protective against this ocular vasospastic response. After hand vibration, subjects taking topical b-blockers had significantly less visual field sensitivity loss in the arcuate zone. This may reflect a local reduction in the systemic sympathetic response to hand vibration by the topical b-blockers. The protective effect was more significant with the b1-selective blocker, betaxolol, than with the nonselective topical b-blocker, timolol, and may explain
S84
Surv Ophthalmol 43 (Suppl 1) June 1999
CHAI ET AL TABLE 7
Multiple Linear Regression Analysis for Factors Influencing Arcuate Zone Visual Field Sensitivities Hand vibration Age Timolol Betaxolol BBS CCB Normal Suspect POAG
b
SE
95% Confidence Interval
P.|t|
20.926 20.015 0.657 0.979 20.143 20.218 20.297 0.236 0.136
0.323 0.009 0.326 0.418 0.550 0.454 0.286 0.333 0.388
21.568 to 20.284 20.033 to 0.002 0.010 to 1.304 0.149 to 1.809 21.236 to 0.949 21.119 to 0.683 20.866 to 0.271 20.426 to 0.897 20.634 to 0.906
0.005 0.085 0.047 0.021 0.795 0.632 0.302 0.481 0.727
SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers; POAG 5 primary open-angle glaucoma. The b coefficients, standard error, 95% confidence interval, and P values for the b coefficients are from the final multiple linear regression model for predicting Hettinger score. R2 for model 5 20%.
the apparently better preservation of visual function on visual field testing with betaxolol than timolol despite poorer intraocular pressure control.6,26,27 This finding may be related to the nonselective blockade of vascular b2-receptors responsible for vascular wall relaxation by nonselective b-blockers17,29 and/or to betaxolol’s calcium channel blocking properties.43 The trend in the paracentral zone was identical to the findings in the arcuate zone, but the differences were too small to be statistically significant in the sample size tested. The protective effect of topical beta-blockers is further illustrated in the visual field sensitivity changes in different diagnostic categories. Subjects with primary open-angle glaucoma had the lowest reductions in visual field sensitivity after hand vibration and the highest percentage of topical betablocker usage. Conversely, the control group had no subjects instilling topical b-blockers but the greatest reduction in visual field sensitivity. Glaucoma suspects were intermediate in their responses and level of b-blocker usage. As the distribution of topical b-blocker usage was significantly different among the
different diagnostic categories, these observations probably reflect the effects of pharmacologic b-blockade and the proportion of subjects within each diagnostic category taking topical b-blockers. Other demographic variables may also affect ocular vasospastic tendency in response to hand vibration. Subjects less than 55 years of age exhibited a greater mean reduction in visual field sensitivity in the arcuate and paracentral zones than subjects 55 years of age or older. This finding was of borderline significance and may reflect a higher prevalence and degree of degenerative vascular conditions in the older population that may reduce the compliance and reactivity of ocular blood vessels. In our previous study, we found a similar pattern in the vasospastic response of peripheral blood vessels in response to hand vibration.15 Thus, the younger population may be more susceptible to vasospasm and chronic or intermittent ocular ischemia, which may contribute to subsequent nerve fiber loss. The HS reflects vasospasm of the vessels in the hand and is indicative of systemic vasospasm, whereas changes in the visual field sensitivity possi-
TABLE 8
Multiple Linear Regression Analysis for Factors Influencing Paracentral Zone Visual Field Sensitivities Hand vibration Age Timolol Betaxolol BBS CCB Normal Suspect POAG
b
SE
95% Confidence Interval
P.|t|
1.377 0.005 0.189 0.897 20.882 0.328 22.001 21.733 21.087
1.460 0.010 0.264 0.341 0.696 0.408 1.502 1.458 1.469
21.523 to 4.277 20.014 to 0.024 20.335 to 0.713 0.220 to 1.574 22.265 to 0.501 20.483 to 1.139 24.984 to 0.982 24.437 to 1.354 24.005 to 1.831
0.348 0.603 0.475 0.010 0.209 0.424 0.186 0.293 0.461
SBB 5 systemic b-blockers; CCB 5 Ca21 channel blockers; POAG 5 primary open-angle glaucoma. The b coefficients, standard error, 95% confidence interval, and P values for the b coefficients are from the final multiple linear regression model for predicting Hettinger scores. R2 for model 5 24%.
S85
VISUAL FIELD CHANGES AND HAND VIBRATION
and “beta-blocker,” and “Hettinger.” Several articles that were not found by our MEDLINE search were taken from the references of other articles. Physiology, pharmacology, and ophthalmology texts were consulted. All available articles and abstracts were reviewed. The Medmont M600W manual and Medmont Australia were consulted regarding technical data for the M600W and comparative trials. Articles written by Hettinger were translated from German to English. English abstracts from articles not written in English were used where a translated version was not available. Fig. 3. Relationship between changes in visual field (VF) sensitivity in the paracentral and arcuate zones (r 5 0.29, P 5 0.003).
bly reflect ischemia of the ocular nervous tissues. The relationship between systemic and ocular vasospasm is unclear and may contribute to the poor correlation between mean HS and changes in visual field sensitivities after hand vibration. Variability in systemic beta-receptor binding between betaxolol and timolol,40 and between individuals, makes it difficult to determine the magnitude of the systemic effects of the topical medications. This factor further confounds any comparison of ocular and systemic vasospasm.
Conclusion Long-term, intermittent ocular vasospasm and resultant ocular ischemia may contribute to optic nerve damage in glaucoma. The measurement of changes in visual field sensitivities after a hand vibration stimulus with 2-minute visual field tests before and after the hand vibration stimulus may be useful in identifying patients with a susceptibility to ocular vasospasm. If patients with an ocular vasospastic tendency can be identified, this trait may be able to be modified pharmacologically. That visual field sensitivities are significantly reduced in the arcuate zones after a hand vibration stimulus indicates intraocular neural ischemia and reduction of visual function. Subjects instilling topical b-blockers demonstrated smaller reductions in visual field sensitivity, and these agents may be protective against intermittent ocular vasospasm. The b1-selective blocker, betaxolol, may provide greater protection than the nonselective beta-blocker, timolol.
Method of Literature Search The MEDLINE database (1966–1998) was employed with the key words “hand vibration,” “ocular vasospasm,” “vasospasm” and “hand,” “vasospasm”
References 1. Azuma T, Ohhashi T, Sakaguchi M: Vibration-induced hyperresponsiveness of arterial smooth muscle to noradrenaline with special reference to Raynaud’s phenomenon in vibration disease. Cardiovasc Res 12:758–764, 1978 2. Azuma T, Ohhashi T, Sakaguchi M: An approach to the pathogenesis of “white finger” induced by vibratory stimulation: acute but sustained changes in vascular responsiveness of canine hindlimb to noradrenaline. Cardiovasc Res 14: 725–730, 1980 3. Boles Carenini AB, Sibour G, Boles Carenini B: Differences in longterm effect of timolol and betaxolol on the pulsatile ocular blood flow. Surv Ophthalmol 38:S118–S124, 1994 4. Brown DA, Coyle IR, Beaumont PK: The automated Hettinger test in the diagnosis and prevention of repetition strain injuries. Appl Ergonomics 16:113–118, 1985 5. Carter CJ, Brooks DE, Doyle L, Drance SM: Investigations into a vascular etiology for low-tension glaucoma. Ophthalmology 97:49–55, 1990 6. Collignon-Brach J: Longterm effect of topical beta-blockers on intraocular pressure and visual field sensitivity in ocular hypertension and chronic open-angle glaucoma. Surv Ophthalmol 38:S149–S155, 1994 7. Drance SM: Glaucoma—changing concepts: Bowman Lecture. Eye 6:337–345, 1992 8. Drance SM, Douglas GR, Wijsman K, Schulzer M, Britton RJ: Response of blood flow to warm and cold in normal and lowtension glaucoma patients. Am J Ophthalmol 105:35–39, 1988 9. Farkilla M, Pyykko I: Blood flow in the contralateral hand during vibration and hand grip contractions of lumberjacks. Scand J Work Environ Health 5:368–374, 1979 10. Flammer J: The vascular concept of glaucoma. Surv Ophthalmol 38:S3–S6, 1994 11. Gasser P: Ocular vasospasm: A risk factor in the pathogenesis of low tension glaucoma. Int Ophthalmol 13:281–290, 1989 12. Gasser P, Flammer J: Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol 111:585–588, 1991 13. Gasser P, Flammer J: Influence of vasospasm on visual function. Doc Ophthalmol 66:3–18, 1987 14. Gasser P, Flammer J, Guthauser U, Mahler F: Do vasospasms provoke ocular diseases? Angiology 41:213–220, 1990 15. Goldberg I, Chai E, Chia A, Benscher C, Bauman A, Chen J: The Hettinger hand vibration test, vasospasm and glaucoma. Surv Ophthalmol 43(Suppl 1):S66–S78, 1999 16. Grunwald JE, Riva CE, Stone RA, Keates EU, Petrig BL: Retinal autoregulation in open-angle glaucoma. Ophthalmology 91:1690–1694, 1984 17. Guyton AC: The autonomic nervous system: the adrenal medulla, in Guyton AC (ed): Textbook of Medical Physiology. Philadelphia, WB Saunders, 1986, pp 686–697 18. Hamard P, Hamard H, DuFaux J: Blood flow rate in the microvasculature of the optic nerve head in primary open angle glaucoma: A new approach. Surv Ophthalmol 38:S87– S94, 1994 19. Harris A, Sergott RC, Spaeth GL, Katz JL, Shoemaker JA,
S86
20. 21. 22. 23.
24.
25. 26. 27. 28. 29. 30.
31.
32.
Surv Ophthalmol 43 (Suppl 1) June 1999 Martin BJ: Color Doppler analysis of ocular blood velocity in normal-tension glaucoma. Am J Ophthalmol 118:642–649, 1994 Hayreh SS, Piegers DJ, Heistud DD: Serotonin-induced constriction of ocular arteries in atherosclerotic monkeys. Arch Ophthalmol 115:220–228, 1997 Hesse RJ: Color Doppler ultrasound measurement of betablocker response in normal tension glaucoma. Neuroophthalmol 15:259–263, 1995 Hettinger T: A test for recognition of disposition to inflammations of the tendon sheaths. Int Z Angew Physiol Einschl Arbeitsphysiol 16:472–479, 1957 Hettinger T: Eine Modifikation des Hauttemperaturtestes zur Erkennung der Disposition zu Sehnenscheidenentzundungen. Int Z Angew Physiol Einschl Arbeitsphysiol 17:271– 275, 1958 Hettinger T, Beck W: The reaction capacity of the peripheral vessels as a dispositional factor of the occurrence of diseases of the joints. Int Z Angew Physiol Einschl Arbeitsphysiol 16:250–264, 1956 Hyvarinen J, Pyykko I: Vibration frequencies and amplitudes in the aetiology of traumatic vasospastic disease. Lancet 1: 791–794, 1973 Kaiser HJ, Flammer J, Messmer C, et al: Thirty-month visual field follow-up of glaucoma patients treated with beta-blockers. J Glaucoma 1:153–155, 1992 Kaiser JH, Flammer J, Stumpfig D, Hendrickson P: Longterm visual field follow-up of glaucoma patients treated with beta-blockers. Surv Ophthalmol 38:S156–S159, 1994 Kitazawa Y, Shirai H, Go FU: The effect of Ca21-antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 227:408–412, 1989 Martin XD, Rabineau PA: Vasoconstrictive effects of topical timolol on human retinal arteries. Graefes Arch Clin Exp Ophthalmol 227:526–530, 1989 Meyer P, Flammer J, Luscher TF: Endothelium-dependent regulation of the ophthalmic microcirculation in the perfused porcine eye: role of nitric oxide and endothelins. Invest Ophthalmol Vis Sci 34:3614–3621, 1993 Michelson G, Groh MJM, Groh MEM, Gründler A: Advanced primary open-angle glaucoma is associated with decreased ophthalmic artery blood flow velocity. Ger J Ophthalmol 4:21–24, 1995 Michelson G, Scmaub B, Langhans MJ, et al: Principle, valid-
CHAI ET AL
33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.
ity, and reliability of scanning laser Doppler flowmetry. J Glaucoma 5:99–105, 1996 Nordmann J, Roncin J, Denis P, et al: Contrast sensitivity as an early indicator of acute mountain sickness. Am J Ophthalmol 111:651–653, 1991 Olsen N, Petring OU: Vibration elicited vasoconstrictor reflex in Raynaud’s phenomenon. Br J Industr Med 45:415– 419, 1988 Ravalico G, Pastori G, Toffoli G, Crocé M: Visual and blood flow responses in low-tension glaucoma. Surv Ophthalmol 38:S173–S176, 1994 Schroter G: Zur Eingung des Hettinger-testes dur die Erkennung der Disposition zu Uberlastungsschaden. Int Arch Gewerbepathol Gewerbehyg 23:99–105, 1967 Trew DR, Smith SE: Postural studies in pulsatile ocular blood flow: II. Chronic open angle glaucoma. Br J Ophthalmol 75:71–75, 1991 Usui T, Iwata K: Finger blood flow in patients with low tension glaucoma and primary open-angle glaucoma. Br J Ophthalmol 76:2–4, 1992 Vingrys AJ, Helfrich KA: The Opticom M-600™: A new LED automated perimeter. Clin Exp Optom 73:3–17, 1990 Vuori ML, Ali-Melkkilä T, Kaila T, et al: b1- and b2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation. Acta Ophthalmol 71:682–685, 1993 Welch R: The measurement of physiological predisposition to tenosynovitis. Ergonomics 16:665–668, 1973 Welsh CL: The effect of vibration on digital blood flow. Br J Surg 67:708–710, 1980 Yu DY, Su EN, Crinjle SJ, et al: Systemic and ocular vascular roles of the antiglaucomoa agents b-adrenergic antagonists and calcium entry blockers. Surv Ophthalmol 43(Suppl 1): S219–S222, 1999
We thank David Brown for his invaluable assistance with the operation and maintenance of the equipment. This study was supported by research grants from Eye Associates, Sydney, Australia and Alcon Australia. The authors did not indicate any proprietary or commercial interest in any product or concept discussed in this article. Reprint address: Ivan Goldberg, MB BS, FRACO, FRACS, Park House, Floor 4, Suite 2, 187 Macquarie St., Sydney, NSW, Australia 2000.