Flicker Sensitivity in Treated Ocular Hypertension

Flicker Sensitivity in Treated Ocular Hypertension MILAN E. TYTLA, PhD, GRAHAM E. TROPE, MD, PhD, J. RAYMOND BUNCIC, MD

Abstract: Reductions in flicker sensitivity in ocular hypertension are thought to precede manifest glaucomatous damage, but the proportion of patients with ocular hypertension reported to have losses in flicker sensitivity (50-90%) is far out of step with the proportion of ocular hypertensive patients in whom clinically defined glaucoma will develop (5-30%). The authors examined the possibility that the flicker losses in some of these patients represent not early glaucomatous damage, but instead a transient influence of raised intraocular pressure (lOP) on an otherwise normal eye. Temporal contrast sensitivity was measured in 26 patients with ocular hypertension and in 22 patients with primary open-angle glaucoma (POAG) before and after hypotensive treatment (timolol). Compared with normotensive controls, all POAG patients exhibited sensitivity losses before treatment which remained unchanged after treatment. The ocular hypertensive patients were divided into three groups, which may reflect differing risks of glaucoma conversion. Group I patients (8/26) had normal flicker sensitivity, and thus appear to be resistant to high lOP. Group II patients (9/26) showed initial losses which disappeared with lowered lOP. They probably have not yet suffered damage but appear to be sensitive to high lOP. Group III patients (9/26) had losses that persisted despite lowered lOPs. The similarity of their response to that of the POAGs suggests that group III patients have already suffered early glaucomatous damage. Ophthalmology 1990; 97:36-43

Primary open-angle glaucoma (POAG) is a principal cause of blindness worldwide. Unfortunately, signs permitting initial diagnosis indicate that irreparable neural damage and consequent permanent visual loss have already occurred. The typical patient with glaucoma has cupping of the optic disc and/or visual field loss, and has had abnormally high intraocular pressure (lOP). The patient with ocular hypertension, on the other hand, has raised lOP and is otherwise clinically normal and asymptomatic. Although glaucoma is intimately associated with high lOP, glaucomatous damage will ultimately develop in not more than 30% of untreated ocular hypertensive Originally received: June 19, 1989. Revision accepted: August 28, 1989. From the Department of Ophthalmology, University of Toronto, Toronto. Presented in part at the annual meetings of the Association for Research in Vision and Ophthalmology, Sarasota, May 1986, and the Canadian Ophthalmological Society, Vancouver, June 1986. Supported by M.R.C. Canada, The MacDonald Foundation, University of Toronto, and the Canadian National Institute for the Blind. Reprint requests to Milan E. Tytla, PhD, Department of Ophthalmology, Hospital for Sick Children, 555 UniverSity Ave, Toronto, Ontario, Canada M5G 1X8.

36

patients. I - 3 Therein lies the fundamental problem of managing ocular hypertension: namely, the detection of glaucoma-destined patients with ocular hypertension, in order to provide the earliest possible prophylactic treatment. Factors such as age, level of lOP, family history, diabetes, and other vascular diseases are associated with increased risk of glaucoma development in the ocular hypertensive population. But independently or taken together, these factors are unreliable predictors in the individual case. Because of this uncertainty, ocular hypertensive patients will either undergo unnecessary, potentially hazardous, life-long treatment, or if left untreated, glaucomatous damage may develop. By the time glaucomatous field loss is initially detected, up to 40% of retinal ganglion cells may have suffered irreversible damage. 4 Thus, well before this stage of the disease, slow and steady damage has occurred involving a large proportion of optic nerve fibers, which passes undetected by standard clinical tests of vision. Clearly, these tests do not require mediation by neurons afflicted in the early stage of the disease. One promising approach to the problem of early detection has involved the measurement of the psychophysical or electrophysiological response to flickering stimuli in patients with ocular hypertension and POAG.

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In psychophysical studies that have compared the flicker sensitivity of ocular hypertensive patients with normal controls, 50 to 90% of those with ocular hypertension were found to have losses which paralleled those exhibited by virtually all glaucoma patients.5- 9 (The interocular comparison of flicker sensitivities appears not to be a sensitive indicator of abnormality in ocular hypertension. 10) Usually, maximum loss occurs in the mid-frequency range, often sparing the lowest frequencies and the critical fusion frequency. Studies involving the response of cortically and retinally evoked potentials to flickering stimuli have yielded comparable detection rates among those with ocular hypertension. 7 ,1 1-13 Such a high proportion of these patients (50-90%) with glaucomatous losses in flicker sensitivity is interesting. Does it mean that the majority of people with ocular hypertension has early glaucoma as defined by tests of flicker sensitivity? If so, this figure far exceeds the most liberal estimate (30%) of glaucoma-destined ocular hypertensives as defined by the established criteria of visual field or optic disc abnormalities. Among normals, however, flicker sensitivity is inversely related to lOP within the normal range, 14 and the amplitude of the visually evoked potential when driven by coarse, flickering stimuli is dramatically attenuated in normals during artificially elevated IOp. 15 Thus, we examined the possibility that in some of the patients with this condition the loss does not represent permanent neuronal damage, but rather a temporary influence of high lOP on an otherwise healthy and perhaps resilient optic nerve head or retina. To this end, we measured the flicker sensitivity of a sample of patients with ocular hypertension before, during, and after hypotensive treatment and compared their results with untreated normal controls and with newly treated POAGs.

SUBJECTS AND METHODS The stimulus was a spatially homogeneous disc 50 in diameter viewed at 57 cm. It consisted of a white lightpipe (15 cm long X 5 cm diameter) with frosted glass covering one end, transilluminated by an array of 33 Hewlett-Packard (Palo Alto, CA) high-efficiency, lightemitting diodes (555 nanometers) at the other end. The disc's luminance could be sinusoidally modulated at rates from 5 to 100 Hz (well beyond the critical fusion frequency) by a custom-built amplifier driven by a function generator. Over that range, calibration with a Spectra Brightness Spot Meter (Burbank, CA) indicated that both contrast (maximum , 93%) and time-averaged luminance (70 cd/m2) were steady and independent of frequency . The disc was centered in an equiluminant surround (50 0 X 50 0 ) and the subject viewed its center, or one of two fixation marks which placed the disc 20 0 eccentric in the superior field lying along meridians 45 0 and 135 0 • The experimenter monitored the subject's eye throughout the experiment, and if fixation deviated from the current fixation point, the data were omitted and the trial was repeated. The untested eye was occluded with a white eye patch.

The critical fusion frequency was first measured in each eye for each of the three locations to establish the range of visible frequencies. With contrast at maximum, frequency was increased and then decreased to determine the points of just disappearance and just reappearance of the flicker. The mean of four such ascending-descending pairs of readings was taken as the critical fusion frequency. The contrast sensitivity (l/threshold) of each eye was measured with the descending method of limits. Starting with a randomly chosen frequency (less than the critical fusion frequency) and with central fixation, the contrast was smoothly reduced from just suprathreshold until the flicker just disappeared. The mean of four such readings constituted threshold. The starting contrast and the rate of its reduction were varied between trials to minimize anticipatory responses. This procedure was repeated with the remaining two field locations and continued until the frequency range (5 Hz to critical fusion frequency) was exhausted. Measures were taken at frequencies of 5, 10, 20, 30, 40, and 50 Hz unless the patient's critical fusion frequency shortened the range. At least ten practice trials preceded data collection. Twenty-six normotensive individuals with no history of ophthalmologic problems constituted the control sample. They ranged in age from 26 to 68 years. Fourteen of these were tested twice, 4 weeks apart in order to assess the extent of test-retest practice. Twenty-six patients, 28 to 61 years of age with lOPs greater than 21 mmHg had no sign of disc cupping (cup-to-disc ratio ~ 0.3), no repeatable visual field loss (Humphrey Visual Field Analyzer, central-30 and central-60) and corrected monocular visual acuities of 6/6 or better formed the ocular hypertension patient sample. Twenty-two of these patients had bilateral ocular hypertension, three had one normotensive eye, and one had early POAG in the fellow eye. Twentytwo patients 39 to 62 years of age participated in the POAG group. Each had lOPs greater than 21 mmHg, cup-to-disc ratios of at least 0.6, and repeatable visual field loss in both eyes. Their visual acuities ranged from 6/5 to 6/15. The cup-to-disc ratios represent a subjective assessment combining both vertical and horizontal axes. The ocular hypertensive patients and POAGs had not been treated previously, and were tested immediately before and on several occasions after the start of treatment with timolol (0.5 % 12 hourly). Informed consent was obtained from each patient, and the hypotensive treatment was part of the treatment protocol.

RESULTS Figure I A illustrates the mean flicker sensitivity of the right eyes of the 26 normal controls on the first occasion of measurement. Consistent with previous reports,6,16,17 the normal central field had higher sensitivity at all but the highest frequencies, but had a lower critical fusion frequency (46.9 Hz) than the nasal (56.0 Hz) and temporal (54.2 Hz) sites. The two peripheral loci did not differ significantly in sensitivity. The test-retest results for 14 of these controls are depicted in Figure I B only for the central 37

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location for the sake of clarity. At all three test sites, mean sensitivity was consistently but insignificantly higher on the second test (central: P> 0.18; nasal: P> 0.24; temporal: P > 0.22). Thus, this amount of practice had a trivial influence on sensitivity. The manner of data presentation is shown in Figure 2. In the upper panels, the pretreatment results of a representative POAG eye are plotted along with the normal mean and ±2.8 standard deviation. At almost all frequencies, the patient's sensitivity is below normal, but especially in the range of 20 to 30 Hz. This loss is quantified in the lower panels, where relative sensitivity (log [patient sensitivity ..;- normal sensitivity]) is plotted against frequency for each site. Ordinate values of zero represent equality with the normal mean, negative values indicate sensitivity loss, and values lying below the lower dashed line (-0.35) fall outside the lower 2.8 standard deviation of the normal distribution averaged across frequency. With this criterion of abnormality, only 1 %of normals will be classified as abnormal. It can be seen that the sensitivity of this POAG eye falls significantly below the normal mean in the mid-frequency range for all three test sites with maximum loss occuning at 20 to 30 Hz centrally and 30 Hz peripherally. Typical of most POAGs, the temporal field showed the greatest loss, followed by the nasal then the central field. Notice also that at 30 Hz this patient's sensitivity in the temporal field was nearly ten times below the normal mean, whereas his critical fusion frequency (52 Hz) was within normal bounds. This general pattern of pretreatment sensitivity loss was exhibited by each eye of the 22 POAG patients and essentially confirms Tyler's6 finding. Four weeks after the start of hypotensive treatment, not one eye of a single POAG patient showed a significant departure from pretreatment levels ofloss despite sometimes large reductions in lOP. Figure 3 gives two examples for the eye with the greater lOP and greater loss of two patients with POAG. Patient 1, 62 years of age, had initial lOPs of 38 mmHg in the right eye and 30 in the left, a cup-to-disc ratio of 0.8, and Bjerrum-area scotomas in both eyes. Patient 2, 35 years of age, had early POAG with initial lOPs of 23 mmHg in the right eye and 22 mmHg in the left, cup-todisc ratios of 0.6 in the right eye and 0.7 in the left, and only a suspicious nasal step in the right field. After 4 weeks of treatment, no significant change in sensitivity was observed, despite normal lOPs. All POAG patients have been followed for at least 1 year since treatment, and like patients 1 and 2, no patient has improved from pretreatment levels despite normal pressures. Nineteen patients have remained stable, the conditions of the remaining three worsened and required surgical treatment. The 26 ocular hypertensive patients were divided into three groups. The first group, 8(30.8 %) of the 26 patients all of whom had bilateral ocular hypertension, showed no loss of contrast sensitivity in either eye. An example is provided in Figure 4: patient 3, 29 years of age, with normal discs and visual fields and initial lOPs of23 mmHg in the right eye and 22 mmHg in the left, and 25 mmHg in the right eye and 22 mmHg in the left, 5 weeks later. His sensitivity fell comfortably within the normal range 38

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Fig I. A, flicker sensitivity as a function of temporal frequency for the right eye of 26 normal controls at the three test locations in the visual field. The arrows indicate the critical fusion frequency for each location . B, flicker sensitivity for the central locus upon initial test and retest at 4 weeks for 14 of the normals. The retest increase in sensitivity for all three test sites was insignificant.

in both eyes on both test occasions and has remained so without treatment for 2 years after the initial test. The second group consisted of9 (34.6%) of26 patients. Seven had bilateral ocular hypertension, one had a normotensive fellow eye, and one had early POAG in the fellow eye. Each hypertensive eye showed an initial sensitivity loss similar to the POAG response, but unlike the POAGs exhibited normal sensitivity after 4 weeks of treatment. One example is provided in Figure 5A: patient 4, 32 years of age, with hypertension in the right eye (initial

TYTLA et al

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Temporal Frequency (Hz) Fig 2. Top, mean flicker sensitivity for the normal sample (grey zone =±2.8 standard deviation [SD] and for a representative primary open-angle glaucoma (POAG) patient. Bottom, sensitivity loss for this patient expressed as relative sensitivity (log [patient sensitivity 7 normal sensitivity]) at each temporal frequency. Negative ordinate values indicate sensitivity loss. Values below the lower dashed line (-0.35 log unit) are significantly below normal with 99% confidence. The maximal depression of sensitivity at 20 to 30 Hz shown by this POAG patient was typical of the entire POAG sample.

lOP, 27 mmHg) and a normal left eye (initial lOP, 15 mmHg), shows the characteristic pattern of loss in only the suspicious right eye before treatment. Four weeks after treatment to the right eye, its sensitivity was normal. Patient 4 is interesting because the substantial recovery in

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o Fig 3. Flicker sensitivity loss for the more involved eye of two primary open-angle glaucoma patients A, right eye of patient I; B, right eye of patient 2; before treatment (top) and 4 weeks into treatment (bottom). Representative of all 22 patients with primary open-angle glaucoma, no significant change of sensitivity was seen upon reduction of intraocular pressure (lOP).

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Temporal Frequency (Hz) eyes showed pretreatment losses of sensitivity, but 4 weeks after treatment of both eyes, only the hypertensive eye recovered normal sensitivity. The eye with glaucoma remained unchanged. These two patients also illustrate that practice alone cannot account for the normalization of sensitivity in the treated hypertensive eyes of this second group. The remaining 9 patients with ocular hypertension (34.6% of the total) comprised the third group. Seven had bilateral hypertension, and two had a normotensive fellow eye. Each hypertensive eye exhibited an initial sensitivity loss, but despite the posttreatment normalization ofIOP, showed no subsequent change in sensitivity. Figure 6 presents a representative example: patient 6 with lOPs of 28 mmHg in the right eye and 23 mmHg in the left before treatment and 18 mmHg in the right eye and 17 mmHg in the left 4 weeks into treatment. Despite a slight improvement with lower pressures in both eyes, her sensitivity stayed abnormal for virtually all frequencies, and has remained so for 2 years.

DISCUSSION Previous studies have shown that the glaucomatous eye usually exhibits flicker losses which are greater in the peripheral than in the central field. 6 ,8,18 This was true for our data as well. The largest proportion (18/22 or 82%) of our POAG sample showed the greatest sensitivity loss in the temporal field at the frequency of 30 Hz. Thus, this combination of field locus and frequency is the most sensitive indicator of glaucomatous visual loss in our test. Figure 7 summarizes our data for the more involved eye of both POAG patients and ocular hypertensive patients by plotting relative sensitivity before treatment against relative sensitivity after treatment for the superior temporal field locus at 30 Hz. It can be seen that all patients

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with POAG exhibited significant sensitivity losses which did not resolve with treatment: all data points cluster about the unity line beyond the normal range. This finding is consistent with the rest of their ophthalmologic findings indicating that these patients have suffered irreversible ganglion cell loss. It also is evident that most patients with POAG exhibited greater losses than most patients with ocular hypertension. The patients with ocular hypertension could be classified into three groups (Fig 7), each comprising approximately one third of the total sample, based on flicker sensitivity and the influence of reduced lOP on it. This classification scheme may reflect progressive glaucoma risk. In group I, the lack of a sensitivity loss in the presence of high lOP suggests that no glaucomatous damage has occurred. As well, these patients seem to be fully tolerant of high lOP and perhaps are at least risk of glaucoma developing. Group II exhibited glaucoma-like losses in flicker sensitivity when lOP was high which disappeared after normalization of lOP. The patients in this group seem to be sensitive to high lOP but apparently also have not yet suffered permanent damage. Perhaps glaucoma may eventually develop in some of these patients. Group III exhibited irretrievable loss: like the POAG group, their data cluster about the unity line outside the normal range. We suspect that they have already suffered very early glaucomatous damage, and if untreated are the ones most likely to have clinically detectable glaucoma within their lifetimes. We point out that the proportions of ocular hypertensive patients in the three classes may be biased, partly because of the small sample size but also because all patients were referrals to a tertiary care practice (GET). Thus, the patients presented here could be from the higher risk end of the population of those with ocular hypertension. The known risk factors of age, initial lOP, family history, high myopia, diabetes, and cardiovascular disease were

TYTLA et al •

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Temporal Frequency (Hz) virtually identically distributed across our three groups, but this does not imply that these factors are to be ignored in prognosis. A case in point is patient S (Fig SB). Whereas her hypertensive left eye showed the recovery characteristic of group II patients, this eye is nonetheless at very high risk because of the presence of manifest glaucoma in the fellow eye. However, the return to normal sensitivity in her hypertensive eye with normal pressures suggests that with continued treatment this eye may avoid the fate of its fellow. Our group III exhibited permanent reductions in flicker sensitivity while maintaining clinically normal vision. Standard clinical visual tests involve small stationary and/

or slowly moving stimuli. Thus, chronically high lOP appears to affect the visual mechanisms which mediate low spatial and high temporal frequencies before those which mediate high spatial and low temporal frequencies. A similar conclusion was reached in recent pattern evokedpotential studies of monkeys with chronic ocular hypertension. 19.20 Studies of the cat and monkey optic nerve indicate that retinal ganglion cells with the largest caliber axons prefer stimuli oflow spatial and high temporal frequency.21-23 Recent results of histologic examinations of optic nerve sections from monkeys with chronic lOP elevation24 and of sections of human glaucomatous optic nerves25 indicate that ganglion cells with stout axons are 41

OPHTHALMOLOGY

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Temporal Frequency (Hz) indeed the first to atrophy, followed by axons of smaller caliber. The permanent loss exhibited by group III patients may represent a functional consequence of this ordered loss of ganglion cells in early subclinical glaucoma. The more pronounced flicker losses along with the presence of visual field deficits in the POAG group presumably represent the advancement of the process to include the smaller axons. The recovery of normal sensitivity by group II patients is intriguing. We do not understand the basis of this transient visual loss. Graded acute hypoxia26 and relative ischemia27 (s;100 minutes) have been shown to temporarily attenuate the response of single retinal ganglion cells in normal cats, and recovery occurs within minutes after the acute event. Elevated lOP also retards or blocks axoplasmic transport of retinal ganglion cells. 28 - 3o Reduced flicker sensitivity may result from a depleted supply of neurotransmitter at the terminal bud of the axon. 7 In the normal rae l and monkey,32 transport normalizes within 2 to 4 hours of cessation of acute lOP elevation. These mechanisms may indeed be responsible for the temporarily diminished evoked-potential amplitudes demonstrated in normals with acutely elevated IOP. IS Each of our ocular hypertension patients was tested within 3 to 5 hours of treatment onset (when lOPs were reduced), and none showed a significant change in sensitivity at that time. Thus, these mechanisms (in the acute form) are not responsible for the reversible loss in our group II. Unfortunately, we cannot find animal studies showing reversible effects after chronic periods of hypoxia or relative ischemia, or studies on the rate of transport recovery after chronic ocular hypertension. In summary, our results provide evidence that monitoring flicker sensitivity in patients with ocular hypertension before and after hypotensive treatment may help to single out those at high risk of glaucoma developing, as

42

well as to monitor the success of treatment before manifest glaucoma damage has occurred. Long-term follow-up will verify whether our prognostic speculations are correct.

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Relative Sensitivity pre-treatment Fig 7. Relative sensitivity posttreatment as a function of pretreatment at 30Hz for the temporal visual field locus. Results for the eye with the greater initial loss are plotted. The diagonal line represents no pre- or posttreatment difference. The dashed lines define the lower limits of normal sensitivity (P = 0.01). Ocular hypertension (OHT) group I was not treated: posttreatment measures were taken 3 to 6 weeks after initial measurement (pretreatment). All other patients were treated (posttreatment, 4-6 weeks after treatment onset). POAG = primary open-angle glaucoma.

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REFERENCES

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