Alvin Eisner

Breast Cancer Medications and Vision: Effects of Treatments for Early-stage Disease

This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.

Identifying factors associated with falls in postmenopausal breast cancer survivors: a multi-disciplinary approach

OBJECTIVE To identify neuromuscular, balance, and vision factors that contribute to falls in recently treated breast cancer survivors (BCS) and explore links between fall risk factors and cancer treatment. DESIGN Case-control plus prospective observation. SETTING Comprehensive cancer center. PARTICIPANTS BCS (N=59; mean age, 58y) within 2 years of chemotherapy completion and/or on adjuvant endocrine therapy. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Objective measures of postural control, vision, and neuromuscular function included: (1) a sensory organization test (SOT), (2) a visual assessment battery, (3) muscle mass by dual energy x-ray absorptiometry, and (4) neuromuscular function with strength by repetition maximum, power by timed stair climb, and gait speed by 4m walk. Falls were self-reported for the past year (retrospective) and monthly for 6 months (prospective). RESULTS Fifty eight percent of BCS reported falls in the past year. BCS with a history of falls had lower SOT scores with a vestibular deficit pattern in postural control (P<.01) and took longer to read letters on the contrast sensitivity chart (P<.05). Vestibular score on the SOT mediated the relationship between treatment and falls among BCS who received chemotherapy only, but not adjuvant endocrine therapy. CONCLUSIONS Results of this project suggest that balance disturbances of vestibular origin and delays in detecting low contrast visual stimuli are associated with falls in BCS. Future studies that track falls and fall risk factors in BCS from diagnosis through treatment are warranted, as are studies that can identify treatment-related vestibular dysfunction and altered visual processing.

Short wavelength automated perimetry and tamoxifen use

Background/aims: Oestrogen receptors (ORs) have been reported to be present in the retina, and the selective oestrogen receptor modulator tamoxifen has been reported to affect colour vision. This study aimed, therefore, to determine whether standard doses of tamoxifen affect visual sensitivities mediated via short wavelength sensitive (SWS) cones. Methods: Two types of visual fields were measured for middle aged women who were being treated with 20 mg of tamoxifen daily as adjuvant therapy for early stage breast cancer. Visual fields were measured using short wavelength automated perimetry (SWAP) and frequency doubling perimetry (FDP). For SWAP, 24-2 visual fields were analysed. No subjects had tamoxifen retinopathy or other eye disease. For each type of visual field, mean deviations (MDs) were assessed as a function of the duration of tamoxifen use, using a cross sectional design. In addition, the difference between the two types of MDs was computed after standardisation of each type of MD separately, and this difference itself was evaluated as a function of the duration of tamoxifen use. Duration dependent changes for SWAP were further evaluated as a function of eccentricity within the visual field, and the visual field data were compared with foveal data obtained psychophysically. Results: SWAP sensitivities depended on the duration of tamoxifen use. Subjects who used tamoxifen for about 2 years or less were significantly more likely than subjects who had longer use to have high MDs. The difference between the standardised SWAP and FDP MDs likewise was significantly related to the duration of use, whereas duration of use effects for FDP itself were reduced or absent. Although the duration of use effect observed for SWAP was strongest in the peripheral portion of the visual field, there was evidence of changes in SWS cone mediated vision even at the fovea. Conclusion: Standard dosages of tamoxifen can affect SWAP visual fields. The effects of tamoxifen are not equivalent for SWAP and FDP, indicating that tamoxifen affects some types of visual pathways preferentially or selectively. SWS cone pathways, in particular, are affected. SWAP appears able to reveal effects of tamoxifen occurring years before completion of the standard 5 year regimen of use.

Profound reductions of flicker sensitivity in the elderly : can glaucoma involve the retina distal to ganglion cells ?

Flicker sensitivities were measured for more than 100 people age 60 and older with stimulus-conditions originally designed to obtain estimates of preretinal absorption by the lens and macular pigment. Flicker sensitivities were measured on two chromatic backgrounds: a 1000-td, 480-nm background and a 5800-td, Wratten 33 background (approximately metameric with 633 nm). Testing sessions were administered at 18-month intervals across a 3-yr period. No subject tested had a history of glaucoma or ocular hypertension at the time of entry into the study. For ten subjects, however, flicker sensitivity was sometimes reduced by more than 2.0 log units from the mean norm for at least one of the two backgrounds. For most other subjects, flicker sensitivities were within 0.5 log units of the mean norms. On retrospective analysis, the profound reductions of flicker sensitivity (PRFS) were associated significantly with (a) advanced age (perhaps especially when combined with relatively high intraocular pressure), and (b) the use of cardiovascular medications. The PRFS probably were associated with (c) female sex, and (d) large intraocular pressure fluctuations. In addition, the majority of subjects with PRFS were found to have evidence of glaucomatous cupping or field loss. These results suggest that PRFS result from glaucoma or share etiologies with low-tension glaucoma. The use of cardiovascular medications suggested that PRFS could depend on retinal dysfunction rather than on optic nerve compromise alone. Predicted results from two additional subject populations support this possibility. For young healthy subjects, flicker threshold vs illuminance curves attained very steep slopes for sufficiently short wavelength tests on sufficiently extreme long wavelength backgrounds (655 nm, 50,000 td); the steep slopes coincided with the breakdown of effective M-cone isolation. Reductions of flicker sensitivity on the 5800-td Wratten 33 background depended correspondingly on test wavelength for subjects with well-documented low-tension glaucoma.

Nonmonotonic effects of test illuminance on flicker detection: a study of foveal light adaptation with annular surrounds

This study examined the detectability of flicker for small long-wavelength foveal test stimuli centered within larger long-wavelength surround stimuli. Flicker visibility was evaluated as a function of surround and test illuminance and as a function of test wavelength, of the time elapsed following test or surround onset, and of surround dimensions. Consistent with prior flicker threshold-versus-illuminance results [Vision Res. 26, 917 (1986)], flicker threshold decreased abruptly once the surround illuminance became sufficiently great. However, as test illuminance was increased above flicker threshold, flicker again vanished. Flicker reappeared at still higher test illuminances, as middle-wavelength-sensitive (M-) cone-mediated flicker threshold was exceeded. Meanwhile, the time required for the surround to render flicker visible increased at a rapidly accelerating rate with decreasing surround illuminance; it increased at a more sporadic rate with increasing test illuminance. At bright enough surround illuminances, flicker did not vanish with increasing test illuminance. These and other results are compatible with a framework derived from previous dark-adaptation data [Vision Res. 32, 1975 (1992)]. In that framework the test stimulus itself induces losses of flicker sensitivity by sufficiently perturbing retinal response during states or stages of adaptation that fail to cause spectrally antagonistic processes to redress that perturbation adequately. The relevant adaptation processes, which can require minutes, involve an adaptation pool that includes (and is affected by) the test stimulus.

Multiple components in photopic dark adaptation

After extinction of a 580-nm bleach, the rate of decrease of the logarithm of visual threshold to a foveal long-wavelength test is not described by an exponentially shaped function. There is a period of time roughly midway between extinction of the bleach and complete recovery of sensitivity when the threshold does not continue to decrease. The duration of this period can be up to about a minute, depending on the illuminance of the bleach. The departure from an exponential time course of recovery during this period is more evident when the test stimulus is a disk that is defocused on the retina and sinusoidally modulated at 1 Hz than when the test stimulus is a sharp-edged disk that is either flashed for 160 msec or sinusoidally modulated at 1 Hz. Losses rather than plateaus of sensitivity with time are sometimes apparent--depending on the observer and stimulus parameters--roughly midway through recovery when the test is a defocused disk modulated sinusoidally at 1 Hz.

Foveal adaptation abnormalities in early glaucoma

Foveal sensitivities were measured after onset of adapting background fields for each of the following four groups of subjects aged 40-70 years: (1) low-tension glaucoma subjects with minimal field loss in the test eye, (2) primary open-angle glaucoma subjects with minimal field loss in the test eye, (3) normal control subjects, and (4) subjects originally enrolled as control subjects but subsequently found, on the basis of masked clinical evaluation, to be suspect for glaucoma despite ostensibly normal intraocular pressures. We found that the desensitization of a short-wavelength-sensitive-cone-mediated response after onset of a 580-nm background field was diminished from that of normal observers for low-tension glaucoma subjects but not for primary open-angle glaucoma subjects. The desensitization was also diminished for a glaucoma-suspect subjects aged 60-70 years. In contrast, the flicker sensitivity instabilities that persisted after onset of a long-wavelength background field for the majority of subjects with primary open-angle glaucoma [J. Glaucoma Suppl. 3, S19 (1994)] occurred only infrequently among the other subject groups. These results imply that glaucoma often involves the fovea, probably by affecting retinal subtractive adaptation processes, although with different consequences for different types of glaucoma. The results also suggest that undiagnosed low-tension glaucoma may not be rare in the general aging population.

Suppression of Flicker Response with Increasing Test Illuminance: Roles of Temporal Waveform, Modulation Depth, and Frequency

This study examined the detectability of flicker for small foveal long-wavelength test stimuli centered within surrounding long-wavelength annular adaptation stimuli. Flicker threshold-versus-illuminance (tvi) curves were analyzed for four different test-stimulus waveforms--sine-wave, square-wave, and rapid-on sawtooth and rapid-off sawtooth flicker--at temporal frequencies ranging from 12 to 21 Hz and at temporal modulation depths ranging from approximately 50% to 100%. For all stimulus combinations that were examined involving temporal frequencies above 12 Hz, the resultant flicker tvi curves shared the following characteristic features: First, at operationally dim surround illuminances, there was always a single elevated threshold for detection of flicker. Second, some surround illuminance always could be found for which flicker threshold decreased abruptly, typically by approximately 1.5 log units within 0.1 log unit of surround illuminance increase. Third, when test illuminance was incremented above this lower flicker threshold, flicker always vanished; when test illuminance was incremented still further, flicker reappeared. Finally, at sufficiently bright surround illuminances flicker did not disappear with increasing test illuminance. Although these effects held for all waveforms, the abrupt decrease of flicker threshold occurred at brighter surround illuminances for sawtooth than for sine-wave flicker, and at brighter surround illuminances for sine-wave than for square-wave flicker, at least for fully modulated waveforms (of a given temporal frequency). Moreover, when modulation depth was adjusted so that any two different waveforms had the same first-harmonic contrast, the resultant flicker tvi curves became identical when plotted as first-harmonic amplitude versus surround illuminance. This identity held for any given temporal frequency, even though the flicker tvi curves for 12-Hz fully modulated sine-wave or square-wave flicker did not manifest flicker response suppression, whereas the flicker tvi curves for sawtooth flicker did. These and other results imply that the first-harmonic contrast of the test stimulus fully determines the shape of the entire flicker tvi curve and that the dc component of the test stimulus helps to cause flicker response suppression. The results also demonstrate that first-harmonic equivalence is only a necessary, not a sufficient, condition for linearity.

Losses of foveal flicker sensitivity during dark adaptation following extended bleaches

Flicker sensitivity to a small foveal test stimulus can decrease appreciably during the period of dark adaptation that follows extinction of a bleach. For 20 min diameter, long wavelength tests that followed 70% L cone bleaches of various wavelengths, 18 Hz flicker sensitivity decreased precipitously (i.e. within about 45 sec) by about 1.5-2.0 log units beginning at about 100-200 sec following extinction of the bleach. For short wavelength tests that followed long wavelength bleaches, the corresponding precipitous losses of flicker sensitivity were relatively small and early; flicker sensitivity decreased by about 0.6-1.0 log units beginning no later than 60 sec following extinction of the bleach. Whenever flicker sensitivity decreased precipitously, the losses of flicker sensitivity were followed by plateaus of M cone dominated flicker sensitivity. For combinations of test and bleaching wavelengths that did not cause flicker sensitivity to decrease precipitously, flicker sensitivity instead decreased gradually over a prolonged period of time, and incorporated a substantial L cone contribution. The precipitous suppression of flicker sensitivity found for certain combinations of bleaching and test wavelengths appears to depend on the action of a broadly tuned, red-green spectrally opponent process.

VITREO-RETINAL TRACTION AND ANASTROZOLE USE

Purpose This study tested a prediction stemming from the hypothesis that anastrozole users experience heightened vitreo-retinal traction. This hypothesis was based on the knowledge that menopause increases the risk of intraocular tractional events such as posterior vitreous detachments (PVDs). Methods Retinal thickness was measured for 3 groups of amenorrheic women: (1) anastrozole users and (2) tamoxifen users undergoing adjuvant therapy for early-stage breast cancer, and (3) control subjects not using hormonal medication. Foveal shape indices were derived for subjects without PVDs. Results For anastrozole users, the distance to the temporal side of the fovea became less than the distance to the nasal side at a sufficient height above the foveal base. This effect did not exist for control subjects; the between-group difference was appreciable. Results concerning tamoxifen users were inconclusive. Conclusions The foveas of women using anastrozole appear to be subjected to more tractional force than are the foveas of women not using any hormonal medication.