Effect of Brimonidine on Retinal Vascular Autoregulation and Short-term Visual Function in Normal Tension Glaucoma




Purpose


To assess whether brimonidine 0.15% alters retinal vascular autoregulation and short-term visual function in normal tension glaucoma patients who demonstrate retinal vascular dysregulation.


Design


Nonrandomized clinical trial.


Methods


In this prospective study, 46 normal tension glaucoma patients not previously treated with brimonidine underwent retinal vascular autoregulation testing and visual function assessment using frequency doubling technology perimetry and equivalent noise motion sensitivity testing. We measured blood flow in a major temporal retinal artery with subjects seated and then while reclined for 30 minutes. Patients having a change in retinal blood flow with posture change outside the range previously found in healthy subjects were classified as having retinal vascular dysregulation. They were treated with brimonidine 0.15% for 8 weeks and designated for retesting.


Results


Twenty-three patients demonstrated retinal vascular dysregulation at the initial visit. Younger age ( P = .050) and diabetes ( P = .055) were marginally significant risk factors for retinal vascular dysregulation. After the 8-week course with brimonidine, 14 of the 17 patients who completed the study showed a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation ( P < .0001). We found no significant changes in frequency doubling technology perimetry or in motion detection parameters following treatment with brimondine ( P > .09 for all tests performed).


Conclusions


Brimonidine significantly improved impaired retinal vascular autoregulation in normal tension glaucoma patients, but short-term alteration in visual function could not be demonstrated.


Brimonidine is an alpha2 adrenoceptor agonist that modulates retinal vascular tone by altering nitric oxide signaling. The effect of brimonidine on retinal vessel tone is consistent with the observation that retinal vessels are not innervated. Interestingly, phakic patients receiving topical brimonidine have vitreous brimonidine levels sufficient to mediate retinal vascular modulatory effects.


There is compelling evidence supporting the role of impaired nitric oxide signaling in primary open-angle glaucoma (POAG). When soluble guanylate cyclase, the intracellular receptor for nitric oxide, is knocked out in a murine model, intraocular pressure (IOP) increases nominally (∼1–2 mm Hg), there is abnormal retinal vascular reactivity to nitric oxide donators, and optic nerve degeneration ensues. With the exception of 1 study, several research groups found positive associations between NOS3 (coding for endothelial nitric oxide synthase) genetic polymorphisms or other biomarkers of nitric oxide signaling in association with POAG. Furthermore, female reproductive health attributes, systemic hypertension, and cigarette smoking modify the relation between NOS3 polymorphisms and POAG. Finally, polymorphisms in the genomic region corresponding to the caveolin genes, which code for proteins that reciprocally control NOS3 activity in endothelial caveolar membranes, are also associated with POAG.


Previously, we demonstrated that some normal tension glaucoma (NTG) patients exhibit retinal vascular dysregulation and proposed that retinal blood flow instability induced by posture change could contribute to disc hemorrhage and progressive optic neuropathy. Furthermore, we showed that topical brimonidine corrected retinal vascular dysregulation in 6 NTG patients. Correction of retinal vascular dysregulation may explain why topical brimonidine was superior to timolol in preserving visual field in NTG patients after 3 years of treatment, as reported in the Low Pressure Glaucoma Treatment Study.


In this study, we prospectively evaluate the effect of brimonidine 0.15% on retinal hemodynamics in NTG patients with retinal vascular dysregulation who have not been previously exposed to this agent. Secondarily, we assessed whether brimonidine improved visual function in these patients. Glaucoma patients exhibit selective deficits in processing moving or flickering stimuli. Therefore, we chose motion sensitivity and frequency doubling technology perimetry, 2 tests that leverage this particular aspect of visual function, in our analysis.


Methods


Patients


This is a prospective, nonrandomized clinical trial of POAG patients with a history of untreated IOP <22 mm Hg. We recruited patients from the practices of 5 of the authors (D.J.R., A.V.T., T.C.C., M.W., and L.R.P.). Prior to study commencement, the Institutional Review Board at Massachusetts Eye & Ear Infirmary approved all aspects of this investigation. Each subject signed written informed consent to participate in the trial, which was registered with ClinicalTrials.gov (identifier: NCT01105065 ).


POAG patients aged 35–80 years old were eligible for the study. All patients had untreated IOP <22 mm Hg and open angles on gonioscopy in both eyes. There were at least 2 reliable Humphrey 24-2 (Zeiss-Humphrey Instruments, Inc, San Leandro, California, USA) Swedish Interactive Threshold Algorithm visual fields showing reproducible glaucomatous loss in at least 1 eye. Patients were excluded from the study if there was: a history of prior brimonidine treatment; use of more than 2 IOP-lowering medications; evidence of exfoliation or pigment dispersion syndrome; diabetic retinopathy; or history of ocular laser/incisional surgery in either eye. In order to facilitate the retinal blood flow measurements, we included only subjects with refractive error between −10 and +10 diopters, no lens opacities greater than 1 + cortical spokes or 2 + nuclear sclerosis, and pupillary dilation of at least 6 mm following mydriasis.


Forty-six patients met study eligibility criteria; 25 were untreated while the remaining 21 received topical glaucoma medications (latanoprost [n = 8], bimatoprost [n = 4], travoprost [n = 4], timolol [n = 2], timolol + latanoprost [n = 1], timolol + bimatoprost [n = 1], and timolol + travoprost [n = 1]). The left eye underwent hemodynamic testing in 44 patients; the right eye was used in the remaining 2 patients.


Retinal Vascular Autoregulation Testing Protocol


At approximately 10 AM, we allowed subjects to sit for 15 minutes and then measured blood pressure and heart rate using a Keller Vital Signs Monitor (Keller Medical Specialties, Antioch, Illinois, USA). We measured seated IOP in both eyes using Goldmann applanation tonometry (Haag Streit USA, Mason, Ohio, USA) and 1 eye was dilated with tropicamide 1%. Baseline seated ocular perfusion pressure (OPP) was estimated using the standard formula: OPP = ⅔ MAP − IOP, where MAP refers to mean arterial pressure. The factor of two-thirds adjusts for the decline in blood pressure between the brachial and ophthalmic artery with the subject sitting. We used the Canon CLBF 100 Laser Blood Flowmeter (Canon Inc, Tokyo, Japan) to measure baseline retinal arterial blood column diameter and centerline blood speed, which allows for automatic calculation of the blood flow rate. We chose a site along either the inferior temporal retinal artery (29 subjects) or the superior temporal retinal artery (17 subjects) adjacent to the optic disc for baseline measurements. Prior work demonstrates that seated measures of retinal blood flow with the CLBF are valid and reproducible.


Following the baseline measurements, the subjects assumed a posture typically used for face-on x-rays, reclining on their right side with their head supported by a foam wedge making a 24-degree angle from the horizontal. Subjects reclined for 30 minutes while brachial blood pressure and heart rate were automatically measured at 5-minute intervals. Laser Doppler blood flow measurements were obtained from the same arterial site that was used at baseline after approximately 15 and 30 minutes of reclining. A 30-minute reclining time ensures that a new equilibrium condition is reached. Previous studies have indicated that a period of at least 5–8 minutes is required for the retinal vasculature to adjust to an altered OPP. Immediately following the 30-minute laser Doppler measurement, with the subject still reclining, we used the Perkins handheld applanation tonometry (Haag Streit USA) to remeasure IOP in the eye undergoing hemodynamic testing. In the reclined position, OPP was estimated using the following formula: OPP reclining = MAP reclining − IOP reclining , where MAP reclining is the mean brachial artery blood pressure measured in the left arm with the subject reclining on the right side. In a clinical trial comparing Goldmann and Perkins applanation tonometry, IOP was approximately 1 mm Hg lower using Perkins compared to Goldmann applanation tonometry. Thus, any difference between Goldmann and Perkins applanation tonometry has minimal impact on the calculation of OPP reclining . Subsequently, blood pressure, heart rate, and laser Doppler measurements were repeated after the subjects were reseated for 15 minutes.


Only patients who exhibited retinal vascular dysregulation continued in the study. We defined retinal vascular dysregulation based on the percentage change between the retinal blood flow measured while reclining for 30 minutes and the baseline seated measures. Previously, we found that healthy subjects exhibited a +6.5% ± 12% blood flow change induced by 30 minutes of reclining. Thus, we defined the normal range of blood flow autoregulation as within 2 standard deviations of the mean percentage change found in this group, or −17.5% to +30.5%. Patients with a retinal blood flow change induced by posture outside this range were classified as exhibiting retinal vascular dysregulation. These patients began an 8-week course of brimonidine 0.15% 3 times a day in both eyes. Subsequently, they returned at 10 AM and repeated the testing protocol described above. We obtained retinal hemodynamic measurements at the same retinal arterial site used during the initial visit. Designations of retinal vascular dysregulation and normal retinal vascular autoregulation are reproducible. In our study each patient served as his or her own control in that we measured hemodynamic changes at the same site of the same eye both before and after treatment with brimonidine. Similarly each patient underwent visual function testing, described below, in the eye that had hemodynamic studies both before and after 8-week treatment with brimonidine 0.15%.


Visual Function Testing Protocols


At each study visit, prior to retinal vascular autoregulation testing, we performed frequency doubling technology perimetry and equivalent noise motion sensitivity tests. For frequency doubling technology perimetry, we used the full-threshold N-30 protocol to determine the visual field mean deviation, pattern standard deviation, and test duration in the eye that had hemodynamic testing.


The equivalent noise method measures internal noise and sampling efficiency, which are respectively associated with the dysfunction and the nonfunction of retinal ganglion cells. A PC microcomputer with Matlab (MacBook Pro, Apple, Cuoertino, California) and the Psychophysics Toolbox was used to present stimuli on a 21-inch Viewsonic GS790 CRT monitor (ViewSonic, Walnut, California). We set the monitor’s spatial resolution to 1024 × 768 (subtending 36 degrees × 27 degrees) with a refresh rate of 100 Hz and a mean luminance of 50 cd/m 2 . With the subjects positioned in a chin and forehead rest, they viewed the screen situated 57 cm in front of the eye that had hemodynamic testing while the fellow eye was patched. If necessary, patients wore spectacles for their best-corrected near vision.


Random dot motion stimuli were presented within 1 of 3 circular apertures with a radius of 4 degrees. The apertures were centered at 0 degrees (fovea) and at 8 degrees eccentricity in the inferior and superior visual field. Dot directions were drawn from a normal distribution whose mean and standard deviation were varied by a computer staircase. Random dot noise stimuli were composed of 100 independent black or white dots with a Michelson contrast of 75% that maintained a constant mean luminance level. Each dot subtended 0.19 degrees (6 pixels) in diameter and was initially randomly positioned within a circular region that subtended 4 degrees in diameter. The position of each dot was updated every 3 video frames (40 msec). If a dot’s displacement would take it to a position outside the aperture, its position was wrapped to the opposite side of the aperture. Each dot had a lifetime of 3 displacements (120 msec), after which it was randomly repositioned within the aperture. The initial lifetime was random to avoid all dots expiring simultaneously. Stimuli were presented for 500 msec with abrupt onset and offset. The direction of motion of each dot was drawn from a wrapped Gaussian circular uniform distribution whose mean and standard deviation were under computer control.


The subject’s task was to maintain fixation on a central dot and to identify whether the mean direction of the moving dots was clockwise or counterclockwise from the 12 o’clock (upwards) position. The fixation point provided feedback that was white following a correct trial and black following an incorrect trial. Subjects provided their responses with a mouse, but if they were uncomfortable with using the mouse, the experimenter recorded their verbal responses.


Motion sensitivity was tested with an equivalent noise paradigm that was used to estimate internal noise and sampling efficiency for each observer. Under equivalent noise analysis, performance is represented by


σ2i+σ2eNsamp=σobsσ2i+σ2eNsamp=σobs
σ i 2 + σ e 2 N s a m p = σ o b s

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Jan 8, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Effect of Brimonidine on Retinal Vascular Autoregulation and Short-term Visual Function in Normal Tension Glaucoma
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