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. Author manuscript; available in PMC: 2012 Jan 28.
Published in final edited form as: Vision Res. 2010 Sep 8;51(2):235–242. doi: 10.1016/j.visres.2010.08.036

The Impact of Intraocular Pressure Reduction on Retinal Ganglion Cell Function Measured using Pattern Electroretinogram in Eyes Receiving Latanoprost 0.005% versus Placebo

Mitra Sehi 1, Dilraj S Grewal 1, William J Feuer 1, David S Greenfield 1
PMCID: PMC3025061  NIHMSID: NIHMS233844  PMID: 20813123

Abstract

Purpose

To evaluate the impact of intraocular (IOP) reduction on retinal ganglion cell (RGC) function measured using pattern electroretinogram optimized for glaucoma (PERGLA) in glaucoma suspect and glaucomatous eyes receiving latanoprost 0.005% versus placebo.

Methods

This was a prospective, placebo-controlled, double masked, crossover clinical trial. One randomly selected eye of each subject meeting eligibility criteria was enrolled. At each visit, subjects underwent five diurnal measurements between 8:00 am and 4:00 pm consisting of Goldmann IOP, and PERGLA measurements. A baseline examination was performed following a four-week washout period, and repeat examination after randomly receiving latanoprost or placebo for four-weeks. Subjects were then crossed over to receive the alternative therapy for four weeks following a second washout period, and underwent repeat examination. Linear mixed-effect models were used for the analysis.

Results

Sixty-eight eyes (35 glaucoma, 33 glaucoma suspect) of 68 patients (mean age 67.4 ±10.6 years) were enrolled. The mean IOP (mmHg) after latanoprost 0.005% therapy (14.9±3.8) was significantly lower than baseline (18.8±4.7, p<0.001) or placebo (18.0±4.3), with a mean reduction of −20 ± 13%. Mean PERGLA amplitude (μv) and phase (π-radian) using latanoprost (0.49 ± 0.22 and 1.71 ± 0.22, respectively) were similar (p>0.05) to baseline (0.49±0.24 and 1.69±0.19) and placebo (0.50±0.24 and 1.72±0.23). No significant (p>0.05) diurnal variation in PERGLA amplitude was observed at baseline, or using latanoprost or placebo. Treatment with latanoprost, time of day, and IOP were not significantly (p>0.05) associated with PERGLA amplitude or phase.

Conclusion

Twenty percent IOP reduction using latanoprost monotherapy is not associated with improvement in RGC function measured with PERGLA.

Keywords: glaucoma, retinal ganglion cell, pattern electroretinogram, intraocular pressure, latanoprost

Introduction

Glaucoma is a progressive optic neuropathy known to cause progressive loss of retinal ganglion cells (RGC) and their axons (Johnson & Morrison, 2009, Varma, et al., 2008, Weinreb & Khaw, 2004). The pattern electroretinogram optimized for glaucoma (PERGLA) is a non-invasive technology that objectively measures RGC function (Bowd, et al., 2009, Porciatti & Ventura, 2004, Sehi, et al., 2009). The PERG response is a mass potential that sums information primarily from the electrical potentials of the inner retina and in particular the RGCs (Ben-Shlomo, et al., 2005, Price, et al., 1988). In experimental models of glaucoma elevated IOP has been associated with reduced PERG measurements consistent with RGC dysfunction (Johnson, et al., 1989) (Viswanathan, et al., 2000). The glaucoma specific PERGLA algorithm has been shown to be potentially useful as a measure of detecting early glaucomatous damage (Bach, et al., 2006, Hood, et al., 2005, Parisi, et al., 2006, Porciatti, et al., 1987). It has been demonstrated that reversal of RGC dysfunction can occur following pharmacologic reduction of IOP in glaucomatous eyes with early standard automated perimetry (SAP) defects (Ventura & Porciatti, 2005). Sehi and colleagues have recently shown that reversal of RGC dysfunction occurs following surgical reduction of IOP and may be quantified using PERGLA (Sehi, et al., In press).

Latanoprost 0.005% (Xalatan™, Pfizer Inc., New York, NY) is a synthetic, highly selective FP receptor (prostaglandin F2α receptor; PGF2α) agonist (Resul, et al., 1993) that has been demonstrated to reduce IOP in patients with ocular hypertension (Camras, 1996, Fristrom & Nilsson, 1993, Hotehama, et al., 1993, Nagasubramanian, et al., 1993, Villumsen & Alm, 1992, Watson & Stjernschantz, 1996), open angle glaucoma (Hotehama et al., 1993), normal-tension glaucoma (Rulo, et al., 1996), and in normotensive subjects (Ziai, et al., 1993). Prospective trials have demonstrated a therapeutic efficacy similar or superior to that of timolol maleate 0.5% dosed twice daily (Alm, et al., 1995). The ocular hypotensive effect of this medication is primarily related to an increase in uveoscleral outflow, as demonstrated in primates.(Bito, et al., 1993, Resul, et al., 1997, Weinreb, 2001) Using fluorophotometry, the mechanism of IOP reduction in humans has been reported to involve both increased uveoscleral and a possible mild increase in conventional outflow (Dinslage, et al., 2004).

We hypothesized that IOP reduction, using latanoprost 0.005% as monotherapy would improve RGC function compared to placebo. The purpose of this investigation was to evaluate the impact of IOP reduction on RGC function measured using PERGLA in glaucoma suspect and glaucomatous eyes receiving latanoprost 0.005% versus placebo.

Methods

This study was designed as a prospective, placebo-controlled, double masked, crossover clinical trial. Eyes categorized as perimetric glaucoma (PG) and glaucoma suspect (GS) meeting eligibility criteria were prospectively enrolled. Glaucomatous optic neuropathy was defined as narrowing of the neuroretinal rim, notching, excavation, or RNFL defect. PG eyes had glaucomatous optic nerve damage and repeatable SAP abnormality defined as a glaucoma hemifield test (GHT) “outside normal limits” or pattern standard deviation (PSD) outside 95% normal limits. All patients had prior SAP experience and those with SAP abnormalities had at least one confirmatory visual field examination. Eyes with suspected glaucoma consisted of eyes with ocular hypertension (OHT) or pre-perimetric glaucoma and were categorized in a combined group (GS). Patients with OHT were characterized by IOP ≥ 24 mmHg with normal optic discs and normal SAP. Pre-perimetric glaucoma patients consisted of those with glaucomatous optic neuropathy on funduscopic examination and review of stereoscopic optic disc photographs but normal SAP.

All participants signed a consent form approved by the Institutional Review Board for Human Research at the University of Miami that was in agreement with the provisions of the Declaration of Helsinki. Exclusion criteria consisted of best-corrected visual acuity (BCVA) less than 20/40, spherical equivalent refractive error of >+3.00 DS or < −7.00 DS, untreated IOP >32 mmHg, corneal or retinal pathology, prior intraocular surgery except for uncomplicated cataract extraction, age <18 or >80 years, unreliable SAP (>33% rate of fixation losses, false positives and false negatives), contraindication to latanoprost 0.005%, and PERGLA signals originating from eye movement characterized by a threshold voltage exceeding ±25 μV. All participants underwent complete ophthalmic examination including slit lamp biomicroscopy, dilated stereoscopic examination, gonioscopy, Goldmann applanation tonometry, ultrasound pachymetry (DGH 55 Pachmate, DGH Technology Inc, Exton, PA), refraction and visual acuity measurement and photography of the optic disc, and SAP (Carl-Zeiss Meditec, Dublin, CA; SITA standard strategy, program 24-2) at baseline. Five diurnal measurements consisting of PERGLA amplitude (μV) and phase (π-radian) (PERGLA, Lace Ellectronica, Glaid Version 1.2, Pisa, Italy), IOP and blood pressure (BP) measurements were performed at the baseline session and at two sessions after randomly receiving latanoprost 0.005% and placebo for a four-week period. The rationale for the four-week duration of the treatment was based on several studies that have demonstrated significant IOP reduction following a three to four-week treatment using latanoprost (Rulo, et al., 1996, Drance, et al., 1998, Tomita, et al., 2004, Dirks et al., 2006; Kiuchi et al., 2007). We considered 2 safety measures during the washout period: 1) a safety IOP check at 2 weeks during washout (Figure 1); and 2) a visual field measurement at each of the 4 diurnal sessions. The patient was excluded at the two-week safety visit or the first diurnal visit if IOP rose above 32mmHg.

Figure 1.

Figure 1

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Flowchart illustrates the study design consisting of a screening visit and 3 diurnal examinations that included 5 measurements of intraocular pressure, blood pressure, and pattern electroretinogram testing. A baseline examination was performed following a four-week washout period, and repeat examination after randomly receiving latanoprost 0.005% or placebo for four-weeks. Subjects were then crossed over to receive the alternative therapy for 4 weeks following a second washout period, and underwent repeat examination.

Each measurement IOP, BP, and PERGLA measurement was repeated twice at each session and an average measurement was recorded. Mean ocular perfusion pressure (MOPP, in mmHg) was defined as the difference between 2/3 of mean arterial pressure and IOP (Gherghel, et al., 2000).

Figure 1 represents a flowchart that illustrates the study design. The study protocol included a screening visit and 3 diurnal examinations that included 5 measurements between 8:00 am and 4:00 pm consisting of IOP, BP, and PERGLA testing. One randomly selected eye of each subject meeting eligibility criteria was enrolled. A baseline examination was performed following a four-week washout period, and repeat examination after randomly receiving latanoprost 0.005% or placebo dosed once daily at night for four-weeks. A randomization list was maintained and masked study medications were provided (Pfizer Inc., New York, NY) in identical bottles labeled with the assigned randomization number directly to the clinical center and stored under refrigeration. Subjects were then crossed over to receive the alternative therapy for 4 weeks following a second washout period, and underwent repeat examination.

Pattern Electroretinogram Examination

Steady-state PERG optimized for glaucoma (PERGLA; Lace Ellectronica, Glaid Version 1.2, Pisa, Italy) was used on both eyes simultaneously to measure the RGC function as described by Porciatti and Ventura.(Porciatti & Ventura, 2004) All subjects underwent refraction corrected for 30 cm. Pupils were undilated and had a diameter of ≥ 2mm. The skin was cleansed and prepared using electrode prep pads. Five gold-plated electrode cups with 9mm diameter filled with conductive gel (Parker Laboratories, Inc.; Fairfield, NJ) were taped on the central forehead, temples and lower eyelids. A pre-adaptation period of 3 minutes was allowed prior to recording PERGLA. The PERGLA system evaluates the electrodes’ impedance automatically. The impedance is considered acceptable when it is lower than 5000 Ohm, and an LED provides feedback to the operator regarding each electrode. There is also an oscilloscope in live mode that provides feedback about the background noise. Black and white horizontal bars subtending a visual angle of 25°were presented in counter-phase on a video monitor placed at 30 cm. Spatial frequency was 1.64 cycle/degree and temporal frequency was 8.14 Hz (cycle/second). The target luminance was 40 cd/m2 and the background luminance was 4 cd/m2 using a 98% contrast. Each presentation consisted of 300 registered sweeps after exclusion of the first 30 sweeps to allow a steady-state recording. There is no gaze tracking system provided in this device. However, there is a mechanism incorporated that automatically rejects unacceptable signals originating from blinking or eye movements over a threshold voltage of ±25 microvolts (μV). The acquisition time for each sweep was 122.8 milliseconds. Discrete Fourier transform (DFT) was used to isolate the sinusoidal component at the reversal frequency (16.28 Hz), and measure its amplitude in μV (1/2 of the peak to trough amplitude) and phase lag in π-radians compared to the stimulus frequency. A phase decrease of 0.1 π-radians is equivalent to 3.1 ms delay in response latency (Porciatti, et al., 2005). To help with the clinical interpretation of results, PERGLA provides deviations of amplitude and phase from age-predicted averages, expressed in standard deviation (SD) units.

One experienced investigator was responsible for all aspects of data collection for PERGLA. For each patient an average of two measurements was used. Each measurement consisted of two separate sequential series, each of which was composed of 300 artifact-free signal registrations. Outcome measures consisted of PERGLA amplitude (μv) and phase (π-radian).

Statistical Analysis

Statistical analysis was performed using JMP software version 8.0 (SAS Inc., Cary, NC, USA). The sample size was calculated at the commencement of study. The estimated sample size for an alpha level of 5%, and a power of 80% was 68 to detect a 0.17μV change in amplitude from baseline after latanoprost therapy. Student’s T-test, chi-square test, and analysis of variance (ANOVA) with Tukey HSD were performed to compare clinical characteristics between groups. Intraclass correlation coefficient (ICC), coefficient of variability (CoV), and variance component analysis were performed to examine the reproducibility and variability of data.

Linear mixed-effects models were constructed with both fixed and random effects included to investigate the impact of IOP, MOPP, SAP MD, ocular diagnosis (PG, GS), treatment, time of day, IOP × time, treatment × time, and IOP × treatment on PERGLA amplitude and phase. Categorical and continuous variables were simultaneously tested for their association with outcome measures as fixed effects. Random patient effects were used to accommodate serial dependence within patients in the responses over time. All tests were two-sided and a p-value of < 0.05 was considered significant.

Results

One hundred and two patients were enrolled in this study. Thirty four patients were excluded for the following reasons: 23 patients withdrew prior to completion of the protocol, 2 patients developed increased IOP during the washout period deemed to be unsafe for the optic nerve, 2 patients developed ocular allergy, and 7 patients had poor quality PERGLA signal. Sixty-eight eyes of 68 patients (mean age 67.4±10.6 years) were included in the analysis consisting of 35 eyes with perimetric glaucoma (PG) and 33 glaucoma suspect (GS) eyes, comprised of 9 pre-perimetric glaucoma (glaucomatous optic neuropathy and normal SAP) and 24 ocular hypertensive (OHT, no optic neuropathy, normal SAP) eyes. 46 patients (23 glaucoma, 18 OHT, 5 pre-perimetric glaucoma) were using topical anti-glaucomatous treatment prior to the initiation of this study. All subjects were medically stable with controlled IOP and only non-progressing eyes were enrolled. During the study interval, no clinically detectable change in the optic nerve or visual field was identified in any patient. A standard visual field was performed at baseline and at the conclusion of the 3-month study. Although there were insufficient number of visual field examinations to statistically judge if visual field progression had occurred, the average SAP MD and PSD at baseline (−1.8 ± 4.3 and 2.6 ± 2.7dB, respectively) and at the last study visit (−2.1 ± 4.9 and 2.8 ± 2.8dB, respectively) were similar (p= 0.36, p = 0.45).

Table 1 describes the clinical characteristics of the study population. Baseline mean IOP, BP, MOPP, PERGLA amplitude and PERGLA phase were similar between the PG and GS eyes.

Table 1.

Baseline clinical characteristics of the study population (n = 68).

Mean ± SD (range) PG (n = 35) GS (n = 33) p-Value
Age (yrs) 69.1 ± 8.0 65.6 ± 12.6 0.20
Gender 0.87a
 Male 10 9
 Female 25 24
Ethnicity 0.70a
 White 27 27
 African American 1 7
 Other 1 5
Intraocular pressure (mm Hg) 18.8 ± 4.9 (10–36) 18.9 ± 4.0 (12.2–32.4) 0.80
PERGLA amplitude (μV) 0.48 ± 0.20 0.17–1.49) 0.50 ± 0.27 (0.08–1.65) 0.39
PERGLA phase (π-radian) 1.69 ± 0.20 (1.28–2.37) 1.69 ± 0.17 (1.14–2.20) 0.92
Systolic blood pressure (mm Hg) 128.3 ± 12.9 (100–164) 129.1 ± 13.1 (108–172) 0.57
Diastolic blood pressure (mm Hg) 78.6 ± 8.7 (60–107) 80.2 ± 6.9 (49.5–98) 0.06
Ocular perfusion pressure (mm Hg) 44.7 ± 7.9 (22.5–65.3) 45.5 ± 6.8 (28.8–64.2) 0.34
SAP mean deviation (dB) −2.4 ± 3.6 (−17.24 to 1.98) −0.16 ± 1.7 (−2.66 to 2.23) <0.001
SAP pattern standard deviation (dB) 3.3 ± 2.7 (1.03–13.4) 1.8 ± 0.7 (1–2.2) <0.001
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Student’s t-test; SD = standard deviation; PG = perimetric glaucoma; GS = glaucoma suspect; PERGLA = pattern electroretinogram optimized for glaucoma; SAP = standard automated perimetry.

*

Chi-square.

Mean IOP (mmHg) after using latanoprost 0.005% for four weeks (14.9±3.8) was significantly (p<0.001) lower compared with baseline (18.8±4.7) and placebo (18.0±4.3) with a mean reduction of −20±13%. As illustrated in Figure 2, the IOP using latanoprost was significantly (p<0.001) less than baseline and placebo at all time-points measured during the diurnal period. Peak IOP (using latanoprost or placebo) was at 8:00–10:00 AM; and trough IOP was at 2:00 PM. MOPP (mmHg) using latanoprost (48.1±6.0) was significantly (p<0.001) greater compared to baseline (45.1±7.4) or placebo (44.6±6.2).

Figure 2.

Figure 2

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Histogram illustrates the mean intraocular at each of five diurnal time points obtained at the baseline session compared with treatment using latanoprost 0.005% and placebo. The IOP at the latanoprost session was significantly (p < 0.001) lower compared with baseline and placebo at all time-points.

Mean PERGLA amplitude (μv) and phase (π-radian) using latanoprost 0.005% (0.49±0.22 and 1.71±0.22, respectively) were similar (p >0.05) to baseline (0.49±0.24 and 1.69±0.19) and placebo (0.50±0.24 and 1.72±0.23). The amounts of amplitude deviation from normal (in SD unit) at the baseline (−2.28 ± 1.97), placebo (−2.34 ± 1.84) and latanoprost sessions (−2.37 ± 1.85) were similar (p > 0.05). The amplitude deviation was outside 2 SD from age-predicted normals in 19 glaucoma suspect and 17 glaucomatous eyes. Figure 3 represents a box-and-whisker plot illustrating the distribution of PERGLA amplitude (A) and phase (B) values at baseline, latanoprost and placebo sessions. The whiskers represent the minimum and maximum values; the ends of the box represent the 25th and 75th percentiles and the horizontal line inside the box represents the median at the 50th percentile value.

Figure 3.

Figure 3

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Distribution of pattern electroretinogram amplitude (A) and phase (B) values at the baseline, latanoprost and placebo sessions. The whiskers represent the minimum and maximum values; the ends of the box represent the 25th and 75th percentiles and the horizontal line inside the box represents the median at the 50th percentile value.

Figure 4 represents a scatter plot of PERGLA amplitude (A) and phase (B) stratified by ocular diagnosis (GS and PG) and demonstrates similar (p>0.05) values at baseline compared with latanoprost treatment. A more than 84% increase in PERGLA amplitude due to latanoprost therapy was observed in 4 OHT females who were between 62–76 years of age, had no optic neuropathy and were all under topical anti-glaucomatous treatment prior to washout and participation in the study. The amount of IOP decline was between 3–8.4mmHg at the latanoprost session compared to baseline in these 4 patients. We examined the relationship between change in IOP and change in PERGLA amplitude (Figure 5) and PERGLA phase and found no significant association (p>0.05).

Figure 4.

Figure 4

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Scatter plot of pattern electroretinogram amplitude (A, left) and phase (B, right) values demonstrates similar values at baseline compared with latanoprost 0.005% treatment among the study population of glaucoma suspects (GS) and eyes with perimetric glaucoma (PG).

Figure 5.

Figure 5

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Scatter plot of pattern electroretinogram (PERGLA) amplitude values illustrates the relationship between change in PERGLA response and change in intraocular pressure after latanoprost 0.005% treatment among the study population of glaucoma suspects (GS) and eyes with perimetric glaucoma (PG).

Table 2 demonstrates the PERGLA amplitude (A) and phase (B) using latanoprost 0.005% compared with placebo at each diurnal time point. Neither PERGLA amplitude nor PERGLA phase showed any significant change at any time point using latanoprost compared to placebo (p>0.05). There was no significant interaction between treatment and time of day for either PERGLA amplitude (p=0.14) or phase (p=0.42) and its inclusion did not alter the statistical significance of the other variables in the model. Table 3 summarizes the results of linear mixed-effects models and demonstrates that the PERGLA amplitude and phase were not associated (p>0.05) with time of day, treatment with latanoprost or placebo, IOP, severity of visual field loss, MOPP or any other clinical parameter.

Table 2.

PERGLA amplitude (A) and phase (B) using latanoprost 0.005% compared with placebo at each diurnal time point.

Time Placebo
 Latanoprost
 Difference
Mean SE Mean SE Mean SE p-Value
A. PERGLA amplitude (μV)
8:00 0.50 0.03 0.47 0.03 0.03 0.04 0.40
10:00 0.51 0.03 0.50 0.02 0.02 0.04 0.68
12:00 0.49 0.03 0.54 0.03 0.05 0.04 0.21
14:00 0.498 0.03 0.486 0.03 0.01 0.04 0.76
16:00 0.49 0.03 0.47 0.03 0.02 0.04 0.63
B. PERGLA phase (π-radian)
8:00 1.68 0.02 1.71 0.03 0.03 0.03 0.30
10:00 1.68 0.02 1.71 0.02 0.03 0.03 0.33
12:00 1.74 0.03 1.69 0.02 0.05 0.04 0.23
14:00 1.73 0.03 1.70 0.03 0.03 0.04 0.39
16:00 1.76 0.03 1.73 0.03 0.04 0.03 0.27
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SE = standard error.

Table 3.

The relationship between diurnal PERGLA amplitude and phase with various clinical parameters at different sessions, using linear mixed-effects models.

PERGLA amplitude (μV)
 PERGLA phase (π-radian)
Estimate SE p-Value Estimate SE p-Value
IOP (mm Hg) 0.003 0.002 0.14 −0.0009 0.002 0.68
Time 0.54 0.063
 8:00 −0.009 0.010 −0.016 0.013
 10:00 −0.003 0.010 −0.025 0.013
 12:00 0.016 0.010 0.007 0.013
 14:00 −0.004 0.010 0.004 0.013
 16:00 Reference Reference
Treatment session 0.17 0.26
 Baseline −0.015 0.008 −0.015 0.010
 Latanoprost 0.012 0.009 0.004 0.011
 Placebo Reference Reference
IOP × timea 0.094 0.36
Treatment × time a 0.058 0.38
Treatment × IOPa 0.26 0.42
Ocular diagnosis 0.54 0.38
 GS 0.014 0.02 −0.011 0.012
 PG Reference Reference
Mean deviation (dB) 0.006 0.004 0.15 0.002 0.004 0.44
Mean ocular perfusion pressure (mm Hg) −0.001 0.001 0.40 −0.001 0.001 0.40
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IOP = intraocular pressure; BL = baseline; PG = perimetric glaucoma; GS = glaucoma suspect.

Reference = in a linear model, one of the outcome categories for each fixed effect serves as the reference category and the response of other categories is examined relative to it.

a

Coefficients and standard errors of non-significant interactions omitted.

We examined the reproducibility and variability of PERGLA measurements using the intraclass correlation coefficient (ICC) and coefficient of variation (CoV), assuming that the change in variability between sessions was not due to the effect of differing treatments during the periods of the crossover. It is likely that this analysis underestimates the actual reproducibility of our measurements, since it does not include true within or between trial replicates. The ICC (PERGLA amplitude and phase) was 0.73 and 0.40 at baseline, and 0.72 and 0.43 using latanoprost. The CoV (PERGLA amplitude and phase) was 24.2% and 9% at baseline, and 22.8% and 10.1% using latanoprost. Table 4 demonstrates variance component estimates for pattern electroretinogram optimized for glaucoma (PERGLA) amplitude and phase at the baseline and latanoprost sessions. For PERGLA amplitude the highest variance component was due to patient variance but not for PERGLA phase. In this analysis measurements made at different times were considered as five replicate measures. At the latanoprost session the variability caused by differences between patients, was reduced compared with baseline.

Table 4.

Variance component estimates for pattern electroretinogram optimized for glaucoma (PERGLA) amplitude and phase at the baseline and latanoprost sessions. For PERGLA amplitude the highest variance component was due to patient variance but not for PERGLA phase. In this analysis measurements made at different times were considered as five replicate measures.

Parameter Variance component Parameter estimate Percentage of total variance (%)
PERGLA amplitude at baseline Patients 0.04 73.1
Time 0.0002 0.4
Unexplained variability 0.01 26.5
PERGLA amplitude at latanoprost session Patients 0.03 67.8
Time 0.0005 1.0
Unexplained variability 0.02 31.2
PERGLA phase at baseline Patients 0.01 36
Time 0.0002 0.6
Unexplained variability 0.02 63.4
PERGLA phase at latanoprost session Patients 0.009 17.6
Time 0.00 0
Unexplained variability 0.04 82.4
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PERGLA = pattern electroretinogram optimized for glaucoma.

The PERGLA provides measures of variability, and noise for amplitude and phase. The amplitude variability (0.32 ± 0.24; 0.34 ± 0.23; 0.32 ± 0.31 respectively) and noise (0.18 ± 0.12; 0.17 ± 0.15; 0.16 ± 0.15 respectively) were similar (p > 0.05) at the baseline, placebo and latanoprost sessions. We calculated the signal-to-noise ratio (SNR) at each diurnal session (signal amplitude divided by noise level). The SNRs at the baseline, placebo, and latanoprost diurnal sessions (2.95 ± 2.21; 3.08 ± 2.17; 3.23 ± 2.15) were similar (p > 0.05, one way ANOVA).

Discussion

The total RGC population in a glaucomatous eye consists of RGCs that are physiologically normal, dysfunctional, nonviable, and atrophic undergoing variable stages of degeneration. Quantification of RGC function is of considerable interest to clinicians and scientists who seek biomarkers for early diagnosis, prediction and identification of progression, and response to therapeutic interventions. Measurement of RGC dysfunction would also serve as a useful endpoint for glaucoma clinical trials involving IOP lowering and potentially non-IOP lowering therapy.

Prior studies have suggested that PERGLA may represent a biomarker for RGC dysfunction. Ventura and Porciatti (Ventura & Porciatti, 2005) retrospectively reported that the recovery of PERGLA amplitude might indicate the reversal of RGC dysfunction as observed in 12 of 25 glaucomatous eyes that underwent various methods of pharmacologic reduction in IOP during a 1–3 month period of time. Porciatti and colleagues (Porciatti & Nagaraju, 2010) showed that in a mouse model of glaucoma head-up body posture causes IOP reduction (5–6mmHg) and improvement of PERGLA amplitude within a 20-minute time frame. They suggest that the observed improvement of PERGLA amplitude is consistent with IOP-dependent reversible RGC dysfunction. Wittström et al. (Wittstrom, et al., 2010) showed improvement in multifocal ERG among 11 glaucomatous eyes after trabeculectomy. In a prospective study of 47 eyes that underwent surgical IOP reduction for uncontrolled IOP, Sehi et al. (Sehi, et al., In press) recently reported that the mean postoperative PERGLA amplitude (0.46±0.22 μV) significantly increased compared to preoperative PERGLA amplitude (0.37±0.18 μV). A 50% postoperative reduction in IOP was achieved compared to baseline (20 mmHg). No change in PERGLA response was observed among un-operated fellow eyes.

In the present study, we designed and executed a prospective randomized placebo-controlled crossover clinical trial designed to examine the relationship between IOP reduction and RGC function measured using PERGLA. Latanoprost and placebo were administered and both investigator and patient were masked to identity of the treatment. Using latanoprost, a mean 20% reduction in IOP from baseline (approximately 19 mmHg) was observed at all diurnal time-points, which is consistent with prior reports in normotensive eyes (Cheng, et al., 2009). Latanoprost has been reported to reduce IOP approximately 20% in normal eyes (Mishima, et al., 1997), and 21% in eyes with normal-tension glaucoma (Cheng et al., 2009, Rulo, et al., 1996). Eyes treated with latanoprost had similar PERGLA responses compared to eyes receiving placebo. No association was identified between IOP reduction and PERGLA amplitude after accounting for age and severity of disease.

Other studies have failed to show a reversal of RGC dysfunction as a result of moderate IOP reduction. Tytla and colleagues (Tytla, et al., 1990) measured flicker sensitivity among a group of OHT and POAG patients before, during and after IOP lowering treatment with timolol 0.5% and examined temporal contrast sensitivity in treated eyes compared to untreated normal controls. They found that 100% of eyes with POAG and 65% of eyes with ocular hypertension had no improvement in flicker sensitivity. Nesher and colleagues (Nesher, et al., 1990) examined the PERG in 21 patients with ocular hypertension who had received unilateral timolol 0.5% therapy for a minimum of 6 years and found that mean PERG amplitude was similar between placebo-treated and timolol-treated eyes.

When studies arrive at different conclusions, one must critically compare the methodology, study population, and analysis methods used in each study to help explain the apparent differences in outcomes. The magnitude of IOP reduction in the present study (20%) and in other studies using timolol 0.5%, (Nesher, et al., 1990, Tytla, et al., 1990) was less than the amount of IOP reduction observed after incisional glaucoma surgery (50%) (Sehi, et al., In press) which may have contributed to our inability to identify an improvement in PERGLA response. The baseline IOP in our study (19 mmHg) was related to enrollment of eyes with normal-tension glaucoma and glaucoma suspects, and may have contributed the results we observed. Many studies have demonstrated that PERG amplitude is diminished in early glaucoma (Ringens, et al., 1986) (Bach & Hoffmann, 2008, Bach & Speidel-Fiaux, 1989, Bach et al., 2006, Falsini, et al., 2008, Hood et al., 2005, Marx, et al., 1988, Porciatti et al., 1987, Riva, Salgarello, et al., 2004, Ventura, et al., 2005, Ventura, et al., 2006) and may be unable to detect further change in eyes with moderate or advanced glaucoma due to the narrow dynamic range of amplitude measurements and overlap between normal and glaucomatous eyes (Sehi et al., 2009, Yang & Swanson, 2007). PERGLA responses may be associated with non-RGC cell populations and may not reflect isolated RGC function (Demb, 2008, Viswanathan, et al., 1999) Although a large part of the PERGLA biopotential is generated by RGCs, but it still depends on the responses from the entire circuitry and might still be affected to a lesser degree by non-RGC populations.(Demb, 2008, Viswanathan, et al., 2001). PERGLA amplitude is strongly correlated with visual acuity and media opacity (Porciatti & Ventura, 2004) therefore care must be taken to exclude eyes with moderate cataract or poor vision. Finally, We observed moderate variability of PERGLA measurements in our study consistent with previous reports (Bowd, et al., 2009, Fredette, et al., 2008, Porciatti & Ventura, 2004, Sehi et al., 2009, Yang & Swanson, 2007). Using a variance component analysis we found that the largest component of total variability was due to overall differences between patients, and was not due to repeated measures at different time points. It is possible that PERGLA variability may limit its ability to detect reversal of RGC dysfunction. It is also possible that a modest decrease in IOP (20%) may be insufficient to improve the signal generated by the RGC population.

To our knowledge, this report describes the first prospective randomized placebo-controlled crossover clinical trial designed to examine the relationship between IOP reduction and RGC function measured using PERGLA. In this study with an average IOP reduction of 20% from baseline, latanoprost 0.005% monotherapy was not associated with improvement in PERGLA response. Further prospective studies with more robust IOP lowering are warranted in order to better understand the relationship between IOP and PERGLA response, and the potential role of PERGLA as a biomarker for RGC dysfunction in glaucoma clinical trials.

Acknowledgments

Support: This study was supported in part by the Maltz Family Endowment for Glaucoma Research, Cleveland, Ohio; a grant from Mr. Barney Donnelley, Palm Beach, FL; The Kessel Foundation, Bergenfield, New Jersey; Source of support: an unrestricted grant from Research to Prevent Blindness P30-EY14801, New York, New York, an unrestricted grant from Pfizer Inc, New York.

Footnotes

Financial interest: The authors have no financial interest in any drug, device or technique described in this paper. Dr. Greenfield has served as a consultant and has received research support from Pfizer Inc.

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