20. Panmacular subthreshold diode micropulse laser (SDM ... · national Society for Clinical Electrophysiology of Vision guidelines.18 Both eyes were tested simultaneously and recorded

Abstract

Purpose: To determine the effect of panmacular sub-threshold diode micropulse laser (SDM) on optic nerve function in eyes with glaucomatous optic neuropathy (GON).Method: A medical records review identified all patients with advanced primary open-angle glaucoma (POAG) evaluated by visually evoked potential (VEP) testing before and after SDM treatment. Additional testing including pattern electroretinography (PERG), and mesopic visual acuity and mesopic visual field testing using Omnifield resolution perimetry (ORP). Results: 88 eyes of 48 consecutive patients were included for study, 20 male and 28 female, aged 57-94 (average: 79). All patients had GON and visual field loss prior to treatment. Pretreatment, IOPs ranged 6-23 mmHg (average: 13) on 0-3 (average: 1.6) medications. 33 eyes had had prior glaucoma surgery. Snellen visual acuities (VA) ranged 20/15 to count fingers (median 20/60). Prior to treatment, both VEPs and ORPs of all eyes were abnormal. Following SDM, Snellen VA was improved (p = 0.005) and IOP was unchanged. VEP P1 amplitudes (p = 0.001) and mesopic VA and automated perimetry were significantly improved (p < 0.0001, respectively). Conclusion: Panmacular SDM produced significant improvements in optic nerve function by VEP, PERG, chart VA, mesopic VA, and mesopic automated

Correspondence: Jeffrey K. Lutrull, MD, Private Practice, 3160 Telegraph Rd, Suite 230, Ventura, CA 93003, USA.E-mail: [email protected]

Glaucoma Research 2018-2020, pp. 281-294 Edited by: John R. Samples and Paul A. Knepper © 2018 Kugler Publications, Amsterdam, The Netherlands

20. Panmacular subthreshold diode micropulse laser (SDM) as neuroprotective therapy in primary open-angle glaucomaJeffrey K. Luttrull1,2,3, John R. Samples4, David Kent5, Bryant J. Lum6

1Private Practice, Ventura, CA, USA; 2Ojai Retinal Technologies, LLC; 3Retinal Protective Sciences, LLC; 4The Eye Clinic, Portland, OR, USA; 5The Vision Clinic, Kilkenny, Ireland; 6Ventura Ophthalmology, Ventura, CA, USA

perimetry. These improvements were achieved without IOP lowering. Further study is indicated to determine if SDM might be neuroprotective and aid the clinical management of glaucoma. Summary: In an observational retrospective cohort study, panmacular SDM laser was found to significantly improve VEP amplitudes and automated perimetry in eyes with glaucomatous optic neuropathy.

1. Introduction

Many patients diagnosed with primary open-angle glaucoma (POAG) suffer progressive glaucomatous optic neuropathy (GON) and visual loss despite nor-malization of intraocular pressure (IOP). 1 The reason for this remains unclear.2,3 The absence of another modifiable factor beyond IOP control has brought the search for neuroprotective measures to the fore. However, to date, no clinically effective neuroprotec-tive treatment has been identified.3

At the same time, attempts to explain the therapeutic effects of photocoagulation for retinal disease had proved futile, based as they were on what turned out to be a false premise: the therapeutic value and necessity of photocoagulation.4 Freed from the photo-coagulation prerequisite, a new understanding of the mechanism of retinal laser treatment emerged which, for the first time, successfully explained all observed

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effects of traditional retinal photocoagulation for con-ventional applications, such as diabetic retinopathy (DR) and central serous chorioretinopathy, but also successfully predicted novel new uses of retinal laser treatment never before considered.4-16

Low-intensity/high-density subthreshold diode micropulse laser (SDM) was the first therapeutic retinal laser strategy to abandon the precepts of photocoag-ulation.4 By design, SDM is clinically effective while reliably precluding laser-induced retinal damage. Because SDM is sublethal to the target retinal pigment epithelium (RPE), it has no known adverse treatment effects. SDM has been shown to be effective for traditional retinal laser indications such as diabetic macular edema, proliferative DR, central serous cho-rioretinopathy, and branch retinal vein occlusion.4-12 However, the elimination of laser-induced retinal damage by SDM allowed an improved understanding of the therapeutic mechanism of retinal laser treatment and successful prediction of a number of new retinal laser applications precluded by photocoagulation, and thus never considered in the photocoagulation era.13-16 These include treatment of other acquired and inherited retinopathies, including reversal of tolerance to anti-VEGF medications in neovascular age-related macular degeneration (AMD); and improved retinal and visual function in dry AMD, Stargardt’s disease, and retinitis pigmentosa (RP). 13,15,16 The mechanism and clinical behavior of SDM has been described as a “reset to default” phenomenon.13 Reset theory postulates that the primary mode of retinal laser action is sublethal activation of RPE heat shock proteins (HSPs), which triggers a cascade of events leading to intra-cellular repair, improved RPE function and cytokine expression and response, normalized retinal autoreg-ulation, reduced markers of chronic inflammation, and reparative acute inflammation and immunomodula-tion.12-17

All chronic progressive retinopathies are fundamen-tally neurodegenerative disorders. Thus, the effects of SDM in DR, AMD, and RP suggested that SDM should be also beneficial in another important ocular neurode-generative disorder: POAG.12-17 This chapter will focus on the neuroprotective effects of SDM in eyes with advanced POAG manifest by GON and/or visual field loss.

2. Methods

These studies adhered to the tenets of the Declaration of Helsinki. Following approval of an investigational review board, the records of all patients undergoing panmacular SDM in a private vitreoretinal practice (Jeffrey K. Luttrull) were reviewed to identify those with advanced GON who had undergone panmacular SDM for the primary outcome of pre- and post-treat-ment VEP testing results. Advanced GON was defined in this study by the presence of optic nerve cupping and/or visual field loss attributable to POAG. Exclusions included loss to follow up, media opacity, inability to perform or cooperate with testing, uncon-trolled IOP, amblyopia, other non-glaucomatous optic nerve disease, and ocular surgery within six months of SDM treatment. In addition to VEP, these eyes were evaluated prior to treatment by clinical examination, fundus photography (red free, infrared, and auto-fluorescence), spectral-domain optical coherence tomography (OCT), and automated perimetry (Omnifield resolution perimetry, ORP). Earlier treated patients were also evaluated before and after SDM by pattern electroretinography (PERG).

VEP, ORP, and PERG were each performed one week prior and within one month following SDM treatment.

2.1. VEP testing VEP was performed using an office-based commer-cially available system (Diopsys™ NOVA-TR, Diopsys, Inc., Pine Brook, NJ, USA) approved by the FDA for both research and clinical use. Testing was performed according to manufacturer guidelines (www.diopsys.com). All subjects were refracted prior to testing and corrected for the 1 meter testing distance with a trial frame. Gold active, ground, and reference electrodes (1 cm cup) were used to record the VEP. Following skin cleaning and abrasion, conductive gel was used to adhere the electrodes to the scalp. VEP amplitude, latency, and alpha-wave activity (8-13 Hz) from the primary visual cortex were measured using one Grass gold active-channel electrode, one reference electrode, and one ground electrode placed according to manufacturer recommendations following con-firmation of adequate testing impedance. An elastic headband was used to maintain electrode position on the scalp. Subjects then placed their head in a

Panmacular subthreshold diode micropulse laser as neuroprotective therapy in primary open-angle glaucoma 283

chinrest/headrest and were instructed to gaze at the center of the monitor at eye level and centered along the midline. The VEP measurements were recorded for each eye separately in a darkened room, undilated.18 Testing was performed at two levels of stimulus contrast.

2.2. PERG testingPERG was performed using standard protocols of a commercially available system (Diopsys® Nova-ERG, Diopsys Corp., Pine Brook, NJ, USA) according to Inter-national Society for Clinical Electrophysiology of Vision guidelines.18 Both eyes were tested simultaneously and recorded individually, undilated, and refracted for the 60 cm testing distance. For all visual stimuli, a luminance pattern occupying a 25° visual field is presented with a luminance reversal rate of 15 Hz.

The PERG “Concentric Ring” (CR) visual stimulus optimized for analyzing peripheral retinal sensitivity was employed, presenting with a circle of one luminance and an outer ring with the contrasting luminance. The concentric ring stimulus used two sub-classes of stimuli with an inner circle occupying a visual field of 16° and 24°, respectively. The concentric ring stimuli used a mean luminance of 117.6 cd/m2 with a contrast of 100%.

Patient and equipment preparation were carried out according to Diopsys™ guidelines. Signal acquisition and analysis followed a proprietary glaucoma screening protocol. Test indices available for analysis included “Magnitude D” [MagD(μV)], “Magnitude (μV)” [Mag(μV)], and the “MagD(µV)/Mag(µV)” ratio. MagD(μV) is the frequency response of the time-domain averaged signal in microvolts (µV). Inner retinal and/or ganglion cell dysfunction cause signal latencies resulting in magnitude and phase variability that reduce MagD(µV) by phase cancelation. Mag(μV) measures the frequency response of the total signal in microvolts (µV). Mag(μV) reflects the signal strength and electrode impedance of the individual test sessions, as well as a gross measure of inner retina and ganglion function. The MagD(µV)/Mag(µV) ratio thus provides a measure of patient response normalized to that particular test’s electrical quality, hence minimizing inter-test variability. In the healthy eye, MagD(μV) should roughly equal Mag(μV). Thus, the closer MagD(µV)/Mag(µV) to unity, the more normal retinal function.

2.3. Omnifield testingOmnifield resolution perimetry (ORP) (Sinclair Tech-nologies, Inc., Media, PA, USA) is a mesopic threshold test of the central 20° diameter visual field, measuring logMAR visual acuity by the identification of Landolt C positioning at programmed intercepts (in distinction to detection of a light source against a photopic background, as is accomplished with standard static computerized threshold field testing). Thus, the Omnifield mimics the environment of real-life visual tasks.19 At each intercept, the Landolt C’s are flashed on a monitor for 250 ms in one of four positions. The patient signals their recognition of the correct Landolt C position by deflecting a joystick in the direction of the C opening on the response pad. Fixation is monitored and an interactive algorithm adjusts the size of the Landolt C’s to determine a threshold of the letter size, below which the patient can no longer correctly respond. Testing is performed at fixation and at 17-24 intercepts out to 10° eccentricity. Reported outcomes include the BA6 (the best acuity at any intercept within 6° of fixation); the GMA (the average acuity from all intercepts weighted inversely from fixation within the central 10° of visual angle); and the VA (the area under the curve plotting threshold acuity vs intercept area as a measure of area of measureable visual acuity to a maximum Visual Area of 400°). In addition to digital readouts of the BA6, GMA, and VA, a false-color topographic map is constructed to provide a graphic depiction of the logMAR visual acuities in the central 20° of the central visual field.16 ORP has not been validated or systematically compared to other forms of automated perimetry. Therefore, the results we report do not represent absolute or comparable values. In the current study, ORP is used as a measure of mesopic visual function, and compared only to itself, before and after SDM treatment.

2.4. SDM treatmentFollowing informed consent and pupillary dilation, topical proparacaine was applied to the cornea. A Mainster macular contact lens (Ocular Instruments, Mentor, Ohio, magnification factor 1.05 x) was placed on the cornea with the aid of viscoelastic. Under minimum slit-lamp illumination, the entire posterior retina, including the fovea, circumscribed by the major vascular arcades was “painted” with 1200-2000


Table 1. Eye-level characteristics, N (%) or Mean (SD)

Total Number of Eyes 88Eye OD 45 (51.1) OS 43 (48.9)Pre-Treatment AMP, Low Contrast (Nmiss = 6) 8.8 (4.0)Pre-Treatment AMP, High Contrast (Nmiss = 4) 10.4 (4.2)Pre-Treatment LAT, Low Contrast (Nmiss = 6) 126.6 (16.5)Pre-Treatment LAT, High Contrast (Nmiss=3) 119.9 (16.1)Post-Treatment AMP, Low Contrast (Nmiss=1) 9.1 (3.9)Post-Treatment AMP, High Contrast (Nmiss=1) 11.8 (5.4)Post-Treatment LAT, Low Contrast (Nmiss=1) 124.1 (16.7)Post-Treatment LAT, High Contrast (Nmiss=1) 119.5 (13.3)

Eye-level characteristics. N: number. SD: standard deviation. OD: right eye. OS: left eye. LAT: latency. N=number. Nmiss: number of missing data values. Amp, High Contrast: P1 wave amplitude in microvolts.

Table 2. VEP indices. Summary of calculated difference (post- minus pre-SDM treatment)

Variable Mean (SD) Median (IQR) p-valueAMP, Low Contrast (Nmiss = 7) 0.57 (4.15) 0.90 (–1.80, 2.60) 0.33AMP, High Contrast (Nmiss = 6) 1.59 (4.59) 0.85 (–0.90, 3.00) 0.001LAT, Low Contrast (Nmiss = 7) –2.27 (21.69) –1.00 (–12.70, 6.80) 0.27LAT, High Contrast (Nmiss = 5) –0.78 (16.76) –0.90 (–7.80, 5.90) 0.72

This table shows the mean and median differences for the covariates of interest. Each row shows the difference (post- minus pre-treat-ment) in amplitude (AMP) or latency (LAT) at two contrast options. In order to test whether the mean difference is different from zero, a linear mixed models predicting the measure was performed, using an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept. The p-values are those associated with the time (pre- vs post-treatment) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero. Only the high contrast amplitude (AMP, High Contrast) is significantly different pre-treatment vs post-treatment. This method accounts for inter-eye correlation. SD: standard deviation. IQR: inter quartile range. Nmiss: number of missing values. AMP: P1 wave amplitude in microvolts.

Fig. 2. Comparison of post- to pre-treatment VEP P1 amplitudes (in microvolts). Note significant improvements in VEP P1 amplitudes after SDM treatment.

Fig. 1. Scatter graph of VEP P1 amplitudes (in microvolts) before and after SDM treatment. Note significant improvements in VEP P1 amplitudes after SDM treatment.


confluent spot applications of SDM (“panmacular” treatment). The laser parameters used were 810 nm wavelength, 200um aerial spot size, 5% duty cycle; 1.4 W power, and 0.15 second duration (Oculight SLx, Iris Medical/Iridex Corp., Mountain View, CA, USA).

2.5. Statistical analysisAll data was anonymized prior to statistical analysis. Frequencies, means, and medians were calculated to summarize the data. The models included fixed eye effects and a random patient intercept to account for inter-eye correlation. Additional hierarchical linear models to explore the association between the difference (post- minus pre-treatment) and pre-treat-ment values were also performed. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

3. Results

One patient (one eye) was lost to follow up prior to post-operative testing, leaving 88 eyes of 48 consecutive patients for study. These were 20 males and 28 females, aged 57–94 years (average: 79). IOPs ranged 6-23 mmHg (average: 13) on 0-3 (average: 1.6) topical medications. None used systemic glaucoma medication. Most patients reported prior laser trabeculoplasty. Thri-ty-three eyes had undergone prior trabeculectomy and/or placement of an anterior chamber shunt.

Coincident retinopathies included dry AMD (51 eyes); wet AMD (7 eyes); moderate to high myopia (17 eyes); mild non-proliferative DR (11 eyes); and RP (2 eyes). Several eyes had more than one concurrent retinopathy. Twelve eyes of six patients had no retinopathy coincident with GON.

Preoperative Snellen visual acuities ranged 20/15 to counting fingers with a median of 20/60. Postoperative-ly, Snellen VAs were unchanged, as were IOPs. There were no adverse treatment effects. In particular, there were no cases of treatment-associated visual loss or laser-induced retinal damage.

The VEP responses of all study patients were abnormal prior to treatment. All VEP indices improved following treatment, with high contrast amplitudes (P1) significantly improved (p = 0.001) (Tables 1 and 2; Figs. 1 and 2).

PERG testing was performed on 42 consecutive eyes of 22 patients with GON. PERG 24° Concentric Scan Mag(uv) amplitudes (42 eyes) ranged 0.51–1.64 uV (average: 1.15) before treatment and 0.7–1.93 uV (average: 1.25) after treatment, for an average improvement of 0.10 uV (9%) (P = 0.05). All other PERG measures were also improved following treatment, but not significantly in this small sample (Table 3; Figs 3 and 4).

ORP visual field testing was performed in 85/88 eyes before and after SDM treatment (two patients being unable to perform Omni testing). All study eyes demonstrated abnormal visual fields by ORP prior to SDM treatment. After treatment, automated perimetry was improved in 71/85 eyes by all ORP indices (BA6 p < 0.0001, GMA p = 0.003, and VA p < 0.0001) (Tables 4 and 5; Figs 5-7).

Because right eyes were routinely tested prior to left eyes, an analysis was performed to determine the influence of practice on ORP test results. As all study patients were naïve to ORP, this model assumes that:

1. experience with ORP would improve testing results, and thus;

2. the first test result (on the right eye), without benefit of prior experience, would be poor compared to subsequent testing.

Applying this analysis and comparing the ORP results of right to left eyes prior to treatment, and the magnitude of improvement between right and left eyes after treatment, no significant differences were found. This indicates that the ORP improvements we report reflect the effect of SDM treatment, and are not attributable (Table 6).

In this study, as in the prior studies of SDM for chronic progressive retinopathies (CPRs), linear regression analyses of VEP, PERG, and ORP results all demon-strated significant changes in a negative direction, indicating that the eyes with the worst preoperative testing results were improved most by treatment.13,15,16


Table 3. Summary of calculated difference (post- minus pre-treatment), Concentric Ring PERG eyes

Variable Mean (SD) Median (IQR) p-valueM(d)/M(μv) Ratio, 24° 0.00 (0.20) 0.00 (–0.12, 0.15) 0.93M(d)/M(μv) Ratio, 16° 0.04 (0.20) 0.05 (–0.10, 0.17) 0.30M(d) Measure, 24° 0.05 (0.30) 0.03 (–0.14, 0.27) 0.38M(d) Measure, 16° 0.04 (0.25) 0.05 (–0.11, 0.20) 0.43M(μv) Measure, 24° 0.10 (0.33) 0.08 (–0.09, 0.33) 0.05M(μv) Measure, 16° 0.03 (0.31) 0.05 (–0.13, 0.22) 0.45

The mean and median differences (post- minus pre-treatment) for the covariates of interest are shown. In order to test whether the mean difference is different from zero, linear mixed models predicting the measure were performed using an indicator for time as a covariate, adjusting for left or right eye, and including a random patient intercept. The p-values are those associated with the time (pre- vs post-) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero. This method accounts for inter-eye correlation. Note that only the 24° M(μV) improved significantly following SDM NPT. M(d): frequency response of the time-domain averaged signal in microvolts (µV). M(μv): reflects the signal strength and electrode impedance of the individual test sessions. 16°: 16° retinal stimulus area. 24°: 24° retinal stimulus area. IQR: interquartile range. SD: standard deviation.

Fig. 3. Scatter graph of PERG 24° concentric ring (CR) scan amplitudes (Mag(μv) in microvolts, μv) before and after SDM treatment.

Fig. 4. Comparison of post- minus pre-treatment 240 Mag(μv) amplitudes before and after SDM.


Table 5. Summary of calculated difference (post- minus pre-treat-ment) for ORP testing

Variable Mean (SD) Median (IQR) p-value

BA 6°, LogMAR –0.17 (0.34)

–0.11 (–0.30, 0.00)

< 0.0001

GMA, LogMAR –0.15 (0.31)

–0.10 (–0.24, 0.02)

0.003

Visual Area (Nmiss = 3) 70.5 (92.7) 51 (16, 122) < 0.0001

The mean and median differences for the covariates of interest are shown. Each row shows the difference (post- minus pre-treatment) in BA 6°, GMA, or Visual Angle (for only those eyes with improvable Pre-Treatment Visual Area and not equal to 400°). In order to test whether the mean difference is different from zero, linear mixed models predicting the measure were performed using an indicator for time as a covariate, adjusting for left or right eye, and including a random patient intercept. The p-values are those associated with the time (pre- versus post-) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero. All measures are significantly different pre-treatment vs post-treatment. This method accounts for inter-eye correlation. BA6: best logMAR visual acuity within 6° of fixation. GMA: global macular logMAR visual acuty. Nmiss: number of missing values. SD: standard deviation. IQR: interquartiles range.

Table 4. Eye-level characteristics for ORP testing, N (%) or Mean (SD)

Total Number of Eyes 85Eye OD 44 (51.8) OS 41 (48.2)Pre-Treatment BA 6°, LogMAR 0.4 (0.3)Pre-Treatment GMA, LogMAR 1.0 (0.5)Post-Treatment BA 6°, LogMAR 0.2 (0.3)Post-Treatment GMA, LogMAR 0.8 (0.5)Secondary Analysis of Visual AngleTotal Number of Eyes 64Eye OD 33 (51.6) OS 31 (48.4)Pre-Treatment Visual Area (Nmiss = 3) 200.4 (124.3)Post-Treatment Visual Area (Nmiss = 1) 271.2 (124.5)

N: number. Nmiss: number of missing values. OD: right eye. OS: left eye. BA6: best mesopic logMAR visual acuity within 6° of fixation. GMA: global macular acuity. VA: visual area, in degrees. N: number. Nmiss: number of missing values. SD: standard deviation. Secondary analysis of Visual Angle includes only eyes which were improvable, with a visual area less than maximum of 400° prior to SDM treatment.

Fig. 5. Scatter graph of Omnifield resolution perimetry visual area (VA) before and after SDM treatment. Note significant improve-ments in recordable visual areas following SDM treatment (BA6 and GMA also showed similar levels of improvement following SDM).

Fig. 6. Comparison of post- to pre-treatment values for Omnifield resolution perimetry visual area. Note significant improvements following SDM treatment (BA6 and GMA showed similar levels of improvement following SDM).



Fig. 7. Omnifield resolution perimetry findings for patients with primary open angle glaucoma and glaucomatous optic neuropathy. Each row represents a diff erent patient and eye. (Left column) Before SDM. (Right column) Aft er SDM. BA6: best logMAR visual acuity within 6° of fixation. GMA: global macular logMAR visual acuity. VA: visual area. Note improvements in all indices following panmacular SDM.


4. Discussion

Information theory states that unexpected events are the most important, as they contain the greatest amount of new information.20 The findings we report are examples of such new information, gained only as the result of the unexpected discovery in 2000 that, rather than therapeutic, retinal photocoagulation is nothing more than an adverse treatment effect.4

Despite the new understanding of the mechanism of retinal laser treatment afforded by SDM (“Reset” theory), and successful prediction of unprecedented new retinal laser applications based on this under-standing, the reasoning for retinal laser treatment as neuroprotective therapy in POAG may not be immediately clear.12,15-17

First, the cause(s) of POAG are not entirely known.1 Once considered a single disease characterized by the abnormality of elevated IOP, most patients with POAG suffer progressive optic nerve damage and visual loss despite IOPs in the normal range and IOP lowering. Currently, POAG is regarded as several diseases at the molecular level, based in part on the determina-tion of a number of genetic mutations that cause the disease, which involve loss of retinal ganglion cells and progressive optic neuropathy that may or may not be associated with elevated IOPs.1 Recognition that IOP lowering alone is often insufficient to prevent visual loss has led to increased interest in neuroprotection.2-3 While a number of therapies may have neuroprotec-tive properties, none has thus far demonstrated clear clinical benefits.1-3,21 The effects of SDM in POAG are thus both unique and potentially important, demonstrating significant improvements in optic nerve function by VEP, ganglion cell function by PERG, and both photopic

(chart) and mesopic (ORP) visual function following treatment.

Second, the ganglion cell axons that constitute the optic nerve lie in the inner retina, with complex connections to other retinal elements, and ultimately, to the photoreceptors of the outer retina. Damage to, or dysfunction of, other — including outer — retinal elements may lead to retrograde optic nerve dysfunction and atrophy, such as is seen in RP and Leber’s optic atrophy, for example.22,23

Third, retinal homeostasis is principally maintained by the RPE via the exquisitely complex interplay of chemical mediators both elaborated by, and directed at, the RPE.24 Retinal ganglion cells and the optic nerve are thus dependent on the health and function of the RPE through RPE-derived cytokines, including some, such as pigment epithelial derived factor (PEDF), known to be neuroprotective.25

Fourth, retinal laser treatment is known to alter RPE cytokine expression, including causing upregulation of PEDF.26-28

Consistent with the proposed mechanism of action, which invokes prompt improvement in retinal function following laser-induced HSP activation, improvements in retinal and visual function can be documented by electrophysiology and automated perimetry within 24 hours of SDM treatment.15,16 In-vivo studies demonstrate that HSP activation, a first step in the acute inflammatory response, initiates a cascade of events normalizing RPE cell function, cytokine expression, and retinal autoregulation, suppressing apoptosis, reducing features of chronic inflammation, and provoking reparative immune responses that may include recruitment to the RPE of bone marrow-de-rived stem cells.13-17,21-30 Homeostasis describes the

Table 6. Comparing tests across eyes at pre-treatment visit and in the difference between visits, Mean (SD)

Pre-Treatment Visit DifferenceOS OD p-value OS OD p-value

BA 6°, LogMAR 0.35 (0.33) 0.43 (0.36) 0.27 –0.14 (0.34) –0.19 (0.33) 0.50

GMA, LogMAR 0.92 (0.48) 1.04 (0.58) 0.31 –0.09 (0.31) –0.20 (0.31) 0.13

Visual Area 253.7 (133.3) 249.5 (144.5) 0.89 36.1 (89.9) 61.2 (88.7) 0.21

The results of comparisons across eyes at pre-treatment visits and in the difference between visits are shown. We can see that pre-treat-ment visits, visual acuity measures BA 6° and GMA are improved in the left eye on average, but not significantly. Also, there is a smaller difference in pre- to post-treatment measures among left eyes on average, but again non-significant. These findings indicate that if there is a practice effect or learning curve influence on the Omni automated perimetry results, it is not significant.


activity of living entities maintaining normal function. Thus, we describe the effects of SDM via the reset phenomenon as “homeotrophic”, meaning to return toward, or restoring, normal function.13-17 While this concept is central to other therapeutic approaches like gene therapy, the homeotrophy stimulated by SDM is entirely mediated by native physiologic processes. Thus, the effects of SDM are renewable and without adverse treatment effect.4,12,13-17

The underlying abnormalities of POAG may be aggravated by age-related and environmental factors, including oxidative stress, fostering disease progression. A stereotypical chronic inflammatory cascade, common to chronic progressive diseases, develops that specifically targets the retinal ganglion cell layer.1-3,21-24 Activation of microglia, a common finding in neurodegenerative disorders, in the retina and optic nerve, appears to contribute to the degen-erative processes in POAG.32 The improvements in ganglion cell, optic nerve, and visual function we find indicate that SDM is able to rescue dysfunctional, but viable, retinal elements, including ganglion cells.33-35 Maintenance of these homeotrophic effects by periodic retreatment may thus slow disease progression and reduce the risk of visual loss in POAG.

PERG is a measure of retinal function obtained via signals from the inner retina and ganglion cell layer. PERG responses have been shown to improve after IOP lowering in POAG, and after SDM for chronic progressive retinopathies including dry AMD and RP.15,34-37 This commonality in the context of the understanding of retinal laser effects afforded by reset theory suggested SDM might be neuroprotective in POAG.15,34-37 In the current study, we find that, as predicted, SDM improves the PERG in POAG. However, the PERG responses in these eyes with POAG are different from the responses seen in other chronic progressive retinopathies.15,16 In retinopathies, SDM improves signal latencies, an important indicator of retinal function, and thus, health, most significantly. In POAG, however, the signal amplitude (Mag(uv)) was most improved, echoing the VEP, which also demonstrates greater improvement in signal amplitudes than latencies. The reason for this difference in PERG response between other retinopa-thies and POAG is unclear. However, it is consistent with the reset theory prediction that SDM, as a “non-specif-ic trigger of disease-specific repair”, will improve each

chronic progressive retinopathy/neurodegeneration in a different way, characteristic and reflective of the underlying disease process.13,15

Because the PERG measures activity of the inner retina, it also reflects contributions of the outer retinal elements.18,32-36 Thus, in the absence of otherwise clinically identifiable retinal disease (such as in POAG), the PERG largely reflects ganglion cell layer function; while in the presence of overt retinal disease (such as AMD), the PERG may reflect mainly abnormalities arising in the outer retina. (Here, the previously noted characteristic disease-type PERG “signatures” may be useful to distinguish the predominant disorder, overt retinal diseases especially reducing signal latencies, while POAG appears to especially signal amplitudes.) The VEP, however, is not generally affected by retinal disease. In contrast to the PERG, the VEP has not been reported to improve following treatment of retinal disease, or in response to IOP lowering in POAG.33-36

Improvement in the VEP would therefore be the purest indicator of a potentially neuroprotective effect from any treatment.1,15,21-23,34-36 In the current study, SDM significantly improved VEP P1 amplitudes in eyes with POAG. To our knowledge, it is the first clinical interven-tion to do so.

SDM has been reported to significantly improve visual function by microperimetry and contrast visual acuity testing in a variety of chronic progressive retinop-athies.5,15,16 Most of the eyes we report had a coincident retinopathy. Most were mild, although some more severe. The eyes with the greatest magnitude of visual field improvement were the two eyes with advanced RP (improving from 0° to 238°; and 1° to 316° of visual angle, respectively). Thus, the visual field improve-ments reported here could be, at least in part, due to improvements in retinal, rather than optic nerve, function following SDM retinal protection therapy (RPT).15 However, 10/12 eyes without a coincident clinical retinopathy also demonstrated significant visual field improvements after panmacular SDM. This, and the different PERG signature of SDM in POAG compared to simple retinopathies, suggest that the improvements in visual function we report following SDM in POAG derive from SDM-elicited RPE-mediated effects on the ganglion cell layer and optic nerve that can properly be considered “neuroprotective”, rather than from improvements in retinal function .1-3,22,24,35


The ubiquity of HSPs and the effectiveness of micropulsed laser trabeculoplasty (MLT), and micropulsed transscleral diode laser treatment of the pars plana (MPPT) indicate that the reset phenomenon is not unique to the retina.11-15,30,32,38-40 In MLT, trabecular filtration is improved by sublethal thermal laser stimulation. Similarly, MPPT presumably reduces aqueous production and/or increases uveoscleral outflow via sublethal thermal photostimulation of the pars plana.40 The retinal, optic nerve, ciliary body, trabecular, and uveoscleral dysfunctions in POAG may illustrate a universal stimulus-response (all improving following sublethal micropulsed photostimulation as per the reset phenomenon), but may also reflect a common underlying defect. In this regard, we believe that the findings of this study offer fertile grounds for further investigation. Confirmation of the findings of this pilot study by formal randomized prospective study is necessary. Confirmed, our findings may offer an important new conceptual understanding of the pathogenesis of POAG, as well as a new tool in clinical disease management.

5. Summary

Many if not most patients with POAG experience progressive visual loss despite maximal IOP lowering. The mechanism(s) of retinal laser treatment, described as the “Reset to Default” phenomenon, suggested that low-intensity/high-density SDM should improve retinal and visual function in any and all chronic progressive retinopathies. As all chronic progressive retinopathies — including AMD, DR, and RP — are neurodegenerative, and share this characteristic in common with POAG, reset theory and the findings of prior studies of SDM for chronic progressive retinopathies predicted that SDM should also be effective (neuroprotective) in POAG. We present evidence in the form of significant improve-ments in PERG, VEP, and photopic (chart) and mesopic

(ORP) visual function testing, that the effects of SDM in POAG are neuroprotective, as predicted. That these improvements are produced by selective sublethal laser treatment of the RPE indicates the presence of an underlying retinopathy in POAG. POAG retinopathy can be characterized by:

1. the absence of a clinically identifiable retinal morphologic or imaging abnormality in the pre-atrophic stage;

2. histologic and proteomic features of neurode-generation shared with other chronic progressive retinopathies;

3. reversible loss of neurotrophism and pre-apop-totic cellular dysfunction affecting retinal ganglion cells and the optic nerve, and thus visual function, following SDM, reflecting significant capacity for functional rescue and the potential for periodic retreatment to slow disease progression; and

4. that these effects appear to be mediated by the RPE, which we have shown to be dysfunctional in POAG by virtue of the response to SDM. Our results suggest that such a “POAG retinopathy”, left untreated, may help explain progression of POAG despite IOP lowering.

Acknowledgements

The authors wish to thank Taylor Blachley, of the Department of Biostatistics and Ophthalmology, University of Michigan School of Medicine (MI, USA) for his assistance in the data analysis.

Dr. Jeffrey K. Luttrull wishes to acknowledge the following financial disclosures: Ojai Retinal Technol-ogies, LLC: managing member, patent, equity; Retinal Protection Sciences, LLC: CEO, CMO, equity; Ocular Proteomics, LLC: consultant; Replenish, Inc.: patent, equity. The authors have no financial conflicts.


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