Functionally Guided Retinal Protective Therapy for Dry · PDF fileFunctionally Guided Retinal Protective Therapy ... therapy for dry age-related macular and inherited retinal degenerations:

Retina

Functionally Guided Retinal Protective Therapy for DryAge-Related Macular and Inherited Retinal Degenerations:A Pilot Study

Jeffrey K. Luttrull1–3 and Benjamin W. L. Margolis2–4

1Private Practice, Ventura, California, United States2Ojai Retinal Technologies, LLC, Ojai, California, United States3EyEngineering, Inc., Ojai, California, United States4Santa Clara University, Dynamics and Control Systems Laboratory, Santa Clara, California, United States

Correspondence: Jeffrey K. Luttrull,3160 Telegraph Road, Suite 230,Ventura, CA 93003, USA;[email protected].

Submitted: September 11, 2015Accepted: November 30, 2015

Citation: Luttrull JK, Margolis BWL.Functionally guided retinal protectivetherapy for dry age-related macularand inherited retinal degenerations: apilot study. Invest Ophthalmol Vis Sci.2016;57:265–275. DOI:10.1167/iovs.15-18163

PURPOSE. To review the results of retinal function testing in eyes undergoing panmacularsubthreshold diode micropulse laser (SDM) prophylaxis for chronic progressive retinal disease.

METHODS. The records of all patients undergoing prophylactic panmacular SDM for high-riskage-related macular degeneration (AMD) and inherited photoreceptor degenerations (IRDs)examined by pattern electroretinography (PERG), automated microperimetry (AMP), andCentral Vision Analyzer (CVA) testing before and after treatment were reviewed.

RESULTS. A total of 158 consecutive eyes of 108 patients with AMD and 10 consecutive eyes of8 patients with IRDs, evaluated both before and after SDM by PERG, were eligible for study.The IRD diagnoses included rod–cone degeneration (four eyes), cone–rod degeneration(three eyes), and Stargardt’s disease (three eyes). In AMD, AMP was performed in 40consecutive eyes, and CVA in the subsequent 73 consecutive eyes concurrent with PERG. TheSDM treatment consisted of 1800 to 3000 confluent spots throughout the retinacircumscribed by the major vascular arcades, including the fovea (‘‘panmacular’’). Testingwas performed 1 week before and by 1 month after treatment. Results indicated that 149/168eyes were improved by primary PERG measures: 139/158 eyes with AMD by PERG low-contrast scan Magnitude D (MagD)(lV)/Magnitude (Mag)(lV) ratios (P ¼ 0.0001) and 10/10eyes with IRDs by 240 concentric ring scan MagD(lV)/Mag(lV) ratios (P ¼ 0.002). Snellenvisual acuity (VA) was unchanged, but macular sensitivity by AMP (P ¼ 0.0439) and mesopiccontrast VA by CVA (P ¼ 0.006) were improved. There were no adverse treatment effects.

CONCLUSIONS. Our findings suggest a role for SDM as retinal protective therapy in chronicprogressive retinal diseases. Pattern electroretinography enables (early, preventive) function-ally guided, rather than (late, therapeutic) image-guided, disease management.

Keywords: laser, macula, pattern electroretinogram, microperimetry, age-related maculardegeneration, retinitis pigmentosa, prophylaxis, retinal protection, retinal function testing,functionally guided disease management, prevention, central vision analyzer, contrastsensitivity

The complications of chronic progressive retinal diseases,such as diabetic retinopathy (DR) and age-related macular

degeneration (AMD), constitute major causes of visual lossworldwide.1 Currently, retinal imaging and visual acuity (VA)testing guide management.2 As end-organ structural damageand vision loss are late disease manifestations, treatmentinstituted at this point must be intensive, often prolongedand expensive, frequently failing to improve VA, and rarelyrestoring normal vision.3

Subthreshold diode micropulse laser (SDM) has been shownto be effective treatment for a number of retinal disorderswithout adverse treatment effects.4–12 By virtue of its safety andeffectiveness, SDM has been proposed as preventive treatmentfor DR.10 Recently, the ‘‘Reset to Default’’ hypothesis for SDMaction has been proposed.12 Reset Theory suggests SDM mightprotect the retina and slow progression of many chronicprogressive retinal diseases.11,12

On the basis of morphologic data suggesting slowing of AMDprogression following SDM (Luttrull JK, unpublished data,2012), 15 years of clinical experience with SDM, the conceptsof Reset Theory, and the absence of adverse treatment effects,SDM was offered in a retinal practice (JKL) as prophylaxis/retinal protection for high-risk AMD and inherited retinaldegenerations (IRDs). Herein we report the results of retinaland visual function testing in a group of patients evaluatedbefore and after SDM prophylaxis by pattern electroretinogra-phy (PERG), automated microperimetry (AMP), and CentralVision Analyzer (CVA) testing.

METHODS

This study adhered to the tenets of the Declaration of Helsinkiand was approved by an investigational review board (WesternIRB). The records of all patients in a retina subspecialty practice

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who were receiving SDM prophylaxis for high-risk AMD(defined by the presence of multiple large, diffuse, or bilateralmacular drusen; macular pigment disturbance; extrafoveal orsubfoveal geographic pigment atrophy; and/or choroidalneovascularization in the fellow eye) and IRDs, tested byPERG before and after SDM, were reviewed. In many eyes withAMD, additional visual function testing using AMP and CVA wasdone as well. Exclusionary criteria included other obfuscatingocular disease including epiretinal membrane or prior mem-brane peeling; DR; macular edema (except in retinitispigmentosa); current or prior macular retinal vascular occlu-sion; prior macular choroidal neovascular membrane (CNVM);optic atrophy or advanced glaucomatous nerve damage; poorPERG test quality and/or reliability indicated by poor electricalconductivity or excessive (five or more) testing artifacts;subfoveal CNVM in the treated eye; active CNVM in the felloweye requiring anti-VEGF treatment within 1 month before SDMtreatment, or between the time of SDM treatment andpostoperative testing; and loss to follow-up before postoper-ative testing. Testing was performed within 1 week before SDMtreatment, and within 1 month after treatment. As the settingfor this pilot study was a solo private clinical retinal practice,the choice of testing modalities used reflected availabletechnology, not necessarily ideal technology.

Pattern Electroretinography Testing

Pattern electroretinography was performed by using standardprotocols of a commercially available system (Diopsys Nova-ERG; Diopsys Corp., Pine Brook, NJ, USA) according toInternational Society for Clinical Electrophysiology of Visionstandards.13 Both eyes were tested simultaneously andrecorded individually, undilated, and refracted for a 60-cmtesting distance. For all visual stimuli, a luminance patternoccupying a 258 visual field was presented with a luminancereversal rate of 15 Hz.

For IRDs, a PERG ‘‘concentric ring’’ visual stimulusoptimized for analyzing peripheral retinal sensitivity was used,presenting with a circle of 1 luminance and an outer ring withthe contrasting luminance. The concentric ring stimulus usedtwo subclasses of stimuli with an inner circle occupying avisual field of 168 and 248. The concentric ring stimuli used amean luminance of 117.6 cd/m2 with a contrast of 100%.

For AMD, in addition to the CR scans, contrast sensitivity(CS) stimuli were used, presenting a ‘‘checkerboard’’-like gridof 64 3 64 cells, alternating luminance levels, recording a high-contrast (HC) test with a mean luminance of 112 cd/m2 and acontrast of 85%, and a low-contrast (LC) test with a meanluminance of 106.4 cd/m2 and a contrast of 75%.

Patient and equipment preparation were carried outaccording to Diopsys guidelines. Signal acquisition and analysisfollowed a standard glaucoma screening protocol.14 Testindices available for analysis included ‘‘Magnitude D’’(MagD[lV]), ‘‘Magnitude (lV)’’ (Mag[lV]), and the‘‘MagD(lV)/Mag(lV)’’ ratio. Magnitude D is the frequencyresponse of the time-domain–averaged signal in microvolts(lV). Inner retinal and/or ganglion cell dysfunction causesignal latencies resulting in magnitude and phase variabilitythat reduce MagD(lV) by phase cancelation. Magnitude (lV)measures the frequency response of the total signal inmicrovolts (lV). Magnitude (lV) reflects the signal strengthand electrode impedance of the individual test sessions, as wellas a gross measure of inner retina and ganglion function. TheMagD(lV)/Mag(lV) ratio thus provides a measure of patientresponse normalized to that particular test’s electrical quality.In the healthy eye, MagD(lV) should roughly equal Mag(lV).Thus, the closer MagD(lV)/Mag(lV) is to unity, the morenormal the macular function.

Automated Microperimetry Testing

Automated microperimetry (MAIA; Centervue, Inc., Fremont,CA, USA) testing was performed according to manufacturerrecommendations. Following pupillary dilation, the patientwas seated at the MAIA instrument with the head positionedand aligned to the testing screen. The patient was asked tomaintain fixation on the fixation target and to signal notice oflight points appearing on the instrument screen, projected atvarious thresholds and locations within the macular region, bydepressing a hand-held button. Data thus recorded includedpercentage-reduced thresholds, average threshold, and percentinitial and final fixation preferences (P1 and P2).

Central Vision Analyzer Testing

Central Vision Analyzer was performed in accordance withmanufacturer guidelines (Visoptics, Mechanicsberg, PA, USA).The CVA is an FDA-approved measure of visual acuity. Athresholding algorithm is used to dynamically determinelogMAR central VA at six different levels of contrast undermesopic testing conditions, ranging from 99% to 35%, andsimulating real-world visual demands, using an interactivecomputer interface. Each eye was tested undilated and bestcorrected.

Subthreshold Diode Micropulse Laser Treatment

Following informed consent and pupillary dilation, topicalproparacaine was applied to the cornea. A Mainster macularcontact lens (magnification factor 31.05; Ocular Instruments,Mentor, OH, USA) was placed on the cornea with the aid ofviscoelastic. Under minimum slit-lamp illumination, the entireposterior retina circumscribed by the major vascular arcadeswas ‘‘painted’’ with 1800 to 3000 confluent spot applicationsof SDM (‘‘panmacular’’ treatment). The laser parameters usedwere 810-nm wavelength, 200-lm aerial spot size, 5% dutycycle; and 1.4-W power and 0.15-second duration (OculightSLx; Iris Medical/Iridex Corp., Mountain View, CA, USA).

Statistical Analysis

All data was de-identified before statistical analysis. All analyseswere performed by using linear mixed models predicting themeasure, with an indicator for time as a covariate, adjusting forleft or right eye, and including a random patient intercept tocorrect for possible intereye correlation. Finally, univariatelinear mixed models, predicting the difference (post- minuspretreatment) with pretreatment value as covariate, wereperformed. The coefficients and P values from six such modelswere compared.

Definitions

In the following, ‘‘macular function’’ and ‘‘retinal function’’refer to the physiology and electrophysiology of the retina. Incontrast, ‘‘visual function’’ is used to refer to measurementssuch as VA, visual fields, and CS.

RESULTS

In all, 220 eyes of 166 patients undergoing panmacular SDMprophylaxis for high-risk AMD and IRDs, between June 2012and August 2015, were identified. These included 210 eyes of158 patients treated for AMD; and 10 eyes of 8 patients treatedfor IRDs. Of these, 158 consecutive eyes of 108 patients withAMD, and 10 consecutive eyes of 8 patients with IRDs wereevaluated before and after SDM by PERG and thus eligible for

Functionally Guided Retinal Protective Therapy IOVS j January 2016 j Vol. 57 j No. 1 j 266


study. The IRD diagnoses included rod–cone degeneration(four eyes), cone–rod degeneration (three eyes), and Star-gardt’s disease (three eyes). Fifty-two eyes with AMD weretreated before the beginning of PERG testing and thusineligible for study. In the eligible AMD group, 25 patientswere treated bilaterally. In the remainder, the fellow eye wasexcluded. The most common reasons for fellow eye exclusionin the AMD group were inactive CVNM or disciform scarring,epiretinal membrane, or current or prior retinal vascularocclusion. In the IRD group, the fellow eye of two patients wasblind. Four patients with IRDs elected initial treatment in oneeye only.

Visual function testing was performed in 113 consecutiveAMD eyes concurrently with PERG, including AMP in 40consecutive eyes, and CVA testing in the subsequent 73consecutive eyes.

Overall, 149/168 eyes were improved by PERG after SDM.Snellen VAs, ranging from 20/20 to count fingers preopera-tively, were unchanged (P¼ 0.75, SD pre- versus postoperative¼ �0.016). Patients with geographic atrophy frequentlyreported prompt subjective lightening or disappearance oftheir prior central scotoma. There were no adverse treatmenteffects, such as treatment-associated visual loss, or evidence oflaser-induced retinal damage by clinical examination, spectral-domain optical coherence tomography, or fundus photography(Figs. 1–3).

Of 158 eyes with high-risk dry AMD, 139 were improved byPERG after SDM. Post SDM, CS HC MagD(lV)/Mag(lV) ratioswere not significantly improved (P ¼ 0.09). However, CS LCMagD(lV)/Mag(lV) ratios (P ¼ 0.0001) and CS LC MagD(lV)amplitudes (P ¼ 0.02) were significantly improved (Figs. 1–4;Tables 1, 2).

Of 10 eyes with IRDs, 10 improved by PERG after SDM.Concentric ring 168 testing was not improved (P ¼ 0.19), butCR 248 MagD(lV)/Mag(lV) ratios (P ¼ 0.002) and MagD(lV)amplitudes (P ¼ 0.006) were both improved (Fig. 5; Table 3).

In AMD, of the preoperative AMP measures, only theaverage thresholds were improved after SDM (P ¼ 0.0439).Central Vision Analyzer testing showed significant improve-ments in VA for all six levels of contrast, from 99% to 35% (Pvalues: 0.049–0.006; Tables 4, 5).

Linear regression analyses revealed significant negativecorrelations for all testing measures in both AMD and IRDs,indicating that the worse the preoperative measure, the greaterthe likelihood of postoperative improvement (Fig. 6; Table 6).

At the time of writing, 28/33 eyes improved by PERG at 1-month post SDM remained improved by PERG at 6 to 9 monthspost SDM.

DISCUSSION

Any treatment that improves retinal function, and thus health,should also reduce disease severity, progression, untowardevents, and visual loss.15,16 In this study, we found thatpanmacular SDM improved retinal and visual function in dryAMD and IRDs without adverse treatment effects.

Recently, the mechanism of retinal laser treatment has beenproposed and its clinical behavior described in ‘‘Reset toDefault Theory.’’12 We believe the results of this study aresupportive of Reset Theory. Fundamental to Reset Theory arecertain predictions. First, SDM treatment should produceprompt improvement in retinal function.4 Second, SDMtreatment should be without any adverse effect by anymeasure.4,9 Third, SDM treatment should produce disease-specific benefits in a wide variety of disorders, including most,if not all, chronic progressive retinal disorders, regardless ofeetiology.5,12 Fourth, SDM treatment should be ‘‘pathoselective,’’improving dysfunctional tissue while having negligible effecton normal tissue. Thus, the more dysfunction present, themore measured improvement anticipated after treatment.12

Fifth, SDM treatment-induced improvements in retinal func-tion, or ‘‘retinal protection,’’ might wear off, needing periodicretreatments to maintain maximum clinical benefits.11,12,17

Our study did not address the final prediction. However, wefound that PERG may be useful for monitoring retinal functionand preventive treatment responses, and it can be comple-mented by AMP and CVA testing. Regarding the first fourclaims, our findings support Reset Theory. Because there arefew similarities between AMD and various IRDs, we reportboth to examine Reset Theory’s prediction of SDM as anonspecific trigger of disease-specific retinal repair. ResetTheory predicts both the positive treatment response acrossthese different diagnoses, as well as the distinctive PERGresponses observed in this study.

Pattern electroretinography was introduced in 1964 byRiggs and associates.18 Unlike ganzfield and focal electroreti-nography (ERG) that use flash stimuli to measure photorecep-tor function, PERG uses projected temporally and spatiallyalternating patterned stimuli of constant illumination togenerate a neuroretinal electrophysiologic response that iseither a series of transient responses at slow reversal rates (<5Hz), or a periodic steady-state response at faster reversal rates(>5 Hz). Originally thought to be simply an alternate form ofERG, PERG was recognized in the 1980s to arise from differentsources, principally the inner retina and ganglion cell layer.19

Pattern electroretinography has since been shown to be anobjective, sensitive, and highly reproducible indicator of bothmacular and ganglion cell function. Performed in a single

TABLE 1. Comparison of Various Measured Values (Post- Minus Pretreatment), PERG Contrast Sensitivity Test Eyes, for High-Risk AMD in Responseto Panmacular SDM Laser Retinal Protective Therapy

Variable Mean (SD) Median (IQR) P Value

MagD(lV)/Mag(lV) ratio, high contrast 0.05 (0.19) 0.04 (�0.07, 0.17) 0.09

MagD(lV)/Mag(lV) ratio, low contrast 0.08 (0.17) 0.08 (0.00, 0.17) 0.001

MagD(lV) measure, high contrast 0.05 (0.32) 0.05 (�0.17, 0.26) 0.37

MagD(lV) measure, low contrast 0.08 (0.25) 0.07 (�0.06, 0.21) 0.02

Mag(lV) measure, high contrast �0.04 (0.34) �0.04 (�0.23, 0.14) 0.42

Mag(lV) measure, low contrast �0.03 (0.33) 0.01 (�0.19, 0.17) 0.55

The table shows the comparisons of interest for the PERG contrast sensitivity test data set. Each row shows the difference (post- minuspretreatment) in MagD(lV)/Mag(lV) ratio, MagD(lV) measure, or Mag(lV) measure at the two contrast options. To test whether the meandifference is different from zero, linear mixed models predicting the measure were used, with an indicator for time as a covariate, also adjusting forleft or right eye. The P values are those associated with the time (pre versus post) regression coefficient. A significant P value indicates that themean difference is significantly different from zero. The table shows that MagD(lV)/Mag(lV) ratio, low contrast, as well as MagD(lV) measure, lowcontrast, are significantly higher post treatment than pre treatment (positive values indicate higher posttreatment values, negative values indicatehigher pretreatment values). This method accounts for intereye correlation. IQR, interquartile range.



center by experienced personnel, PERG has been shown to be

reliable and highly repeatable.18–25 As ours was a clinic-based

pilot study, the diagnostic technologies we used are not

necessarily ideal, but simply the technologies available to us.

Of these, we found PERG the most informative. In the absence

of optic nerve disease, PERG responses reflect macular

function, measured at the inner retina and ganglion cell layer

and reflecting input from the outer retina.18–25 Pattern

electroretinography is a sensitive test that can be difficult to

perform well.20 However, as noted above (Odom et al.20), we

also found that PERG done in a single location on the same

machine by the same technician with the same technique can

provide useful and consistent information.20,21

As one of the earliest detectors of ganglion cell dysfunction,

PERG is a sensitive predictor of glaucoma and progression,

anticipating visual field loss by years, and improves following

FIGURE 1. Infrared (left) and fundus autofluorescence photographs (right) of right eye (top) and left eye (bottom) of a patient with AMD andgeographic pigmentary atrophy 3 months after panmacular SDM treatment. Visual acuity of right eye before and after treatment, 20/100. Visualacuity of left eye before treatment, 20/70; after treatment, 20/50. Note absence of retinal laser lesions.



normalization of intraocular pressure.22–24 As a measure ofmacular function, PERG is reduced by AMD and othermaculopathies and responsive to therapies for neovascularAMD.25 However, the result of any testing method will vary in aparticular patient over time, even in the absence of clinicalchange. At times, such variability may make interpretation oftest results difficult or even misleading. This is also true forPERG, but less so than for tests requiring higher levels ofpatient cooperation, such as visual field testing. Thus, it may bedifficult to make a judgment on a particular patient, on aparticular day, based on a single test result, particularly in anovel test application. Constrained by economic consider-ations and patient fatigue, serial testing in clinical practice forresult averaging is impractical. Thus, it is reassuring that theSDM treatment effects, detected most sensitively by PERG,were consistent, robust, highly significant, and appear to besustained for at least 6 months postoperatively in mostpatients. We expect that prospective trials will reveal the

duration of the typical treatment response and indicate theideal times to consider retreatment in order to maintain themaximum treatment benefits, reducing reliance on individualepisodic testing results.

Of note is that many treated AMD eyes, and both eyes withStargardt’s disease, had extensive macular geographic atrophyincluded in confluent panmacular SDM treatment (Fig. 1).These eyes had the poorest preoperative testing responses.However, linear regression analysis showed that these eyes alsohad the greatest improvements after treatment, by allmeasures. While a discussion of the implications of thisobservation is beyond the scope of this article, it is clear that

FIGURE 2. Spectral-domain optical coherence tomography of eye withhigh-risk AMD before (above) and after (below) panmacular SDMretinal protective therapy. Note absence of retinal laser damage.

FIGURE 3. Posttreatment fundus autofluoresence photograph of eyewith age-related geographic atrophy, after panmacular SDM retinalprotective therapy. Note absence of laser lesions. Visual acuity beforetreatment, 20/200; after treatment, 20/60.

TABLE 2. Comparison of Various Measured Values (Post- Minus Pretreatment), Concentric Ring Scan Eyes With High-Risk AMD Treated WithPanmacular SDM Laser Retinal Protective Therapy


MagD(lV)/Mag(lV) ratio, 248 0.02 (0.21) 0.01 (�0.09, 0.12) 0.44

MagD(lV)/Mag(lV) ratio, 168 0.05 (0.22) 0.07 (�0.10, 0.20) 0.07

MagD(lV) measure, 248 0.04 (0.38) 0.02 (�0.20, 0.23) 0.52

MagD(lV) measure, 168 0.04 (0.26) 0.03 (�0.13, 0.21) 0.27

Mag(lV) measure, 248 0.01 (0.36) 0.00 (�0.18, 0.20) 0.86

Mag(lV) measure, 168 �0.04 (0.36) �0.03 (�0.21, 0.15) 0.41

The table shows the comparisons of interest for the PERG concentric ring test data set. Each row shows the difference (first post- minuspretreatment) in MagD(lV)/Mag(lV) ratio, MagD(lV) measure, or Mag(lV) measure at 248 and 168. To test whether the mean difference is differentfrom zero, linear mixed models predicting the measure were used, with an indicator for time as a covariate, also adjusting for left or right eye. The P

values are those associated with the time (pre versus post) regression coefficient. A significant P value indicates that the mean difference issignificantly different from zero. The table shows that all comparisons are not statistically significant. This method accounts for intereye correlation.



functional tissue responsive to therapy remains within areas ofgeographic atrophy (Figs. 1, 2, 6; Table 6).

Paralleling the PERG responses, we found that VA measuredby CVA testing significantly improved in AMD eyes, along withmacular sensitivity measured by AMP. Improvements in visualfunction captured by AMP and CVA are important, indicating abenefit from SDM treatment in the overall quality of visual

function that is not revealed by conventional chart VA testing.

As loss of CS is the earliest visual abnormality in AMD, and thus

a sensitive indicator of disease, it is notable that the

improvements in dry AMD following SDM were reflected most

by measures of CS. The SDM-elicited improvements in visual

function, particularly measured by CVA testing under mesopic

conditions, suggest a practical benefit for patients with dry

FIGURE 4. Scatterplots of AMD PERG high- and low-contrast MagD(lV)/Mag(lV) ratios before and after SDM treatment.



AMD, who often note difficulty reading and functioning in low-light and low-contrast settings, common activities of dailyliving.26–29

Identifying a benefit from prophylactic treatment of chronicprogressive retinal diseases morphologically is inherentlyproblematic. Abnormal retinal (physiologic) function precedesanatomic derangement and loss of visual function. It is initiallyasymptomatic and associated with normal retinal imaging.Abnormal visual function, by contrast, is generally symptom-atic, resulting from anatomic derangements such as loss ofphotoreceptors, or the development of macular edema. Thus,reflecting advanced disease and end-organ damage detectableby retinal imaging, visual loss may be difficult to treat and isoften irreversible. Likewise, retinal degeneration in chronicdisease usually develops slowly, often over decades of retinaldysfunction, making morphologic detection of preventivetreatment effects difficult, and then only after the fact. Ascurrent retinal disease management is predicated on the resultsof retinal imaging, treatment is necessarily offered late in thedisease process. Treatment of advanced disease is most difficultand least rewarding, needing to be more potent, intensive,prolonged, usually more expensive, and still unlikely to restorenormal VA. Interventions before visual loss and abnormalitiesdetectable by retinal imaging thus offer the best prospect forpreservation of normal visual function. Therefore, preventivetreatments must necessarily be guided by retinal functiontesting rather than retinal imaging or VA testing. We call this‘‘functionally guided (disease) management’’ (FGM). By allow-ing early diagnosis and disease monitoring before the onset ofretinal anatomic changes, we expect FGM to improve visualoutcomes when compared to current practices.

High-density/low-intensity SDM was developed in 2000 andfirst reported in 2005 as effective treatment for diabeticmacular edema without laser-induced retinal damage.4 Sub-threshold diode micropulse laser applies sublethal thermallaser stimulation selectively to the RPE and has been reportedto be effective for a number of retinal disorders withoutadverse treatment effects. In addition to DME, these includesevere nonproliferative and proliferative DR, branch retinalvein occlusion, and central serous chorioretinopathy.4–10,12

Unlike conventional photocoagulation for DME, SDM improvesmacular sensitivity by AMP.27 Based on these observations, the‘‘Reset to Default Theory’’ of SDM action was proposed toT

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TABLE 4. Summary of Calculated Difference (Post- Minus Pretreat-ment) for Eyes With Age-Related and Inherited Retinal DegenerationsTreated With Panmacular SDM Retinal Protective Therapy, AMP EyesAccounting for Possible Intereye Correlation


Reduced threshold

(Nmiss ¼ 8) 2.72 (16.98) 0.00 (�6.75, 6.75) 0.8487

Average threshold 11.12 (28.02) 0.35 (�0.85, 2.65) 0.0439

P1 �4.85 (33.30) 0.50 (�12.00, 7.50) 0.4664

P2 �0.08 (21.04) 0.00 (�5.50, 5.00) 0.9049

The table shows the comparisons of interest for the AMP data set.Each row shows the difference (follow-up minus pre operation) inreduced and average threshold as well as P1 and P2. To test whetherthe mean difference is different from zero, linear mixed modelspredicting the measure were used, with an indicator for time(preoperative versus follow-up) as a covariate, also adjusting for leftor right eye. The P values are those associated with the time(preoperative versus follow-up) regression coefficient. A significant P

value indicates that the mean difference is significantly different fromzero. Only average threshold is significantly different preoperativelyversus follow-up. Nmiss, number of missing data points for the reducedthreshold measure; P1, initial fixation preference; P2, final fixationpreference.



describe the clinical behavior of SDM.12 Reset Theory suggestsRPE heat-shock protein (HSP) activation as the principaltherapeutic mechanism of SDM and all other forms of retinallaser treatment (other than cautery).30 By triggering HSP-mediated RPE repair, RPE function, and thus health, isimproved, leading to normalization of RPE cytokine expressionand retinal autoregulation. Although HSP activation has longbeen theorized as one possible mechanism of retinal lasertreatment, Reset Theory suggests the primacy of this pathway

(via SDM’s elimination of prior models, which theorizedbenefits from retinal photocoagulation) and provides aframework for understanding the resultant clinical implicationsarising from this mechanism.10–12 The power of any theoryrests in its ability to predict. Reset Theory has successfullypredicted the unprecedented observation that SDM couldreverse drug tolerance in neovascular AMD.12 Reset Theoryalso predicted the treatment responses in dry AMD and IRDswe report here.

FIGURE 5. Scatterplots of IRD PERG 248 concentric ring MagD(lV)/Mag(lV) ratios and MagD(lV) amplitudes before and after SDM treatment.



TABLE 5. Summary of Calculated Difference (Post- Minus Pretreatment), Visual Acuity on LogMAR Scale Measured by the Central Visual AcuityAnalyzer in Eyes With Age-Related and Inherited Retinal Degenerations Treated With Panmacular SDM Retinal Protective Therapy

Variable N Mean (SD) Median (IQR) P Value

99% Contrast 73 �0.146 (0.511) �0.073 (�0.336, 0.114) 0.02

75% Contrast 73 �0.148 (0.488) �0.058 (�0.301, 0.107) 0.01

65% Contrast 73 �0.151 (0.458) �0.109 (�0.301, 0.067) 0.006

53% Contrast 73 �0.107 (0.444) �0.032 (�0.248, 0.097) 0.049

43% Contrast 73 �0.103 (0.370) 0.000 (�0.250, 0.058) 0.02

35% Contrast 73 �0.104 (0.416) �0.044 (�0.248, 0.105) 0.03

The table shows the difference (post- minus pretreatment) in logMAR visual acuity at six levels of contrast measured under mesopic testingconditions. To test whether the mean difference is different from zero, linear mixed models predicting the visual acuity were used, with an indicatorfor time as a covariate, also adjusting for left or right eye. The table shows significant improvement at all contrast levels. This method accounts forintereye correlation.

FIGURE 6. Scatterplots of the linear regression analysis of the dry AMD PERG MagD(lV)/Mag(lV) (top) and MagD(lV) (bottom) ratios. Note thenegative slope, statistically significant in each, indicating that the worse the preoperative value, the greater the degree of postoperativeimprovement.



In principle, improved retinal function and health, ifmaintained, should produce long-term benefits, reducing boththe rate of disease progression and incidence of adverse events.Our findings support the Reset Theory suggestion that, as anonspecific stimulus of disease-specific retinal repair, SDM mayproduce salutary effects in a number of unrelated chronicprogressive retinopathies. Further study is needed to confirmour findings and will reveal whether such effects, which maybe thought of as ‘‘homeotrophic’’ as they normalize tissuefunction, will lead to long-term clinical benefits in AMD andIRDs. Longer experience with SDM for complications of DR isencouraging in this regard5,8–10,12 (Fig. 7).

Primary immutable disease factors such as age, diabetesmellitus, or inherited genetic defects are not amenable to HSP-mediated retinal repair. However, it is interesting to note thatthe presence of such abnormalities alone is generallyinsufficient to cause visual loss, as patients with chronicprogressive retinopathies may enjoy normal or near-normalvisual function for decades before developing clinical retinop-athy and experiencing visual loss. This suggests that it may besecondary abnormalities, caused by the immutable defect,accumulating over time both ‘‘upstream’’ and ‘‘downstream’’from the primary defect, that cause the cell death and anatomicderangement that result in visual loss. These secondaryabnormalities are the ones most amenable to SDM-stimulatedHSP-mediated repair.5,9–12,16 By mitigating the effects of suchsecondary defects, retinal degeneration and visual loss mightthus be delayed if not prevented. Only controlled long-term

studies can determine if SDM retinal protective therapy will behelpful in this regard. However, before long-term treatmentbenefits can be hoped for, early improvements, such as thosewe reported here in dry AMD and IRDs, must be achieved.

This study had limitations common to pilot studies. Itreported a small group of patients from a single centerreceiving a novel treatment assessed in a novel way. The datawere obtained by retrospective review of medical recordsdeveloped in the course of clinical patient care, rather thanthrough a controlled prospective experimental protocol.However, while the data were limited and imperfect, they arenot uninformative or unimportant.31 The primary outcomemeasure derives from a well-known, objective, and reproduc-ible measure of macular function, PERG, and is echoed bymeasures of visual function including AMP and CVA. Consistentwith 15 years of clinical experience and prior reports, weobserved SDM to consistently, safely, and significantly improveretinal and visual function in chronic progressive retinaldegenerations including dry AMD and IRDs. This suggests thatSDM, as retinal protective therapy, followed by timelyfunctionally guided retreatment, has the potential to slowdisease progression and reduce complications and visual lossover time in these disorders.32 As a prompt indicator of retinaltreatment effects, PERG may be valuable as a surrogateindicator in the development of new retinal therapies.33 Quickdetermination of whether or not a new treatment improvesretinal function (and thus retinal health) may expediteidentification of therapies with promise, and abandonment of

TABLE 6. Comparison of Various Measured Values (Post- Minus Pretreatment), of PERG Contrast Sensitivity Testing of Eyes With Dry Age-RelatedMacular Degeneration

Variable Mean (SD) Median (IQR) P Value*

MagD(lV)/Mag(lV) ratio, high contrast 0.04 (0.19) 0.05 (�0.06, 0.14) 0.0334

MagD(lV)/Mag(lV) ratio, low contrast 0.11 (0.18) 0.11 (0.02, 0.21) <0.0001

MagD(lV) measure, high contrast 0.03 (0.28) 0.06 (�0.17, 0.24) 0.3348

MagD(lV) measure, low contrast 0.10 (0.25) 0.09 (�0.04, 0.22) 0.0006

Mag(lV) measure, high contrast �0.07 (0.37) �0.05 (�0.30, 0.12) 0.0968

Mag(lV) measure, low contrast �0.04 (0.36) 0.00 (�0.24, 0.13) 0.2688

The table shows the post- minus pretreatment differences of various measures among the PERG contrast sensitivity testing of eyes with dry age-related macular degeneration. Paired t-tests were performed to determine whether each measure differed significantly pre treatment versus posttreatment. MagD(lV)/Mag(lV) ratio, high and low contrast, were both significantly (P¼0.03 and P < 0.0001, respectively) higher, on average, posttreatment. MagD(lV), low contrast, was also significantly (P¼ 0.006) higher post treatment.

* Paired t-tests.

FIGURE 7. Intravenous fundus fluorescein angiograms of eye with severe nonproliferative diabetic retinopathy before (left) and after (right)panretinal SDM. Note decreased micro- and macrovascular leakage, with reperfusion of local ischemia.



those without. These results may provide initial benchmarks.Further research is warranted.

Acknowledgments

The authors thank Taylor Blachley, MS, and David C. Musch, PhD,MPH, of the Department of Biostatistics, University of MichiganMedical School, for their assistance in the statistical analysis ofstudy data; and Stephen H. Sinclair, MD, for his editorial assistance.

The authors alone are responsible for the content and writing ofthe paper.

Disclosure: J.K. Luttrull, None; B.W.L. Margolis, None

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Functionally Guided Retinal Protective Therapy for Dry · PDF fileFunctionally Guided Retinal Protective Therapy ... therapy for dry age-related macular and inherited retinal degenerations: