Any treatment that improves retinal function, and thus health, should also reduce disease severity, progression, untoward events, and visual loss.
15,16 In this study, we found that panmacular SDM improved retinal and visual function in dry AMD and IRDs without adverse treatment effects.
Recently, the mechanism of retinal laser treatment has been proposed and its clinical behavior described in “Reset to Default Theory.”
12 We believe the results of this study are supportive of Reset Theory. Fundamental to Reset Theory are certain predictions. First, SDM treatment should produce prompt improvement in retinal function.
4 Second, SDM treatment should be without any adverse effect by any measure.
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 of eetiology.
5,12 Fourth, SDM treatment should be “pathoselective,” improving dysfunctional tissue while having negligible effect on normal tissue. Thus, the more dysfunction present, the more measured improvement anticipated after treatment.
12 Fifth, SDM treatment-induced improvements in retinal function, or “retinal protection,” might wear off, needing periodic retreatments to maintain maximum clinical benefits.
11,12,17 Our study did not address the final prediction. However, we found that PERG may be useful for monitoring retinal function and preventive treatment responses, and it can be complemented by AMP and CVA testing. Regarding the first four claims, our findings support Reset Theory. Because there are few similarities between AMD and various IRDs, we report both to examine Reset Theory's prediction of SDM as a nonspecific trigger of disease-specific retinal repair. Reset Theory predicts both the positive treatment response across these different diagnoses, as well as the distinctive PERG responses observed in this study.
Pattern electroretinography was introduced in 1964 by Riggs and associates.
18 Unlike ganzfield and focal electroretinography (ERG) that use flash stimuli to measure photoreceptor function, PERG uses projected temporally and spatially alternating patterned stimuli of constant illumination to generate a neuroretinal electrophysiologic response that is either a series of transient responses at slow reversal rates (<5 Hz), or a periodic steady-state response at faster reversal rates (>5 Hz). Originally thought to be simply an alternate form of ERG, PERG was recognized in the 1980s to arise from different sources, principally the inner retina and ganglion cell layer.
19 Pattern electroretinography has since been shown to be an objective, sensitive, and highly reproducible indicator of both macular and ganglion cell function. Performed in a single 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 normalization of intraocular pressure.
22–24 As a measure of macular function, PERG is reduced by AMD and other maculopathies and responsive to therapies for neovascular AMD.
25 However, the result of any testing method will vary in a particular patient over time, even in the absence of clinical change. At times, such variability may make interpretation of test results difficult or even misleading. This is also true for PERG, but less so than for tests requiring higher levels of patient cooperation, such as visual field testing. Thus, it may be difficult to make a judgment on a particular patient, on a particular day, based on a single test result, particularly in a novel test application. Constrained by economic considerations and patient fatigue, serial testing in clinical practice for result averaging is impractical. Thus, it is reassuring that the SDM treatment effects, detected most sensitively by PERG, were consistent, robust, highly significant, and appear to be sustained for at least 6 months postoperatively in most patients. We expect that prospective trials will reveal the duration of the typical treatment response and indicate the ideal times to consider retreatment in order to maintain the maximum treatment benefits, reducing reliance on individual episodic testing results.
Of note is that many treated AMD eyes, and both eyes with Stargardt's disease, had extensive macular geographic atrophy included in confluent panmacular SDM treatment (
Fig. 1). These eyes had the poorest preoperative testing responses. However, linear regression analysis showed that these eyes also had the greatest improvements after treatment, by all measures. While a discussion of the implications of this observation is beyond the scope of this article, it is clear that functional tissue responsive to therapy remains within areas of geographic atrophy (
Figs. 1,
2,
6;
Table 6).
Paralleling the PERG responses, we found that VA measured by CVA testing significantly improved in AMD eyes, along with macular sensitivity measured by AMP. Improvements in visual function captured by AMP and CVA are important, indicating a benefit 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 AMD, who often note difficulty reading and functioning in low-light and low-contrast settings, common activities of daily living.
26–29
Identifying a benefit from prophylactic treatment of chronic progressive retinal diseases morphologically is inherently problematic. Abnormal retinal (physiologic) function precedes anatomic derangement and loss of visual function. It is initially asymptomatic and associated with normal retinal imaging. Abnormal visual function, by contrast, is generally symptomatic, resulting from anatomic derangements such as loss of photoreceptors, or the development of macular edema. Thus, reflecting advanced disease and end-organ damage detectable by retinal imaging, visual loss may be difficult to treat and is often irreversible. Likewise, retinal degeneration in chronic disease usually develops slowly, often over decades of retinal dysfunction, making morphologic detection of preventive treatment effects difficult, and then only after the fact. As current retinal disease management is predicated on the results of retinal imaging, treatment is necessarily offered late in the disease process. Treatment of advanced disease is most difficult and least rewarding, needing to be more potent, intensive, prolonged, usually more expensive, and still unlikely to restore normal VA. Interventions before visual loss and abnormalities detectable by retinal imaging thus offer the best prospect for preservation of normal visual function. Therefore, preventive treatments must necessarily be guided by retinal function testing rather than retinal imaging or VA testing. We call this “functionally guided (disease) management” (FGM). By allowing early diagnosis and disease monitoring before the onset of retinal anatomic changes, we expect FGM to improve visual outcomes when compared to current practices.
High-density/low-intensity SDM was developed in 2000 and first reported in 2005 as effective treatment for diabetic macular edema without laser-induced retinal damage.
4 Subthreshold diode micropulse laser applies sublethal thermal laser stimulation selectively to the RPE and has been reported to be effective for a number of retinal disorders without adverse treatment effects. In addition to DME, these include severe nonproliferative and proliferative DR, branch retinal vein occlusion, and central serous chorioretinopathy.
4–10,12 Unlike conventional photocoagulation for DME, SDM improves macular sensitivity by AMP.
27 Based on these observations, the “Reset to Default Theory” of SDM action was proposed to describe the clinical behavior of SDM.
12 Reset Theory suggests RPE heat-shock protein (HSP) activation as the principal therapeutic mechanism of SDM and all other forms of retinal laser treatment (other than cautery).
30 By triggering HSP-mediated RPE repair, RPE function, and thus health, is improved, leading to normalization of RPE cytokine expression and retinal autoregulation. Although HSP activation has long been theorized as one possible mechanism of retinal laser treatment, Reset Theory suggests the primacy of this pathway (via SDM's elimination of prior models, which theorized benefits from retinal photocoagulation) and provides a framework for understanding the resultant clinical implications arising from this mechanism.
10–12 The power of any theory rests in its ability to predict. Reset Theory has successfully predicted the unprecedented observation that SDM could reverse drug tolerance in neovascular AMD.
12 Reset Theory also predicted the treatment responses in dry AMD and IRDs we report here.
In principle, improved retinal function and health, if maintained, should produce long-term benefits, reducing both the rate of disease progression and incidence of adverse events. Our findings support the Reset Theory suggestion that, as a nonspecific stimulus of disease-specific retinal repair, SDM may produce salutary effects in a number of unrelated chronic progressive retinopathies. Further study is needed to confirm our findings and will reveal whether such effects, which may be thought of as “homeotrophic” as they normalize tissue function, will lead to long-term clinical benefits in AMD and IRDs. Longer experience with SDM for complications of DR is encouraging in this regard
5,8–10,12 (
Fig. 7).
Primary immutable disease factors such as age, diabetes mellitus, or inherited genetic defects are not amenable to HSP-mediated retinal repair. However, it is interesting to note that the presence of such abnormalities alone is generally insufficient to cause visual loss, as patients with chronic progressive retinopathies may enjoy normal or near-normal visual function for decades before developing clinical retinopathy and experiencing visual loss. This suggests that it may be secondary abnormalities, caused by the immutable defect, accumulating over time both “upstream” and “downstream” from the primary defect, that cause the cell death and anatomic derangement that result in visual loss. These secondary abnormalities are the ones most amenable to SDM-stimulated HSP-mediated repair.
5,9–12,16 By mitigating the effects of such secondary defects, retinal degeneration and visual loss might thus be delayed if not prevented. Only controlled long-term studies can determine if SDM retinal protective therapy will be helpful in this regard. However, before long-term treatment benefits can be hoped for, early improvements, such as those we reported here in dry AMD and IRDs, must be achieved.
This study had limitations common to pilot studies. It reported a small group of patients from a single center receiving a novel treatment assessed in a novel way. The data were obtained by retrospective review of medical records developed in the course of clinical patient care, rather than through a controlled prospective experimental protocol. However, while the data were limited and imperfect, they are not uninformative or unimportant.
31 The primary outcome measure derives from a well-known, objective, and reproducible measure of macular function, PERG, and is echoed by measures of visual function including AMP and CVA. Consistent with 15 years of clinical experience and prior reports, we observed SDM to consistently, safely, and significantly improve retinal and visual function in chronic progressive retinal degenerations including dry AMD and IRDs. This suggests that SDM, as retinal protective therapy, followed by timely functionally guided retreatment, has the potential to slow disease progression and reduce complications and visual loss over time in these disorders.
32 As a prompt indicator of retinal treatment effects, PERG may be valuable as a surrogate indicator in the development of new retinal therapies.
33 Quick determination of whether or not a new treatment improves retinal function (and thus retinal health) may expedite identification of therapies with promise, and abandonment of those without. These results may provide initial benchmarks. Further research is warranted.