Commentary: Hyperreflective dots - An imaging biomarker of inflammation?

Today, with the advancement of optical coherence tomography (OCT) technology, small punctate lesions measuring only a few microns can be easily detected. The study by Hanumunthadu et al.[1] have presented their astute findings of hyperreflective dots (HRDs) in eyes with central serous chorioretinopathy (CSC) and have renewed our interest in this novel and enigmatic observation. A brief reappraisal of the historical literature related to HRDs will help us understand the finer nuances of this entity.

HRDs (or hyperreflective foci) were described using OCT in 2009 by Coscas et al.[2] who reported their presence in neovascular age-related macular degeneration (AMD). These HRDs were noted in all retinal layers, especially around fluid accumulation in intraretinal cystoid spaces. At the same time, Bolz et al.[3] in 2009 showed HRDs in patients with diabetic macular edema (DME). Similar to the observations by Coscas et al., they observed HRDs in all the retinal layers and found them to be unrelated to microaneurysms (on slit-lamp biomicroscopy and fundus photography). While these studies could not determine the significance of HRDs, they generated a great interest among retina and uveitis specialists in determining the cause and significance of these findings. Subsequently, several authors observed HRD in other conditions such as retinal vein occlusions (RVOs),[4] CSC,[5] and Coats disease,[6] among others.

We now know that HRDs are typically described as well-circumscribed punctate lesions (approximately 20–40 μm in diameter) of equal or higher reflectivity than the retinal pigment epithelium.[7] There are a number of theories regarding the etiopathogenesis of HRDs. In the absence of a direct histopathological correlation, only indirect associations can be drawn. We rely on the conclusions drawn by various authors from OCT scans and other imaging tools such as infrared imaging.[2478] Certain authors such as Bolz et al.[3] have postulated that these foci may represent small intraretinal protein and/or lipid deposits which may be precursors of hard exudates. However, since then, there have been studies which differentiated HRD from lipid exudates based on their morphology.[789] In addition, HRDs show rapid resolution and reduction in the number following therapies such as antivascular growth factor agents (anti-VEGF) and corticosteroids, which is inconsistent with intraretinal lipid. These studies hypothesize that HRDs could represent activated glial cells (the primary immune cells in the retina) which migrate and secrete proinflammatory mediators.[10]

The study by Chatziralli et al.[11] tested the hypothesis that HRDs can independently predict visual outcome in patients with macular edema due to various causes. On the same lines, Coscas et al.[8] evaluated the prognostic value of HRDs in eyes with neovascular AMD. These studies showed that higher number of HRDs were significantly associated with suboptimal gains in visual acuity with standard anti-VEGF therapies. Nonresponders to anti-VEGF therapy were found to have high number of HRD on OCT scans. These findings, coupled with the popular hypothesis that HRDs are inflammatory in origin, led authors such as Hwang et al.[7] and Coscas et al.[8] to believe that anti-inflammatory therapies such as intravitreal dexamethasone implants may have a greater role in eyes with high number of HRDs.

In the context of CSC, Ojima et al.[5] in 2007 observed punctate areas of intense reflectivity (which today we recognize as HRDs) more frequently with chronic CSC compared with acute cases. Since there are very few articles in the literature that describe HRDs in CSC,[51213] it is not clear whether the pathogenesis of HRDs in CSC is similar to AMD, DME, and RVO, among other conditions. The study by Hanumunthadu, et al.[1] further helps us understand that alterations such as increased choroidal thickness, higher neurosensory detachment, and chronicity of the disease may result in development of HRD. However, questions still remain – are HRDs formed as a result of inflammation across the entire spectrum of retinal pathologies ranging from AMD, to DME, and CSC? Thus far, we do not have data from cytokine or interleukin analysis from intraocular fluids in eyes with HRD to demonstrate higher levels of proinflammatory mediators compared with control subjects (with no or few HRDs). We also recognize that the theory of microglial migration and proliferation does not have a direct histological correlation. Could the increased choroidal hyperpermeability in CSC directly impact the immune cell migration? The location of HRDs within the retinal layers may also have prognostic significance, but this has not been addressed satisfactorily thus far. Based on the evidence (direct and indirect) in the literature, retina specialists world over may be more inclined toward treating patients with HRD on OCT using corticosteroids. Whether this approach will truly impact the outcomes of our patients remains to be evaluated conclusively.