Hyperreflective Foci in Optical Coherence Tomography
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Disease Entity
Hyper-reflective foci (HRF) also known as hyper-reflective dots are described in spectral - domain/swept source optical coherence tomography scans of the macula in various retinal conditions including uveitis[1]. A biomarker is an objective characteristic or parameter which can be measured reproducibly and used to predict the presence or progression of a disease condition[2].
Pathophysiology
The exact histopathological correlation of HRF is still elusive. Initially they were thought to be derived from lipids and lipid laden macrophages hence a precursor of hard exudates. They are thought to be derived from activated microglial cells and hence may indicate an inflammatory component in various retinal vascular and degenerative conditions. They have also been postulated as precursors of hard exudates hence made of lipid and lipid-laden macrophages. They have also been thought to arise from migrating retinal pigment epithelial (RPE) cells and disintegrating photoreceptors, in patients with corresponding fundus pigmentary changes[3].
History
Hyper-reflective foci were first described by Coscas et al in 2009 in patients with wet age-related macular degeneration[4]. They described them as small round or dot-like lesions distributed throughout all the retinal layers and in fluid containing cystoid spaces. Bolz et al in 2009 described them in treatment-naive patients with diabetic macular edema and since then these lesions have been extensively researched as potential biomarkers in various retinal conditions as markers of progression and response to treatment[5].
Characteristic features in imaging
Hyper-reflective foci are typically dot-like or round, regular lesions seen in all the retinal layers and choroid. Their reflectivity is similar to the retinal nerve fiber layer and less than 30 microns in size. They typically lack back-shadowing and do not have a representative visible fundus lesion. They are differentiated from hard exudates by the presence of back shadowing, irregular margins, variable size, corresponding yellowish fundus lesions, and their location in the outer plexiform layer. They are differentiated from blood vessels by the presence of back shadowing, size > 30 microns, and the location at the inner retinal layers. HRF present in the macula 1500 microns from the centre of the fovea are usually considered significant in various studies evaluating them.
Recently these foci have also been found in the choroid in various conditions like diabetic macular edema. They have been postulated to occur due to the outward migration of the activated microglial cells following disruption of the ellipsoid zone and external limiting membrane in various retinal conditions.
Significance in Diabetic macular edema (DME)
Diabetic macular edema (DME) is the commonest cause of visual morbidity in patients with diabetic retinopathy. Though various anti-VEGF agents and steroid implants are available for managing DME, it is still difficult to predict the response to therapy in these patients. Hence biomarkers are essential to choosing the suitable therapeutic agent and predicting treatment response in patients with DME.
Bolz et al described HRF to be made of intra-retinal proteins and lipids and hence precursors of hard exudates in patients with DME[5]. But since then it has been established that HRF is distributed through all retinal layers instead of the outer plexiform layer only and can be seen in patients with diabetes mellitus without any background retinopathy[6]. Microglial cells are activated by ischemia and inflammation and become large and develop an amoeboid shape. This triggers an inflammatory response with an up-regulation of VEGF with the activation of more microglial cells. It was shown that increased HRF at baseline correlated with increased CD 14 levels, a biomarker expressed exclusively by macrophages and microglial cells[7]. All these support the fact that HRF are activated microglial cells and may represent the inflammatory component of diabetic macular edema. The systematic review by Huang et al in September 2022 showed that though it has been established that the number of HRF decreases after treatment, the exact role of HRF as a predictor of response to treatment is still unclear[8].
Hyper-reflective foci in the choroid (HCF) are also gaining significance in DME. They were found to be associated with HRF in patients with DME highlighting the role of the choroid in the pathogenesis of DME[9].
In patients with dry AMD, HRF are associated with calcified drusens[10]. The HRF in patients with dry AMD have been postulated to arise from degenerating photoreceptors and RPE cells, whereas they may be composed of activated microglial cells which actively phagocytose lipids in wet AMD[11]. The presence of HRF in patients with intermediate AMD proved to be an independent risk factor for conversion to neovascular AMD in 24 months and HRF within drusenoid lesions independently predicted the development of geographic atrophy[12]. The presence of HRF at the edge of atrophic areas predicted the growth and expansion of the same[13]. The presence of HRF at baseline in cases with choroidal neovascularization was associated with poor prognosis and the treatment switch from Ranibizumab to Aflibercept demonstrated anatomical and improvement in visual acuity. The presence of outer retinal HRF was considered to be precursors of type 3 neovascularization[14].
Significance in Retinal vein occlusion (RVO)
HRF have been studied extensively in patients with central and branch retinal vein occlusions. They are more concentrated in the outer retinal layers and the external limiting membrane. Two types of HRF have been identified, fine and confluent types. Fine HRF are seen in the areas of extravasation of blood, and confluent HRF are present in unaffected areas and may be associated with the absorption of water and other molecules[15]. Studies have shown that increased numbers at baseline are associated with sub-optimal response with anti-VEGF therapy and that these patients are known to benefit from dexamethasone implants[16].
Significance in Retinal dystrophies
HRF have been commonly described in dystrophies like retinitis pigmentosa and Stargardts disease. In retinitis pigmentosa both retinal and choroidal HRF have been described. they are presumed to originate from the disrupted RPE cells and pigment migration and are seen in the inner retinal layers overlying areas of atrophy. they were observed to migrate to the outer retinal layers in the later stages of the disease which was accompanied by ellipsoid zone and ELM disruption[17]. The disruption of the outer retinal layers was associated with choroidal hyperreflective foci. In Stargardt's disease, choroidal hyper reflective foci were found to correlate with foveal atrophy[18].
Significance in Uveitis Macular edema
HRF were found to be commonly associated with uveitis macular edema[19]. At baseline they were found to be distributed throughout all retinal layers and responded to treatment. with resolution of edema, persistent HRF were mainly seen in the inner retinal layers. Studies have shown that the number and distribution of HRF correlated positively with central macular thickness[20].
Limitations
The main limitation of using HRF as a biomarker is that they are counted manually. Though many semi-automated and fully automated counting protocols are available for research purposes, they are yet to be used in general practice.
References
- ↑ Echols BS, Clark ME, Swain TA, Chen L, Kar D, Zhang Y, Sloan KR, McGwin G Jr, Singireddy R, Mays C, Kilpatrick D, Crosson JN, Owsley C, Curcio CA. Hyperreflective Foci and Specks Are Associated with Delayed Rod-Mediated Dark Adaptation in Nonneovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2020 Nov;4(11):1059-1068. doi: 10.1016/j.oret.2020.05.001. Epub 2020 May 7. PMID: 32389889; PMCID: PMC8709925.
- ↑ Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010 Nov;5(6):463-6. doi: 10.1097/COH.0b013e32833ed177. PMID: 20978388; PMCID: PMC3078627.
- ↑ Fragiotta S, Abdolrahimzadeh S, Dolz-Marco R, Sakurada Y, Gal-Or O, Scuderi G. Significance of Hyperreflective Foci as an Optical Coherence Tomography Biomarker in Retinal Diseases: Characterization and Clinical Implications. J Ophthalmol. 2021 Dec 17;2021:6096017. doi: 10.1155/2021/6096017. PMID: 34956669; PMCID: PMC8709761.
- ↑ Coscas G, De Benedetto U, Coscas F, Calzi CI, Vismara S, Roudot-Thoraval F, Bandello F, Souied E. Hyperreflective dots: a new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration. Ophthalmologica. 2013;229(1):32-7.
- ↑ 5.0 5.1 Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C; Diabetic Retinopathy Research Group Vienna. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009 May;116(5):914-20. doi: 10.1016/j.ophtha.2008.12.039. PMID: 19410950.
- ↑ Schreur V, de Breuk A, Venhuizen FG, Sánchez CI, Tack CJ, Klevering BJ, de Jong EK, Hoyng CB. RETINAL HYPERREFLECTIVE FOCI IN TYPE 1 DIABETES MELLITUS. Retina. 2020 Aug;40(8):1565-1573. doi: 10.1097/IAE.0000000000002626. PMID: 31356496; PMCID: PMC7392582.
- ↑ Arthi M, Sindal MD, Rashmita R. Hyperreflective foci as biomarkers for inflammation in diabetic macular edema: Retrospective analysis of treatment naïve eyes from south India. Indian J Ophthalmol. 2021 May;69(5):1197-1202. doi: 10.4103/ijo.IJO_2627_20. PMID: 33913858; PMCID: PMC8186614.
- ↑ Huang H, Jansonius NM, Chen H, Los LI. Hyperreflective Dots on OCT as a Predictor of Treatment Outcome in Diabetic Macular Edema: A Systematic Review. Ophthalmol Retina. 2022 Sep;6(9):814-827. doi: 10.1016/j.oret.2022.03.020. Epub 2022 Mar 30. PMID: 35367382.
- ↑ Roy, Rupak MS∗; Saurabh, Kumar MS†; Shah, Dhaivat MS∗; Chowdhury, Maitreyi MS∗; Goel, Sugandha MS∗. Choroidal Hyperreflective Foci: A Novel Spectral Domain Optical Coherence Tomography Biomarker in Eyes With Diabetic Macular Edema. Asia-Pacific Journal of Ophthalmology: July-August 2019 - Volume 8 - Issue 4 - p 314-318
- ↑ Schlanitz F. G., Sacu S., Baumann B., et al. Identification of drusen characteristics in age-related macular degeneration by polarization-sensitive optical coherence tomography. American Journal of Ophthalmology . 2015;160(2):335–344.
- ↑ Khanifar A. A., Koreishi A. F., Izatt J. A., Toth C. A. Drusen ultrastructure imaging with spectral domain optical coherence tomography in age-related macular degeneration. Ophthalmology . 2008;115(11):1883–1890. doi: 10.1016/j.ophtha.2008.04.041
- ↑ Nassisi M, Fan W, Shi Y, Lei J, Borrelli E, Ip M, Sadda SR. Quantity of Intraretinal Hyperreflective Foci in Patients With Intermediate Age-Related Macular Degeneration Correlates With 1-Year Progression. Invest Ophthalmol Vis Sci. 2018 Jul 2;59(8):3431-3439. doi: 10.1167/iovs.18-24143. PMID: 30025092.
- ↑ . Sleiman K., Veerappan M., Winter K. P., et al. Optical coherence tomography predictors of risk for progression to non-neovascular atrophic age-related macular degeneration. Ophthalmology . 2017;124(12):1764–1777. doi: 10.1016/j.ophtha.2017.06.032.
- ↑ Sacconi R., Sarraf D., Garrity S., et al. Nascent type 3 neovascularization in age-related macular degeneration. Ophthalmology Retina . 2018;2(11):1097–1106. doi: 10.1016/j.oret.2018.04.016.
- ↑ Ogino K., Murakami T., Tsujikawa A., et al. Characteristics of optical coherence tomographic hyperreflective foci in retinal vein occlusion. Retina . 2012;32(1):77–85. doi: 10.1097/IAE.0b013e318217ffc7.
- ↑ Kang J.-W., Lee H., Chung H., Kim H. C. Correlation between optical coherence tomographic hyperreflective foci and visual outcomes after intravitreal bevacizumab for macular edema in branch retinal vein occlusion. Graefes Archive for Clinical and Experimental Ophthalmology . 2014;252(9):1413–1421. doi: 10.1007/s00417-014-2595-5.
- ↑ Nagasaka Y., Ito Y., Ueno S., Terasaki H. Number of hyperreflective foci in the outer retina correlates with inflammation and photoreceptor degeneration in retinitis pigmentosa. Ophthalmology Retina . 2018;2(7):726–734. doi: 10.1016/j.oret.2017.07.020.
- ↑ Battaglia Parodi M., Sacconi R., Romano F., Bandello F. Hyperreflective foci in stargardt disease: 1-year follow-up. Graefes Archive for Clinical and Experimental Ophthalmology . 2019;257(1):41–48. doi: 10.1007/s00417-018-4167-6.
- ↑ Grewal D. S., O’Sullivan M. L., Kron M., Jaffe G. J. Association of disorganization of retinal inner layers with visual acuity in eyes with uveitic cystoid macular edema. American Journal of Ophthalmology . 2017;177:116–125. doi: 10.1016/j.ajo.2017.02.017.
- ↑ Berasategui B, Fonollosa A, Artaraz J, Ruiz-Arruza I, Ríos J, Matas J, Llorenç V, Diaz-Valle D, Sastre-Ibañez M, Arriola-Villalobos P, Adan A. Behavior of hyperreflective foci in non-infectious uveitic macular edema, a 12-month follow-up prospective study. BMC Ophthalmol. 2018 Jul 20;18(1):179. doi: 10.1186/s12886-018-0848-5. PMID: 30029623; PMCID: PMC6053782.
