Advances in Diagnosis and Therapy of Retinal Diseases

This issue of the Asia-Pacific Journal of Ophthalmology (APJO) includes a series of articles on recent advances in the diagnosis and therapy of retinal diseases, written by leading experts in the field. Arrigo, Aragona, and Bandello address the role of inflammation in nonexudative and exudative age-related macular degeneration (AMD), which is characterized by various proinflammatory stimuli and involvement of proinflammatory or inflammatory cells and mediators including biochemical pathways.¹ The results of recent basic science and clinical studies paved the way to develop intravitreal medical therapies as an attempt to treat nonexudative (dry) AMD, or at least to reduce its progression.¹

Improvements in imaging techniques to visualize the surface and deeper structures of ocular tissue, in particular of the retinal and optic nerve, have revolutionized clinical and scientific ophthalmology, mainly through the clinical introduction of optical coherence tomography and OCT-based angiography. These noninvasive techniques with a spatial resolution of up to 1 µm allowed a markedly deeper understanding of the etiology and pathogenesis of ocular diseases and a profound improvement in their diagnosis, and in particular, an improvement in their monitoring for early detection of progression. Szeto et al² describe in this APJO issue recent advances in clinical applications of these imaging methods for retinal diseases. In particular, they refer to multimodal retinal imaging methods, such as ultra-widefield fundus angiography, in addition to fundus autofluorescence besides OCT and OCT-based angiography. The diseases covered include AMD, polypoidal choroidal vasculopathy, diabetic macular edema, central serous chorioretinopathy, retinal vein occlusion, and uveitis.

The latest developments in exploring the genetic background of major retinal diseases are presented by Chen et al.³ They discuss the application of candidate gene mutational and association analyses, linkage analysis, genome-wide association studies, transcriptome analysis, next-generation sequencing including targeted deep sequencing, whole exome sequencing, and whole genome sequencing. The application of these technologies resulted in the identification of a panoply of genes. Future studies will be directed to validate individual genes and to develop polygenic risk markers for the major retinal diseases. The use of artificial intelligence may further help in the advanced analysis of genetic and lifestyle data for the establishment of predictive factors for the risk of the onset, progression, and prognosis of retinal diseases. It will be a step in the direction to individualized precision medicine.

Although perimetry belongs to the oldest techniques applied in clinical ophthalmology, direct fundus microperimetry has only recently been used on a larger scale for scientific and clinical purposes in retinology.⁴ As described by Hori and colleagues, microperimetry together with modern imaging techniques, can provide insights into the physiology and pathology of macular diseases. A previous limitation of microperimetry, that is, fundus movements during the examination, have been addressed by the application of automated eye tracking systems. Disadvantages of microperimetry include the time and concentration required from the examinee.

An update on the diagnosis and management of retinal vein occlusions has been given by Romano et al.⁵ They describe the necessity to undertake a thorough evaluation of cardiovascular risk factors in patients with retinal vein occlusions and to differentiate the nonischemic type from the ischemic type of retinal vein occlusions. They also discuss treatment modalities including retinal laser coagulation and intravitreal medical therapy with anti-vascular endothelial growth factor antibodies and intravitreally applied steroids.

Somisetty and colleagues give a detailed review of systemic (and select intravitreal) medications, along with illicit drugs, that are capable of causing various patterns of retinal toxicity.⁶ They highlight the importance of carefully assessing the history of medication and drugs taken, and describe the clinical retinal changes and multimodal imaging features. In detail, they describe the retinal side-effects of drugs affecting the retinal pigment epithelial (eg, hydroxychloroquine, thioridazine, pentosan polysulfate sodium, dideoxyinosine), causing retinal vascular occlusion (quinine, oral contraceptives), cystoid macular edema/retinal edema (nicotinic acid, sulfa containing medications, taxels, glitazones), crystalline deposition (tamoxifen, canthaxanthin, methoxyflurane), uveitis, miscellaneous, and subjective visual symptoms (digoxin, sildenafil). In addition, the impact of recently clinically introduced chemotherapeutics and immunotherapeutics (such as tyrosine kinase inhibitors and immune checkpoint inhibitors) are discussed.

As members of the Asia-Pacific Vitreo-retina Society, Ruamviboonsuk and 19 experts in the field report the newest recommendations for the diagnosis and therapy of polypoidal choroidal vasculopathy.⁷ It includes a comprehensive review on the definition of the disease, diagnostic procedures including the application of multimodal imaging for baseline and follow-up examinations, and therapy including the intravitreal application of anti-VEGF monotherapy or combination with photodynamic therapy. Concern was expressed that strong evidence supporting the noninferiority of anti-VEGF monotherapy compared to combination therapy was lacking. The report contains also discussions of potential future directions, such as polygenic risk score assessment, and application of criteria from noninvasive multimodal imaging without the requirement of indocyanine green angiography for the diagnosis.

The final article of this APJO issue addresses the safety and efficacy of brolucizumab as intravitreal medication for the therapy of neovascular AMD, as shown in major studies and based upon real-world experiences.⁸ The intraocular injection of the anti-VEGF agent brolucizumab as a single-chain antibody fragment delivers more molecules at equivalent volumes as compared with aflibercept, resulting in a longer effect with the result of a lower reinjection frequency. While brolucizumab was approved by the US Food and Drug Administration (FDA) in 2019 for the therapy of neovascular AMD, post hoc investigations had to be stopped due to an unexpectedly high occurrence of intraocular inflammations. Real-world data as compared with the post hoc studies eventually showed, however, a lower incidence of intraocular inflammations, so that the treatment protocol was amended. Subsequently, the US FDA approved the use of brolucizumab for the therapy of diabetic macular edema in 2022.

Advances in the diagnosis and therapy of retinal diseases are evolving. Gene manipulation, new approaches using epigenetics and degenerative retinal diseases, and retinal organoids in treating retinal diseases are not covered in this special issue but have good potential applications in the future.^9–13