Inflammation and Immune Pathways in Myopia: An Overview on Pathomechanisms and Treatment Prospects

Over the past few decades, the prevalence of myopia has significantly increased, especially in East and Southeast Asian countries, where the prevalence of myopia in school leavers is now around 80%. The risk of myopia related complications such as myopic macular degeneration, retinal detachment, cataract, glaucoma, visual impairment and blindness, all increase with increased severity of myopia without any safe threshold of myopia for any of its known ocular complications.Various specially designed contact lenses and spectacle lenses has been developed to prevent myopic progression. The Orto‐K treatment contact lenses are worn during the night to decrease the corneal refractive power so that during the day you can see far without optical correction. Peripheral hyperopic refraction is assumed to increase the progression of myopia. To correct the relative peripheral hyperopic refraction various contact lenses and glasses have been developed so that the central myopic refractive error is fully corrected and the peripheral refraction corrected to the direction of hyperopia in relation to the central correction.The main aims this presentation is to highlight the chalenges, related to conducting and reporting these studies, and with a few examples show differences between statistically significant and in practice significant treatment benefits.There is a large individual variation in the progression of myopia. Progression of myopia in two same aged myopics with the same myopia can significantly differ from each other. Myopia progresses generally more in the early stages. The most significant factors causing variation in myopia progression are parental myopia, time and intensity spent on near work, time spent outdoors, age of myopia onset, and change in refraction prior to the myopia examination point. Especially the wide range range in baseline refraction and age at the beginning of the research intervention makes reliable randomization challenging. Comparability would be improved if the randomisation to the treatment and control group could be carried out for example half or one year before beginning the treatment intervention. In this way, the potential effects of the natural progression of myopia in study groups could be taken into account.The the difference between treatment and control groups are often reported as percentage benefit, which actually does mean much. For example 50% benefit of treatment can be received from refraction canges 0.1 D vs 0.2 D, which is practicaly nothing or 1.0 D vs. 2.0. It is also important to report in what period of time the benefit of treatment occurs and when the treatment is no longer beneficial, instead of reporting about sustained benefit, when the changes between the groups do not change.Before new therapies are generally introduced, several independent studies on the benefits and potential harms and complications of treatments shuld be conducted with sufficiently large datasets.The presentation discusses, with some practical examples, in more detail about these and other factors potentially affecting on the reliability of clinical studies about myopia treatment.

Atropine Treatment for Myopia

PurposeThis review discusses the etiology and pathogenesis of myopia, prevention of disease progression and worsening axial elongation, and emerging myopia treatment modalities.IntroductionPediatric myopia is a public health concern that impacts young children worldwide and is associated with numerous future ocular diseases such as cataract, glaucoma, retinal detachment and other chorioretinal abnormalities. While the exact mechanism of myopia of the human eye remains obscure, several studies have reported on the role of environmental and genetic factors in the disease development.MethodsA review of literature was conducted. PubMed and Medline were searched for combinations and derivatives of the keywords including, but not limited to, “pediatric myopia”, “axial elongation”, “scleral remodeling” or “atropine.” The PubMed and Medline database search were performed for randomized control trials, systematic reviews and meta-analyses using the same keyword combinations.ResultsStudies have reported that detection of genetic correlations and modification of environmental influences may have a significant impact in myopia progression, axial elongation and future myopic ocular complications. The conventional pharmacotherapy of pediatric myopia addresses the improvement in visual acuity and prevention of amblyopia but does not affect axial elongation or myopia progression. Several studies have published varying treatments, including optical, pharmacological and surgical management, which show great promise for a more precise control of myopia and preservation of ocular health.DiscussionUnderstanding the role of factors influencing the onset and progression of pediatric myopia will facilitate the development of successful treatments, reduction of disease burden, arrest of progression and improvement in future of the management of myopia.

To elucidate the molecular processes associated with the development of myopic macular degeneration (MMD), we measured the intraocular concentrations of molecular factors in emmetropic and myopic eyes. This is a retrospective clinic-based case-control study that included eyes undergoing routine cataract surgery whereby aqueous humour samples were obtained. We measured the concentrations of pigment epithelium derived factor(PEDF), matrix metalloproteinase 2(MMP-2), tissue inhibitor of metalloproteinase(TIMP-2), vascular endothelial growth factor isoform A(VEGF-A), interleukin 8(IL-8), interleukin 6(IL-6), C-reactive protein(CRP), angiopoietin 2(Ang2), and amphiregulin. 38 eyes (axial length (AL): 22.4–32.4 mm), including 12 highly myopic (HM) eyes (AL ≥ 26.5 mm) without MMD and 12 HM eyes with MMD but without neovascularization were included. Eyes with MMD were found to have significantly lower VEGF-A levels (p = 0.007) and higher MMP-2 levels (p = 0.02) than control eyes after adjusting for age and gender. MMP-2 levels correlated positively (r = 0.58, p = 0.002), while VEGF-A levels correlated negatively with longer axial length (r = −0.75, p < 0.001). Both the concentrations of VEGF-A (P = 0.25) and MMP-2 (P = 0.69) were not significantly associated with MMD after adjusting for AL. These findings suggest that the predominant mechanism underlying the development of non-neovascular MMD may be axial elongation, driven in part by MMP-2 related mechanisms.

Myopia is the most widespread refractive error caused by an increase in the axial length (AL) of the eyeball, and is also a major risk factor for other blinding eye diseases, seriously endangering human health and quality of life. Investigating practical methods to control the progression of myopia is therefore crucial. The only medication that has been shown to effectively delay the progression of myopia over an extended period of time is atropine. Although they have more adverse effects, atropine eye drops with a high concentration work best to correct myopia. Atropine at low concentrations can slow the progression of myopia, however the results might not be very noticeable. It is of great significance to explore the application of drugs to suppress myopia in combination with low-concentration atropine in the treatment of myopia. This study investigated the role and mechanism of 0.01% atropine combined with carteolol hydrochloride in the treatment of myopia. By establishing a model of form-deprivation myopia in guinea pigs, we examined the protective effect of 0.01% atropine combined with carteolol hydrochloride on myopia in guinea pigs and further explored the mechanism of scleral remodeling mediated by mitochondrial dysfunction. We found that 0.01% atropine combined with carteolol hydrochloride refined mitochondrial dysfunction-induced extracellular matrix degradation by activating the PGC-1α/NRF2/HO-1 signaling pathway, thereby suppressing scleral remodeling and the progression of form-deprivation myopia in guinea pigs. In conclusion, 0.01% atropine combined with carteolol hydrochloride may be an effective strategy for the treatment of myopia.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-12800-2.

BackgroundMyopia, characterized by excessive axial elongation of the eyeball, has become a significant global public health issue, particularly in Asia. Severe myopia increases the risk of ocular complications, including retinal degeneration and glaucoma. Recent studies have identified the role of scleral extracellular matrix remodeling and endoplasmic reticulum (ER) stress in myopia pathogenesis. Our previous study identified scleral ER stress as a critical factor in myopia development. This study aimed to investigate the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone, in mitigating scleral ER stress and its effects on myopia progression in a mouse myopia model under masked condition.MethodsA lens-induced myopia (LIM) mouse model was utilized to evaluate the effects of 4-PBA administered as eye drops. Mice received varying concentrations of 4-PBA or phosphate-buffered saline (PBS) as a control. Changes in refractive error and axial length were measured to assess myopia progression. In addition, further experiments were also conducted under masked conditions, where the experimenter was unaware of the treatment was being applied, for the three conditions of 2%, 0.5% 4-PBA eye drops or vehicle treatment of LIM mice.ResultsAdministration of 4-PBA at concentrations of 0.5% and higher significantly suppressed the myopic shift in refraction and axial elongation associated with myopia compared to mice in the PBS control group. In a blinded, masked experiment, 2% and 0.5% 4-PBA eye drops also suppressed the progression of myopia in a dose-dependent manner.ConclusionsThis study demonstrated that 4-PBA effectively mitigated myopia progression in a mouse model by targeting scleral ER stress. The dose-dependent suppression of myopic shifts and axial elongation under masked experimental condtion highlights the potential of 4-PBA as a therapeutic agent for managing myopia. These findings pave the way for further research and potential clinical applications in myopia treatment.

Advances in biomedical study of the myopia-related signaling pathways and mechanisms.

To measure the concentration of cytokines in the aqueous humour of eyes with exudative age-related macular degeneration (AMD). The clinical interventional study included a study group of 18 patients with exudative AMD and a control group of 20 patients undergoing routine cataract surgery. Age did not vary significantly (p = 0.36) between study group (80.8 ± 6.4 years) and control group (77.0 ± 9.9 years), nor did gender (p = 0.75). During the interventions, aqueous humour samples were obtained, in which the concentration of cytokines was measured using a solid-phase chemiluminescence immunoassay. Macular thickness was measured by optical coherence tomography (OCT). In the study group as compared to the control group, significantly higher concentrations were measured for epithelial growth factor (EGF) (p = 0.017), human growth factor (HGF) (p= 0.048), intercellular adhesion molecule-1 (ICAM1) (p = 0.028), interleukin 12p40 (IL12p40) (p = 0.009), interleukin 1a2 (IL1a2) (p = 0.01), interleukin 3 (IL3) (p = 0.02), interleukin 6 (IL6) (p = 0.006), interleukin 8 (IL8) (p = 0.02), monocyte chemoattractant protein-1 (MCP-1) (p = 0.048), monokine induced by interferon gamma (MIG) (p = 0.016), matrix metalloproteinase 9 (MMP9) (p = 0.004) and plasminogen activator inhibitor 1 (PAI1) (p = 0.006). Macular thickness was significantly associated with the concentrations of EGF (p = 0.001), HGF (p = 0.02), ICAM1 (p = 0.001), interleukin 12p40 (p = 0.006), IL 1a2 (p = 0.002), MIG (p = 0.001), MMP9 (p < 0.001) and PAI1 (p = 0.01). Interleukin 6 and MCP-1 showed significant associations with the height of retinal pigment epithelium detachment. Numerous cytokines are associated with the presence and the amount of exudative AMD.

:Myopia occurs in more than 50% of the population in many industrialized countries and is expected to increase; complications associated with axial elongation from myopia are the sixth leading cause of blindness. Thus, understanding its etiology, epidemiology, and the results of various treatment regiments may modify current care and result in a reduction in morbidity from progressive myopia. This rapid increase cannot be explained by genetics alone. Current animal and human research demonstrates that myopia development is a result of the interplay between genetic and the environmental factors. The prevalence of myopia is higher in individuals whose both parents are myopic, suggesting that genetic factors are clearly involved in myopia development. At the same time, population studies suggest that development of myopia is associated with education and the amount time spent doing near work; hence, activities increase the exposure to optical blur. Recently, there has been an increase in efforts to slow the progression of myopia because of its relationship to the development of serious pathological conditions such as macular degeneration, retinal detachments, glaucoma, and cataracts. We reviewed meta-analysis and other of current treatments that include: atropine, progressive addition spectacle lenses, orthokeratology, and multifocal contact lenses.

Purpose: Recent histomorphometric and clinical studies suggested that axial myopic elongation occurs through an enlargement of Bruch's membrane (BM) in the retroequatorial and equatorial region, leading to a thinning of choroid and sclera at the posterior pole. Thickness of the retina and choriocapillaris and RPE‐density in the macular region and BM thickness in any region remain independent of axial length. The equatorial‐to‐retroequatorial BM enlargement may be caused by an epidermal growth factor (EGF)‐associated RPE activity. Experimental studies in guinea pigs and monkeys showed a reduction in axial elongation by intravitreally applied blockers of EGF family members and the EGF receptor, and an increase in axial elongation by intravitreally applied EGF family members. In a clinical study, the intraocular EGF amount correlated with longer axial length. It led to the hypothesis, that ocular axial elongation is associated with EGF, and that further axial elongation may be prevented by an EGF blockade. We examined here the safety of intravitreally applied panitumumab, an EGF receptor blocker, already in clinical systemic use in oncology for two decades.Methods: The phase‐1 study included highly myopic adult patients with myopic macular degeneration. The eyes received one to two intravitreal injections of 0.6 mg (60 μl), 1.2 mg (120 μl) or 1.8 mg (180 μl) panitumumab.Results: The study included 10 patients (age 57–72 years, axial length: 29.10 mm–32.67 mm). Examined at day 1, 7, and 28 and at 2 and 3 months after the injections, the injected eyes did not show any intraocular inflammation or morphologic or functional changes, assessed by retinal electroretinography, perimetry, optical coherence tomography, tonometry and visual acuity measurement.Conclusions: The preliminary observations of these 10 patients are in agreement with a notion of an intraocular tolerability of panitumumab repeatedly injected intravitreally in doses of 0.6, 1.2 or 1.8 mg.

Myopia has become a leading cause of blindness and therefore a serious world health issue recently. This can be attributed to its extreme phenotypes on the „upper end of the scale”, namely high and pathologic myopia. Cases of high myopia with a rapid progression carry the risk of advancing into pathologic myopia, a condition that is associated with potentially blinding complications. Even with all the recent developments in many areas of ophthalmology have been encountered lately, progressive high myopia continues to remain an unjustly neglected field in many parts of the world. Because of their markedly different visual consequences, it is indispensable to distinguish between the two main classes of myopia. Common forms account for the vast majority of the cases. These are practically simple refractive errors that may be well corrected with the conventional visual aids like spectacles, contact lenses or refractive laser surgery. Early onset progressive high myopia (eoHM), in contrast, is not simply a refractive error that can be rescued with optical lenses or refractive surgery, but is potentially a vision threatening disease. The disparate genetic backgrounds also point to the basic differences between common versus early- onset high myopia (eoHM) forms. The manner of inheritance of the common forms is polygenic or multifactorial, i.e. both environmental factors and genetic predisposition are almost equally responsible for these cases. As opposed to this, early-onset high myopia is inherited in a Mendelian manner with one single causative, highly penetrant gene mutation, practically with minimal influence of environment or behaviour. The monogenic manner of inheritance further underlines the severity of this condition, and its specific mode of inheritance covers a wide range of forms including autosomal dominant, autosomal recessive or X-linked recessive. One of the most curious and exceptional modes of transmission is that seen for Myopia-26, displaying X-linked dominant, female-limited inheritance. Due to an explicit increase in the prevalence of such conditions lately, an urgent need for genuine, targeted treatment in the form of gene therapy is recognized. To devise such treatment options however, we need to thoroughly understand the exact molecular mechanisms of refractive errors and myopia development. Albeit nearly 270 genes associated with myopia have been identified so far, the underlying pathways through which these genes influence refractive error development remain obscure in most of the cases. To our current knowledge, eye growth, i.e. refractive development is guided locally within the eye, and the general pathomechanism of refractive error development is assumed to be based on a retina-to-sclera signalling cascade guided by light stimuli in the retina. Myopia genes may accordingly act at any point of this route; and dysfunction of either (disorder of retinal cell function, or signal processing as well as changes in the target tissue) may lead to the derailment of emmetropization, i.e. to refractive error development. The trait of myopia is quite complex, however, and the genes responsible for the myopic trait are accordingly also multiple. Therefore a genuine solution for treating myopia in its complexity is a challenge for the future. At present we only have the alternative of halting the progression of high myopia in order to prevent the development of vision threatening pathological complications. Four main classes of myopia control currently exist, i.e. pharmacological, optical, environmental/ behavioural, and surgical options. Since the underlying causes of myopia onset and progression are diverse; the treatment approaches should likewise be combined from the different groups to reach optimum results. Pathognomic feature of early-onset, progressive myopia is an uncontrolled, life-long elongation of the eyeball. Characteristically, the scleral tissue is biomechanically weakened in progressive high myopic eyes. As a result, the mechanical stretching and thinning of all three layers of the eye occurs along with gradual and excessive axial elongation; and this leads to the formation of vision-threatening degenerative lesions on the retina with age. Logically, the weakened scleral tissue needs to be the primary treatment target in such cases in order to retard excessive axial elongation, and to prevent the potentially blinding complications of pathological myopia. Posterior scleral reinforcement surgery was devised to this end almost a hundred years ago; and notwithstanding the novel alternative trials, this surgical procedure remains the only method of scleral reinforcement for now. In our clinical practice we encounter numerous cases of early-onset progressive high myopia (eoHM). Besides providing these children with adequate optical correction for their myopic refractive error; we perform posterior scleral reinforcement in order to prevent the development of irreversible visual lo

Purpose: To report a case of excessive axial length elongation following vitrectomy for rhegmatogenous retinal detachment.Case summary: A 21-year-old male patient presented to our hospital with visual impairment. The patient had previously undergone computed tomography in our emergency room for a facial contusion 3 years prior to his current visit. Axial lengths of 27.23 mm in the right eye and 27.62 mm in the left eye were recorded at that time. The patient had no previous ocular history. Fundus examination revealed extensive retinal detachment with macular involvement and hypotony retinopathy in the left eye. Retinal detachment surgery was subsequently performed on the left eye. Following the surgery, intraocular pressure in the left eye increased and intraocular pressure-lowering medications were administered. At 3 months postoperatively, the patient developed additional retinal detachment in the right eye, prompting retinal detachment surgery. Unlike the contralateral eye, the intraocular pressure remained well-controlled postoperatively. Axial length measurement was performed due to the complaint of left eye protrusion. The axial lengths were 27.76 mm and 31.41 mm in the right and left eyes, respectively. There was a significant increase in the axial length of the left eye but not in that of the right eye compared to 3 years prior.Conclusions: Gas tamponade, preoperative ocular hypotension, and postoperative ocular hypertension can cause excessive axial length elongation in cases of rhegmatogenous retinal detachment in young patients with high myopia.

Efficacy and safety of traditional Chinese medicine external interventions in juvenile myopia: A systematic review and meta-analysis

PurposeWe used systematic review and meta-analysis to identify and assimilate evidence quantifying blindness and visual impairment (VI) associated with myopic macular degeneration (MMD), then derived models to predict global patterns....

PurposeTo investigate the predictive factors for myopic macular degeneration (MMD) and progression in adults with myopia.MethodsWe examined 828 Malay and Indian adults (1579 myopic eyes) with myopia (spherical equivalent (SE)...