Diffuse retinal pigment epitheliopathy and review năm 2024

Central serous chorioretinopathy (CSCR) is a disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium (RPE). It is a self-limited macular disease marked by distortion, blurry vision, and metamorphopsia. Other causes for RPE leaks, such as choroidal neovascularization, inflammation, or tumors, should be ruled out to make the diagnosis. Choroidal neovascularization is also an uncommon complication of CSCR.

CSCR has, over time, proved difficult to classify and decribe which has in turn, made treatment and study design difficult. [1] Classically, CSCR is caused by one or more discrete isolated leaks at the level of the RPE as seen on fluorescein angiography (FA). However, it is now recognized that CSCR may present with diffuse retinal pigment epithelial dysfunction (eg, diffuse retinal pigment epitheliopathy, chronic CSCR, decompensated RPE) characterized by persistent neurosensory retinal detachment overlying areas of RPE atrophy and pigment mottling. Broad areas of granular hyperfluorescence that contain one or many subtle leaks are seen using FA. This presentation is generally referred to as chronic CSCR. Most authors consider the definition of chronic CSCR to be the persistence of subretinal fluid for greater than 3 months. [2, 3] The CSCR international study group has woked using multiple imaging modalities to develop a clinical classification system that would provide consistency among clinicans using fundus autofluorescence, fundus fluorescein angiography, indocyanine green angiography and optical coherence tomography. [4]

CSCR most commonly occurs in males and is associated with psychosocial factors such as stress and type A personality and with corticosteroid exposure. It has a high rate of recurrence.

Treatment consists of observation, focal laser, reduced fluence photodynamic therapy, and mineralocorticoid antagonists.

Pathophysiology

The pathophysiology of CSCR is still unclear but it is well established that the choroid and choroidal parameters as well as its influence on the retinal pigment epithelium play key roles. Other factors, including catecholamines and corticosteroids which have long been understood to play a role in CSCR likely exert their effect thru their influence on the choroid and RPE.

Previous hypotheses for the pathophysiology have included abnormal ion transport across the RPE and focal choroidal vasculopathy. The advent of indocyanine green (ICG) angiography has highlighted the importance of the choroidal circulation to the pathogenesis of CSCR. ICG angiography has demonstrated both multifocal choroidal hyperpermeability and hypofluorescent areas suggestive of focal choroidal vascular compromise. With further imaging advances, the theory of a pachychoroidal driven process has incorporated findings such as increased choroidal thickness, dilated choroidal veins and thinning of the inner choroid to the CSCR disease process. It has also linked CSCR to other choroidal disease processes such as polyploidal choroida. vasculopathy. Some investigators believe that initial choroidal vascular compromise subsequently leads to secondary dysfunction of the overlying RPE. [5, 6, 7, 8]

Studies using multifocal electroretinography have demonstrated bilateral diffuse retinal dysfunction even when CSCR was active only in one eye. [9] These studies support the belief of diffuse systemic effect on the choroidal vasculature.

Corticosteroids have a direct influence on the expression of adrenergic receptor genes and, thus, contribute to the overall effect of catecholamines on the pathogenesis of CSCR. Consequently, multiple studies have conclusively implicated the effect of corticosteroids in the development of CSCR. Carvalho-Recchia et al showed in a series that 52% of patients with CSCR had used exogenous steroids within 1 month of presentation as compared with 18% of control subjects. [10]

Daruich et al examined the role of the mineralocorticoid pathway in the pathophysiology of CSCR. Study in a rodent model led to the observation that overexpression of a mineralocorticoid receptor expressed in vascular endothelial cells can result in up-regulation of calcium-dependent potassium channel, which is associated with vasodilation. [11] This association may suggest the therapeutic mechanism underlying treatment with mineralocorticoid antagonists.

Type A personalities, systemic hypertension, and obstructive sleep apnea may be associated with CSCR. [12] The pathogenesis here is thought to be elevated circulating cortisol and epinephrine, which affect the autoregulation of the choroidal circulation. Furthermore, Tewari et al demonstrated that patients with CSCR showed impaired autonomic response with significantly decreased parasympathetic activity and significantly increased sympathetic activity. [13]

Recent genome wide association studies have identified genes which may play a role in CSCR based on choroidal parameters. [14] Choroidal thickness and the complement system were used as starting points to identify CHF and VIPR2 as potential susceptibility loci. [15] CHF has previously been identified as a disease susceptibility gene in age related macular degeneration (AMD). Subsequent studies demonstrated protective and risk conferring haplotypes for chronic CSCR within the CHF gene. [16] These studies have highlighted the potential role that the complement cascade plays in the pathogenesis of CSCR. Genome wide association studies published in 2022 also further showed the close association between age related macular degeneration, demonstrating that CSCR shared disease susceptibility loci for age related macular degeneration and macular choroidal neovascularization with AMD. Known genes associated with AMD that were shared by CSCR included CHF, C2/FB, TNFRSF10A and ARMS. These authors also identified two new loci not associated with AMD but associated with chronic CSCR in the Japanese population - WBPL1 and GATA5. [17] In examining macular neovascularization, authors found associations shared between CSCR and both AMD and polyploidal choroidal vasculopathy. Loci implicated in the developmemt of macular neovascularization in CSCR and AMD included again, ARMS, CHF while loci associated with both CSCR and polyploidal choroidal vasculopathy included COL4A3 and B3GALTL. [18]

Helicobacter pylori infection has also been implicated in the pathogenesis of CSCR. Cotticelli et al showed an association between H pylori infection and CSCR. [19] The prevalence of H pylori infection was 78% in patients with CSCR compared with a prevalence of 43.5% in the control group. The authors proposed that H pylori infection may represent a risk factor in CSCR. While still controversial, other groups have continued to pursue this hypothesis based on case series. [20, 21] Zavoloka et al also reported that treatment of H pylori infection decreased the duration and symptoms associated with CSCR. [22] Can et al demonstrated that choroidal thickness increases with H pylori infection and then normalizes after treatment. [23] However, others have found no association with choroidal thickness and H pylori infection. [24]

Epidemiology

Frequency

United States

Kitzmann et al reviewed the incidence of CSCR in Olmsted County, Minnesota. They evaluated the period from 1980-2002. They found the mean annual age-adjusted incidence of CSCR to be 9.9 cases per 100,000 population for men and 1.7 cases per 100,000 population for women. [25]

International

Liew et al reviewed the epidemiology of CSCR in Australia. They found an incidence rate of 10 cases per 100,000 population in men. The rate of CSCR in this study was 6-fold higher in men than in women. [21] In the population-based Beijing Eye Study 2011, the estimated prevalence of CSCR in the Chinese population older than 50 years was 0.14%. [26]

Mortality/Morbidity

Serous retinal detachments typically resolve spontaneously in most patients, with most patients (80-90%) returning to 20/25 or better vision. Even with return of good central visual acuity, many of these patients still notice dyschromatopsia, loss of contrast sensitivity, metamorphopsia, or, rarely, nyctalopia.

Patients with classic CSCR (characterized by focal leaks) have a 40-50% risk of recurrence in the same eye.

Risk of choroidal neovascularization from previous CSCR is considered small (< 5%) but has an increasing frequency in older patients diagnosed with CSCR. [27, 28]

A subset of patients (5-10%) may fail to recover 20/30 or better visual acuity. These patients often have recurrent or chronic serous retinal detachments, resulting in progressive RPE atrophy and permanent visual loss to 20/200 or worse. The final clinical picture represents diffuse retinal pigment epitheliopathy.

Otsuka et al reviewed a subset of patients who presented with a severe variant of CSCR over a mean follow-up period of 10.6 years. [29] These patients were characterized by multifocal lesions and bullous retinal detachments with shifting fluid and fibrin deposition. During the follow-up period, 52% of patients experienced recurrences of CSCR ranging from 1-5 episodes. However, 80.4% of eyes (n=46) returned to a visual acuity of better than 20/40 and 52% returned to a visual acuity of 20/20 or better. Eventually, patients reached a state of quiescent disease.

Tsai et al reviewed a population-based cohort of CSCR patients from the Taiwan national health insurance research database from 2000-2007. They identified CSCR as an independent risk factor for ischemic stroke. After adjusting for age, sex, and comorbidities, CSCR had a 1.56-fold increased risk of stroke compared with controls. [30] Using this same database, patients with CSCR were also found to be at increased risk for rhegmatogenous retinal detachment (7.85 times) and central retinal vein occlusions (3.15 times). [31, 32]

Race

CSCR appears uncommon among African Americans but may be particularly severe among Hispanics and Asians. However, one study suggests that CSCR is underdiagnosed in African Americans, underestimating its prevalence in this group of patients. [33]

Sex

Classically, CSCR is most common in male patients aged 20-55 years with type A personality. This condition affects men 6-10 times more often than it affects women. However, as society has shifted, the prevalence of CSCR in women has increased. Spaide et al reported a male-to-female ratio of 2.6:1. [34]

Age

Patients may present with a later age of onset (>50 y). Spaide et al reviewed 130 consecutive patients with CSCR and found the age range at first diagnosis to be 22.2-82.9 years, with a mean age of 49.8 years. [34]

Changes in the presentation and demographics of CSCR are observed with increasing age at first diagnosis. Classically, patients tend to be male and present with focal, isolated RPE leaks in one eye.

Patients diagnosed at age 50 years or older are sometimes found to have bilateral disease, demonstrate a decreased male predominance (2.6:1), and show more diffuse RPE changes. Furthermore, these patients are more likely to have systemic hypertension or a history of corticosteroid use. [35] These older patients are more likely to have choroidal neovascularization.

Prognosis

The overall prognosis of CSCR is relatively good. Up to 90% of patients return to 20/25 or better vision after a single bout of CSCR, though with mild residual symptoms. However, with multiple recurrent episodes and RPE decompensation, visual acuity changes. [29] Development of choroidal neovascularization can also adversely affect the visual prognosis, although this is rare. [27, 28]

Serous retinal detachments typically resolve spontaneously in most patients, with most patients (80-90%) returning to 20/25 or better vision. [36, 37, 38] Risk factors for bullous serous retinal detachments in CSCR appear associated with systemic diseases such has kidney failure and autoimmune diseases. Systemic steroid use is also associated with this presentation. Poor prognostic signs include poor vision at presentation and history of renal transplant. [39]

Patients with classic CSCR (characterized by focal leaks) have a 40-50% risk of recurrence in the same eye. [36, 38, 40]

Even with return of good central visual acuity, many of these patients still notice dyschromatopsia, loss of contrast sensitivity, metamorphopsia, or nyctalopia. [36]

These patients often have recurrent or chronic serous retinal detachments, resulting in progressive RPE atrophy and permanent visual loss to 20/200 or worse. The final clinical picture represents diffuse retinal pigment epitheliopathy.

Risk of choroidal neovascularization from previous CSCR is considered small (< 5%) but has an increasing frequency in older patients diagnosed with CSCR. [27, 40] These patients can be treated with intravitreal injection of anti-VEGF agents, including aflibercept, ranibizumab, or bevacizumab.

Patient Education

Because of the concomitant risk of CSCR recurrence of and the small risk of choroidal neovascularization, patients with CSCR must be educated regarding the risk of choroidal neovascularization, which requires prompt intervention.

If possible, patients should avoid stressful situations. Patient participation in stress-reducing activities (eg, exercise, meditation, yoga) is recommended.

Recent evidence associates systemic hypertension with CSCR, but it is unknown as to whether careful control of systemic hypertension will reduce the incidence of CSCR.

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Author

Specialty Editor Board

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, American Glaucoma Society

Disclosure: Nothing to disclose.

Steve Charles, MD Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

Andrew A Dahl, MD, FACS Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center

Andrew A Dahl, MD, FACS is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Intraocular Lens Society, American Medical Association, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Medical Society of the State of New York, New York State Ophthalmological Society, Outpatient Ophthalmic Surgery Society

Disclosure: Nothing to disclose.

Additional Contributors

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, James C Folk, MD, to the development and writing of this article.

What is retinal pigment epitheliopathy?

Retinal pigment epithelium (RPE) is formed from a single layer of regular polygonal cells arranged at the outermost layer of the retina. The outer side of the RPE is connected to Bruch's membrane and the choroid, while the inner side is connected to the outer segment of photoreceptor cells.

How do you treat retinal pigment epithelium?

Treatment. Currently no treatment for serous PED is proven effective, nor are recommendations for treatment guidelines established. Several strategies, however, have been used to treat vascularized PEDs, including laser photocoagulation, photodynamic therapy (PDT), intravitreal steroids and anti-VEGF therapy.

Can retinal pigment epithelium be repaired?

In mammals, RPE regeneration is extremely limited; small lesions can be repaired by the expansion of adjacent RPE cells, but large lesions cannot be repaired as remaining RPE cells are unable to functionally replace lost RPE tissue.

What are the symptoms of retinal pigment epithelium?

Symptoms can vary depending on the size of the RPE tear and location. A common presenting symptom of RPE tear is sudden and severe central vision loss. Other symptoms can include increased metamorphopsia, scotomas, photopsias.