This article reviews the similarities and differences between central serous retinopathy (CSR) and age-related macular degeneration (AMD), with a focus on their genetic and clinical features.
Recent genome studies have identified five genetic loci associated with an increased risk of CSR, three of which are also implicated in the development of AMD.1 The remaining two loci are linked to a decreased risk of AMD.1 Studies have found that patients with a history of CSR have been shown to have an elevated risk of developing exudative AMD.2
This review aims to provide clinicians with a comprehensive comparison of CSR and AMD, emphasizing diagnostic differentiation through multimodal imaging, evidence-based treatment strategies, and key considerations for patient education and follow-up care.
Overview of CSR
CSR is typically associated with unilateral vision loss due to the accumulation of subretinal fluid, resulting in a neurosensory detachment between the retina and the retinal pigment epithelium (RPE).
Patients often present with decreased vision and metamorphopsia, particularly when the fovea is involved. Other common symptoms include micropsia, reduced contrast sensitivity, and diminished color saturation.
Risk factors for central serous retinopathy
Risk factors for CSR include:
- Type A personality
- Obstructive sleep apnea
- Hypertension
- Poor cardiovascular health
- Pregnancy
- Caffeine use
- Helicobacter pylori infection
- Both exogenous and endogenous steroid use
- Sildenafil
- Methylenedioxymethamphetamine (MDMA)
CSR is more common in men, with a male-to-female ratio ranging from 3:1 to 5:1 depending on the study.3 Steroids have the strongest known association with CSR;4 Garg et al. reported elevated endogenous cortisol levels in patients with acute CSR compared to age-matched controls.5
Moreover, other studies have shown that exogenous steroid use—whether administered intravenously, topically, or via nasal spray—is also associated with CSR.5 The link between CSR and Type A personality may be related to stress-induced increases in glucocorticoid levels.6
Imaging findings with CSR
On fundus exam, patients often display a transparent or yellow, circumscribed, dome-shaped elevation of the sensory retina, which may resemble a blister. RPE mottling is a feature that can be present in both acute and resolved chronic CSR.7
While the diagnosis is typically clinical, ancillary testing such as fluorescein angiography (FA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) is useful for confirming the diagnosis, assessing for chronicity, ruling out other conditions, monitoring progression, and guiding treatment.7
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CSR and AMD Differential Diagnosis Cheat Sheet
This differential diagnosis cheat sheet outlines key symptoms, risk factors, and diagnosis and management tips to help with discerning CSR from AMD and managing both conditions.
Clinical findings of CSR on OCT:
- Presence of subretinal fluid (SRF) at the macula
- Pigment epithelial detachment (PED) is different from CSR, they may co-exist, but not always
- Choroidal thickening; pachychoroid
- Outer retinal layer thinning in chronic cases
- A straight RPE line is present in non-inflammatory conditions, versus a wavy line in inflammatory diseases8
- Shaggy photoreceptors at the posterior edge of the sensory detachment suggest chronicity
Figure 1: Macular OCT with chronic CSR.
Figure 1: Courtesy of Elizabeth Davis, OD, FAAO.
Fluorescein angiography (FA):
- Common patterns include inkblot (31%), smokestack (12%), and minimally enlarging spots (7%)9
- FA is useful for ruling out the presence of subretinal neovascularization
- Disc leakage is not a feature of CSR9
Clinical findings of CSR on FAF:
- Highlights areas of RPE damage
- Acute: Hypofluorescence at the site of leakage due to blockage of RPE fluorescence from overlying fluid; hyperfluorescence at the area of neurosensory detachment
- Descending tracts with various FAF intensities depending on the status of RPE and photoreceptors
- Hyperautofluorescence in the macula is due to lipofuscin accumulation in damaged photoreceptors and altered molecules within lysosomes10
Figure 2: FAF imaging of CSR on Optos; the area of hyper-autofluorescence in the macula, more so inferior, is due to the buildup of lipofuscin in damaged photoreceptor outer segments and altered molecules retained within lysosomes.
Figure 2: Courtesy of Elizabeth Davis, OD, FAAO.
Prognosis with CSR
Acute CSR is usually self-limiting, with resolution of subretinal fluid and visual recovery typically occurring within 3 months.11 However, recurrences have been documented in up to 50% of cases within 1 year.
Approximately 15% of patients develop chronic CSR, characterized by persistent subretinal fluid for over 6 months, which may require further evaluation or treatment.11
Treatment
For acute CSR, observation is generally recommended for 3 to 4 months, as spontaneous resolution occurs in most cases within 2 to 3 months.11
Treatment options include:12-14
- Acute CSR (select cases): Half-dose or half-fluence photodynamic therapy (PDT)
- Chronic CSR: Half-dose or half-fluence PDT
- Focal, non-central leakage: Argon laser photocoagulation
- CSR with macular neovascularization: PDT combined with intravitreal anti-vascular endothelial growth factor (VEGF) injection
Steroid discontinuation is highly encouraged; if steroids cannot be stopped, reducing the dose may help accelerate resolution. Coordination between the eyecare provider and the prescribing physician is crucial to ensure both ocular and systemic conditions are managed appropriately.15
A randomized controlled trial examining H. pylori treatment in patients with chronic CSR found faster SRF resolution in the treatment group (9 weeks) compared to controls (11 weeks), although there was no difference in final best-corrected visual acuity.16
Don't forget to download the CSR and AMD Differential Diagnosis Cheat Sheet!
Overview of AMD
The hallmark of AMD is the presence of drusen in the macula. Clinical findings vary widely depending on the stage of the disease. In nonexudative (dry) AMD, findings range from small drusen in early stages to extensive geographic atrophy (GA) in advanced cases. Large areas of GA may expose deep choroidal vessels due to atrophy of the choriocapillaris.17
Exudative (wet) AMD is characterized by the presence of a choroidal neovascular membrane (CNVM), subretinal fluid, or hemorrhage. Dry AMD accounts for 85 to 90% of AMD cases and typically does not cause severe vision loss; however, if it turns into GA, severe vision loss can occur.
In contrast, wet AMD comprises 10 to 15% of cases but is responsible for the majority of severe visual impairment associated with the disease.18 Symptoms vary by severity and may be insidious or of sudden onset. Common complaints include blurred vision, visual distortion, metamorphopsia, micropsia, and central scotoma.19
Risk factors for AMD
Lifestyle, age, diet, and genetics are all major factors in an individual's risk for AMD. Other recognized risk factors include advanced age, tobacco use, cardiovascular disease, hypertension, female sex, Caucasian race, hypercholesterolemia, obesity, hyperopia, family history, and poor tanning ability.20
Key AMD risk factors to keep in mind:
- Individuals over the age of 75 have a threefold increased risk of developing AMD.20
- Tobacco use is also particularly significant; current smokers are twice as likely to experience AMD-related vision loss compared to non-smokers. Ex-smokers also have an elevated risk, whereas those who quit smoking over 20 years prior show no increased risk.21
- Genetic factors also play a role, with several loci linked to the development of AMD and to differential treatment responses in patients with choroidal neovascular membrane (CNVM).22
Imaging findings with AMD
OCT and FA are the most commonly used imaging modalities for detecting CNVM.23 FAF is also commonly used, especially in dry AMD to visualize early, subtle GA.
Clinical findings of AMD on FA
FA findings can be categorized into hypofluorescent and hyperfluorescent patterns. There are fewer causes of hypofluorescence: hemorrhage, lipid exudation, and pigment hyperplasia.24
Causes of hyperfluorescence are more numerous, and include drusen, choroidal neovascular membranes, serous pigment epithelial detachments, and subretinal fibrosis or scars.24
There are two main types of CNVMs on FA:
- Classic CNVMs: Are subretinal and disrupt the RPE; they present as well-defined early hyperfluorescent areas that intensify and enlarge in mid-to-late phases.
- Occult CNVMs: Located beneath the RPE; these are presumed when late-phase choroidal leakage is seen without a defined classic membrane pattern.25
- Fibrovascular PEDs (FVPEDs) show an irregular RPE elevation with stippled or granular hyperfluorescence at 1 to 2 minutes. If the CNVM lies at or below the RPE, late leakage may occur without a clearly demarcated hyperfluorescent region.26
Clinical findings of AMD on OCT
OCT is critical for diagnosing AMD, monitoring disease progression, detecting CNVM or GA, and assessing treatment response:27
- Dry AMD: The size and density of drusen influence disease progression. In advanced dry AMD, OCT reveals RPE and photoreceptor thinning, depression of inner retinal layers (subsidence) due to outer retinal loss, and enhanced visibility of Bruch’s membrane and the underlying choroid (choroidal hypertransmission).28
- Wet AMD: Neovascularization typically originates beneath the RPE, within Bruch’s membrane. If there is a break in Bruch’s membrane, neovascular membranes can extend into the subretinal space. These small choroidal vessels may lead to serous or hemorrhagic neurosensory retinal detachments.29
Figure 3: OCT image of classic exudative AMD.
Figure 3: Courtesy of Elizabeth Davis, OD, FAAO.
Clinical findings of AMD on FAF
FAF is the preferred method for visualizing the RPE in cases of geographic atrophy. RPE atrophy appears as a dark area due to the absence of lipofuscin-containing cells, resulting in reduced autofluorescence.30
Treatment for age-related macular degeneration
AMD is managed through a combination of lifestyle modifications, nutrient supplementation, and pharmacologic interventions.31 For patients with intermediate AMD or advanced AMD in one eye, the Age-Related Eye Disease Studies (AREDS and AREDS2) recommends oral supplementation with vitamins C and E, zinc, copper, lutein, and zeaxanthin to reduce the risk of progression to advanced AMD.32
For neovascular AMD, intravitreal injections of anti-VEGF agents such as ranibizumab, aflibercept, and faricimab are the mainstay of treatment, significantly reducing the risk of vision loss and improving visual acuity in many patients.33
Early detection and treatment to preserve vision with regular follow-ups and monitoring using OCT is the standard of care.34 Emerging treatments for dry AMD, including complement inhibitors like pegcetacoplan and avacincaptad pegol, have shown promise in clinical trials for reducing the progression of geographic atrophy.35
Overall, a multifaceted approach involving patient education, lifestyle changes, and timely medical interventions is crucial for managing AMD effectively.24
Want a summary of this article? Check out the CSR and AMD Differential Diagnosis Cheat Sheet!
Comparison between CSR and AMD
CSR and AMD share several clinical and etiological similarities, which can complicate differential diagnosis and management.36 Both conditions are most common in certain age brackets, age 30 to 50 for CSR and the elderly, especially over 75, for AMD.37 Structural changes in the retina, such as RPE abnormalities, detachment of the pigment epithelium, and CNVM can be noted in both diseases.38
Clinically, both CSR and AMD can present with visual disturbances and central vision loss. OCT can help differentiate between the two conditions; CSR typically shows subretinal fluid without intraretinal fluid, while exudative AMD often presents with intraretinal fluid, PEDs, and CNVM.39 CSR is part of the pachychoroid spectrum of abnormalities (thick choroid) on OCT, whereas AMD will demonstrate a thinner choroid.
Management strategies differ significantly between the two conditions. CSR often resolves spontaneously, and treatment may include observation, laser photocoagulation, or photodynamic therapy. In contrast, AMD, particularly the neovascular form, often requires intravitreal anti-VEGF therapy.40
The genetic link between CSR and AMD
Genetic studies have revealed significant overlap in susceptibility loci between CSR and AMD, suggesting shared pathophysiological mechanisms involving complement regulation and choroidal vascular function.41 Variants in the CFH and ARMS2 genes, well-established risk factors for AMD, have also been associated with CSR, though some CFH alleles appear to have opposing risks for the two diseases.42
A study by Rämö et al. identified five genetic loci linked to CSR that are also implicated in AMD, including CFH, GATA5, CD34/46, NOTCH4, and PREX1, with CFH and NOTCH4 showing inverse associations with AMD.43,44 The genetic overlap, particularly in complement-related loci, highlights potential common pathways that could be helpful in determining future therapeutic targets for both conditions.43
Additionally, patients with CSR are at an increased risk of developing exudative AMD. A nationwide study demonstrated that the risk of exudative AMD was significantly higher in patients with CSR compared to those without CSR.46 On the other hand, a diagnosis of AMD has been identified as a significant risk factor for the development of CSR.47
To learn more about the genetic loci that link CSR and AMD, check out the Glance story, Researchers Identify Genetic Overlap Between CSCR and AMD!
Patient education on CSR and AMD
AMD and CSR are both causes of vision impairment, with AMD being the leading cause of vision loss in individuals over 60 years in the US.48,49 Early stages of AMD are often asymptomatic.
Comprehensive eye evaluations are important to identify and monitor these conditions, as early intervention can prevent severe vision loss.50 Patients with CSR are at an increased risk of developing exudative AMD, further underscoring the need for vigilant screening and follow-up.50
Regular eye examinations with funduscopic exams and ancillary testing are essential for diagnosing AMD and CSR, guiding treatment, and assessing response to therapy.51 Educating patients about the importance of these screenings, along with lifestyle changes, can significantly impact disease progression and visual outcomes.52
Conclusion
The genetic and clinical similarities between CSR and AMD underscore the complexity of these retinal diseases. Studies have identified five genetic loci associated with CSR, three of which increase the risk for AMD, while the other two are inversely related to AMD risk.53
The genetic overlap suggests shared mechanisms involving choroidal vascular function and complement regulation. Furthermore, patients with a history of CSR are at a higher risk of developing exudative AMD, highlighting the importance of monitoring.53
Differentiating between CSR and AMD through imaging can guide more precise patient education and treatment strategies to improve patient outcomes. Ultimately, integrating genetic insights with clinical practice will enhance our ability to manage and treat both conditions effectively.
