32
QUESTION
CENTRAL SEROUS? WHAT NOW? MANAGEMENT OPTIONS FOR CENTRAL SEROUS RETINOPATHY
Lisa C. Olmos de Koo, MD, MBA
First, take a deep breath and try to stay calm (this goes for both the treating physician and the patient). Second, carefully revisit your diagnosis by reviewing the clinical history and imaging studies. Central serous retinopathy (CSR), also known as central serous chorioretinopathy, is a chorioretinal disease that can have a chronic and relapsing course, characterized by the accumulation of subretinal fluid (SRF) in the posterior pole as well as pigment epithelial detachments (PEDs). The exact pathophysiology of this unique condition remains obscure, although retinal pigment epithelial (RPE) dysfunction and hyperpermeability of choroidal vessels are thought to contribute. Hypercortisolic states (eg, external stressors, exogenous steroid administration) may also play a role in triggering episodes in predisposed individuals.
The demographic group most commonly affected by CSR is healthy males in young to middle adulthood. However, CSR has been reported in adults of all age groups and does not appear to have a strong racial or ethnic predisposition. In the past, the frequency of this condition may have been underestimated prior to the era of widespread use of optical coherence tomography (OCT). The classic exam features of CSR include well-circumscribed serous retinal detachments as well as serous PEDs, which are evident on spectral domain OCT (Figure 32-1). Patches of RPE disruption and PEDs, representing resolved acute episodes, are often detected upon careful examination of the fellow eye, as the condition is commonly bilateral. Fundus autofluorescence can be useful in these cases, sometimes demonstrating dependent atrophic RPE tracks. Increased subfoveal choroidal thickness (pachychoroid) in both eyes is another feature that can be seen on enhanced depth imaging OCT.1 Fluorescein angiography (FA) is not required to establish the diagnosis, but it can be helpful in atypical cases and is required for planning photodynamic therapy (PDT), as discussed later. Classic FA patterns include the expansile dot, smokestack, and diffuse patterns of hyperfluorescence (Figure 32-2). Indocyanine green angiography demonstrates choroidal hyperpermeability. More recently characterized OCT angiographic findings include increased choroidal vascular flow.2
Figure 32-1. Spectral domain OCT showing the classic features of CSR with a well-circumscribed pocket of subfoveal fluid.
Figure 32-2. FA showing multiple expansile dots of hyperfluorescence with pooling of dye.
It is important to distinguish the findings of acute CSR from choroidal neovascularization (CNV) because the optimal treatment for these conditions is distinct. Intraretinal fluid or subretinal tissue on OCT and/or hemorrhage noted on fundus exam should prompt consideration of CNV, which may even be secondary to chronic CSR (Figure 32-3). Patients with CNV should be treated promptly with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. Along the same lines, the onset of newly diagnosed CSR over the age of 60 should raise a red flag for CNV and both eyes should be closely evaluated for subtle findings of age-related macular degeneration (AMD). Coexistence of CSR and CNV is possible, especially in cases of chronic, untreated CSR or in older patients. Interestingly, chronic CSR has been associated with the same genetic variants implicated in AMD, but the alleles that confer risk for one condition may be protective for the other, and vice versa.3 There is clearly still much to be learned about the overlap between these 2 conditions.
Figure 32-3. Color fundus photo of the left eye of a patient with known chronic CSR. New subretinal hemorrhage is a clue that this patient has developed secondary CNV.
Once the diagnosis of CSR is established, your first role as the treating physician is to counsel and reassure the patient as well as to establish a schedule of regular monitoring exams. CSR patients appreciate thoughtful counseling about the diagnosis and prognosis. It is helpful to let them know that most patients (90%) recover 20/30 or better visual acuity; however, recurrences occur in 30% to 50%. This potential for recurrence and the bilateral nature of the condition should be discussed, as well as the need to present to the clinic for evaluation and imaging whenever new symptoms are noticed. I usually ask my chronic CSR patients to try to present for evaluation within 2 weeks of the onset of a new symptomatic episode. This becomes especially important over the age of 55, as secondary CNV is more common in this age group.
Avoidance of exogenous steroids is important for CSR patients, as steroids can trigger acute episodes. Steroids may sensitize the eye to adrenergic hormones that in turn may cause choriocapillaris hyperpermeability and RPE cellular degeneration.4 In addition to oral steroids, other often-overlooked steroid sources include inhalers or nasal sprays (eg, those prescribed for asthma or allergies), intra-articular injections (often administered by our orthopedic colleagues), or even topical preparations used for various dermatologic conditions. I like to ask my patients specifically about exposure to any of these steroid preparations, and I review their medication list in detail, including over-the-counter supplements and herbal preparations. When in doubt, ask patients to discontinue supplements whose contents cannot be identified. When I establish a new CSR diagnosis, I usually prepare a letter for the patient’s primary care physician (PCP) requesting avoidance of exogenous steroid whenever possible. In certain medical conditions (eg, asthma, organ transplants, autoimmune or connective tissue disorders), steroids are a mainstay of therapy. In these cases, I communicate with the PCP to ensure that any option for steroid-sparing agents has been considered. If steroid avoidance is not possible, earlier therapy for subfoveal fluid may be indicated. Other medications, such as exogenous testosterone, can also be potential triggers. The complexities of the endocrine interplay in this condition are, as yet, incompletely understood.
Acute CSR has also been associated with increased endogenous cortisol. Ask your CSR patients about their life stressors and take the time listen for a few minutes; you may be surprised by what you hear. Then, ask what kind of things they do to manage their stress level. I encourage my CSR patients to engage in at least 20 minutes a day of a healthy activity of their choosing to distract them from life’s responsibilities and stresses. For many, exercise is extremely effective, whether it be a walk outside after dinner or a brisk run in the morning before work. For some, dedicated time to rest and relax is more effective.
After the initial diagnosis of an acute episode of CSR-related SRF, I usually give a follow-up appointment in approximately 1 month. I generally follow these patients monthly with serial OCTs until I observe complete resolution of macular SRF. Associated PEDs will often, but not always, persist. Of note, these patients can also have extramacular pockets of SRF. I do not follow these closely, because their persistence or resolution will not impact central vision to a measurable degree. At the 2-month mark after initial diagnosis, if I see no decrease in the height of subfoveal fluid or other sign of resolution, I usually begin discussing therapeutic options with the patient. This is a good time to reinitiate contact with the PCP and request that a basic chemistry panel and liver function tests be drawn in preparation for possible medical therapy. If there is no PCP, I do request that they establish care with one at this point. If SRF persists and has not decreased at the 3-month mark from initial presentation or symptom onset, I will generally offer therapy. Therapeutic options for CSR today can be divided into local and systemic.
Laser for chronic CSR is an effective local treatment option. Today, thermal laser is less frequently used than in the past due to the availability of other treatment options as well as the potential for scarring that can result in paracentral scotoma or secondary CNV. However, it can still play a useful role when leakage sites are far from the foveal center and a more permanent solution is desired. These patients can develop new areas of leak after thermal laser, but the site that was treated typically does not leak again. PDT or cold laser is currently preferred over thermal laser and has been proven safe and effective for chronic CSR as well as for acute CSR when more rapid visual rehabilitation is desired.5–7 It has also proven effective for steroid-associated CSR.8 PDT using verteporfin addresses choroidal hyperpermeability by focally reinforcing the RPE’s blood-retinal barrier and has been shown to resolve SRF in over 80% of patients. Verteporfin has a high affinity for abnormal blood vessels and when stimulated by a 689 nm nonthermal light, it produces highly reactive short-lived oxygen radicals, resulting in the selective damage of the dysfunctional blood vessels. This treatment requires intravenous access for both the treatment planning FA and the verteporfin infusion, as well as protection from UV light for 48 to 72 hours post-therapy. The laser spot size should be set to about 1000 μm greater than the area of maximal leakage at 5 minutes on the FA. If there are multiple spots of leakage, one may try to encompass these areas in a single larger spot, or repeat the therapy in a different spot after the first delivery, with first priority to the spot that is closest to the fovea. Reduced fluence settings (300 mW/cm2, 25 J/cm2, 83 seconds) may be used with success. After treatment, monitor for SRF resolution at around 4 to 6 weeks post-therapy. Late recurrences at the treated leaking point(s) are common and can be safely retreated as early as 3 months after the initial treatment. Complications of PDT for CSR are rare but include acute severe vision decrease in 1.5%. Finally, subthreshold micropulse laser has also been utilized with reported success in the literature, but at present its use is not uniformly widespread in the United States.9
Another local therapy for CSR, intravitreal anti-VEGF therapy, is more controversial. There is a mechanistic rationale for the use of this therapy given that these agents decrease vascular permeability, including that of the choriocapillaris. Clinical efficacy has also been demonstrated via several studies and reports in the literature.10 However, clinically the robustness of the therapeutic response to anti-VEGF agents in CSR is less than in CNV or macular edema due to retinal venous occlusion or diabetic retinopathy. Personally, I do not employ anti-VEGF as a first-line therapy for CSR. One important exception is those patients in whom I see evidence of secondary CNV formation, namely intraretinal fluid, subretinal tissue, or frank hemorrhage (see Figure 32-2). In these cases, I advocate treatment of the CNV with careful attention to CSR if it is also present in the fellow eye.
Oral systemic medical therapy for CSR has garnered much attention in the literature in recent years, and it may be favored over local therapy for a variety of patient-specific reasons.11 Personally, I find that medical therapy can be a useful option, especially for patients who have multiple leaking spots in whom laser delivery is more complex. I have also found that systemic agents can be very helpful in the bullous variant of CSR. There are 2 main classes of medications that can be used effectively to treat CSR: metabolism inducers (eg, rifampin) and endogenous mineralocorticoid receptor antagonists (eg, eplerenone, spironolactone). The choice between systemic agents may be informed by their different side effect profiles, as discussed later. Given their mechanisms of action, however, systemic medications are not the optimal choice for CSR patients who depend upon steroid treatments to prevent transplant rejection or to maintain quiescence in chronic inflammatory conditions. Rather, these patients are generally best served by local therapy, such as PDT.8 It is important to inform patients that the use of any oral medication for CSR is off-label, and that there is no US Food and Drug Administration–approved treatment for the condition at the present time. As always, consultation and partnership with the patient’s PCP is recommended.
Eplerenone (Inspra) appears to work via the antagonism of specific mineralocorticoid receptors that would normally allow corticosteroid binding to trigger choroidal vasodilation and contribute to hyperpermeability.12 Eplerenone’s most common side effect is hyperkalemia, necessitating caution in patients with diabetes or renal failure. I usually check a chemistry panel prior to initiation, at 1 month postinitiation, and every 6 months thereafter while on therapy. 50 mg orally daily is the standard dose. Some patients may wish to start at 25 mg daily and ramp up to the full dose after several weeks on therapy. I monitor monthly for resolution and will consider discontinuation after full resolution for 1 month. In cases of relapse, I may consider maintenance dosing of 25 mg daily, which is generally well-tolerated. Spironolactone acts via a similar mechanism of mineralocorticoid receoptor antagnoism; however, it is generally less well tolerated than eplerenone due to the potential for gynecomastia. It is also significantly less expensive, making it more accessible.
Rifampin (Rifadin) is an antibiotic whose mechanism of action in the setting of CSR is induction of the cytochrome P450 pathway to metabolize endogenous or exogenous corticosteroids. It is thus necessary to check liver function tests before initiating treatment. It is also prudent to monitor the liver function tests 1 month after initiating therapy and successively every 3 months if chronic therapy is needed. I also ask patients to abstain from any alcohol intake while on this medication. Rifampin’s effectiveness at treating CSR was first discovered in a patient being concurrently treated for Mycobacterium avium intracellulare. One recent study showed complete response in nearly half of eyes treated with rifampin, including those who had failed other forms of therapy.13 Personally, I prescribe a dose of 300 mg orally daily, and I recommend follow-up monthly with serial OCTs until the fluid has resolved. If fluid does resolve, I discontinue therapy. I do not recommend maintenance therapy with this particular medication due to the rare potential for severe side effects. If there is no reduction in fluid after the first month of therapy, I may consider increasing the dose. If no effect is seen 1 month after 600 mg daily, I generally discontinue the therapy. Side effects of rifampin range from rashes, gastrointestinal upset, and flu-like symptoms to serious and rare complications such as hepatitis and Stevens-Johnson syndrome.
Rarely, some patients with the bullous variant of CSR who develop extensive serous retinal detachments ultimately require repair using vitreoretinal surgical techniques including scleral buckle and vitrectomy with intraocular tamponade. In these cases, care should be taken to exclude treatable diagnoses such as infection or occult neoplasm, and biopsy with analysis of intraocular fluid is warranted at the time of surgery.
Summary
CSR is a fascinating condition whose pathophysiology is, as yet, incompletely understood. Fortunately, visual prognosis is generally favorable. Most patients with acute symptoms can be safely observed initially and offered treatment only if there is no spontaneous recovery. Today, we are fortunate to have an array of effective treatment options for CSR, allowing us to individualize treatment plans for our patients based on their unique social and medical factors.
References
1. Chen G, Tzekov R, Li W, et al. Subfoveal choroidal thickness in central serous chorioretinopathy: a meta-analysis. PLoS One. 2017;12(1):e0169152.
2. Nicolo M, Rosa R, Musetti D, et al. Choroidal vascular flow area in central serous chorioretinopathy using swept-source optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2017;58(4):2002-2010.
3. de Jong EK, Breukink MB, Schellevis RL, et al. Chronic central serous chorioretinopathy is associated with genetic variants implicated in age-related macular degeneration. Ophthalmology. 2015;122(3):562-70.
4. Jampol LM, Weinreb R, Yannuzzi L. Involvement of corticosteroids and catecholamines in the pathogenesis of central serous chorioretinopathy: A rationale for new treatment strategies. Ophthalmology. 2002;109:1765–1766.
5. Lim JI, Glassman AR, Aiello LP, et al. Collaborative retrospective macula society study of photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmology. 2014;121(5):1073-1078.
6. Chan WM, Lai TY, Lai RY, et al. Half-dose verteporfin photodynamic therapy for acute CSC: one-year results of a randomized controlled trial. Ophthalmology. 2008;115:1756-1765.
7. Kim KS, Lee WK, Lee SB. Half-dose photodynamic therapy targeting the leakage point on the fluorescein angiography in acute central serous chorioretinopathy: a pilot study. Am J Ophthalmol. 2014;157:366-373.
8. Breukink MB, Mohabati D, van Dijk EH, et al. Efficacy of photodynamic therapy in steroid-associated chronic central serous chorioretinopathy: a case-control study. Acta Ophthalmol. 2016;94(6):565-572.
9. Scholz P, Altay L, Fauser S. Comparison of subthreshold micropulse laser (577 nm) treatment and half-dose photodynamic therapy in patients with chronic central serous chorioretinopathy. Eye (Lond). 2016;30(10):1371-1377.
10. Ji S, Wei Y, Chen J, et al. Clinical efficacy of anti-VEGF medications for central serous chorioretinopathy: a meta-analysis. Int J Clin Pharm. 2017;39(3):514-521.
11. Pouw AE, Olmos de Koo LC. Oral rifampin for central serous retinopathy: a strategic approach in three patients. Ophthalmic Surg Lasers Imaging Retina. 2015;46(1):98-102.
12. Bousquet E, Beydoun T, Zhao M, et al. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 2013;33:2096-2102.
13. Shulman S, Goldenberg D, Schwartz R. Oral Rifampin treatment for longstanding chronic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol. 2016;254(1):15-22.
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