Although von Graefe described some of the clinical aspects of “relapsing idiopathic detachment of the macula” as early as 1866, it was more than 100 years later that Maumenee, using fluorescein angioscopy, noted that the detachment of the macula resulted from a leak at the level of the retinal pigment epithelium (RPE). The disorder at that time was commonly referred to as central serous retinopathy . Although numerous articles and name changes have been published in the ophthalmic literature, expanding our knowledge of its cause, clinical manifestations, natural course, and treatment, the pathogenesis of this condition remains poorly understood, little is known about the long-term natural course, and treatment is based on observational, uncontrolled studies.
Although the precise pathophysiologic event leading to neurosensory retinal detachment remains unknown, most ophthalmologists today believe that stasis, ischemia, inflammation, or a combination thereof of the inner choroid leads to abnormal permeability and eventual elevation of the RPE in 1 or more serous pigment epithelial detachments. Yet the presence of these pathologic mechanisms in the choroid still cannot replicate the complete constellation of findings in this disorder. In the acute form of the disease, many believe that there is a disruption in the continuity of the detached RPE, leading to focal leakage beneath an overlying neurosensory retinal detachment, the signature of the disorder. This form of mechanical alteration in the integrity of the RPE, referred to as a “blow-out” or “micro rip,” alters its normally impermeable state, leading to serous detachment of the retina. In this sense, the retina seems to be affected only secondarily; whereas the inner choroidal changes represent the primary abnormality of the disorder, leading to the current designation of the disease as central serous chorioretinopathy (CSC). The primary exudative disturbance in the inner choroid, resulting in a macular detachment, is thought to be nonvasogenic, that is, not associated with proliferation of choroidal vessels. The initial avascular nature of CSC distinguishes it from other forms of macular detachment associated with neovascularization of the choroid and eventual disciform scarring. Corticosteroids, either endogenous or exogenous, have been implicated in the disorder. The other distinguishing characteristic noted clinically is the serous pigment epithelial detachment, a clinical manifestation in the fundus that is limited to very few disorders, such as neovascular age-related macular degeneration, polypoidal choroidal neovascularization, and rarely, inflammatory and infiltrative choroidal disorders.
The natural course of acute CSC is believed to be very good with primary cases resolving spontaneously in 3 to 4 months. Yet, a small percentage of cases are known to be associated with recurrent or persistent detachments. In such eyes, the disorder is referred to as chronic CSC, which is arbitrarily defined as detachments lasting 6 months or longer.
A method of therapy for this disorder has never been established clearly on the basis of its safety and efficacy by means of our traditional method, the clinical trial. However, it is well known that laser photocoagulation of a fluorescein-detectable pigment epithelial leak, generally near or at the junction of the attached and detached RPE, can accelerate the resolution of the associated neurosensory detachment. In chronic CSC, there may be focal or multifocal RPE leaks evident on fluorescein angiography, but more commonly, there is persistent, exudative detachment of the neurosensory retina resulting from a zonal or diffuse impermeability state of the RPE, resulting in fluid accumulation from the choroid through abnormal junctions of the RPE into the subretinal space. Attempts at modifying or rejuvenating the RPE, either by the use of drugs that modulate the steroid receptors in the inner choroid or scatter laser photocoagulation in a theoretical attempt to reconstitute the impermeable state of the RPE, have not yet proven to be effective in the therapy of chronic CSC.
Today, current multimethod imaging technology is helpful in the evaluation of a patient with chronic CSC. For example, high-resolution optical coherence tomography detects shallow elevations of the retina, and not surprisingly, a thickening of the choroid. Chronic detachments and geographic zones of atrophy, produced by antecedent exudative detachments, including those gravitating into the inferior fundus, and the acute pigment epithelial leak at the edge of a pigment epithelial detachment, have been noted with fundus autofluorescence even in asymptomatic eyes. The use of indocyanine green angiography (ICGA) also has revealed staining of the inner choroidal vessels in the mid stages of the study, as islands of indocyanine green (ICG) hyperfluorescence from the posterior pole even to the peripheral fundus. The exact identity of this staining material is not known and does not exactly correspond to the generalized or diffuse thickening of the choroid evident with enhanced depth imaging on high-resolution optical coherence tomography. Our group took advantage of this marker, which is present bilaterally in virtually all patients with acute and chronic CSC, to apply reduced fluence photodynamic therapy (PDT) with verteporfin in an attempt to resolve chronic detachments of the neurosensory retina by altering the inner choroidal vasculature. Fluorescein angiography, the standard for identifying an acute RPE leak, is not useful in localizing the inner choroidal staining, as atrophy of the RPE and scleral staining masquerade as choroidal leakage. Actually, the choroidal exudate itself does not stain with the fluorescein molecule; only ICGA demonstrates the exudates. ICGA-guided PDT works successfully for chronic CSC at least temporarily, and this technique has emerged as a standard of care for the ophthalmic community, replacing laser photocoagulation.
In this issue of The Journal, Sawa and associates report their use of ICGA-guided PDT to test its safety and efficacy for treatment of chronic central serous chorioretinopathy with excellent results. They also looked at the intensity of the leakage in the inner choroid and found that those patients with intense or moderately intense choroidal staining on ICGA responded effectively in 100% of these cases, whereas those few without hyperfluorescent staining areas in the choroid responded rarely, if at all. This study further supports the concept of ICGA-guided therapy for chronic CSC, but the authors are correct to point out that their study is not a clinical trial, our standard for evidence-driven clinical decisions. The study design and results, however, do suggest that the degree of staining in the choroid is predictive of a good response to PDT for chronic CSC treatment. What is it about the staining characteristics in these patients who experience a good result or resolution of their detachments? Actually, the exact nature of the staining areas within the choroid is still poorly understood. One explanation may relate to a known protein that is associated commonly with CSC. The diffuse thickening or exudative change within the inner choroidal circulation seen on high-resolution optical coherence tomography may be a result of the presence of fibrin in the areas with intense choroidal staining, but not in other thickened choroidal areas. Gil deVenecia was the first and only physician to observe the presence of fibrin in chronic CSC with histopathologic correlation. The patient reported was unusual in that there was a history of kidney disease and steroid therapy along with all of the clinical manifestations that are highly typical of CSC. In that study, fibrin was noted to occur beneath the RPE, as well as in the subretinal space. The fibrin or fibrinogen originates in the choroid and extends into the subretinal space via the “blow-out” of the RPE. It is well known that ICG conjugates with or stains fibrin in the fundus in any exudative disorder. In contrast, fibrin is transparent on fluorescein angiography, in contrast to other exudates such as lipid deposits, which block choroidal fluorescence, so the presence of fibrin in the inner choroid may reflect the intensity of the hyperfluorescence seen on ICGA. It is also important to keep in mind that the verteporfin molecule used in PDT is biochemically very similar to the ICG molecule and it is likely that there is some bioconjugation of that photosensitizing drug with fibrin. Unfortunately, it is not possible in humans to image verteporfin, because there is no fluorescence of that dye in the visual portion of the spectrum with safe light exposure. Exaggerated PDT responses in the macula for ICGA-guided treatment of CSC are thought to be related to an excessive amount of fibrin present in the subretinal space at the treatment site. This theoretical possibility has lead to the use of half-fluence PDT for the treatment of chronic CSC to modulate the photochemically enhanced thermal response.
The success seen in treating islands of active or intense staining in the inner choroid with ICGA-guided PDT has also led clinicians to treat focal RPE leaks near the fovea with fluorescein guidance. These leaks are known to occur in association with ICG inner choroidal staining and will respond well to PDT without leaving the photocoagulative legacy of photoreceptor and RPE degeneration and the accompanying visual scotoma. Caution in treating such leaks near the fovea is appropriate when there is accompanying fibrin visible on clinical examination because of the potential for an exaggerated response, as alluded to above.
Until additional forms of treatment, such as pharmacologic drugs that suppress corticosteroid receptors in the inner choroid, evolve, ICGA-guided therapy remains the best approach for clinicians to consider for eyes with chronic CSC, particularly if they demonstrate intense or intermediate ICGA hyperfluorescence patterns in the choroid and persistent or progressive detachment with associated degenerative changes in the RPE and photoreceptors accompanied by vision loss.