Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

subretinal fluid. This turbid fluid probably contains too little fibrin. Presumably with higher concentration of fibrin, the subretinal fluid becomes frankly opaque. Eventually, the fibrin plaque undergoes fibrinolysis and in majority it disappears. But fibrin can stimulate the RPE to undergo fibrocytic proliferation and to develop into fibrocyte-like cells. These cells ultimately form a membrane and it acts as a scaffold for secondary cellular proliferation.46 Unusual sequelae of the subretinal fibrin deposit could be RPE rip, vascularization of the scar, and tenting up of the retina in the macula.

Subretinal Lipid Deposits

Occasionally subretinal lipid deposits may be seen in older patients with chronic CSC. They appear as discrete, hard-edged, subretinal accumulations usually at the border of the detachment, sometimes over the detachment and occasionally along the course of the RPE atrophic tracts. Lipid deposits in chronic CSC are seen without any angiographic evidence of CNV.

Atypical Presentation of CSC

They are – Bullous or Severe variant of CSC; Cystoid macular edema; Ring retinal pigment epithelial window defect; Leopard spot pattern; Secondary choroidal vascularization; Retinal telangiectasia with lipid deposition; CSC simulating pattern dystrophy; CSC with retinitis pigmentosa; choroidal folds without any evidence of underlying scleritis and with episcleritis.

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CSC in Women

There is a significant difference in the male to female ratio in CSC cases. Cortisol responses to psychologic stress was found to be more in male than in female.47 CSC in otherwise healthy women tends to occur at an older age than men. The conditions commonly associated with CSC in women are—pregnancy and systemic lupus erythematosus. Elevation of catecholamine, corticosteroids, oestrogen and other hormone levels during pregnancy may be responsible for it. Increased levels of prostacyclin during the second and third trimester may be another important factor. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation.

Natural History

CSC is a self-limited disease, but runs a very unpredictable course. However, the natural course of the disease seems to have 4 distinct patterns:48,49 (1) CSC with a single resolving episode; (2) Recurrent resolving CSC –recovery is complete before the recurrence; (3) Recurrent chronic CSC –recurrence before full recovery; and (4) Chronic CSC - following a single episode without any appreciable recovery. The symptoms / sensory retinal detachment (SRD) persist beyond the usual period of recovery, that is, 6 months. In majority (80 to 90%) spontaneous resolution occurs within 1 to 6 months and in 20% it lingers for more than this period.50 But even after recovery, the quality of vision is not the same as before in all the cases. The improvement of vision may continue for more than 1 year following resolution.

Figure 2: FFA Montage picture showing RPE track in chronic CSC.

Recurrence occurs in about 30 to 50% of all cases and 10% have three or more episodes. Almost 50% of the patients have a recurrence within 1 year of the primary episode. Wang et al51 observed foveal attenuation in cases of 4 months or more duration. Poor visual outcome may also be due to development of cystic degeneration of the macula or cystoid macular edema or due to development of a macular choroidal neovascular membrane.

Chronic CSC

Some investigators consider Diffuse Retinal Pigment Epitheliopathy (DRPE) to be synonymous with chronic CSC. In 1977 Zweng and Little52 coined this term for a condition, which had diffuse hyper - and hypo-pigmentation in the RPE, shallow sensory retinal detachment (SRD), no active fluorescein leak, a chronic

course, often bilateral, recurrent in nature, poor visual prognosis, and the patients were on an average 3.4 years older than those with CSC (Figure 2). Such cases had been documented earlier also, but no name was assigned to it. Initially some investigators thought it to be a separate condition from the CSC. Yannuzzi et al53 described these cases under the heading of “Central Serous Pigment Epitheliopathy” (CSPE). Jalkh et al54 reported their series under the synonym of “Retinal Pigment Epithelial Decompensation” (RPED). Subsequently many investigators considered it to be a more severe and rarer form of CSC occurring in patients older than 50 years, particularly in Asian and Hispanic patients. Castro-Correia et al 48thought it to be the terminal stage of the exudative bullous type of CSC. But a recent study55 had shown that it is the prolonged persistence of chronic SRD, which may be following a single acute episode or in recurrent cases with prolonged recovery time in each episode is required for its development. It is not necessary that the detachment will have to be massive and bullous. This study analyzing the data by logistic regression technique found that persistence of SRD at least for about 1.5 years was needed for development of RPE atrophy. This study also observed that DRPE passes through two stages: (1) Stage of RPE decompensation, which is probably reversible up to a certain period of time. (2) Stage of RPE atrophy. Clinically this stage appears to be a burnt out stage, but FA often reveals few decompensatory leaks and rarely subretinal hemorrhage may occur. It has also been observed55 that not only DRPE cases are detected in the older age group, they are also found to be more common in patients developing their first acute

episode at a later age. DRPE is found to be more common in chronic cases. Moreover, presence of fairly big leaking PED contributes for the development of DRPE. As each and every case of chronic CSC does not develop extensive RPE degeneration, DRPE should be considered as a variant of it.

Bilaterality of CSC

CSC was once considered as a unilateral disease, but now the literature documents 5-35% incidence of bilateral CSC. It has also been documented that this tendency increases with age. According to Gass40, approximately 10 to 25% develop symptomatic detachment in the opposite eye. Bujarborua et al56 found the overall prevalence of bilateral pathology of CSC to be 44.54% at the initial visit using FA as the only investigative procedure. Yannuzzi et al (1979)57 reported that 10% of the patients of their series had a concomitant acute SRD in the fellow eye and additional 12% developed the same during the followup period ranging from 2 to 8 years. They also observed RPE atrophy and pigmentary changes in about 80% of the fellow eyes by the end of their period of observation. Spaide et al58 observed choroidal vascular permeability in both eyes of 96.90% of patients aged 50 years and older, even if the patients had unilateral visual disturbance. Another study23 observed persistence of the choroidal vascular abnormality in the symptomatic eyes after cessation of leakage during the follow-up period that ranged from 6 – 48 months. The majority of the fellow asymptomatic eyes also had similar findings. Shiraki et al59 made

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similar observation in severe variant of CSC. Guyer69 detected many occult small PEDs in the fellow eyes, which were not observed clinically and by FA. Other investigative procedures like multifocal electroretinography61,62, contrast sensitivity63 and assessment of colour vision64 also detected significant changes in the asymptomatic fellow eyes.

Investigative Procedures in CSC

Fluorescein Angiographic Features

Fluorescein angiography in CSC reveals various types of leaks at the level of RPE depending on the stage of the disease. These leaks are seen in about 95% of all cases of all types of CSC.65

Smokestack leak: It is considered to be the classic CSC leak (Figure 3a-c). In general, sensory retinal detachments (SRD) having this type of leak is larger than those with other types of focal leak.28 Rarely the dye spreads inferiorly or horizontally.66 The reported prevalence of smokestack leak in literature varies from 7% to 29%. Shimizu and Tobari67 believed that the osmotic pressure gradient between the two fluid systems leads to unidirectional fluid flow through the functional hole in the pigment epithelium. Marmor68 believed that much of the spread of fluorescein seen angiographically may represent diffusion and convection rather than net fluid influx. A recent study30 believed that besides these factors, a bigger micro RPE rip is needed for the development of

smokestack leak. Occasionally unusual pattern of the ascending column of the dye is seen. Probably presence of fibrin alters the fluid dynamics of the subretinal space and produces the unusual pattern69. One of the authors (DB) had the opportunity of observing more than one smokestack leaks inside the same detached cavity.

Ink-blot Leak: In majority of cases (60%), the point leak(s) that appear in the initial phase of the angiography slowly and symmetrically spread in all sides to about l/4th disc diameter size (inkblot type). This type

Point Leaks: Some leaks do not expand much. These are the so called minimally expanding point leak70, whose expansion is always less than l/5th disc diameter in size. These types of leaks are usually found in subtle serous detachment of the retina.

Besides these - diffuse leak, decompensatory leak, window defects of various sizes and PEDs are visible on FA.

After spontaneous resolution of CSC, the healed scar with persistent leakage may be there for sometime. Whereas, in some cases there is no angiographic finding. PEDs persist till it collapses spontaneously. In case of recurrence of the acute episode, in about 80% of cases, the new point of leakage is located within 1 mm of the previous leak.

Indocyanine Green

Angiographic Features

Several investigators22-26,71 have shown presence of multiple hyperpermeable areas in the choroid (Figure 6a-b), which were often bilateral though one eye was symptomatic. Several studies25, 26, 71 have found the FA

leaks at the level of RPE to be contiguous with the areas of choroidal hyperpermeability, but some such areas were also seen without associated leak.22, 24, 71, 72 However, such areas develop leak in the follow-up period71 Several investigators23, 25 noted choroidal venous dilatation. The smokestack phenomenon is very unusual in ICGA.26,66 A recent OCT study73 found PED (91%) and RPE bulge (89%) in the areas of choroidal vascular hyperpermeability. Even in quiescent CSC, areas of vascular hyper-permeabitity remain visible during ICG video angiography. A study from Japan74 in which 9 eyes with history of CSC were followed up by ICGA for more than 5 years showed choroidal hyperfluorescence in all the eyes and associated choroidal venous dilatation in 6 eyes. Three of these eyes had recurrence during the follow up period.

Optical Coherence

Tomography (OCT)

OCT can detect detachments that remained undetected in FA. It can also detect subretinal deposits like fibrin and subretinal precipitates (Figures 7a-b and 8). Iida and co-workers (2000)75 utilizing OCT 2000 (Carl Zeiss Meditec) found the detached sensory retina to be thickened in acute stage of the disease. Piccolino and co-workers (2005)76 using the Stratus OCT (Carl Zeiss Meditec) could detect changes indicative of even, granulated, and atrophic profiles in the foveal structure in the photoreceptor layer of some detached retina. Some investigators30,77 observed cystoid macular degeneration and foveal atrophy after resolution of the sensory retinal detachment

in eyes having visual loss. They used OCT 2000. Recently introduced Ultra-high resolution OCT provides an axial resolution of approximately 3 μm that allows improved visualization of the external limiting membrane (ELM), photoreceptor inner and outer segment junctions (IS / OS) and identification of pathologic changes in the microstructure of the photoreceptor layer. Fourier-domain OCT (FD-OCT) provides a three dimensional view of these structures.

Fundus Autofluorescence

(FAF) in CSC

This technique is designed to document the presence of lipofuscin in the RPE. Lipofuscin is a mixture of proteins, lipids, and small chromatophores generated as by-products of the retinoid cycle. The accumulation of lipofuscin in the RPE is due to impaired or overwhelmed lysosomal activity, leading to incompletely digested cellular debris78, 79. The presence of FAF is thought to correspond to the accumulation or dispersion of lipofuscin in the subretinal space or RPE. Eandi et al,30 observed hypoautofluorescence corresponding precisely to the site of the focal RPE leak seen on FA in acute CSC cases. Hyperautofluorescence is known to occur beneath a chronic detachment of the retina. This supports the concept that a mechanical defect or absence of RPE accounts for the leakage from the inner choroids to the subsensory space.

Multifocal electroretinography has been used to identify focal regions of decreased retinal function, even in asymptomatic or clinically inactive eyes61.

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Microperimetry (using the Nidek MP-1 microperimeter) has also shown that, despite clinical resolution of CSC, there is lower retinal sensitivity in the macula even with 20/20 vision. Fixation studies showed stability of central fixation.

Differential Diagnosis

Following conditions may have to be differentiated from CSC: Age-related macular degeneration, Presumed ocular histoplasmosis syndrome,Idiopathicuveal effusion syndrome, Harada’s disease, Posterior scleritis, Benign reactive lymphoid hyperplasia of the choroids, Toxoplasmosis, Sympathetic ophthalmia, Disseminated intravascular coagulative disease, Pathological myopia, Uveoscleritis, Choroidal tumours, Pit in optic nerve head, Idiopathic polypoidalchoroidopathy,Severe hypertensive and renal diseases, Collagen-vascular diseases, Macular oedema, Irvine-Gass syndrome.

Management

Non-Drug Treatment

Reduce stress levels: Biofeedback, meditation, taking a philosophical approach to adversity, etc. Yoga may help; caffeine stimulates the pituitary gland and increases the cortisol level. Avoid caffeine containing drinks. Stop excess alcohol consumption. Try to avoid “cortisone treatments” as far as possible. Avoid unnecessary stress like disease, excessive exercise, crash diets, jet lag, pain, lack of sleep etc. Any form of infection increases cortisol levels. Monitor cortisol level if possible.

Medical Treatment

Many drugs had been tried for the treatment of CSC in the past, but without any convincing results. Still certain drugs like beta-blockers, acetazolamide (Diamox), certain anti-glucocorticoid agents and recently Bevacizumab (Avastin) are on use on investigational basis. Certain drug trails are going on to address the main causative factors as per present day’s concept of the disease.

remained unchanged during the month of treatment. It seems therapeutic effect would require longer time.

Bevacizumab (Avastin): Avastin, an antibody to VEGF (0.05 ml/1.25 mg intravitreal) is utilized in CSC cases to reduce the choroidal hyperpermeability and reverse the changes. Originally it was tried in chronic CSC cases. Now it has been tried in acute cases with encouraging result.4

Beta-blockers like metoprolol, nadolol, and trimepranol have been used with controversial results. One recent double blind randomized controlled clinical trial from Iran80 found that propanolol (20mg twice daily) cuts short the period of recovery and thereby eliminates the need for laser therapy. But it does not have any effect on visual recovery and its effect on recurrence rate could not be commented as it had a short term follow-up.

Acetazolamide(Diamox)wasalsoshownto be effective as the propanalol81, but it can not prevent recurrences and final visual recovery did not differ much from the control group. Moreover, this drug is having considerable side affects.

Ketoconazole: This is an anti-fungal drug of Imidazole group. This is used as an adrenocorticoid antagonist in the treatment of Cushing’s syndrome. A preliminary report from Manhattan Eye, Ear & Throat Hospital82 revealed that it lowers the endogenous cortisol level in CSC cases after 4 weeks treatment with 600 mg per day dose of the drug, but the median visual acuity, lesion height and the greatest linear dimension

Laser Photocoagulation in CSC

Since 1967 Laser has been introduced in the treatment of CSC. Light to moderate intensity applications of all modalities of laser like ruby, argon, krypton, diode and dye laser photocoagulation help in resolution of the detachment in CSC. Regarding the indications and time of intervention, the recommendations of Gass (1997)83 can be summarized as follows:

•Wait for 4 months in case of primary episode.

•Wait for 6 months or more if the leak is less than l/4th disc diameter away from the fovea.

•Wait for 1 month in patients with a history of several episodes of detachment in the same eye, if after each episode the patient has regained normal macular function.

•Prompt treatment is required (a) if the detachment is already present for 4 months or longer, (b) if patient has permanent

visual disturbance in either eye secondary to previous episodes of CSC, (c) for occupational reasons.

But regarding the time of intervention following points deserves attention before treating the cases.66

•CSC either in the acute or in the chronic stage affects quality-of-life. Today’s life is very stressful and highly competitive. No one can sit idle with visual problem hoping for an uncertain spontaneous recovery, unless and until they are compelled to because of non-availability of treatment.

•Many patients develop depression and extreme anxiety after acute onset of this disease. It is justifiable that by early treatment the patients should get rid of the annoying symptoms.

•Foveal attenuation occurs in CSC of more than 4 months duration and persistent BCVA reduction despite resolution of the detachment in such a situation.51 This study to be printed. They found no other likely cause of atrophy than the prolonged absence of contact between photoreceptors and retinal pigment epithelium. In this context, the reliability of the history of the patient regarding the duration of the symptoms deserves attention. In such a situation, early treatment is definitely justified.

•Sensory retinal detachment, which marginally spares the fovea, deserves immediate attention.

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Long-Term Outcome of Laser

Treatment in CSC

Annesley et al84 in a long-term follow-up (10 years) of cases treated with photocoagulation observed that visual prognosis is extremely good in more than 85% of laser treated eyes, but 12% of the eyes in their study exhibited marked visual impairment.

Laser Treatment of Variant

of CSC

Gass (1973)85 reported promising anatomical results by argon laser photocoagulation in cases of “bullous retinal detachments associated with multiple serous detachments of the retinal pigment epithelium”, which is a rare variant of CSC. Badrinath and Baig86 did subretinal fluid drainage and photocoagulation in 5 eyes with severe variant of CSC. Though they could settle the retina, complications like incarceration of the retina in 2 eyes, retinal break and development of lenticular opacity in one eye each were observed. Chan et al87 performed pars plana vitrectomy, perfluorocarbon liquid-assisted external drainage, and endolaser in a case of CSC with severe bullous serous retinal detachment. They had opted for this modality of treatment, as they could not apply laser to all the leaking spots. A report from Korea also showed successful result by doing vitrectomy and internal drainage of subretinal fluid in a case of bilateral severe variant of CSC.88

Laser can treat DRPE cases and several investigatorsobservedsettlementofthechronic sensory detachment, slowing down of progression of visual loss and stabilization of vision at certain level. The laser is applied in a grid pattern. Krypton and argon laser have been used successfully for this purpose. How laser photocoagulation helps in resolution of the chronic detachment in DRPE is not yet fully understood. The probable explanations are—photocoagulationreducesleakagebeneath the neurosensory retina by obliterating the choriocapillaries or photocoagulation may rejuvenate the RPE with reconstitution of the posterior blood-retinal barrier in areas of antecedent leakage.

Photodynamic Therapy (PDT) in

CSC

Use of verteporfin and PDT was first reported in 2003 in the setting of CSC. Yannuzzi et al89 used ICG angiography to first identify areas of choroidal hyperpermeability, which were subsequently treated by PDT. Several investigators have begun to use PDT as a first-line therapy for acute focal leaks from CSC with reported success. Most papers describe resolution of subretinal fluid within 1 month of treatment. The mechanism of action of PDT for treating CSC is postulated to be caused by short-term choriocapillaris hypoperfusion and long-term choroidal vascular remodeling. However, the application of conventional PDT in CSC can result in potential complications such as RPE atrophy, choroidal ischemia, and secondary choroidal neovascularization. To enhance the efficacy of PDT in treating CSC while minimizing

its side effects, the dose of verteporfin has been reduced and the time interval between infusion and laser application has also been reduced.90 PDT has also been tried in cases of DRPE.91

ICG mediated photothrombosis is a technique using a low-intensity laser combined with ICG dye infusion to treat focal areas of hyperpermeability in the choroid. An 810-nm laser is applied after infusion of ICG dye. Without prior ICG dye, investigators have also used the 810-nm laser as transpupillary thermotherapy (TTT) with moderate success. But this method is risky. A recent report92 described severe retinal thermal injury in a 31-year-old man following this treatment modality.

Complications of Laser

Treatment

1.Choroidal neovascularization at the site of photocoagulation. Small spot size and high power should be avoided.

2.Coagulation of macular venule or arteriole resulting in foveal ischemia and intra-reti- nal fibrosis. One must be very cautious in treating leaks near the margin of FAZ.

3.Creation of an appreciable positive paracentral scotoma or metamorphopsia secondary to excessive laser burn. Can be avoided by the use of minimal intensity coagulation, by avoiding treatment within FAZ and also by confining laser application to the area of incompetent pigment epithelium as demonstrated by angiography.