Issue: September 2008

Central Serous Retinopathy

MICHAEL COLUCCIELLO, MD

Central serous retinopathy (CSR; ICD-9: 362.41) is an exudative chorioretinopathy

characterized by an exudative neurosensory retinal detachment with or without an
associated detachment of the retinal pigment epithelium (RPE). This disorder results in
metamorphopsia and micropsia. The disease was first recognized by Albrecht von Graefe in
1866, who termed the condition "idiopathic detachment of the macula" and "central
recurrent retinitis."1 Perhaps most appropriately designated a choroidopathy, it is currently
most commonly termed a retinopathy.

EPIDEMIOLOGY

Most cases of the CSR occur in individuals between 20 and 50 years of age. One study
found the age range at first diagnosis to be between 22 and 83 years old. In that study,
patients older than 50 tended to have bilateral disease, systemic hypertension, and a history
of corticosteroid use.2 The overall incidence in men vs women is approximately 6 to 1. In 1
study, mean annual age-adjusted incidences per 100000 were 9.9 for men and 1.7 for
women.3 In women, pregnancy is a known risk factor.4

CSR has been associated with stress and stress hormones (ie, corticosteroids and
epinephrine); individuals with a "type A personality" who are under stress have been shown
to be predisposed to developing the condition.5 There is extensive evidence that those
exposed to exogenous (even topical) corticosteroids (eg, those with asthma, autoimmune
disorders, dermatologic conditions, allergic rhinitis, degenerative disc disease requiring
epidural steroids, and organ transplant patients) or higher levels of endogenous
corticosteroids (Cushing syndrome) or epinephrine (obstructive sleep apnea,6 systemic
hypertension) show a higher frequency of CSR.6 In 1 series, 52% of patients with CSR had
used exogenous steroids within 1 month of presentation as compared to 18% of control
subjects.7 The incidence of CSR in persons with Cushing syndrome was 5% — far higher
than the general population — in 1 small study.8 Sildenafil (Viagra, Pfizer) usage has also
been linked to the development of CSR.9,10

The incidence of recurrence in the ipsilateral eye is approximately 30%; in 1 study the
incidence of signs of CSR in the fellow eye was 32% (symptomatic in 13%).11 One study
associated Helicobacter pylori infection with CSR;12 no further studies have corroborated
this finding.

Michael Colucciello, MD, is a clinical associate in the Department of Ophthalmology at

the University of Pennsylvania School of Medicine in Philadelphia and a retina specialist
practicing with South Jersey Eye Physicians in Moorestown, NJ. He reports no financial
interests in products mentioned in this article. Dr. Colucciello can be reached via e-mail at
michael@macula.us.
PATHOPHYSIOLOGY

Several hypotheses have been offered regarding the pathogenesis of CSR, but none have
been definitively proved. Hypotheses have been offered based on epidemiologic and
angiographic observations.

Patients with CSR may have an increased susceptibility to choroidal and RPE
hyperpermeability with steroids or epinephrine. Impairment in autonomic function may lead
to a focal disturbance/spasm in the choroidal circulation.13

In these patients, choroidal vasoconstriction mediated by epinephrine and potentiated by

corticosteroids may lead to choroidal ischemia and hypermeability.14,15 The exudation of
plasma proteins results in increased oncotic pressure in the extravascular space, inducing a
malfunction of the RPE pump mechanism and disruption of the zonula adherens between
RPE cells, leading to an RPE leak.16 This disruption of the outer blood-retinal barrier then
allows for transudate between the RPE and retina resulting in a neurosensory retinal
detachment.17-19 Damage to active fluid transport mechanisms in the RPE (normally
dehydrating to the subretinal space) may also play a role in the process.20

CLINICAL PRESENTATION

Patients present with an acute onset of central scotoma, metamorphopsia, and micropsia
(detected by Amsler grid). Visual acuity (VA) is often improved with a small hyperopic
correction. There is an decrease in contrast sensitivity and color saturation and an increase
in macular photostresss recovery time.

Contact lens biomicroscopy demonstrates a serous macular neurosensory retinal detachment

without blood. Often, subretinal deposits are noted as "dots" in the area of the serous
detachment (Figure 1). RPE detachments, retinal pigment epithelial mottling and atrophy
(sometimes in a "gutter" configuration), and subretinal fibrin (especially when the episode
occurs during pregnancy) may also be seen. Uncommonly, subretinal lipid is seen in CSR.

EVALUATION

Studies complementary to clinical examination offer information leading to the diagnosis of

CSR, allow for discrimination in the differential diagnosis (Table 1), and give data helpful
in deciding possible therapeutic options.

Table 1. Central Serous Retinopathy Differential Diagnosis

Choroidal Neovascularization due to:

 Exudative AMD
 Multifocal Choroiditis (eg, POHS)
 Degenerative Myopia
 Angioid Streaks

Idiopathic Serous RPE Detachment

Vogt- Koyanagi- Harada Disease

Macular Hole

Optic Nerve Pit

RPE Dystrophy (eg, Best)

Malignant Hypertension

Choroidal Tumors

 Hemangioma
 Metastasis
 Melanoma

Acute Lymphocytic Leukemia

Optical coherence tomography (OCT) (Figure 1 inset) demonstrates many of the signs
listed above, most notably the presence of a neurosensory macular detachment, which may
be subtle. Intravenous fluorescein angiography (IVFA) in CSR demonstrates focal leakage
at the level of the RPE. Pinpoint leakage sites are usually seen; a "classic smokestack"
configuration of fluorescein leakage (Figure 2) is seen in only 10% of cases. In chronic
CSR, a focal granular hyperfluorescence at the level of the RPE can be seen, associated with
areas of atrophy of the RPE.

Figure 1. Clinical biomicroscopic presentation of CSR: serous macular detachment,

with punctuate subretinal deposits in the region of the neurosensory detachment.
Inset: OCT shows macular detachment in the same patient.
Figure 2. Sequential IVFA images (to 6 minutes, right) demonstrate classic
"smokestack" leakage at the level of the RPE with pooling of dye in the sub-
neurosensory retinal space in a patient with an acute episode of CSR.

Indocyanine green angiography (ICG) shows early hypofluorescence and late

hyperfluorescence in areas of involvement. In very late phases, silhouetting of larger
choroidal vessels is seen. ICG may also show subtle (often clinically inapparent) RPE
detachments and areas of choroidal vascular hyperpermeability not detected with IVFA.

Multifocal electroretinography has been used to correlate the signs of CSR with regions of
decreased retinal function and to monitor response to therapy. Microperimetry can measure
retinal-sensitivity changes in CSR. Blood studies are generally not helpful, although
elevated endogenous cortisol levels have been noted with CSR.

NATURAL HISTORY

CSR tends to resolve spontaneously within 8 weeks, with recovery of vision in

approximately 90% of patients. Snellen VA may return to 20/20, but subtle
metamorphopsia, nyctalopia, and dyschromatopsia may persist.

Approximately 30% of patients have recurrences;3 10% have 3 or more. Nearly half of those
patients who experience a recurrence have that recurrence within 1 year of the initial
presentation of CSR. Visual function may progressively decline with each recurrence.
Retinal pigment epitheliopathy (decompensation of the RPE or "sick RPE syndrome"),
cystoid macular degeneration (cystoid foveal changes on OCT without associated
intraretinal leakage of fluorescein dye on IVFA), and CNV can complicate the process,15
especially with multiple recurrences.

DIFFERENTIAL DIAGNOSIS

Considerations for differential diagnosis in CSR include disorders that involve central vision
loss associated with exudative neurosensory retinal detachment.

Neovascular exudative ("wet") age-related macular degeneration (AMD) presents with a

neurosensory macular detachment. Although wet AMD presents in patients over the age of
50, CSR may also initially present in the same group. In wet AMD, in contrast to CSR,
hemorrhagic neurosensory retinal detachments and hemorrhagic RPE detachments may be
noted. Also, subretinal hard exudation is much more common in wet AMD than in CSR.
Soft drusen and a familial history are characteristic of AMD. IVFA in neovascular AMD
demonstrates CNV membranes — areas of leakage rather a focal point, as seen in CSR. The
areas of early leakage on IVFA in wet AMD are typically lacy annular subretinal
hyperfluoresence, seen in "classic" CNV, shallow fibrovascular RPE detachments with
stippled hyperfluoresence, or a combination of the 2 conditions. ICG angiography in
exudative AMD often shows a plaque of hyperfluoresence, rather than silhouetting of the
larger choroidal vessels.

A variant of wet AMD, retinal angiomatous proliferation (RAP), often presents with
intraretinal hemorrhage, which is not seen in CSR. IVFA in RAP demonstrates dilated
capillaries near an area of intraretinal neovascularization that extends to the subretinal space
and leaks. ICG in RAP shows retinal-retinal anastomosis and retinal leakage with a focal
"hot spot" of leakage. Isolated serous or drusenoid RPE detachments in AMD present
without contiguous exudation clinically or on OCT and do not demonstrate leakage on
IVFA.

A macular neurosensory retinal detachment may be associated with other disorders that can
lead to CNV. A multifocal choroiditis, such as presumed ocular histoplasmosis syndrome,
may be associated with an exudative macular detachment in association with CNV. Fundus
lesions typified by multiple choroidal lesions, with or without peripapillary atrophy, are
associated with clinical and angiographic evidence of CNV. Degenerative myopia, in a
highly nearsighted eye, may be associated with exudative CNV, especially when lacquer
cracks are present. Angioid streaks may also be associated with exudative CNV. This
condition may be discerned by the characteristic radial peripapillary linear dark red
subretinal lines that represent regions of Bruch's membrane dehiscence.

Idiopathic serous RPE detachments, which typically occur in younger individuals and may
be associated with metamorphopsia, are not associated clinically with serous retinal
detachment upon examination with ophthalmoscopy or OCT and do not exhibit leakage on
IVFA.

Vogt-Koyanagi-Harada (VKH) disease is a multisystem disease characterized by

granulomatous uveitis with exudative retinal detachment associated with cutaneous,
auditory, and neurologic manifestations. Distinguishing features include the presence of
uveitis and disc edema associated with bilateral exudative retinal detachments, often
involving the macula and inferior retina. Vitiligo, poliosis, meningeal signs with
cerebrospinal fluid pleocystosis, focal neurologic signs, dysacusis, tinnitus, and vertigo are
common systemic manifestations. There is a human leukocyte antigen DR4 genetic
predisposition to the disease, encompassing Hispanic, Asian, Native American, and Middle
Eastern populations. OCT examinations in VKH disease show an exudative retinal
detachment as in CSR, but IVFA shows multiple pinpoint areas of RPE leakage, optic disc
hyperfluoresence and retinal vascular leakage (Figure 3).
Figure 3. IVFA of right and left eyes in a patient with acute VKH syndrome, showing
multiple pinpoint bilateral, symmetric RPE leaks associated with bilateral serous
macular detachments. This patient, who exhibited HLA-DR4, also had vertigo,
dysacusis, vitiligo, headache and a rash.

A macular hole may also be accompanied by a surrounding retinal detachment. A full-

thickness foveal defect characterizes the condition. Approximately 50% of patients with
optic nerve pits develop macular detachments. Congenital optic disc pits are typically
hypopigmented oval or round defects averaging 500 μm (one-third of a disc diameter) in
size, usually in the inferior temporal portion of the optic cup. RPE dystrophies, such as Best
disease, typically appear with bilateral symmetrical foveal or parafoveal RPE pigmentary
changes. Serous macular detachments can be associated with these conditions due to
choroidal neovascularization. Electrooculography is diminished in Best's disease.

Vascular disorders, such as hypertension, may have an associated serous macular

detachment. Choroidal tumors (hemangioma, metastasis, and melanoma) may also have an
associated macular serous retinal detachment. Acute lymphocytic leukemia has been
associated with serous macular detachments.16

TREATMENT OPTIONS

Since the prognosis for CSR is good; 80% to 90% of cases resolve spontaneously within 3
months. Observation is the first option in management. Certainly, if the patient is taking
exogenous corticosteroids, these should be tapered and discontinued if possible.

If the patient is not taking exogenous steroids and the episode does not appear to be
improving after 2 months, if previous episodes have left the patient with residual deficit or
the visual symptoms are affecting the patient's activities of daily living to a significant
extent, or if the patient needs to continue exogenous steroids for treatment of a medical
condition, active treatment should be considered.

Photodynamic therapy (PDT) directed at RPE leaks may hasten resolution of exudation in
CSR by reducing choroidal blood flow in those areas, thus favoring cessation of leakage.
Since there is upregulation of vascular endothelial growth factor (VEGF) locally in areas of
PDT,17 the development of CNV after PDT treatment of CSR is not surprising.18 "Safety-
enhanced" PDT using half-dose verteporfin (Visudyne, QLT/Novartis), compared to the
AMD treatment protocol, has shown promise.19

Laser photocoagulation of RPE leakage sites in CSR can also hasten resolution of leakage,
resulting in resolution of associated serous macular detachment. Laser is only an option for
extrafoveal leakage sites because collateral retinal damage follows laser treatment in all
cases. Laser treatment was shown to be associated with a decreased CSR recurrence rate in
1 study.20 Potential complications include thermal rupture of Bruch's membrane with
hemorrhage, secondary CNV,21 and misplaced laser spots.

Medical treatments have also been investigated: Acetazolamide given in a tapering dose for
6 weeks has been shown to reduce the time for subjective and objective CSR resolution, but
it had no effect on final VA or recurrence rate.22 Most patients in the experimental group in
that study had side effects from the acetazolamide, including paresthesias, nervousness, and
gastric upset. Patients with sulfa allergies should avoid acetazolamide.

The beta adrenergic receptor blocker propranolol and the mixed alpha and beta adrenergic
receptor blocker labetalol have plausible mechanisms of action in CSR if epinephrine is
indeed involved in the pathogenesis of the disorder. Small studies have demonstrated
evidence of efficacy.23,24

Mifepristone (Mifeprex, Danco Laboratories) is an antagonist of progesterone and

glucocorticoid receptors; in a case study, 1 patient with CSR responded well to treatment
with mifepristone.25 The antifungal ketoconazole is an adrenocorticoid antagonist that has
been shown to lower endogenous cortisol; administration was associated with a decreased
height of serous detachment after 8 weeks of treatment in 1 study.26

Intravitreal bevacizumab (Avastin, Genentech) has been investigated for treatment of CSR;
theoretically, the antipermeability characteristics of this antibody to VEGF may allow for
reduced leakage, favoring resorption of the exudative retinal detachment in CSR.27

A summary of treatment options appears in Table 2.

Table 2. Treatments for Central Serous Retinopathy

Observation

Surgical

 Photodynamic Therapy
 Laser Photocoagulation

Medical (Investigational)

 Bevacizumab (Avastin, Genentech)

 Acetazolamide (Diamox Sequels, Duramed)
 Propanolol (Inderal, Wyeth)
 Labetalol (Trandate, Prometheus Laboratories)
 Mifepristone (Mifeprex, Danco Laboratories)
 Ketoconazole (Nizoral, Ortho-McNeil)

CONCLUSION

CSR is characterized by an exudative macular detachment associated with focal points of

RPE hyper-permeability, resulting in vision changes that include metamorphopsia and
micropsia. Accurate diagnosis of CSR via clinical examination and ancillary studies to rule
out differential diagnosis allows for appropriate counselling of the patient: With observation
(and discontinuation of exogenous steroids, if applicable), the natural history is good.
Treatment to hasten resolution of the serous macular detachment should be considered in
patients with chronic cases, in individuals who need to be on a regimen of exogenous
steroids, or in those persons with active CSR who have experienced some irreversible loss
in vision with prior episodes. Treatment options include laser photocoagulation, "safety-
enhanced" PDT, and a (growing) variety of medical treatments as indicated above. With
hope, in the future, a more definitive picture of the pathogenesis will lead to a more specific
treatment regimen and prophylaxis strategy for those predisposed to this condition. RP

REFERENCES

1. von Graefe, A. Ueber central recidivierende retinitis. Graefes Arch Clin Exp
Ophthalmol. 1866;12:211-215.
2. Spaide RF, Campeas L, Haas A, et al. Central serous chorioretinopathy in younger
and older adults. Ophthalmology. 1996;103:2070-2079; discussion 2079-2080.
3. Kitzmann AS, Pulido JS, Diehl NN et al. The incidence of central serous
chorioretinopathy in Olmsted County, Minnesota, 1980-2002. Ophthalmology.
2008;115:169-173.
4. Haimovici R, Koh S, Gagnon DR, Lehrfeld T, Wellik S. Risk factors for central
serous chorioretinopathy: a case-control study. Ophthalmology. 2004;1111:244-249.
5. Yannuzzi LA. Type A behavior and central serous chorioretinopathy. Trans Am
Ophthalmol Soc. 1986;84:799-845.
6. Carvalho-Recchia CA, Yannuzzi LA, Negrao S, et al. Corticosteroids and central
serous chorioretinopathy. Ophthalmology. 2002;109:1834-1837.
7. Leveque TK, Yu L, Musch DC, et al. Central serous chorioretinopathy and risk for
obstructive sleep apnea. Sleep Breath. 2007;11:253-257.
8. Bouzas EA, Scott MH, Mastorakos G, et al. Central serous chorioretinopathy in
endogenous hypercortisolism. Arch Opthalmol. 1993;111:1229-1233.
9. Allibhai ZA, Gale JS, Sheidow TS. Central serous chorioretinopathy in a patient
taking sildenafil citrate. Ophthalmic Surg Lasers Imaging. 2004;35:165-167.
10. Fraunfelder FW, Fraunfelder FT. Central serous chorioretinopathy associated with
sildenafil. Retina. 2008;28:606-609.
11. Bujarborua, D, Chatterjee, S, Choudhury, A, et al. Fluorescein angiographic features
of asymptomatic eyes in central serous chorioretinopathy. Retina. 2005;25:422-429.
12. Cotticelli L, Borrelli M, D'Alessio AC, et al. Central serous chorioretinopathy and
Helicobacter pylori. Eur J Ophthalmol. 2006;16:274-278.
13. Tewari HK, Gadia R, Kumar D, et al. Sympathetic-parasympathetic activity and
reactivity in central serous chorioretinopathy: a case-control study. Invest
Ophthalmol Vis Sci. 2006;47:3474-3478.
14. Prunte C, Flammer J. Choroidal capillary and venous congestion in central serous
chorioretinopathy. Am J Ophthalmol. 1996;121:26–34.
15. 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
16. Giovannini A, Scassellati-Sforzolini B, D'Altobrando E, et al. Choroidal findings in
the course of idiopathic serous pigment epithelial detachment detected by
indocyanine green videoangiography. Retina. 1997;17:286-293.
17. Spitznas M. Pathogenesis of central serous retinopathy: A new working hypothesis.
Graefes Arch Clin Exp Ophthalmol. 1986;224:321-324.
18. Marmor MF. New hypotheses on the pathogenesis and treatment of serous retinal
detachment. Graefes Arch Clin Exp Ophthalmol. 1988;226:548-552.
19. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green
videoangiography of central serous chorioretinopathy. Arch Opthalmol.
1994;112:1057-1062.
20. Marmor M, Tan F. Central serous chorioretinopathy: bilateral multifocal
 electroretinographic abnormalities. Arch Opthalmol. 1999;117:184-188.
21. Spaide RF, Campeas L, Haas A, et al. Central serous chorioretinopathy in younger
and older adults. Ophthalmology. 1996;103:2070-2080.
22. Fackler, T, Bearelly, S, Odom, T, et al. Acute lymphoblastic leukemia presenting as
bilateral serous macular detachments. Photo essay. Retina. 2006;26:710-712.
23. Schmidt-Erfurth U, Schlötzer-Schrehard U, Cursiefen C, et al. Influence of
photodynamic therapy on expression of vascular endothelial growth factor (VEGF),
VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci.
2003;44:4473-4480.
24. Colucciello M. Choroidal neovascularization complicating photodynamic therapy for
central serous retinopathy. Retina. 2006;26:239-242.
25. Chan WM, Lai TY, Lai RY, et al. Safety enhanced photodynamic therapy for
chronic central serous chorioretinopathy: one-year results of a prospective study.
Retina. 2008;28:85-93.
26. Burumcek E, Mudun A, Karacorlu S, et al. Laser photocoagulation for persistent
central serous retinopathy: results of long-term follow-up. Ophthalmology.
1997;104:1981-1982.
27. Schatz H, Yannuzzi LA, Gitter KA. Subretinal neovascularization following argon
laser photocoagulation treatment for central serous retinopathy: complication or
misdiagnosis? Ophthalmology. 1977;83:893-906.
28. Pikkel J, Beiran I, Ophir A, et al. Acetazolamide for central serous retinopathy.
Ophthalmology. 2002;109:1723-1725.
29. Tatham A, Macfarlane A. The use of propranolol to treat central serous
chorioretinopathy: an evaluation by serial OCT. J Ocul Pharmacol Ther.
2006;22:145-149.
30. Prunte C, Sommer M, Orgul S, Flammer J. Mixed alpha-beta-adrenergic antagonist
treatment of central serous chorioretinopathy. Invest Ophthalmol Vis Sci.
1998;39(Suppl):830.
31. Nielsen, J; Weinreb, R; Yannuzzi, L, et al. Mifepristone treatment of chronic central
serous chorioretinopathy. Retina. 2007;27:119-122.
32. Meyerle CB, Freund KB, Bhatnagar P, et al. Ketoconazole in the treatment of
chronic idiopathic central serous chorioretinopathy. Retina. 2007;27:943-946.
33. Torres-Soriano ME, García-Aguirre G, Kon-Jara V, et al. A pilot study of
intravitreal bevacizumab for the treatment of central serous chorioretinopathy (Case
reports). Graefes Arch Clin Exp Ophthalmol. 2008 Jun 4; [Epub ahead of print].