ABOUT THE AUTHORS
Dr. Toussaint is a retina fellow at Cincinnati Eye Institute and University of Cincinnati Department of Ophthalmology.
Dr. Shaikh is a vitreoretinal surgeon at Houston Eye Associates in Texas.
Dr. Sisk performs adult and pediatric vitreoretinal surgery at Cincinnati Eye Institute and is an associate professor of ophthalmology at the University of Cincinnati.

DISCLOSURES: Dr. Sisk is a speaker for Heidelberg Engineering. Drs. Toussaint and Shaikh have no disclosures.
Central serous chorioretinopathy (CSCR) has well-established risk factors for its presentation, but these are infrequently present. In our experience, we’ve observed that many patients with CSCR abuse caffeine. Based on results of an internal review board-approved retrospective case series at our institution, we propose that chronic, excessive caffeine intake may be a modifiable risk factor for CSCR and may be responsible for many “idiopathic” cases. Here, we discuss our investigation in this area.  

Pathophysiology of CSCR

CSCR is a common form of exudative retinopathy typically affecting men between ages 30 and 50 years. It involves focal or multifocal leaks at the level of the retinal pigment epithelium (RPE), usually manifesting as subretinal fluid and pigment epithelial detachment. We don’t fully understand the pathogenesis of CSCR, but it appears to be related to hyperpermeability at the RPE associated with vascular congestion and thickening of the choroidal circulation.1

Symptomatic patients experience micropsia, metamorphopsia and reduced visual acuity. The vast majority of patients experience a single acute episode that spontaneously resolves after three to six months with improvement to baseline visual acuity.1 However, one-third of patients develop chronic or recurrent disease that may create persistent vision impairment from damage to the RPE and photoreceptors.

Non-idiopathic Disease

Most cases of CSCR have been classified as idiopathic. However, steroids have been demonstrated to cause or perpetuate CSCR, particularly in patients who have elevated serum cortisol levels such as those in Cushing’s syndrome, pregnancy or exogenous steroid treatments.2 Reports have also described associations with stress and type A personality, which may be associated with elevated blood cortisol. Case reports have also documented associations with Helicobacter pylori, phosophodiesterase-5 inhibitors and obstructive sleep apnea.

Once the diagnosis of CSCR is made, the most common intervention is to recommend lifestyle changes.
Figure 1. A baseline optical coherence tomography (OCT) image of a patient
who had consumed eight cups of coffee per day (A) and a follow-up OCT
image (B) three months after the patient stopped consuming caffeine.  This
patient had no clinical recurrence of disease.
At our institution this includes a discussion on caffeine intake, limiting exogenous steroid exposure and stress management.  We review medications (both prescription and over-the-counter) and supplements, which provides us an opportunity to discuss other potential lifestyle changes like smoking cessation.

Additional treatments for CSCR include photodynamic therapy (PDT), argon laser, micropulse laser,3 rifampin (Rifadin),4 the antimineralocorticoids spironolactone (Aldactone)5,6 and eplerenone (Inspra), and anti-glucocorticosteroid therapy (mifepristone, ketoconazole and finasteride). Evidence supporting these therapies has mostly been in small, uncontrolled, retrospective case series. One exception is argon laser photocoagulation.7 While short-term results seemed promising, significant recurrence rates8 and the visual sequelae of macular laser have left ophthalmologists searching for alternative therapies.

Role for Guided PDT

The Mechanism of Caffeine in CSCR
What is the mechanism by which caffeine can produce central serous chorioretinopathy (CSCR)? Surprisingly, this is a function of a link between caffeine and endogenous corticosteroids. Patients with CSCR have statistically higher endogenous cortisol levels than age-matched controls.19

Elevated cortisol levels may lead to a reduction in choroidal blood flow and increased intraluminal pressure in the surrounding choriocapillaris. This results in RPE decompensation and detachment. RPE cells express the most common genes involved in the hypothalamic-pituitary axis, leading to the production of cyclic-adenosine-monophosphate (cAMP) and adrenocorticotrophic hormone (ACTH).20

Caffeine consumption elevates both ACTH and cortisol concentrations relative to placebo.21 One proposed mechanism is that caffeine blocks adenosine receptors. Adenosine (A1) receptors accelerate the removal of subretinal fluid while A2 receptors slow this removal.22 Caffeine is a potent antagonist of adenosine.

Chronic caffeine consumption (600 mg/day for one week or 400 mg/day for two weeks) upregulates A2 receptors.23 Interestingly, subjects treated with 400 mg/day of caffeine for one week did not experience changes in adenosine receptor activation. It is quite possible that this dose-dependent effect of caffeine consumption might also result in a dose-dependent change in choroidal thickness and in the balance of A1:A2 receptors contributing to fluid movement across the RPE.

Although most Americans consume some caffeine daily,17,18 it remains unclear why only some of those who abuse caffeine develop CSCR. Likely genetic factors predispose certain individuals.  While a genetic link between caffeine and CSCR has yet to be solidified, genetic variants in complement factor H24 as well as in the age-related macular susceptibility (ARMS2) gene have shown an association with chronic CSCR.25  Risk alleles for CSCR may be protective in age-related macular degeneration.25
Our preferred therapy for patients with subfoveal fluid that fails to resolve after three to four months of observation is fluorescein angiography-guided reduced-fluence PDT. Initial PDT studies for acute and chronic CSCR showed excellent results compared to placebo.9-11 Michele Reibaldi, MD, and colleagues compared full-fluence to reduced-fluence PDT and found no difference in the rates of subretinal fluid resorption or vision improvement.12  To date, many reports have highlighted the success of reduced-fluence PDT, with many studies reporting 80 percent to 90 percent efficacy with a single treatment.12-16

Most patients with CSCR do not have classic risk factors. We have observed significant caffeine consumption among many of our acute and chronic “idiopathic” CSCR patients. Caffeine use is ubiquitous: 80 percent of Americans are reported to ingest caffeine in some form daily.17

Experts vary regarding how much caffeine is safe, ranging between 200 and 400 mg/day (approximately two to four 8-oz. cups of regular coffee).17,18 The Food and Drug Administration and other leading health authorities state that caffeine abuse­—consumption of greater than approximately 500-600 mg of caffeine daily (equivalent to four to seven cups of coffee)—is associated with cardiac dysrhythmia, psychological alterations, dehydration and, in extreme cases, death.17,18

Manifestations of Caffeine Abuse

We investigated the association between CSCR and caffeine with an Institutional Review Board-approved retrospective case series.  We reviewed the records of 76 patients diagnosed with CSCR between 2010 and 2013 at the Cincinnati Eye Institute by a single provider. Twenty-one (28 percent) patients reported exposure to any type of steroid, although we did not think all exposures were causative. Of the 55 cases not associated with steroid use, 38 (69 percent) of patients noted consumption of caffeine. For 20 (36 percent) of the 55 patients, caffeine was the only risk factor for development of CSCR.  

Thirty-eight of the caffeine consumers with non-steroid induced CSCR self-reported “moderate” or greater consumption of caffeine or four cups of coffee per day or more; we found that 24 (63 percent) of them abused caffeine. Among the caffeine abusers, seven (29 percent) had bilateral disease, 13 (54 percent) exhibited subretinal fluid, and five (21 percent) had a pigment epithelial detachment.  We noted bilateral RPE changes in eight of the 24 (33 percent) patients and unilateral RPE changes in 15 (63 percent).  

Figure 2. Fundus autofluoresence images of three patients who abused
caffeine with bilateral central serous chorioretinopathy and high caffeine
intake: a 48-year-old male with a serous retinal detachment who consumed
a half-gallon of Mountain Dew per day (top); 30-year-old male with subretinal
fluid who drank six cans of Mountain Dew daily as well as supplemental
energy drinks (center); and a 53-year-old male with bilateral RPE changes who
consumed four to five cups of coffee per day (bottom).
Of the 24 patients who met the criteria for caffeine abuse, eight patients (33 percent) exhibited decreased subretinal fluid over an average follow-up of 7.6 months after making the lifestyle change to decrease caffeine intake to approximately two caffeinated beverages per day or less.  

Our series suffered from lack of follow-up, as five patients were lost to follow-up after their first visit and eight patients were lost after their three-month visit.

Nine patients overall, five of whom had more than three months of follow up, underwent reduced-fluence PDT. One patient did not have resolution of subretinal fluid despite PDT until after cessation of caffeine.  

Figure 1 shows a baseline OCT image of one patient with subfoveal fluid who was consuming eight cups of coffee per day. (Figure 1A) A follow-up OCT image (Figure 1B) three months after the patient stopped consuming caffeine shows reduction of subretinal fluid. This patient had no clinical recurrence of disease.  

Figure 2 shows fundus autofluoresence images of the macula of both eyes of patients with bilateral CSCR and high caffeine intake. The patient in Figure 2 top is a 48-year-old male who consumed a half gallon of Mountain Dew per day. He had central macular hypoautofluorescence from a serous retinal detachment in the right eye.

Figure 2 center shows a 30-year-old male who drank six cans of Mountain Dew per day as well as supplemental energy drinks. The right eye has small focal areas of macular hypoautofluorescence, and the left eye had hyperautofluorescence associated with serous retinal detachment

The patient in Figure 2 bottom is a 53-year-old male with bilateral irregular hyper- and hypoautofluorescent RPE changes who consumed four to five cups of coffee per day.

Take-home Point
Central serous chorioretinopathy (CSCR) has well-established risk factors for its presentation. However, these are infrequently present. In our patient population, many who presented CSCR also abused caffeine.  We propose that chronic, excessive caffeine intake may be a modifiable risk factor in patients diagnosed with CSCR and may be responsible for many “idiopathic” cases. Future studies on CSCR should evaluate the role of caffeine abuse.
Central serous chorioretinopathy has well-established risk factors. However, these are infrequently present. In our patient population, many patients with CSCR were observed to abuse caffeine. We propose that chronic, excessive caffeine intake may be a modifiable risk factor in patients diagnosed with CSCR and may be responsible for many “idiopathic” cases.  The role of caffeine abuse should be evaluated in future studies of CSCR.  RS



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