CASE STUDY

Rifampin as an Efficacious Therapy for Chronic CSC

An old antibiotic saves the day.

ALANNA NATTIS, DO • ROBERT JOSEPHBERG, MD

Central serous chorioretinopathy (CSC) is characterized by the accumulation of subretinal fluid at the posterior pole of the fundus, leading to a circumscribed area of retinal detachment.^1,2 When located in the central macular area, decreased vision, metamorphopsia, scotoma, and micropsia develop.^1,3

Most cases resolve within a few months with good visual recovery; however, small retinal pigment epithelium changes may remain, and patients may complain of persistent visual disturbances.¹

Despite extensive advances made in the treatment of various macular disorders, there is no universally accepted treatment protocol for patients with CSC. This lack may be secondary to the tendency of CSC to resolve spontaneously with time.³ Additionally, randomized, clinical trials in CSC have been scarce, and we lack a clear treatment target.³

Rifampin (Rifadin, Sanofi, Bridgewater, NJ) has recently come to the forefront of investigation for treatment of chronic CSC. It is thought that rifampin increases the metabolism of endogenous steroids as a consequence of the inductive effect on cytochrome P450 3A4.^4,5 Several reports have highlighted the medication’s efficacy in CSC, particularly in chronic cases.^2,5,6

Here, we review the clinical course of three patients treated with rifampin for chronic CSC, each of which experienced improved vision and resolution of subretinal fluid. Serial examinations were performed using indirect ophthalmoscopy, optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec Inc., Dublin, CA), and fluorescein angiography (FA) (Digital Imaging Systems IMAGEnet2000, Topcon Medical Systems, Oakland, NJ).

CASE 1

A 56-year-old man complained of decreased vision OS for two years at the initial presentation. He denied recent trauma, eye infections, or surgeries. His past medical history included type 2 diabetes mellitus, hypertension, hepatitis C, HIV (on antiretroviral therapy), and chronic renal failure.

The past ocular history was significant for refractive error and nonsurgical trauma OS with documented history of commotio retinae. He had no known medication allergies, and his family history was noncontributory. Medications included emtricitabine/tenofovir (Truvada, Gilead Sciences, Foster City, CA), candesartan (Atacand, AstraZeneca, Wilmington, DE), nevirapine (Viramune, (Boehringer Ingelheim, Ingelheim-Rhine, Germany) aspirin, glipizide (Glucotrol, Pfizer, New York, NY), and tamsulosin.

Best-corrected visual acuity on initial exam was 20/40 OD and 20/50^- OS. Intraocular pressure was 16 mg Hg OU. Slit-lamp examination of the anterior segment was unremarkable. Fundoscopy revealed healthy appearing optic nerves with cup-to-disc ratios of 0.4 OD and 0.5 OS.

The macula appeared flat OD and demonstrated RPE changes OS; OCT of the OS showed subretinal fluid with a pigment epithelial detachment (PED) (macular thickness 423 μm). After discussing treatment options with the patient (observation vs laser vs photodynamic therapy with verteporfin (Visudyne, Bausch + Lomb, Rochester, NY), we decided to observe his presumed chronic CSC.

Unfortunately, the patient was lost to follow-up for five years and reappeared later in our clinic after being given ketorolac (Acular, Syntex, Palo Alto, CA) eyedrops by another provider for unclear reasons (the patient stated he had run out of drops three weeks prior to his visit).

On return exam, his BCVA was count-fingers OS. Dilated exam and OCT showed subretinal fluid OS, with a greatest macular thickness of 419 μm. A decision was made to restart ketorolac TID with follow-up four months later.

Upon follow-up, the patient’s BCVA improved to 20/80 OS; dilated exam revealed persistent subretinal fluid. The OCT at this visit revealed a smaller macular PED OS, with a greatest macular thickness of 283 μm. Ketorolac was continued.

At the next follow-up six months later, the patient’s vision declined to count-fingers at 3 ft OS. Subretinal fluid was demonstrated OS on fundoscopy and OCT. Over the course of the next year, and after discussing treatment options with the patient, he received seven bevacizumab (Avastin, Genentech, South San Francisco, CA) injections OS.

His vision fluctuated between 20/150 and 20/100 OS, but the patient ultimately experienced persistence/worsening of the subretinal fluid OS and an eventual decrease in his vision to count-fingers at 5 ft. At this point, we started a therapeutic trial of rifampin 600 mg PO daily.

Two months after starting rifampin therapy, the BCVA OS improved to 20/200. OCT of the OS revealed complete resolution of subretinal fluid (macular thickness 219 μm). The patient’s response to rifampin is demonstrated in Figure 1.

Figure 1. Clinical course of the patient in Case 1, pre- and post-therapy with rifampin.

CASE 2

A 45-year-old male presented with complaints of decreased/distorted vision OS for “many years.” His past medical history was significant for hyperlipidemia and latent TB infection treated with isoniazid for 12 months (10 years prior to presentation).

His past ocular history was significant for nonsurgical blunt trauma OS as a child. Atorvastatin (Lipitor, Pfizer) was his only medication; he had no known allergies. BCVA at initial visit was 20/20 OD and 20/150 OS. Intraocular pressure was 19 mm Hg OU. The anterior slit lamp exam was unremarkable.

Fundoscopy revealed healthy appearing optic nerves, with cup-to-disc ratios of 0.1 OU, RPE changes in the macula OU, and the presence of subretinal fluid OS. OCT of the OS was remarkable for a small PED (macular thickness 329 μm).

We established a diagnosis of chronic CSC OS, and he was given the option of treatment with PDT, intravitreal bevacizumab injection, or observation; he opted for bevacizumab. After the first bevacizumab injection OS, the patient’s vision remained stable (BCVA 20/150 OS), but OCT revealed persistent subretinal fluid.

Over the following two months, he received two more bevacizumab injections OS. His BCVA improved to 20/60^-2; dilated exam revealed residual, but decreased, subretinal fluid. Treatment options were discussed, and the patient did not wish to have any further intravitreal injections. He was started on 10 mg of oral methotrexate weekly, with folate supplementation.

One month after starting methotrexate, vision OS improved to 20/80. At this point, methotrexate was continued, because funduscopy and OCT OS revealed decreased subretinal fluid (macular thickness 230 μm).

Upon return several months later, BCVA OS declined to 20/100. Dilated exam revealed RPE changes; OCT of the OS showed persistent subretinal fluid (macular thickness 372 μm). Methotrexate was discontinued; we again discussed the option of PDT, but the patient declined. Over the next six months, the patient experienced persistence of subretinal fluid. At this point, we initiated a trial of oral rifampin therapy (600 mg daily).

One month after starting rifampin, BCVA OS improved dramatically to 20/40. Dilated exam revealed RPE mottling, but the macula appeared flat; OCT of the OS showed complete resolution of the subretinal fluid (macular thickness 170 μm). Upon follow-up over the next several months while he was on rifampin therapy, the patient’s vision and exam remained stable. The patient’s response to rifampin is shown in Figure 2 (page 54).

Figure 2. Clinical course of the patient in Case 2, pre- and post-therapy with rifampin.

CASE 3

A 51-year-old man presented with complaints of blurred vision for two years in his left eye. He denied any inciting trauma, eye infections, or visual complaints OD. He had no significant past medical or ocular history, he was not taking any medications, and his family history was noncontributory.

On initial exam, his BCVA was 20/40 OD and 20/400 OS. Intraocular pressure was 14 mm Hg OU. The anterior exam showed 1-2+ nuclear sclerosis, and fundoscopy revealed healthy appearing optic nerves OU with cup-to-disc ratios of 0.2. The macula appeared flat OD, with mild pigment mottling. The macula OS revealed RPE changes and diffuse macular edema. OCT of the OD was unremarkable; OS showed a central macular PED (macular thickness of 335 μm). Fluorescein angiography of the OS showed multiple areas of macular leakage.

Based on his history and exam, we diagnosed the patient with chronic CSC OS. Given the success of our prior two patients, we started a therapeutic trail of 600 mg PO rifampin daily.

At his one-month follow up, the patient’s BCVA OS improved to 20/50. Dilated exam revealed pigment mottling OS, but the macula appeared flat. Repeat OCT of the OS revealed complete resolution of subretinal fluid (macular thickness 166 μm).

Rifampin was continued until his next follow-up visit at four to six weeks, at which point his exam remained stable. The patient’s response to rifampin can be reviewed in Figure 3.

Figure 3. Clinical course of the patient in Case 3, pre- and post-therapy with rifampin.

DISCUSSION

Our case series is unique in that it highlights clinical responses to a variety of treatment options for chronic CSC, and it also supports evidence from other studies suggesting that rifampin should be considered a viable therapeutic option.

Despite different clinical, medical, and ophthalmic histories, rifampin therapy proved successful in each patient with chronic CSC. We believe that rifampin was working on a common physiologic system to resolve subretinal fluid, because it was efficacious in each patient.

Hypercortisolism, hyperadrenalism, and catecholamine response have been hypothesized to be potential risk factors in the well-recognized “type A” nature of patients with CSC.^1,7 There have been many studies linking CSC to clinical entities in which a state of hypercortisolism exists (systemic lupus erythematosus, ulcerative colitis, sarcoidosis); it has been suggested that corticosteroid exposure itself, rather than underlying inflammatory disease process(es), may be the causal factor for CSC in these patients.^1,7

The possible mechanism by which glucocorticoids act as inciting factors for CSC development is poorly understood. Possible mechanisms include increased capillary fragility and hyperpermeability, leading to choroidal circulation decompensation and leakage of fluid into the subretinal space.¹

Additionally, glucocorticoids appear to promote blood coagulation and to affect the production of nitric oxide, prostaglandins, and free radicals, possibly causing choroidal hypoperfusion.¹ Additionally, glucocorticoids are known to inhibit collagen formation (the main constituent of Bruch’s membrane) and to alter ion transport of epithelial cells, primarily through mineralocorticoid receptors.¹ If this is true for the RPE cells, it could explain the cause of RPE dysfunction in CSC.¹

Although usually self-limited, if CSC fails to improve after two to six months and/or is encroaching on the fovea, it is reasonable to consider treatment.³ PDT is considered to be first-line treatment for chronic CSC.⁸ However, it is associated with pigmentary changes, RPE atrophy, choroidal ischemia, and secondary choroidal neovascularization.^3,8

Historically, several other modalities of treatment have been used for chronic CSC, including psychotherapy, adrenocorticotropic hormone, anti-inflammatory medications, retrobulbar tolazoline, antisyphilitic and anti-TB drugs, insulin-free pancreatic extract, thyroid extract, and subconjunctival injections of milk, albumin, and salt solutions.⁹

Focal laser has been shown to be an option for leakage outside the perifoveal area.¹⁰ Other studies have highlighted the utilization of anti-VEGF therapy, methotrexate, aspirin, and ketoconazole.^3,9,11,12

Our case series supplements the current literature highlighting the efficacy of rifampin for the treatment of chronic CSC. In concordance with previous reports, our patients showed decreased subretinal fluid and improvement in VA after just a few weeks, perhaps through rifampin’s antiglucocorticoid properties.

Although we believe further randomized, controlled, prospective studies are needed in the future to help elucidate the true value (both short and long term) of rifampin, it appears to be a promising, cost-effective, and efficacious therapy for chronic CSC.¹³

In addition, it would be interesting to explore rifampin as a treatment option for acute CSC, especially in patients in whom excellent depth perception and VA are vital to their career/lifestyle (eg, pilots, operators of heavy machinery, professional athletes).

Then, perhaps, we could explore the optimal treatment period/duration, as well as incidence of recurrence of CSC, in those treated for acute CSC episodes after rifampin therapy. RP

REFERENCES