Oral Mifepristone for Chronic Central Serous.26

7/28/2019 Oral Mifepristone for Chronic Central Serous.26

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ORAL MIFEPRISTONE FOR CHRONICCENTRAL SEROUS

CHORIORETINOPATHYJARED S. NIELSEN, MD,* LEE M. JAMPOL, MD*

Background: Chronic central serous chorioretinopathy (CCSC) can result in permanent

loss of vision. Unfortunately, many cases of CCSC are not eligible or do not respond to

treatment with thermal laser or photodynamic therapy. Glucocorticoids have been

implicated in the pathogenesis of central serous chorioretinopathy. Mifepristone, an oral

glucocorticoid receptor antagonist, may be helpful in cases of CCSC.

Methods: Mifepristone 200 mg was administered orally to 16 CCSC subjects in

2 separate protocols for up to 12 weeks. Visual acuity, examination, angiography, optical

coherence tomography, and liver function were monitored during the treatment period.

Results: Favorable response to oral mifepristone was seen in CCSC patients with seven

subjects gaining five or more letters of vision and seven subjects having improved opticalcoherence tomography findings. Treatment was well tolerated without serious adverse

effects.

Conclusion: Systemic glucocorticoid receptor antagonism with daily oral mifepristone

does have a beneficial effect in treating some cases of CCSC. Further study is warranted.

RETINA 31:19281936, 2011

Central serous chorioretinopathy (CSC) is typically

a self-limited condition with favorable clinical

outcomes. A minority of cases progress to chronic

central serous chorioretinopathy (CCSC) an often

recurrent, progressive, and persistent variant that canaffect both eyes and results in permanent vision lossfrom retinal thinning with retinal pigment epithelium

(RPE) atrophy.1 Classic CSC is manifest as focal RPE

leakage, often with a pigment epithelial detachment

and accumulation of subretinal fluid. Chronic cases

usually demonstrate diffuse leakage, intraretinal cystic

changes, with extensive RPE and retinal atrophy, and

may show no or very little subretinal fluid. Choroidal

hyperpermeablity on indocyanine green (ICG) angi-

ography2 and thickened choroid best seen on enhanced

depth imaging spectral domain optical coherence

tomography (EDI-sdOCT)3 are typical CSC findings.

The precise mechanism underlying the development

of CSC remains unknown. Primary dysfunction in

CSC may reside in the choroid. Hyperpermeable

choriocapillaris drives leakage through compromised

RPE, leading to secondary retinal changes over time.

Glucocorticoids (GCs) have been implicated in the

pathogenesis of CSC,

46

and it is reasonable to surmisethat anti-GC therapy may be helpful in its treatment.4

Mifepristone (Mifeprex; Danco Laboratories, New

York, NY), more popularly known as RU-486, is an

orally bioavailable, high-affinity, GC receptor antag-

onist.7,8 It is also a potent antiprogesterone agent and is

Food and Drug Administration approved for use as an

abortifacient when coadministered with a prostaglan-

din agent. Mifepristone binds cytosolic GC receptors,

preventing coactivator recruitment rendering the

receptor complex inactive, thus preventing gene

transcription.7 Long-term oral mifepristone has

been investigated for several disorders including

meningioma, depression, Cushing disease, uterine

leiomyomata, endometriosis, diabetes, and obesity.7,8

Long-term treatment with mifepristone is generally

well tolerated and has a typically benign side effect

profile including skin rash, nausea, dizziness, fatigue,

reversible liver transaminase elevation, and endome-

trial hyperplasia.7,8 Presently, the cornerstone of

treatment for recurrent or persistent CSC is verteporfin

(Visudyne; QLT Inc., Vancouver, British Columbia,

Canada) photodynamic therapy (PDT). Laser activa-

tion of verteporfin after infusion generates local

From the *Department of Ophthalmology, Feinberg School ofMedicine, Northwestern University, Chicago, Illinois; and WolfeEye Clinic, West Des Moines, Iowa.

Supported in part by grants from The Macula Foundation, NewYork, NY, and Research to Prevent Blindness Inc., New York, NY.

The authors report no conflicts of interest.Reprint requests: Jared S. Nielsen, MD, Wolfe Eye Clinic, 6200

Westown Parkway, West Des Moines, IA 50266; e-mail: [email protected]

1928


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reactive oxygen species decreasing choroidal perfu-

sion at the target site. Photodynamic therapy may be

associated with rare but sight threatening adverse

effects including choriocapillaris ischemia and RPE

atrophy.9 Many strategies have been used to prevent

PDT-induced injury including reducing verteporfin

dose, reducing laser duration or fluence, and alteringthe timing of infusion and laser delivery.9,10 Successful

treatment rates reported in the literature range

greatly.10 Unfortunately, some patients with CCSC

are not eligible for or do not respond to PDT. We have

investigated whether mifepristone may be helpful in

cases of CCSC.

Material and Methods

Patients with CCSC were enrolled in 2 separate

institutional review boardapproved treatment proto-cols evaluating oral mifepristone 200 mg daily for up

to 12 weeks. The first protocol was a double-masked,

randomized, controlled trial comparing mifepristone

with placebo. The second protocol was an open-label

trial of daily oral mifepristone. For both studies,

eligible patients were required to have active CSC in

one or both eyes of more than 6-month duration, not

amenable or responsive to treatment by thermal laser

photocoagulation or PDT. Individuals who were

pregnant; had irregular vaginal bleeding, hypothy-

roidism, anemia, liver disease, renal disease, choroidal

neovascularization; or were less than 60 days out fromtreatment with either laser or PDT were excluded from

participation.

The two studies differed in design. The first protocol

was a small, randomized, masked, placebo-controlled

trial. Study subjects exited Protocol 1 before 12 weeks

if they did not improve at the regular 4-week

evaluation periods. The second protocol was an

open-label treatment trial and designed to have

patients exit the study only if adverse events were

encountered.

Visual acuity was assessed in both trials at

enrollment and at 4-week intervals. Snellen visual

acuity was used in Protocol 1, whereas best-corrected

Early Treatment Diabetic Retinopathy Study testing

was performed in Protocol 2. Complete ophthalmic

examination, fluorescein angiography, and optical

coherence tomography (OCT) were performed before

enrollment for all patients and repeated every 4 weeks

over the course of treatment. Indocyanine green

angiography was performed at enrollment and on

conclusion of the trial. A serum hepatic panel was

obtained for all subjects at enrollment and was

rechecked after 4 weeks of treatment and on conclusion

of the protocol or more frequently if any abnormality

was encountered. Pregnancy was ruled out by serum

beta HCG in female subjects who were also required to

use two forms of contraception throughout the protocol.

Results

Protocol 1

Eight male subjects with CCSC were enrolled in this

randomized placebo-controlled trial from January 2004

to February 2006. With 4 taking mifepristone 200 mg

daily for up to 12 weeks and 4 taking placebo. Char-

acteristics of all patients are summarized in Table 1. The

mean age was 51.4 with an average duration of 6.8 years

of CSC (2.514 years). Three had a known history of

exogenous steroids, and four were affected bilaterally.

Three subjects had previously been treated with focal

laser, and one had previously received PDT. Vision for allsubjects ranged widely from 20/20+ counting fingers 1 ft

to 2 ft in affected eyes. Initial vision in mifepristone

subjects was worse than the placebo group. Four subjects,

1 taking mifepristone and 3 taking placebo exited the

study before 12 weeks because of no improvement.

Vision changes are summarized in Table 1. Visual acuity

improved by one line in three eyes of three patients taking

mifepristone and in one eye of one patient on placebo.

Two subjects taking mifepristone demonstrated an

improvement in OCT findings, whereas one placebo

patient had some improvement in OCT findings.

Protocol 2

Thirteen white patients, 3 women and 10 men, with

CCSC were enrolled and completed a 12-week

protocol of oral mifepristone 200 mg daily between

October 2007 and January 2011. The clinical

characteristics for all patients are summarized in

Table 2. The mean age for patients was 57.5 years

(range 2081 years). Duration of CSC averaged

6.2 years (215 years). Four patients reported a known

history of corticosteroid use, three patients had been

previously treated with thermal laser, another six with

previous PDT. Four subjects had been treated with

bevacizumab. Pretreatment vision in affected eyes

ranged from 20/16+ counting fingers 3 ft to 3 ft.

Pretreatment best-corrected visual acuity is reported

for all patients in Table 3. Hepatic panel revealed

normal liver transaminase levels in all patients.

Clinical responses are summarized in Table 3. Six

subjects reported some subjective improvement in one

or both eyes at the end of treatment. Six patients were

found to have a five-letter or equivalent improvement

in visual acuity in one or both eyes. Six of the 13

ORAL MIFEPRISTONE FOR CHRONIC CSC NIELSEN AND JAMPOL 1929


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Table 1. Protocol 1 Patient Characteristics and Response to Treatment

Age (Years) Arm PMH

CSCDuration(Years)

PreviousLaser

PreviousPDT

PreviousSteroids

AffectedEye

VisualAcuity Start

ODOS

50 Placebo Gilbert syndrome 14 2 2 2 OU 20/25 + 3 220/20 + 1 2

37 4 2 2 2 OS 20/16 220/32 + 3 2

43 4 2 2 2 OS 20/20 2

20/32 + 2 240 3 2 2 + OD 20/40 + 1 2

20/20 2 3 264 Mifepristone Hypertension 10 + 2 2 OU 20/200 2

CF 2 C63 2.5 2 + + OD 20/252 2

20/252 251 Type 2 diabetes,

kidney stones10 + 2 + OU 20/20 2 2 2

20/32 2 2 263 Hypertension,

hypercholesterolemia7 + 2 2 OU 20/200 2

20/80 2

CF, counting fingers; post tx, post treatment; PMH, past medical history.


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patients experienced an improvement in retinal OCT

findings with decreased retinal edema or subretinalfluid on OCT, with 1 patient developing increased

cystoid macular edema in 1 eye over the course of

treatment. No significant changes in fluoresceinangiography or ICG angiography were found. One

patient developed choroidal neovascularization from

CCSC thought not to be related to mifepristone

treatment and underwent subsequent injection with

bevacizumab. One patient who had a favorable

response to mifepristone in Pilot 1 relapsed and

subsequently completed the Pilot 2 protocol with

a favorable response.5 He also demonstrated a dramatic

response to rechallenge with mifepristone. No patients

experienced any serious adverse events over the course

of treatment including skin rash. No patients were

found to have liver transaminase elevation throughoutthe protocol.

Case Reports

A 63-year-old white male previously reported5 with CCSC for at

least 7 years OD worse than OS with progressive vision loss. He

had been treated previously with thermal laser in the left eye. Visual

acuity was 20/200 in the right eye and 20/80 in the left eye.

Examination revealed extensive pigment atrophy in both the eyes.

Fluorescein angiography demonstrated extensive pigment atrophy

and diffuse leakage. Choroidal hyperpermeability was shown on

ICG angiography (Figure 1). Optical coherence tomography

showed widespread retinal edema and collections of subretinal

fluid. After 12 weeks of mifepristone 200 mg daily, the edema

improved. Vision improved to 20/30 in the left eye but remained 20/

200 in the right eye.5

Four months later after completion of Protocol 1, the patientreturned with complaints of visual deterioration with vision

declining to 20/40 in the left eye and remaining at 20/200 in the

right eye. Evaluation revealed return of macular edema in both the

eyes off the mifepristone. Twenty months after him completing

Protocol 1, his decline had continued. His vision declined to 20/200

in the right eye and 20/80+ in the left eye with worsening macular

edema. Angiographic findings were similar to his original

presentation: diffuse leakage on fluorescein angiography and

choroidal hyperpermeability on ICG. He was enrolled in Protocol

2 and completed another 12-week course of oral mifepristone

200 mg daily. With rechallenge, his vision improved to 20/180+ in

the right eye and 20/50+ in the left eye with complete resolution of

his macular edema (Figure 1). Residual retinal atrophy was noted

OD.OS. Just 4 months after completing the second course of

mifepristone, he again relapsed with accumulation of cystoid

macular edema and vision decline to 20/200 in the right eye and

20/80 in the left eye.

A 38-year-old white female with CCSC for 4 years and a history

of steroid use presented with enlarging scotomata in both the eyes.

Visual acuity was excellent with Early Treatment Diabetic

Retinopathy Study best-corrected visual acuity of 20/16 in the

right eye and 20/25 in the left eye. On examination, she noted to

have diffuse pigmentary changes in both eyes. Fluorescein

angiography showed large extrafoveal leakage in both eyes and

a pigment epithelial detachment in the left eye (Figure 2).

Table 2. Protocol 2 Patient Characteristics

NumberAge

(Years) Sex PMH/POHAffected

Eye Laser Avastin PDTCSC

Duration (Years) Steroids

1 47 F HTN, herniateddisk, eczema

OD 2 2 2 2 2

2 81 M CAD s/p CABG, arthritis,

kidney stones,SB for RRD OD withpoor VA

OS 2 + 2 15 +

3 65 M HTN, hyperlipidemia,previous response toprevious mifepristone

OU + 2 + 9 2

4 81 M HTN, hyperlipidemia,urinary incontinence

OU 2 2 + 10 2

5 54 M GERD, herniated disk OU 2 2 2 12 26 63 M Anxiety, HTN OU 2 2 2 30 27 48 M Depression, anxiety OU 2 2 2 17 28 76 M Osteoarthritis,

prostate cancerOU 2 2 2 10 2

9 38 F Migraines OU 2 2 2 5 +10 58 M HTN, arthritis OU + + + 10 211 20 F Bee sting

and ibuprofen allergyOD 2 + + 2 2

12 59 M Hypertriglyceridemia OU + + + 15 +13 69 M Barrett esophagus OU 2 2 + 12 +

F, female; M, male; VA, visual acuity; PMH, past medical history; POH, past ocular history; HTN, hypertension; CAD s/p CABG,coronary artery disease with bypass graft; GERD, gastroesophageal reflux disease; SB, scleral buckle.



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Choroidal hyperpermeablity was noted on ICG angiography.

Shallow collections of subretinal fluid in both eyes and a small

pigment epithelial detachment were noted on time domain OCT.

After 12 weeks of treatment, her Early Treatment Diabetic

Retinopathy Study best-corrected visual acuity improved to 20/

12.5 and 20/20. All subretinal fluid resolved in the right eye and

improved in the left eye. Ten months after completing the

mifepristone treatment, she presented with worsening of subretinal

fluid in both the eyes with a decrease in vision to 20/40 in the left

eye. She entered into an institutional review boardapproved

compassionate use mifepristone protocol and has responded with

decreased subretinal fluid in both the eyes and some improvement

in vision in the left eye to 20/30 after 12 weeks. She is continuing

this compassionate use protocol.

A 58-year-old white male presented with devastating vision loss

from 10 years of CCSC in both the eyes despite three sessions of

PDT. Vision at presentation was 20/100 in the right eye and

counting fingers 5 ft in the left eye. Severe macular pigmentary

changes and cystoid macular edema were noted on initial

evaluation. Angiography revealed extensive macular leakage in

both the eyes on fluorescein angiography (Figure 3) and choroidal

hyperpermeability in both the eyes on ICG. Large central

intraretinal cysts were demonstrated bilaterally with time domain

OCT. After 12 weeks of oral mifepristone, vision improved to 20/

200 in the left eye and remained at 20/100 in the right eye. Central

macular cystic changes nearly resolved in the left eye, with some

mild improvement in the right eye.

Discussion

Between the 2 small protocols, 16 individuals havetaken oral mifepristone for CCSC, with 1 subject

participating in both protocols. This cohort is

heterogeneous with regard to vision and clinical

severity. Overall, 8 of the 16 patients reported a sub-

jective improvement in vision. Seven subjects demon-

strated an improvement in visual acuity of five letters or

greater. Seven individuals demonstrated improvementof findings on OCT. One subject who participated in

both protocols exhibited initial response to daily

mifepristone, relapsed off the medication, and repeat

response to subsequent rechallenge.

Many of the patients entered into this protocol withadvanced or end-stage pathology. Despite a dramatic

improvement in retinal anatomy, visual improvement

was limited by retinal thinning, neuronal loss, and

RPE atrophy. Patients with less advanced CCSC

would likely benefit more substantially from a vision

standpoint. Systemic mifepristone therapy has a sub-

stantial history of safety, and no issues were revealed

during our limited investigation.

It is clear that a 12-week course of oral mifepristone

is insufficient to resolve all macular edema and

subretinal fluid even in responsive patients. We

speculate that some patients in our 12-week protocol

might have benefited further from extended treatment.

Further investigation should be designed to consider

longer duration treatment.

Endocrine abnormalities are common in patients

with CSC. Haimovici et al11 demonstrated that 38% of

individuals with active acute CSC had elevated 24-hour

urine cortisol and 29% had an abnormal diurnal patternof cortisol secretion. Response to mifepristone may be

more likely in patients with corticosteroid abnormal-

ities. We did not specifically investigate cortisol levels

either before or during mifepristone treatment. One

individual who demonstrated a response to mifepris-

tone was tested after washout and found to have normal

serum cortisol levels. Future CSC mifepristone proto-

cols should investigate whether there is a relationship

between corticosteroid dysfunction and response to

mifepristone.

There are two patients in the study who presented

with only isolated RPE detachments and no choroidal

hyperpermeability on ICG angiography. We believe

that these patients may not have typical CSC and may

represent an entirely different disease entity. No

response was seen to mifepristone.

Table 3. Protocol 2 Response to Mifepristone Treatment

Number

Enroll VisualAcuity OD

Exit VisualAcuity OD

SubjectiveChange

ImagingResults

Enroll VisualAcuity

OS

Exit VisualAcuity

OS

1 20/16 + 1 20/16 + 2 = =20/12.5 20/16 + 1

2 20/400 CF 1 ft = 220/160 + 4 20/160 + 3

3 20/160 20/160 + 4 + +20/80 + 4 20/50 + 1

4 CF 10 ft 20/200 = =20/63 + 3 20/100 + 1

5 20/40 + 4 20/20 + 2 + =20/40 20/32 + 2

6 20/100 20/160 + 2 = +20/200 + 2 20/200

7 20/16 + 4 20/16 + 2 + +CF 3 ft 20/200 2 2

8 20/200 2 4 20/200 + 2 = =20/50 + 2 20/50 + 3

9 20/16 + 3 20/12.5 = +20/25 20/20 2 1

10 20/100 + 2 20/100 2 1 + +CF 5 ft 20/200 2 3

11 20/50 + 3 20/32 + 3 + =20/20 + 1 20/20 + 1

12 20/16 + 1 20/20 + 1 = 220/200 2 1 20/200 2 2

13 20/40 + 1 20/32 + 4 + +10/50 + 4 20/40 + 3

CF, counting fingers.

1932 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2011 VOLUME 31 NUMBER 9


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Special considerations warrant attention during

systemic mifepristone anti-GC therapy. Mifepristone

use as an abortifacient requires exceptional caution

when treating female patients with childbearing

potential. For all patients who may become pregnant,

serum beta HCG before retreatment and two separate

forms of contraception while undergoing therapy should

be used. Mifepristone can induce reversible liver

transaminase elevation. Monitoring of these enzymes

is required during treatment. Adrenal insufficiency is

another rare but potentially serious consequence of anti-

GC therapy. Physicians using systemic mifepristone

Fig. 1. A 63-year-old whitemale with CCSC in both theeyes for 7 years. Initial pre-treatment FA (A) and ICG(B). Optical coherence to-mography responses (C) to 2separate 12-week courses ofmifepristone. FA, fluorescein

angiography.



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need to be able to recognize adrenal insufficiency, make

patients aware of the symptoms, and be ready to direct

treatment if necessary.

Our study is not the first attempt to investigate

systemic anti-GC therapy for CSC. The widely

available antifungal agent ketoconazole exhibts anti-

GC effects at higher doses. Unfortunately, after some

limited initial investigation, ketoconazole has not yet

proven effective for CSC. Meyerle et al12 investigated

ketoconazole 600 mg daily for 4 weeks in 5 patients.

They were able to demonstrate a systemic anti-GC

effect by monitoring urinary cortisol in patients taking

ketoconazole. The authors felt that the results of this

short trial were inconclusive. However, one patient did

demonstrate resolution of subretinal fluid and im-

provement of vision.12 Our experience with mifepris-

tone suggests that longer treatment may be required.

Golshahi et al13 evaluated oral ketoconazole 200 mg

daily in a casecontrol study of patients with acute

CSC. They were unable to ascertain any treatment

effect after 4 weeks. Unfortunately, the 200-mg dose is

likely too low to produce a substantial anti-GC effectin most patients, and the duration of treatment again is

too short.

Fig. 2. A 38-year-old whitefemale with CCSC in both theeyes for 4 years. Baseline FA(A) and OCT responses (B) tomifepristone. FA, fluorescein

angiography.



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This study has many limitations. The inclusion of an

open-label cohort, small size, and wide range of

disease severity limit our ability to draw definitive

conclusions about mifepristone for CCSC. Some of

the clinical responses manifest in our study indicate

that mifepristone may have an important role in the

treatment of CCSC, particularly in patients who do not

respond to other treatment.

All our patients did not respond to 12 weeks of

systemic mifepristone therapy. Many of our patients

are on the more severe end of the disease spectrum and

may be recalcitrant to mifepristone therapy. Perhaps,

CSC is a heterogeneous disease. Glucocorticoid-

mediated disease may simply be a subset of all

patients afflicted with CSC. Patients who have non

GC-mediated CSC are not likely to respond to GC

antagonists.

Our limited experience supports GC receptor

antagonism with systemic mifepristone as a possible

treatment of CCSC. The precise biologic mechanism

underlying the etiology of CSC is unknown. Our

findings add evidence to implicate GCs in the

pathogenesis of CSC. Further investigation is war-

ranted to better understand the efficacy and safety of

systemic mifepristone therapy in CSC.

Key words: antiglucocorticoid therapy, central

serous chorioretinopathy, central serous retinopathy,

glucocorticoid receptor antagonism, optical coherence

tomography, mifepristone, RU-486.

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Fig. 3. A 58-year-old whitemale with CCSC in both theeyes for 4 years. FA (A)and OCT responses (B) tomifepristone. FA, fluoresceinangiography.



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