Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-014-2780-6
MEDICAL OPHTHALMOLOGY
Spironolactone in the treatment of central serous chorioretinopathy – a case series T. R. Herold & K. Prause & A. Wolf & W. J. Mayer & M. W. Ulbig
Received: 1 June 2014 / Revised: 7 August 2014 / Accepted: 11 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Backg rou nd The p athog enes is o f c entral ser ous chorioretinopathy (CSC) is still poorly understood. An animal model of CSC proved that the mineralocorticoid receptor [1] of the choroid also plays a role in CSC. Since there is still no evidence-based therapy for non-self-limiting CSC, this case series evaluates the effect of oral spironolactone in CSC patients. Methods In this interventional, uncontrolled, prospective case series, we present 18 consecutive CSC patients. Patients were treated with spironolactone 25 mg twice daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 12 weeks. Follow– up examinations with BCVA, OCT, and EDI-OCT were performed at 1, 2, and 3 months after starting the treatment. Main outcome measure was a change of subretinal fluid (SRF) (in micrometers) measured by optical coherence tomography. Secondary outcome was a change in central retinal thickness (CRT) (in micrometers) measured by OCT and a change in BCVA. Results The subretinal fluid (SRF; mean) decreased from 219 μm (baseline) to 100 μm (visit 3) (difference 119 μm). Total central retinal thickness (CRT; mean) decreased from 405 μm before treatment (baseline) to 287 μm after treatment (difference 118 μm). The BCVA (in logMAR; mean) increased from 0.32 at baseline to 0.20 at visit 3. Conclusion Our case series could confirm a positive influence of spironolactone on the course CSC. Longer follow-up with a larger number of cases could provide more data about the long-term efficiency, recurrences, and safety of this welltolerated and non-invasive treatment option of CSC. T. R. Herold (*) : K. Prause : A. Wolf : W. J. Mayer : M. W. Ulbig Department of Ophthalmology, University Eye Hospital – LMU, Campus Innenstadt, Klinikum der Universität München, Mathildenstrasse 8, D-80336 Munich, Germany e-mail: [email protected]
Keywords Spironolactone . Central serous retinopathy . Choroid . Subretinal fluid
Introduction Central serous chorioretinopathy (CSC) is a common cause for central vision loss mostly in young men. As a longstanding chronic disease or bilateral involvement CSC can lead to severe, irreversible reduction of visual acuity. CSC has an incidence of approximately 1/10,000 [2], and its pathogenesis is still poorly understood. In general, CSC shows a good prognosis, and spontaneous regression is documented in around 60 % [3]. However, some cases develop a chronic or recurrent course and require an effective and photoreceptorsaving treatment. Latest data reveal that the disease derives from the choroid. It could be proved that there is diffuse choroidal thickening not only in eye with CSC, but also in the fellow eye of the same patients [4]. The increased choroidal leakage and hyperpermeability of the choroidal vessels in CSC has been demonstrated before [5]. Since chronic CSC often causes severe anatomical damage at the level of the retinal pigment epithelium, several approaches such as systemic use of acetazolamide or rifampicin [6], as well as sub-threshold laser treatment [7–9], and intravitreal application of bevacizumab have been evaluated in the past. Additionally, low-fluence, or half-dose, PDT seems to be a promising approach for the disease [10]. Recently, an animal model of CSC proved that the mineralocorticoid receptor which is expressed in the choroid could also play an important role in the pathogenesis of CSC [1]. This receptor is not only subject to mineralocorticoids, but also glucocorticoids. Therefore, competitive antagonists of the MR are likely to prevent
Graefes Arch Clin Exp Ophthalmol
glucocorticosteroids to bind to the mineralocorticoid receptor and could, therefore, be involved in the pathogenesis of CSC in the choroid. The features of CSC in an animal model showed good reversibility during treatment with the MR antagonist eplerenone [1]. This was also proven in a small case series of chronic CSC patients [11]. Spironolactone is another competitive antagonist mainly used in the treatment of hyperaldosteronism, hypertension, and congestive heart failure [12]. Its most common side effect is the increase of the serum potassium level and its effect on arterial blood pressure. Other rare side effects are allergic exanthema and hormonal influence due to antiandrogen effects. The higher rate of antiandrogen effects in spironolactone compared to eplerenone is equalized by the fact that spironolactone is given in a lower and thus well tolerable dose. As the use of systemic MR antagonists given orally in a low dose seems to be a novel promising approach to not self-limiting CSC this case series evaluates the effect of an MR antagonist in 18 consecutive CSC patients presenting with symptoms of CSC for more than 6 weeks. Because the affinity of spironolactone to the MR is much higher than in eplerenone, we chose to evaluate spironolactone as study drug.
Materials and methods Study design This study was an interventional, uncontrolled, open-label, prospective clinical trial. We included consecutive patients with CSC between January 2013 and December 2013 at the Department of Ophthalmology of Ludwig-Maximilians University, Munich, Germany. IRB approval was obtained for this study and all patients were informed about the off- label use of the medication. Inclusion criteria were a symptomatic chronic CSC persistent for more than 6 weeks, with presence of subretinal fluid or cystoid macular oedema involving the fovea on optical coherence tomography (OCT) and active leakage on fluorescein angiography, not regressing for at least 6 weeks. In cases of signs of regression of the subretinal fluid and rise in visual acuity, the patients were not treated or included in the study. In order to avoid other macular disorders than CSC, we only included patients up to the age of 51 years. Exclusion criteria were diabetic retinopathy, previous photodynamic therapy, intravitreal injections, or thermal retinal laser photocoagulation in the past 6 months. Presence of choroidal neovascularisation or other macular disorders was an additional exclusion criterion. Patients with systemic
Table 1 Patients characteristics
M=male, F=female; OD=right eye, OS=left eye
Patient Number
Gender
Age (years)
Affected eye(s)
Duration of symptoms (weeks) before treatment
Previous steroids
Medical problems
1 2 3 4 5 6 7 8 9 10
M M W M M M W M M M
50 52 54 59 43 57 41 51 50 44
OD OS OS OS OD OS OD/OS OD OD OS
6 6 104 6 8 12 6 16 12 6
– – – – – – – – – –
None None None None None None None hypertension None None
11 12 13 14 15 16 17
W M W M W M M
37 40 33 40 50 50 56
OD/OS OD OD OS OS OS OS
6 8 12 16 20 6 36
– – – – – + –
18
M
34
OD
6
–
None None None None None Still disease Morbus Bechterew hypertension None
Graefes Arch Clin Exp Ophthalmol
contra-indications against spironolactone (severe kidney or liver disease, serum potassium level >5.5 mmol/L), concomitant medication with other potassium-sparing diuretic agents, pregnancy, etc., were excluded. Concomitant systemic medication, especially antihypertensive drugs and previous history of systemic steroid use in the past, were specifically asked for and documented. Previous steroid use as a possible trigger or cause of the disease has not been excluded from the study. Treatment Patients were treated with spironolactone 25 mg twice daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 12 weeks. Baseline and follow-up All patients underwent full ophthalmological survey including best-corrected visual acuity (BCVA), clinical examination, and optical coherence tomography using the Macular Thickness map of spectral-domain OCT (Heidelberg Spectralis, Heidelberg Engineering,
Fig. 1 Optical coherence tomography pictures of two patients. a-c Baseline and Visits 2 and 3 of a 37 year-old female patient with CSC. Visual acuity increased from 0.4 logMAR (Baseline) to 0 logMAR (Visit 3). d-f
Heidelberg, Germany) Additionally, enhanced depth imaging (EDI-OCT) was performed. The subfoveal thickness was measured as distance between the outer portion of the hyperreflective line corresponding to the RPE to the inner surface of the sclera if signals were detectable using a single scan. Before starting the medical treatment, fluorescein and indocyanine green angiography (Heidelberg HRA, Heidelberg Engineering, Heidelberg, Germany) were performed to exclude other macular disorders such as choroidal neovascularistion or polypoidal choroidal vasculopathy. We analyzed the central retinal thickness (CRT) by using the macular thickness map. The height of subretinal fluid (SRF) was measured manually in micrometers between the end of the outer segment and the retinal pigment epithelium layer at the highest point of neurosensory detachment. In order to receive the most exact correlation of subretinal fluid, this manual measurement was always performed at the highest point of detachment, also at follow-up visits. Since CSC findings are mostly eccentric and can change location during the period of review, we defined this parameter as important as the CRT reduction measured. BCVA was measured in logarithm of minimal angel resolution (logMAR).
Baseline and Visits 2 and 3 of a 40 year-old male patient with CSC. Visual acuity was 0.4 logMAR at Baseline and 0.2 logMAR at Visit 3
Graefes Arch Clin Exp Ophthalmol
Follow-up examinations with BCVA, OCT, and EDI-OCT were performed at 1 and 3 months after starting the treatment (visits 2 and 3). Arterial blood pressure was checked at each follow-up visit, serum potassium level and creatinine 1 and 2 months after starting treatment. The duration of treatment was limited to 3 months maximum due to potential side effects. In cases where signs and symptoms resolved completely, treatment was stopped earlier. Patients were asked about potential side effects at every follow-up visit.
Results Twenty eyes of 18 patients (14 men and four women) were included in our study. All patients were at least treated with spironolactone for a minimum of 4 weeks and a maximum of 8 weeks (depending on the SRF and BCVA). The mean age was 45.7 years (median 50 years; +/− SD 8). The mean duration of symptoms was 14.6 weeks (minimum 6 weeks, maximum 104 weeks) (see Table 1). In two cases there was a bilateral episode of CSC. One patient reported previous steroid use because of a muscle atrophy years before. Two examples of patients’ optical coherence tomography courses under spironolactone treatment are given in Fig. 1. All patients were scheduled for baseline visit with following visits at 1 month and at the end of therapy after 3 months. Of the patients treated, 78 % (n= 14) showed regression of subretinal fluid and were treated according to protocol with spironolactone for 12 weeks. Two of the patients stopped treatment earlier due to complete regression of subretinal fluid at visit 2, and two patients stopped treatment due to mild side effects.
Main outcome measures Main outcome measure was a change of subretinal fluid (SRF) (in micrometers) measured by optical coherence tomography at 1 and 3 months. Secondary outcome was a change in total central retinal thickness (CRT) (in micrometers) measured by OCT and a change in BCVA. Statistics
Efficacy
Data are provided as mean +/− SD. Statistical analaysis was performed by using SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL, USA). P-Values have been calculated with Wilcoxon-Test. A p-value
MEDICAL OPHTHALMOLOGY
Spironolactone in the treatment of central serous chorioretinopathy – a case series T. R. Herold & K. Prause & A. Wolf & W. J. Mayer & M. W. Ulbig
Received: 1 June 2014 / Revised: 7 August 2014 / Accepted: 11 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Backg rou nd The p athog enes is o f c entral ser ous chorioretinopathy (CSC) is still poorly understood. An animal model of CSC proved that the mineralocorticoid receptor [1] of the choroid also plays a role in CSC. Since there is still no evidence-based therapy for non-self-limiting CSC, this case series evaluates the effect of oral spironolactone in CSC patients. Methods In this interventional, uncontrolled, prospective case series, we present 18 consecutive CSC patients. Patients were treated with spironolactone 25 mg twice daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 12 weeks. Follow– up examinations with BCVA, OCT, and EDI-OCT were performed at 1, 2, and 3 months after starting the treatment. Main outcome measure was a change of subretinal fluid (SRF) (in micrometers) measured by optical coherence tomography. Secondary outcome was a change in central retinal thickness (CRT) (in micrometers) measured by OCT and a change in BCVA. Results The subretinal fluid (SRF; mean) decreased from 219 μm (baseline) to 100 μm (visit 3) (difference 119 μm). Total central retinal thickness (CRT; mean) decreased from 405 μm before treatment (baseline) to 287 μm after treatment (difference 118 μm). The BCVA (in logMAR; mean) increased from 0.32 at baseline to 0.20 at visit 3. Conclusion Our case series could confirm a positive influence of spironolactone on the course CSC. Longer follow-up with a larger number of cases could provide more data about the long-term efficiency, recurrences, and safety of this welltolerated and non-invasive treatment option of CSC. T. R. Herold (*) : K. Prause : A. Wolf : W. J. Mayer : M. W. Ulbig Department of Ophthalmology, University Eye Hospital – LMU, Campus Innenstadt, Klinikum der Universität München, Mathildenstrasse 8, D-80336 Munich, Germany e-mail: [email protected]
Keywords Spironolactone . Central serous retinopathy . Choroid . Subretinal fluid
Introduction Central serous chorioretinopathy (CSC) is a common cause for central vision loss mostly in young men. As a longstanding chronic disease or bilateral involvement CSC can lead to severe, irreversible reduction of visual acuity. CSC has an incidence of approximately 1/10,000 [2], and its pathogenesis is still poorly understood. In general, CSC shows a good prognosis, and spontaneous regression is documented in around 60 % [3]. However, some cases develop a chronic or recurrent course and require an effective and photoreceptorsaving treatment. Latest data reveal that the disease derives from the choroid. It could be proved that there is diffuse choroidal thickening not only in eye with CSC, but also in the fellow eye of the same patients [4]. The increased choroidal leakage and hyperpermeability of the choroidal vessels in CSC has been demonstrated before [5]. Since chronic CSC often causes severe anatomical damage at the level of the retinal pigment epithelium, several approaches such as systemic use of acetazolamide or rifampicin [6], as well as sub-threshold laser treatment [7–9], and intravitreal application of bevacizumab have been evaluated in the past. Additionally, low-fluence, or half-dose, PDT seems to be a promising approach for the disease [10]. Recently, an animal model of CSC proved that the mineralocorticoid receptor which is expressed in the choroid could also play an important role in the pathogenesis of CSC [1]. This receptor is not only subject to mineralocorticoids, but also glucocorticoids. Therefore, competitive antagonists of the MR are likely to prevent
Graefes Arch Clin Exp Ophthalmol
glucocorticosteroids to bind to the mineralocorticoid receptor and could, therefore, be involved in the pathogenesis of CSC in the choroid. The features of CSC in an animal model showed good reversibility during treatment with the MR antagonist eplerenone [1]. This was also proven in a small case series of chronic CSC patients [11]. Spironolactone is another competitive antagonist mainly used in the treatment of hyperaldosteronism, hypertension, and congestive heart failure [12]. Its most common side effect is the increase of the serum potassium level and its effect on arterial blood pressure. Other rare side effects are allergic exanthema and hormonal influence due to antiandrogen effects. The higher rate of antiandrogen effects in spironolactone compared to eplerenone is equalized by the fact that spironolactone is given in a lower and thus well tolerable dose. As the use of systemic MR antagonists given orally in a low dose seems to be a novel promising approach to not self-limiting CSC this case series evaluates the effect of an MR antagonist in 18 consecutive CSC patients presenting with symptoms of CSC for more than 6 weeks. Because the affinity of spironolactone to the MR is much higher than in eplerenone, we chose to evaluate spironolactone as study drug.
Materials and methods Study design This study was an interventional, uncontrolled, open-label, prospective clinical trial. We included consecutive patients with CSC between January 2013 and December 2013 at the Department of Ophthalmology of Ludwig-Maximilians University, Munich, Germany. IRB approval was obtained for this study and all patients were informed about the off- label use of the medication. Inclusion criteria were a symptomatic chronic CSC persistent for more than 6 weeks, with presence of subretinal fluid or cystoid macular oedema involving the fovea on optical coherence tomography (OCT) and active leakage on fluorescein angiography, not regressing for at least 6 weeks. In cases of signs of regression of the subretinal fluid and rise in visual acuity, the patients were not treated or included in the study. In order to avoid other macular disorders than CSC, we only included patients up to the age of 51 years. Exclusion criteria were diabetic retinopathy, previous photodynamic therapy, intravitreal injections, or thermal retinal laser photocoagulation in the past 6 months. Presence of choroidal neovascularisation or other macular disorders was an additional exclusion criterion. Patients with systemic
Table 1 Patients characteristics
M=male, F=female; OD=right eye, OS=left eye
Patient Number
Gender
Age (years)
Affected eye(s)
Duration of symptoms (weeks) before treatment
Previous steroids
Medical problems
1 2 3 4 5 6 7 8 9 10
M M W M M M W M M M
50 52 54 59 43 57 41 51 50 44
OD OS OS OS OD OS OD/OS OD OD OS
6 6 104 6 8 12 6 16 12 6
– – – – – – – – – –
None None None None None None None hypertension None None
11 12 13 14 15 16 17
W M W M W M M
37 40 33 40 50 50 56
OD/OS OD OD OS OS OS OS
6 8 12 16 20 6 36
– – – – – + –
18
M
34
OD
6
–
None None None None None Still disease Morbus Bechterew hypertension None
Graefes Arch Clin Exp Ophthalmol
contra-indications against spironolactone (severe kidney or liver disease, serum potassium level >5.5 mmol/L), concomitant medication with other potassium-sparing diuretic agents, pregnancy, etc., were excluded. Concomitant systemic medication, especially antihypertensive drugs and previous history of systemic steroid use in the past, were specifically asked for and documented. Previous steroid use as a possible trigger or cause of the disease has not been excluded from the study. Treatment Patients were treated with spironolactone 25 mg twice daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 12 weeks. Baseline and follow-up All patients underwent full ophthalmological survey including best-corrected visual acuity (BCVA), clinical examination, and optical coherence tomography using the Macular Thickness map of spectral-domain OCT (Heidelberg Spectralis, Heidelberg Engineering,
Fig. 1 Optical coherence tomography pictures of two patients. a-c Baseline and Visits 2 and 3 of a 37 year-old female patient with CSC. Visual acuity increased from 0.4 logMAR (Baseline) to 0 logMAR (Visit 3). d-f
Heidelberg, Germany) Additionally, enhanced depth imaging (EDI-OCT) was performed. The subfoveal thickness was measured as distance between the outer portion of the hyperreflective line corresponding to the RPE to the inner surface of the sclera if signals were detectable using a single scan. Before starting the medical treatment, fluorescein and indocyanine green angiography (Heidelberg HRA, Heidelberg Engineering, Heidelberg, Germany) were performed to exclude other macular disorders such as choroidal neovascularistion or polypoidal choroidal vasculopathy. We analyzed the central retinal thickness (CRT) by using the macular thickness map. The height of subretinal fluid (SRF) was measured manually in micrometers between the end of the outer segment and the retinal pigment epithelium layer at the highest point of neurosensory detachment. In order to receive the most exact correlation of subretinal fluid, this manual measurement was always performed at the highest point of detachment, also at follow-up visits. Since CSC findings are mostly eccentric and can change location during the period of review, we defined this parameter as important as the CRT reduction measured. BCVA was measured in logarithm of minimal angel resolution (logMAR).
Baseline and Visits 2 and 3 of a 40 year-old male patient with CSC. Visual acuity was 0.4 logMAR at Baseline and 0.2 logMAR at Visit 3
Graefes Arch Clin Exp Ophthalmol
Follow-up examinations with BCVA, OCT, and EDI-OCT were performed at 1 and 3 months after starting the treatment (visits 2 and 3). Arterial blood pressure was checked at each follow-up visit, serum potassium level and creatinine 1 and 2 months after starting treatment. The duration of treatment was limited to 3 months maximum due to potential side effects. In cases where signs and symptoms resolved completely, treatment was stopped earlier. Patients were asked about potential side effects at every follow-up visit.
Results Twenty eyes of 18 patients (14 men and four women) were included in our study. All patients were at least treated with spironolactone for a minimum of 4 weeks and a maximum of 8 weeks (depending on the SRF and BCVA). The mean age was 45.7 years (median 50 years; +/− SD 8). The mean duration of symptoms was 14.6 weeks (minimum 6 weeks, maximum 104 weeks) (see Table 1). In two cases there was a bilateral episode of CSC. One patient reported previous steroid use because of a muscle atrophy years before. Two examples of patients’ optical coherence tomography courses under spironolactone treatment are given in Fig. 1. All patients were scheduled for baseline visit with following visits at 1 month and at the end of therapy after 3 months. Of the patients treated, 78 % (n= 14) showed regression of subretinal fluid and were treated according to protocol with spironolactone for 12 weeks. Two of the patients stopped treatment earlier due to complete regression of subretinal fluid at visit 2, and two patients stopped treatment due to mild side effects.
Main outcome measures Main outcome measure was a change of subretinal fluid (SRF) (in micrometers) measured by optical coherence tomography at 1 and 3 months. Secondary outcome was a change in total central retinal thickness (CRT) (in micrometers) measured by OCT and a change in BCVA. Statistics
Efficacy
Data are provided as mean +/− SD. Statistical analaysis was performed by using SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL, USA). P-Values have been calculated with Wilcoxon-Test. A p-value
