Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-015-2989-z
RETINAL DISORDERS
Oral Rifampin treatment for longstanding chronic central serous chorioretinopathy Shiri Shulman 1,2 & Dafna Goldenberg 1,2 & Roy Schwartz 1,2 & Zohar Habot-Wilner 1,2 & Adiel Barak 1,2 & Nurit Ehrlich 1,2 & Anat Loewenstein 1,2 & Michaella Goldstein 1,2
Received: 14 October 2014 / Revised: 25 January 2015 / Accepted: 4 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose To investigate the effect of oral Rifampin in patients with chronic central serous chorioretinoapthy (CSCR). Methods This was a prospective pilot study of patients with chronic CSCR with persistent subretinal fluid (SRF) for at least 3 months, who were treated with oral Rifampin 300 mg twice per day for 3 months and had 6 months of follow-up. All patients underwent a complete ocular examination and a spectral domain optical coherence tomography (SD-OCT) scan monthly from baseline until month 4, and then at month 6. Fluorescein angiography (FA) was performed at baseline and at the end of the study. Results Fourteen eyes of 12 patients were included in the study, nine men and three women. Mean age was 58.5 years (range 32–80). Mean duration of SRF prior to study entry was 28.4 months. Forty-two percent of eyes were treated previously for CSR with thermal laser, PDT, or intravitreal bevacizumab. Mean best corrected visual acuity (BCVA) at presentation was 20/60 and improved to a mean of 20/50 at month 3 (P>0.05). Retinal thickness was reduced by 25.3 %, 21.2 %, and 21 % on months 1, 2, 3, respectively (P0.05). SRF was reduced in nine eyes (64 %) and completely resolved in six eyes (42.8 %) at month 3 This paper was presented in part in the American Academy of Ophthalmology meeting, New Orleans, LA, USA, November 2013. * Shiri Shulman [email protected] 1
Department of Ophthalmology, Tel-Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel
2
Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
following 3 months of treatment, and four out of these six eyes remained fluid free at month 6. Two patients stopped the treatment after 2 months due to adverse events. Conclusions Oral Rifampin may be a therapeutic option in patients with longstanding chronic CSCR. Keywords Central Serous Chorioretinopathy . Optical Coherence Tomography . Cytochrome P450 . Rifampin
Introduction Central serous chorioretinopathy (CSCR) is characterized by the development of neurosensory retinal detachment mainly at the posterior pole [1]. In the majority of patients, CSCR is selflimiting with a favorable visual prognosis. However, in 1020 % of cases, patients may develop progressive visual loss mainly secondary to persistent serous retinal detachment, cystoid macular degeneration, or retinal pigment epithelium decompensation [2, 3]. The pathogenesis of the disease is still not completely understood. Current studies emphasize the role of the choroid in the disease. Choroidal vessel staining seen on mid-phase ICG angiography probably represents choroidal hyperpermeability. The role of the choroid is further supported by the enhanced depth imaging (EDI) OCT finding of a thickened choroid in eyes with CSCR as well as fellow eyes [4]. An association with high levels of cortisol has been noted in patients with CSCR, whether derived from endogenous secretion such as in Cushing's disease, from stressful life conditions, or due to exogenous steroid therapy [5]. The exact role of corticosteroids in CSCR pathogenesis is not completely understood. Proposed mechanisms in the choroid include effects on vascular autoregulation, potentiation of vascular reactivity, or prothrombotic steroid effect [6]. A
Graefes Arch Clin Exp Ophthalmol
recent study identified mineralocorticoid receptors in choroidal tissue, associated with vasodilatation of choroidal vessels and hypothesized that glucocorticoids activate mineralocorticoid receptors and may, therefore, cause or aggravate CSCR manifestations [7]. According to these theories, several modalities have been proposed for the treatment of chronic CSCR. Photodynamic treatment (PDT) with verteporfin which can reduce choroidal vessel permeability and subsequent leakage [8–14], intravitreal anti-VEGF injections [14], and systemic pharmacologic therapy that can alter glucocorticoid and mineralocorticoid metabolism [7, 15–18]. Rifampin, an antibacterial drug widely used in the treatment of tuberculosis and leprosy, has recently been reported to have anti-oxidative, anti-apoptotic, and anti-angiogenic effects [19]. Rifampin is known to induce cytochrome P450 3A4, therefore, having the potential to alter the metabolism of steroids [20], and may lead to an improvement in CSCR manifestations. The first report on the effect of Rifampin in chronic CSCR was described by Ravage and Packo during the American Society of Retina Specialists meeting in 2010. They reported on one patient with tuberculosis and chronic CSCR receiving Rifampin at a dosage of 300 mg twice daily as part of his antituberculosis treatment. This patient experienced a significant improvement in CSCR manifestations. His symptoms recurred once the Rifampin was stopped and improved again with reinstitution of the drug, establishing a causal relationship. One year later, the same group presented at the Association for Research in Vision and Ophthalmology meeting, a retrospective case series of five patients treated with Rifampin using the same dosage, demonstrating a favorable response in two of them. The only case report published to date is of a patient with chronic CSCR of 2 years' duration in whom the SRF resolved after 1 month of Rifampin treatment. [21] The aim of our pilot study was to evaluate prospectively the efficacy of oral Rifampin treatment administered for a period of 3 months in cases of chronic CSCR with persistent subretinal fluid (SRF) accompanied by visual loss. The primary outcome measurement was the reduction in the amount of SRF at month 3. Secondary outcome measures were change in best-corrected visual acuity (BCVA) and change in the choroidal thickness after treatment.
Methods Patients This was a prospective study on 14 eyes (12 consecutive patients) with chronic CSCR who were treated with oral Rifampin at a dosage of 300 mg twice daily for 3 months,
and followed for additional 3 months after cessation of the drug. The study was conducted between April 2011 and August 2013 at the Tel Aviv Medical Center. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board (IRB) of Tel Aviv Medical Center. Written informed consent was obtained from all patients. Inclusion criteria included age >18 years and a history of chronic idiopathic CSCR of more than 3 months' duration with evidence of persistent SRF. Patients were either treatment naïve, previously treated with intravitreal injection of bevacizumab more than 3 months prior to study entry, or had undergone thermal laser or PDT more than 6 months prior to study entry. Exclusion criteria included recent treatment for CSCR such as thermal laser or PDT less than 6 months prior to study entry, intravitreal anti-VEGF injection less than 3 months prior to study entry, any ocular disease other than CSCR, liver disease history or altered liver function tests, alcohol usage, pregnancy, and use of any drugs that may interact with Rifampin. A detailed history including concomitant disease and medication usage was taken. All patients underwent a complete ophthalmological evaluation at baseline and at 1, 2, 3, 4, and 6 months, including assessment of BCVA, slit lamp biomicroscopy, tonometry, and dilated fundoscopy, as well as Heidelberg Spectralis Spectral Domain Optical Coherence Tomography (SD-OCT, Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography (FA) was performed at baseline and at the end of follow-up. FA was performed in order to confirm the diagnosis of CSCR and to exclude eyes with any other retinal disorder that may be associated with SRF. BCVA was measured using a Snellen chart. SD-OCT imaging All participants were examined using Heidelberg Spectralis SD-OCT. The retinas of both eyes were first scanned by a horizontal high speed raster scanning protocol of a 20° X 20° quadrangular area. Central macular thickness (CMT) was obtained, and the maximal height of SRF was measured. In addition, in order to demonstrate changes in choroidal thickness, EDI technique [22, 23] was used. The choroid was scanned with 20° horizontal and vertical single crosssection EDI scans through the center of the fovea. To ensure high quality and noise reduction, we used the eye tracking system and averaging technique. Each choroidal scan consisted of 100 averaged OCT frames. Images were converted to white on black grayscale to sharpen the contrast and allow a more accurate measurement. Foveal choroidal thickness was measured from both vertical and horizontal scans, using the Spectralis built-in caliper module, as the vertical distance between the outer margin of the hyper-reflective retinal pigment epithelium layer and the choroidoscleral
Graefes Arch Clin Exp Ophthalmol
interface and was performed by a single ophthalmologist specializing in ocular imaging (DG). The follow-up acquisition mode, which is unique to the Spectralis, was used in all follow-up visits and automatically placed follow-up scans in precisely the same location where previous follow-up scans were performed. Laboratory tests Systemic laboratory work-up included a complete blood count and liver function tests at baseline and at 1 and 3 months post treatment initiation. Following the confirmation of normal liver function tests at baseline, the patients were included in the study and received oral Rifampin at a dosage of 300 mg twice daily for 3 months. Statistical analysis Statistical analysis was performed using SAS for Windows version 9.3. BCVA results were converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Change over time with regard to BCVA, choroidal thickness, and CMT were evaluated using an analysis of variance with repeated measures (time points). The mixed model was employed since it enabled us to include in the analysis patients with some missing values. Pair-wise comparisons between each time point and baseline level were performed whenever an overall significant time trend was noticed. Significance levels for these comparisons were corrected for multiple testing using Hochberg's GT2 method. Because of the small group numbers, binary variables were compared between subjects using the Fisher's exact test. Correlation between continuous variables were analyzed using the Spearman correlation test.
Results Fourteen eyes of 12 patients were included in the study. There were nine men and three women. The mean age was 58.5 years (range 32–80). Four patients (33 %) reported the recent use of corticosteroids; two used steroid inhalers for asthma and two used systemic steroids. Of the latter, one received chronic steroid replacement therapy after a pituitary tumor excision and one received a course of prednisone for a sudden hearing loss. Only one patient had to continue steroid treatment during the study. Six out of 14 eyes (43 %) were previously treated for CSCR with a variety of treatment modalities such as thermal laser, PDT, and intravitreal bevacizumab injections. Previous treatments of all patients included in the study are summarized in Table 1. All eyes demonstrated longstanding SRF prior to study enrollment with a mean duration of 28.4 months (range 4–36).
Mean BCVA at baseline was 0.65 LogMAR (range 0.3-1) improving to 0.4 and 0.5 at months 3 and 4, respectively. BCVA remained stable by month 6, 3 months following cessation of study treatment. This improvement, however, was not found to be statistically significant. Figure 1 depicts visual acuity changes during the study period. Mean CMT at baseline was 350.3 μ (SD 127 μ) improving to 262.2 μ, 277.7 μ, and 278 μ at months 1, 2, and 3, respectively (P 0.05
Two patients discontinued the Rifampin treatment after 2 months. One developed acute cholecystitis probably due to chronic cholelythiasis. Nevertheless, the treating physician recommended discontinuing the treatment. The second patient was found to have an increase in blood pressure and was advised to stop Rifampin treatment. None of the remaining patients developed any liver function or blood count abnormalities as a result of the treatment.
Discussion Our study is the first prospective study that demonstrates a beneficial effect of Rifampin on longstanding CSCR. We described a series of 14 eyes of 12 patients with a diagnosis of CSCR associated with visual deterioration who
Fig. 2 change in mean central macular thickness (CMT) in μ from baseline to month 6. (P< 0.05)
were treated with oral Rifampin at a dose of 300 mg twice daily for 3 months. The dosage regimen was chosen as it has been shown to be effective for the treatment of CSCR in a previously published [21] case report. In addition, Mårde Arrhén et al. [24] demonstrated that an induction of cytochrome P450 3A4 occurs only with a daily dose of 500 mg Rifampin, but not with lower doses, therefore, supporting our decision to choose the 600 mg/day dose for this pilot study. Nine out of 14 eyes showed an improvement or resolution of macular SRF. CMT improved rapidly from 350 μ at baseline to 262 μ at month 1, and remained stable throughout the 3-month treatment period as well as 3 months after the cessation of the drug (month 6) with a mean thickness of 278 μ and 258 μ, respectively (P
RETINAL DISORDERS
Oral Rifampin treatment for longstanding chronic central serous chorioretinopathy Shiri Shulman 1,2 & Dafna Goldenberg 1,2 & Roy Schwartz 1,2 & Zohar Habot-Wilner 1,2 & Adiel Barak 1,2 & Nurit Ehrlich 1,2 & Anat Loewenstein 1,2 & Michaella Goldstein 1,2
Received: 14 October 2014 / Revised: 25 January 2015 / Accepted: 4 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose To investigate the effect of oral Rifampin in patients with chronic central serous chorioretinoapthy (CSCR). Methods This was a prospective pilot study of patients with chronic CSCR with persistent subretinal fluid (SRF) for at least 3 months, who were treated with oral Rifampin 300 mg twice per day for 3 months and had 6 months of follow-up. All patients underwent a complete ocular examination and a spectral domain optical coherence tomography (SD-OCT) scan monthly from baseline until month 4, and then at month 6. Fluorescein angiography (FA) was performed at baseline and at the end of the study. Results Fourteen eyes of 12 patients were included in the study, nine men and three women. Mean age was 58.5 years (range 32–80). Mean duration of SRF prior to study entry was 28.4 months. Forty-two percent of eyes were treated previously for CSR with thermal laser, PDT, or intravitreal bevacizumab. Mean best corrected visual acuity (BCVA) at presentation was 20/60 and improved to a mean of 20/50 at month 3 (P>0.05). Retinal thickness was reduced by 25.3 %, 21.2 %, and 21 % on months 1, 2, 3, respectively (P0.05). SRF was reduced in nine eyes (64 %) and completely resolved in six eyes (42.8 %) at month 3 This paper was presented in part in the American Academy of Ophthalmology meeting, New Orleans, LA, USA, November 2013. * Shiri Shulman [email protected] 1
Department of Ophthalmology, Tel-Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel
2
Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
following 3 months of treatment, and four out of these six eyes remained fluid free at month 6. Two patients stopped the treatment after 2 months due to adverse events. Conclusions Oral Rifampin may be a therapeutic option in patients with longstanding chronic CSCR. Keywords Central Serous Chorioretinopathy . Optical Coherence Tomography . Cytochrome P450 . Rifampin
Introduction Central serous chorioretinopathy (CSCR) is characterized by the development of neurosensory retinal detachment mainly at the posterior pole [1]. In the majority of patients, CSCR is selflimiting with a favorable visual prognosis. However, in 1020 % of cases, patients may develop progressive visual loss mainly secondary to persistent serous retinal detachment, cystoid macular degeneration, or retinal pigment epithelium decompensation [2, 3]. The pathogenesis of the disease is still not completely understood. Current studies emphasize the role of the choroid in the disease. Choroidal vessel staining seen on mid-phase ICG angiography probably represents choroidal hyperpermeability. The role of the choroid is further supported by the enhanced depth imaging (EDI) OCT finding of a thickened choroid in eyes with CSCR as well as fellow eyes [4]. An association with high levels of cortisol has been noted in patients with CSCR, whether derived from endogenous secretion such as in Cushing's disease, from stressful life conditions, or due to exogenous steroid therapy [5]. The exact role of corticosteroids in CSCR pathogenesis is not completely understood. Proposed mechanisms in the choroid include effects on vascular autoregulation, potentiation of vascular reactivity, or prothrombotic steroid effect [6]. A
Graefes Arch Clin Exp Ophthalmol
recent study identified mineralocorticoid receptors in choroidal tissue, associated with vasodilatation of choroidal vessels and hypothesized that glucocorticoids activate mineralocorticoid receptors and may, therefore, cause or aggravate CSCR manifestations [7]. According to these theories, several modalities have been proposed for the treatment of chronic CSCR. Photodynamic treatment (PDT) with verteporfin which can reduce choroidal vessel permeability and subsequent leakage [8–14], intravitreal anti-VEGF injections [14], and systemic pharmacologic therapy that can alter glucocorticoid and mineralocorticoid metabolism [7, 15–18]. Rifampin, an antibacterial drug widely used in the treatment of tuberculosis and leprosy, has recently been reported to have anti-oxidative, anti-apoptotic, and anti-angiogenic effects [19]. Rifampin is known to induce cytochrome P450 3A4, therefore, having the potential to alter the metabolism of steroids [20], and may lead to an improvement in CSCR manifestations. The first report on the effect of Rifampin in chronic CSCR was described by Ravage and Packo during the American Society of Retina Specialists meeting in 2010. They reported on one patient with tuberculosis and chronic CSCR receiving Rifampin at a dosage of 300 mg twice daily as part of his antituberculosis treatment. This patient experienced a significant improvement in CSCR manifestations. His symptoms recurred once the Rifampin was stopped and improved again with reinstitution of the drug, establishing a causal relationship. One year later, the same group presented at the Association for Research in Vision and Ophthalmology meeting, a retrospective case series of five patients treated with Rifampin using the same dosage, demonstrating a favorable response in two of them. The only case report published to date is of a patient with chronic CSCR of 2 years' duration in whom the SRF resolved after 1 month of Rifampin treatment. [21] The aim of our pilot study was to evaluate prospectively the efficacy of oral Rifampin treatment administered for a period of 3 months in cases of chronic CSCR with persistent subretinal fluid (SRF) accompanied by visual loss. The primary outcome measurement was the reduction in the amount of SRF at month 3. Secondary outcome measures were change in best-corrected visual acuity (BCVA) and change in the choroidal thickness after treatment.
Methods Patients This was a prospective study on 14 eyes (12 consecutive patients) with chronic CSCR who were treated with oral Rifampin at a dosage of 300 mg twice daily for 3 months,
and followed for additional 3 months after cessation of the drug. The study was conducted between April 2011 and August 2013 at the Tel Aviv Medical Center. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board (IRB) of Tel Aviv Medical Center. Written informed consent was obtained from all patients. Inclusion criteria included age >18 years and a history of chronic idiopathic CSCR of more than 3 months' duration with evidence of persistent SRF. Patients were either treatment naïve, previously treated with intravitreal injection of bevacizumab more than 3 months prior to study entry, or had undergone thermal laser or PDT more than 6 months prior to study entry. Exclusion criteria included recent treatment for CSCR such as thermal laser or PDT less than 6 months prior to study entry, intravitreal anti-VEGF injection less than 3 months prior to study entry, any ocular disease other than CSCR, liver disease history or altered liver function tests, alcohol usage, pregnancy, and use of any drugs that may interact with Rifampin. A detailed history including concomitant disease and medication usage was taken. All patients underwent a complete ophthalmological evaluation at baseline and at 1, 2, 3, 4, and 6 months, including assessment of BCVA, slit lamp biomicroscopy, tonometry, and dilated fundoscopy, as well as Heidelberg Spectralis Spectral Domain Optical Coherence Tomography (SD-OCT, Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography (FA) was performed at baseline and at the end of follow-up. FA was performed in order to confirm the diagnosis of CSCR and to exclude eyes with any other retinal disorder that may be associated with SRF. BCVA was measured using a Snellen chart. SD-OCT imaging All participants were examined using Heidelberg Spectralis SD-OCT. The retinas of both eyes were first scanned by a horizontal high speed raster scanning protocol of a 20° X 20° quadrangular area. Central macular thickness (CMT) was obtained, and the maximal height of SRF was measured. In addition, in order to demonstrate changes in choroidal thickness, EDI technique [22, 23] was used. The choroid was scanned with 20° horizontal and vertical single crosssection EDI scans through the center of the fovea. To ensure high quality and noise reduction, we used the eye tracking system and averaging technique. Each choroidal scan consisted of 100 averaged OCT frames. Images were converted to white on black grayscale to sharpen the contrast and allow a more accurate measurement. Foveal choroidal thickness was measured from both vertical and horizontal scans, using the Spectralis built-in caliper module, as the vertical distance between the outer margin of the hyper-reflective retinal pigment epithelium layer and the choroidoscleral
Graefes Arch Clin Exp Ophthalmol
interface and was performed by a single ophthalmologist specializing in ocular imaging (DG). The follow-up acquisition mode, which is unique to the Spectralis, was used in all follow-up visits and automatically placed follow-up scans in precisely the same location where previous follow-up scans were performed. Laboratory tests Systemic laboratory work-up included a complete blood count and liver function tests at baseline and at 1 and 3 months post treatment initiation. Following the confirmation of normal liver function tests at baseline, the patients were included in the study and received oral Rifampin at a dosage of 300 mg twice daily for 3 months. Statistical analysis Statistical analysis was performed using SAS for Windows version 9.3. BCVA results were converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Change over time with regard to BCVA, choroidal thickness, and CMT were evaluated using an analysis of variance with repeated measures (time points). The mixed model was employed since it enabled us to include in the analysis patients with some missing values. Pair-wise comparisons between each time point and baseline level were performed whenever an overall significant time trend was noticed. Significance levels for these comparisons were corrected for multiple testing using Hochberg's GT2 method. Because of the small group numbers, binary variables were compared between subjects using the Fisher's exact test. Correlation between continuous variables were analyzed using the Spearman correlation test.
Results Fourteen eyes of 12 patients were included in the study. There were nine men and three women. The mean age was 58.5 years (range 32–80). Four patients (33 %) reported the recent use of corticosteroids; two used steroid inhalers for asthma and two used systemic steroids. Of the latter, one received chronic steroid replacement therapy after a pituitary tumor excision and one received a course of prednisone for a sudden hearing loss. Only one patient had to continue steroid treatment during the study. Six out of 14 eyes (43 %) were previously treated for CSCR with a variety of treatment modalities such as thermal laser, PDT, and intravitreal bevacizumab injections. Previous treatments of all patients included in the study are summarized in Table 1. All eyes demonstrated longstanding SRF prior to study enrollment with a mean duration of 28.4 months (range 4–36).
Mean BCVA at baseline was 0.65 LogMAR (range 0.3-1) improving to 0.4 and 0.5 at months 3 and 4, respectively. BCVA remained stable by month 6, 3 months following cessation of study treatment. This improvement, however, was not found to be statistically significant. Figure 1 depicts visual acuity changes during the study period. Mean CMT at baseline was 350.3 μ (SD 127 μ) improving to 262.2 μ, 277.7 μ, and 278 μ at months 1, 2, and 3, respectively (P 0.05
Two patients discontinued the Rifampin treatment after 2 months. One developed acute cholecystitis probably due to chronic cholelythiasis. Nevertheless, the treating physician recommended discontinuing the treatment. The second patient was found to have an increase in blood pressure and was advised to stop Rifampin treatment. None of the remaining patients developed any liver function or blood count abnormalities as a result of the treatment.
Discussion Our study is the first prospective study that demonstrates a beneficial effect of Rifampin on longstanding CSCR. We described a series of 14 eyes of 12 patients with a diagnosis of CSCR associated with visual deterioration who
Fig. 2 change in mean central macular thickness (CMT) in μ from baseline to month 6. (P< 0.05)
were treated with oral Rifampin at a dose of 300 mg twice daily for 3 months. The dosage regimen was chosen as it has been shown to be effective for the treatment of CSCR in a previously published [21] case report. In addition, Mårde Arrhén et al. [24] demonstrated that an induction of cytochrome P450 3A4 occurs only with a daily dose of 500 mg Rifampin, but not with lower doses, therefore, supporting our decision to choose the 600 mg/day dose for this pilot study. Nine out of 14 eyes showed an improvement or resolution of macular SRF. CMT improved rapidly from 350 μ at baseline to 262 μ at month 1, and remained stable throughout the 3-month treatment period as well as 3 months after the cessation of the drug (month 6) with a mean thickness of 278 μ and 258 μ, respectively (P
