ORIGINAL ARTICLE
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 00, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0173
Treatment of Chronic Central Serous Chorioretinopathy with Oral Methotrexate Majid Abrishami, MirNaghi Mousavi, Seyedeh-Maryam Hosseini, and Amir Norouzpour
Abstract
Purpose: To evaluate the effects of oral methotrexate (MTX) in patients with chronic central serous chorioretinopathy (CSC). Methods: This is an interventional, prospective uncontrolled clinical trial, which included 23 eyes of 23 consecutive patients presenting with chronic symptomatic CSC and persistent subretinal fluid (SRF) for longer than 3 months. All patients were treated with 7.5 mg/week of oral MTX for 12 weeks. The best corrected visual acuity (BCVA), central macular thickness (CMT), SRF, and total macular volume recorded by monthly optical coherence tomography were analyzed. Complete blood count and serum liver enzymes level were monitored. Results: Mean duration of CSC was 13 months (3–36 months). Mean BCVA improved from 20/40 at baseline to 20/30 at the third month and 20/28 at the sixth month (P = 0.002 and 0.003, respectively). Mean CMT decreased from 375 mm at baseline to 278 mm and 265 mm at the third and sixth month (P = 0.002 and 0.007, respectively). Mean total macular volume decreased from 9.33 mm3 at baseline to 8.48 and 8.31 mm3 at the third and sixth month (P = 0.001 and 0.001, respectively). Thirteen (62%) eyes achieved complete resolution of SRF. No MTX-associated toxicity was detected. Conclusion: Low-dose oral MTX may be an alternative therapeutic option for the treatment of chronic CSC. This study paves the way for a randomized clinical trial comparing the effects of MTX treatment with photodynamic therapy or observation.
cently, antivascular endothelial growth factor agents30–32 and corticosteroid antagonists such as mifepristone,33 ketoconazole,34 and eplerenone.35 However, CSC treatment has not been well defined.16 Methotrexate (MTX) has been proposed as an alternative therapeutic option for CSC treatment.36 MTX is an antimetabolic agent commonly used in low dosages for the treatment of different systemic and ophthalmic inflammatory disorders. However, the antisteroid effects of MTX37 as well as the role of glucocorticoids in the pathogenesis of CSC38 may provide insights into the use of MTX as a potential therapeutic option for treatment of CSC. In this study, we prospectively evaluated the effects of oral MTX in 23 consecutive patients presenting with chronic CSC.
Introduction
C
entral serous chorioretinopathy (CSC) is characterized by the accumulation of subretinal fluid (SRF), causing a well-circumscribed serous retinal detachment, which commonly affects the macula.1 CSC typically affects young and middle-aged adults, with men affected more commonly than women.2 CSC usually has a self-limiting natural course, with complete spontaneous resolution in most cases.3 However, in some patients it becomes chronic with persistent SRF, which may lead to long-term visual impairments.4,5 Some associated findings include Type A personality,6 Cushing’s syndrome,7 pregnancy,8,9 systemic steroid use,10 collagen vascular diseases,11–13 and obstructive sleep apnea.14 However, the exact pathogenesis of CSC remains obscure.2,15 As a result of multiple hypotheses for CSC pathogenesis, various treatments have been proposed.16 The therapeutic options may include psychotherapy,17 medical therapy such as a-adrenergic18 and b-adrenergic19 inhibitors and acetazolamide,20 retinal laser photocoagulation,21–23 photodynamic therapy (PDT),24–28 transpupillary thermotherapy,29 and re-
Methods Study design This study is an interventional, prospective uncontrolled clinical trial of 23 patients presenting with chronic
Retina Research Center, Khatam-Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
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symptomatic CSC and persistent SRF for longer than 3 months, consecutively between Feb 2013 and Feb 2014 at the Department of Ophthalmology in Khatam-Al-Anbia Eye Hospital, Mashhad, Iran. The study was approved by the Institutional Review Boards of Mashhad University of Medical Sciences (MUMS) and adhered to the tenets of the Declaration of Helsinki. The diagnosis was established with spectral domain optical coherence tomography (SD-OCT) and fundus fluorescein angiography (FFA) imagings. A detailed history of concomitant diseases, current or prior use of medications, and any interventions for CSC treatment before the referral to us were taken.
Eligibility criteria We included patients with visual symptoms lasting longer than 3 months and persistent SRF involving the fovea on SD-OCT as well as the presence of an active leakage at the level of the retinal pigment epithelium (RPE) on FFA. The patients were recommended PDT, and only those who refused PDT were offered a therapeutic trial of MTX. Exclusion criteria included the following: (1) previous treatment with laser photocoagulation, PDT, intravitreal bevacizumab (IVB), or any other therapeutic options within 3 months before the referral to us; (2) evidence of choroidal neovascularization (CNV), polypoidal choroidal vasculopathy, or any other cause of visual impairments; (3) systemic contraindication for MTX treatment such as pregnancy, which was ruled out by laboratory tests, liver or hematologic diseases, and abnormal results of blood analysis at baseline; (4) women who did not use a safe contraceptive method within 3 months before the onset of treatment; all included women were strongly recommended to use a safe contraceptive method within the trial period.
Baseline and follow-up examinations At baseline, we obtained the best corrected visual acuity (BCVA), SD-OCT, and FFA (Heidelberg Engineering, Heidelberg, Germany). BCVA was evaluated with the Snellen chart converted to logarithm of minimal angle resolution (Log MAR). On SD-OCT imagings, the macular thickness map was used to obtain total macular volume and central macular thickness (CMT). SRF was assessed by manually measuring the distance between the outer segment and the RPE. The maximum SRF on all OCT cross sections has been included in the statistical analysis. The potential risks and benefits of the treatment were completely discussed with the patients, and an informed consent was obtained before treatment. Volunteer patients were treated with a dose of 7.5 mg of oral MTX per week along with 1 mg of folic acid supplementation per day for 12 weeks and then monitored for 3 months without any medication. The MTX dose and duration of treatment were selected on the basis of data showing possible effects of MTX in CSC treatment with such dose and duration.36 BCVA and OCT testing were obtained at monthly followup visits for 6 months after starting the treatment with MTX. Treatment tolerance was assessed by blood analysis— differential complete blood count (CBC, diff), liver function tests (LFTs), and serum liver enzymes level—performed at baseline and monthly after the onset of MTX treatment.
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The treatment would be stopped in cases of significant rise of serum liver enzymes, abnormal LFTs, or any disorder in results of CBC.
Main outcome measures The primary outcomes were CMT, SRF, and total macular volume changes recorded by monthly OCT. The secondary outcomes were changes in BCVA—in Log MAR—within 6 months after starting MTX treatment and the percentage of eyes achieving complete resolution of CSC, which is defined as the absence of SRF on all OCT cross sections.
Analysis Variables before and after treatment were compared using the repeated measures test. If the result of the test was significant, we compared the data at baseline with data at third and sixth month, using the LSD method with Bonferroni adjustment. A P value < 0.05 was considered statistically significant.
Results Patient characteristics Forty-four patients were referred to our center with chronic symptomatic CSC. After an extensive discussion on current therapeutic options as well as the potential risks and benefits of MTX treatment with each patient, 25 patients preferred to be treated with MTX. Two patients were excluded because of evidences of other cause of visual impairments. Finally, 23 eyes of 23 patients were included in the study. Two patients lost the follow-up after 3 months, and 21 patients completed the follow-up visits.
Table 1.
Characteristics of the Included Cases
Demographics Mean age Age range Sex Mean duration of CSC Bilateral symptomatic CSC Outcomes Mean baseline BCVA (Log MAR) Mean BCVA at 3 months (Log MAR) Mean BCVA at 6 months (Log MAR) Mean baseline CMT (mm) Mean CMT at 3 months (mm) Mean CMT at 6 months (mm) Mean baseline SRF (mm) Mean SRF at 3 months (mm) Mean SRF at 6 months (mm) Mean baseline total macular volume (mm3) Mean total macular volume at 3 months (mm3) Mean total macular volume at 6 months (mm3)
42 years 30 to 58 years 70% male 13 months 0.09% cases 0.308 (0–0.699) 0.183 (0–0.699) 0.159 (0–0.398) 375 278 265 165 85 64 9.33
(201–754) (181–490) (176–451) (82–337) (0–194) (0–256) (7.96–12.17)
8.48 (7.65–9.56) 8.31 (6.58–9.80)
BCVA, best corrected visual acuity; CMT, central macular thickness; CSC, central serous chorioretinopathy; Log MAR, logarithm of minimal angle resolution; SRF, subretinal fluid.
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FIG. 1. Mean BCVA before and after treatment with methotrexate (mean – SEM). Mean BCVA improved from 20/ 40 at baseline to 20/30 at third month and 20/28 at sixth month (P = 0.002 and 0.003, respectively). BCVA, best corrected visual acuity; SEM, standard error of the mean.
The mean age of the patients was 42 years (ranged from 30 to 58 years). Sixteen cases (70%) were men. The mean duration of CSC was 13 months (ranged from 3 to 36 months). The left eye was involved in 14 (61%) cases. Two patients (9%) had bilateral symptomatic CSC, with 1 eye having acute CSC and the other with chronic CSC; therefore, the chronic eye was included in our analysis. No patient had a history of systemic or topical corticosteroid use. Four patients had been frequently treated with IVB. Two eyes were pseudophakic. Two patients had a history of hypothyroidism, and had been using levothyroxine. The characteristics of our series are summarized in Table 1.
Effect of MTX on visual acuity Mean BCVA was 20/40 (0.308 Log MAR, ranged from 0 to 0.699) at baseline, 20/30 (0.183 Log MAR, ranged from 0 to 0.699) at third month, and 20/28 (0.159 Log MAR, ranged from 0 to 0.398) at sixth month. BCVA at third and sixth month improved significantly compared to the baseline BCVA (P = 0.002 and 0.003, respectively) (Fig. 1).
Effect of MTX on total macular volume Mean total macular volume decreased significantly from 9.33 mm3 (ranged from 7.96 to 12.17 mm3) at baseline to 8.48 mm3 (ranged from 7.65 to 9.56 mm3) and 8.31 mm3 (ranged from 6.58 to 9.80 mm3) at the third and sixth month (P = 0.001 and 0.001, respectively) (Fig. 2).
Effect of MTX on CMT Mean CMT measured on OCT testing decreased significantly from 375 mm (ranged from 201 to 754 mm) at baseline to 278 mm (ranged from 181 to 490 mm) and 265 mm (ranged from 176 to 451 mm) at the third and sixth month (P = 0.002 and 0.007, respectively) (Fig. 3).
Effect of MTX on SRF Mean SRF decreased from 165 mm (ranged from 82 to 337 mm) at baseline to 85 mm (ranged from 0 to 194 mm) and 64 mm (ranged from 0 to 256 mm) at the third and sixth month, respectively (Fig. 4). Sixty-two percent of the eyes
FIG. 2. Mean total macular volume before and after treatment with methotrexate (mean – SEM). Mean total macular volume decreased from 9.33 mm3 at baseline to 8.48 mm3 at third month and 8.31 mm3 at sixth month (P = 0.001 and 0.001, respectively).
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FIG. 3. Mean CMT before and after treatment with methotrexate (mean – SEM). Mean CMT decreased from 375 mm at baseline to 278 mm at third month and 265 mm at sixth month (P = 0.002 and 0.007, respectively). CMT, central macular thickness.
(13 eyes) achieved complete resolution of SRF, on average, 4 months after the start of MTX treatment. SRF recurred in 2 eyes (9%) 8–12 weeks after stopping MTX use.
Probable prognostic factor(s) of visual outcome BCVA in 58% of patients who had a complete resolution of SRF improved to 20/20 (Fig. 5a, b). Mean BCVA in the remaining 42% of patients was 20/52, ranged from 2/20 to 20/28. We hypothesized that, in our series, the disruption of foveal photoreceptor inner segment/outer segment (IS/OS) junction and/or external limiting membrane (ELM) lines may affect the visual outcome despite complete resolution of SRF. We defined the disruption of IS/OS and ELM lines as the loss of hyper-reflective lines at the appropriate anatomical location and manually measured the length of the disruption of IS/ OS and ELM lines (Fig. 5c, d). The mean disruption lengths of IS/OS and ELM lines in those whose final BCVA did not improve to 20/20 despite a complete resolution of SRF were 2716 mm and 747 mm, respectively. The range of IS/OS disruption length was from 1818 mm to 3900 mm, while that of ELM disruption length was from 0 to 1289 mm. Pearson correlation coefficients showed that the length of IS/OS and
FIG. 4. Mean SRF before and after treatment with methotrexate (mean – SEM). Mean SRF decreased from 165 mm at baseline to 85 mm at third month and 64 mm at sixth month. SRF, subretinal fluid.
ELM disruptions is correlated with poor final visual acuity (P = 0.001 and 0.031, respectively). However, linear regression analysis with the stepwise method showed that only the IS/OS line disruption is associated with poor visual outcome (P = 0.001) and the ELM line disruption did not significantly affect the visual outcome (P = 0.649).
Treatment tolerance Tolerance to the treatment was evaluated monthly at every follow-up visit. None of the patients has shown any severe MTX side effects. CBC remained in the normal range for all patients at the follow-up period. One patient reported mild nausea at the day of MTX use, and 1 patient showed a 2-fold increase in serum liver enzymes level 2 months after starting MTX treatment, which returned spontaneously to the baseline 1 month later. He remained asymptomatic during the follow-up period.
Discussion Many therapeutic options have been suggested for the treatment of CSC. Previous medical treatments had no proven
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FIG. 5. Changes of OCT and fundus fluorescein angiography (FFA) imagings before and after treatment with methotrexate. (a, b) A 39-year-old man with chronic CSC in the right eye as well as persistent SRF for 24 months. Baseline OCT shows a maximum 101 mm SRF (a). BCVA improved from 9/10 at baseline to 10/10 at 6 months with a complete resolution of SRF and intact IS/OS junction and ELM lines (b). (c, d) A 56-year-old woman with chronic CSC in the right eye and persistent SRF for 12 months. Baseline OCT shows a maximum 124 mm SRF (c). Baseline BCVA was 4/10, which remained unchanged up to 6 months despite complete resolution of SRF (d). The disrupted IS/OS junction line was 2912 mm in length (arrows) while the ELM was intact. (e, f) FFA of a 30-year-old man shows a typical smokestack pattern of leakage at baseline (e), while angiography at 6 months shows no site of leakage (f). CSC, central serous chorioretinopathy; ELM, external limiting membrane; IS/OS, inner segment/outer segment; OCT, optical coherence tomography.
influence on the disease, and the results of studies on the effects of different laser modalities in treatment of CSC are controversial and not conclusive.39 In addition, focal laser photocoagulation increases the risk of macular scar formation and secondary CNV.40,41 PDT still carries the risk of RPE atrophy, choriocapillary hypoperfusion, and the development of CNV, especially with standard-dose PDT.16,42 Half-dose PDT seems to be effective and safe, but its long-term efficacy is unknown.43,44 Nevertheless, PDT still remains expensive and it is not covered for CSC by most insurance institutions and may not be financially available to a majority of patients. Subthreshold diode laser micropulse photocoagulation has been attempted showing some promise with early results but requires further studies.45 The use of IVB for CSC treatment is still under debate as long as there are contradictory reports in the literature.46–48 There is still little evidence to support the use of acetazolamide20 or mifepristone,33 and the promise of ketoconazole and eplerenone is short-lived.34,35 Another therapeutic option that may be helpful in the treatment of chronic CSC might be MTX.36 In our chronic
CSC cases, treatment with low-dose oral MTX was accompanied by concomitant improvement in BCVA and decrease in CMT, SRF, and total macular volume (Figs. 1–4). SRF was completely resolved in 62% of our cases, on average, 4 months after the start of treatment with MTX. BCVA in 58% of patients who had a complete resolution of SRF improved to 20/20 (Fig. 5a, b). Mean BCVA in the remaining 42% of patients was 20/52, ranged from 2/20 to 20/28. We hypothesized that, in our series, the disruption of foveal photoreceptor IS/OS junction and/or ELM lines may affect the visual outcome despite complete resolution of SRF. It was reported that the loss of IS/OS junction line and ELM line integrity affects the visual outcome in eyes with CSC.49 Our results showed that, in our series, the integrity of IS/OS junction line may be a prognostic factor that affects the visual outcome significantly (Fig. 5c, d). The success rate of our series may be comparable with that of other studies evaluating the effect of PDT. The visual acuity of eyes treated with PDT improved 1–4 lines on the vision testing chart, and OCT imagings demonstrated complete resolution of SRF in 60%–75% of eyes.26,27
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However, the duration of CSC in these studies is longer than that in our study, and the mean baseline visual acuity of the eyes is lower than that of our patients.26,27 Although the benefits of MTX treatment may be comparable with that of PDT, MTX may not induce the long-term anatomical alterations in the RPE or choriocapillaries associated with the application of PDT. However, possible direct effects of MTX on the RPE and choroid should not be ignored. The mechanism of action of MTX is complex. It may include immune suppression, raising of extracellular cyclic adenosine monophosphate levels,50 and antiangiogenesis.51 Moreover, animal models showed that MTX induces a reduction of steroid receptor expression.37 Although the exact pathogenesis of CSC has not been clearly understood, many studies reported that the accumulation of SRF in cases with CSC is associated with high levels of glucocorticoids.38,52 We hypothesized previously that high levels of glucocorticoids in cases with CSC may cause persistence of the focal leakage into the subretinal space (Norouzpour, A. and Abrishami, M., 2015). Therefore, on the basis of this hypothesis, MTX might decrease the focal leakage into the subretinal space, as shown in Fig. 5e and f, through counteracting the glucocorticoid effects. In addition, our results showed that most complete resolutions of SRF have occurred on an average of 4 months after the onset of treatment. Delayed maximal effects of MTX and a little tendency to CSC recurrence at the second and third months after stopping MTX might be explained by a reversible MTX-induced reduction in steroid receptor gene expression in chorioretinal tissues. Other studies investigating the effects of MTX on the steroid receptor expression might support this insight.37
Limitation Our study was limited by the small sample size and the lack of a control group. As the natural course of CSC remains unpredictable,53 it is not clear whether the improvement in visual acuity and OCT findings is related to MTX treatment or the natural course of the disease. However, the rapid improvement in visual acuity and OCT findings at the time of MTX administration may imply the efficacy of MTX treatment. A randomized controlled clinical trial is needed to increase the validity of the results. The MTX dose and duration of the treatment were constant in our study. MTX may take up to 6 months to produce its full anti-inflammatory effects.54 However, its effects in CSC treatment have not been well recognized yet. Increases in the dose and/or the duration of MTX treatment might increase its effects and reduce the recurrence rate of CSC. In addition, the follow-up period may not be long enough to show the long-term recurrence rate of CSC after MTX treatment. Further studies are needed to determine the optimal dosage and duration of treatment, as well as the longterm recurrence rate of CSC.
Conclusion Low-dose oral MTX may be an alternative therapeutic option for the treatment of chronic CSC. Further clinical investigations are needed to confirm the beneficial effects of MTX in the treatment of CSC and to compare costs and benefits of MTX treatment with other therapeutic options
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such as PDT. The data of this study pave the way for a randomized clinical trial comparing the effects of MTX treatment with PDT or observation, which would be the next step to further investigate the efficacy of MTX in CSC.
Acknowledgments The authors would like to acknowledge Drs. Touka Banaee, Nasser Shoeibi, MohammadReza Ansari, Naghmeh Tehranian, Ali Saadat for the referral of patients to them. This study was funded by the Mashhad University of Medical Sciences.
Author Disclosure Statement No competing financial interests exist.
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33. Nielsen, J.S., Weinreb, R.N., Yannuzzi, L., and Jampol, L.M. Mifepristone treatment of chronic central serous chorioretinopathy. Retina. 27:119–122, 2007. 34. Meyerle, C.B., Freund, K.B., Bhatnagar, P., et al. Ketoconazole in the treatment of chronic idiopathic central serous chorioretinopathy. Retina. 27:943–946, 2007. 35. Bousquet, E., Beydoun, T., Zhao, M., et al. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 33:2096–2102, 2013. 36. Kurup, S.K., Oliver, A., Emanuelli, A., et al. Low-dose methotrexate for the treatment of chronic central serous chorioretinopathy. A retrospective analysis. Retina. 32: 2096–2101, 2012. 37. Yang, X.J., Wang, H.C., Chen, Y.P., et al. Examination of the effects of methotrexate on histological and steroid receptor changes in the endosalpinx of the rat. Eur. J. Obstet. Gynecol. Reprod. Biol. 146:193–199, 2009. 38. Bouzas, E.A., Karadimas, P., and Pournaras, C.J. Central serous chorioretinopathy and glucocorticoids. Surv. Ophthalmol. 47:431–448, 2002. 39. Ciardella, A.P., Guyer, D.R., Spitznas, M., and Yannuzzi, L.A. Central serous chorioretinopathy. In: Ryan, S.J., ed. Retina, 3rd edition. St Louis: Mosby Inc; 2001; p. 1153. 40. Ficker, L., Vafidis, G., While, A., and Leaver, P. Long-term follow-up of a prospective trial of argon laser photocoagulation in the treatment of central serous retinopathy. Br. J. Ophthalmol. 72:829–834, 1988. 41. Ross, A., Ross, A.H., and Mohamed, Q. Review and update of central serous chorioretinopathy. Curr. Opin. Ophthalmol. 22:166–173, 2011. 42. Inoue, R., Sawa, M., Tsujikawa, M., and Gomi, F. Association between the efficacy of photodynamic therapy and indocyanine green angiography findings for central serous chorioretinopathy. Am. J. Ophthalmol. 149:441–446.e441– e442, 2010. 43. Karim, S.P., and Adelman, R.A. Profile of verteporfin and its potential for the treatment of central serous chorioretinopathy. Clin. Ophthalmol. 7:1867–1875, 2013. 44. Erikitola, O.C., Crosby-Nwaobi, R., Lotery, A.J., and Sivaprasad, S. Photodynamic therapy for central serous chorioretinopathy. Eye. 28:944–957, 2014. 45. Koss, M.J., Beger, I., and Koch, F.H. Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy. Eye. 26:307–314, 2012. 46. Artunay, O., Yuzbasioglu, E., Rasier, R., et al. Intravitreal bevacizumab in treatment of idiopathic persistent central serous chorioretinopathy: a prospective, controlled clinical study. Curr. Eye Res. 35:91–98, 2010. 47. Bae, S.H., Heo, J.W., Kim, C., et al. A randomized pilot study of low fluence photodynamic therapy versus intravitreal ranibizumab for chronic central serous chorioretinopathy. Am. J. Ophthalmol. 152:784–792. e2, 2011. 48. Chung, Y.R., Seo, E.J., Lew, H.M., and Lee, K.H. Lack of positive effect of intravitreal bevacizumab in central serous chorioretinopathy: meta-analysis and review. Eye. 27: 1339–1346, 2013. 49. Yalcinbayir, O., Gelsken, O., Akova-Budak, B., et al. Correlation of spectral domain optical coherence tomography findings and visual acuity in central serous chorioretinopathy. Retina. 34:705–712, 2014. 50. Cronstein, B.N. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol. Rev. 57:163–172, 2005.
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51. Munoz, R., Shaked, Y., Bertolini, F., et al. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. Breast. 14:466–479, 2005. 52. Carvalho-Recchia, C.A., Yannuzzi, L.A., Negrao, S., et al. Corticosteroids and Central Serous Chorioretinopathy. Ophthalmology. 109:1834–1837, 2002. 53. Bujarborua, D. Long-term follow-up of idiopathic central serous chorioretinopathy without laser. Acta Ophthalmol. Scand. 79:417–421, 2001. 54. Galor, A., Jabs, D.A., Leder, H.A., et al. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology. 115: 1826–1832, 2008.
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Received: January 11, 2015 Accepted: June 5, 2015 Address correspondence to: Dr. Seyedeh-Maryam Hosseini Retina Research Center Khatam-Al-Anbia Eye Hospital Mashhad University of Medical Sciences Ghareni Boulevard Mashhad 91959-61151 Iran E mail: [email protected]; [email protected]
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 00, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0173
Treatment of Chronic Central Serous Chorioretinopathy with Oral Methotrexate Majid Abrishami, MirNaghi Mousavi, Seyedeh-Maryam Hosseini, and Amir Norouzpour
Abstract
Purpose: To evaluate the effects of oral methotrexate (MTX) in patients with chronic central serous chorioretinopathy (CSC). Methods: This is an interventional, prospective uncontrolled clinical trial, which included 23 eyes of 23 consecutive patients presenting with chronic symptomatic CSC and persistent subretinal fluid (SRF) for longer than 3 months. All patients were treated with 7.5 mg/week of oral MTX for 12 weeks. The best corrected visual acuity (BCVA), central macular thickness (CMT), SRF, and total macular volume recorded by monthly optical coherence tomography were analyzed. Complete blood count and serum liver enzymes level were monitored. Results: Mean duration of CSC was 13 months (3–36 months). Mean BCVA improved from 20/40 at baseline to 20/30 at the third month and 20/28 at the sixth month (P = 0.002 and 0.003, respectively). Mean CMT decreased from 375 mm at baseline to 278 mm and 265 mm at the third and sixth month (P = 0.002 and 0.007, respectively). Mean total macular volume decreased from 9.33 mm3 at baseline to 8.48 and 8.31 mm3 at the third and sixth month (P = 0.001 and 0.001, respectively). Thirteen (62%) eyes achieved complete resolution of SRF. No MTX-associated toxicity was detected. Conclusion: Low-dose oral MTX may be an alternative therapeutic option for the treatment of chronic CSC. This study paves the way for a randomized clinical trial comparing the effects of MTX treatment with photodynamic therapy or observation.
cently, antivascular endothelial growth factor agents30–32 and corticosteroid antagonists such as mifepristone,33 ketoconazole,34 and eplerenone.35 However, CSC treatment has not been well defined.16 Methotrexate (MTX) has been proposed as an alternative therapeutic option for CSC treatment.36 MTX is an antimetabolic agent commonly used in low dosages for the treatment of different systemic and ophthalmic inflammatory disorders. However, the antisteroid effects of MTX37 as well as the role of glucocorticoids in the pathogenesis of CSC38 may provide insights into the use of MTX as a potential therapeutic option for treatment of CSC. In this study, we prospectively evaluated the effects of oral MTX in 23 consecutive patients presenting with chronic CSC.
Introduction
C
entral serous chorioretinopathy (CSC) is characterized by the accumulation of subretinal fluid (SRF), causing a well-circumscribed serous retinal detachment, which commonly affects the macula.1 CSC typically affects young and middle-aged adults, with men affected more commonly than women.2 CSC usually has a self-limiting natural course, with complete spontaneous resolution in most cases.3 However, in some patients it becomes chronic with persistent SRF, which may lead to long-term visual impairments.4,5 Some associated findings include Type A personality,6 Cushing’s syndrome,7 pregnancy,8,9 systemic steroid use,10 collagen vascular diseases,11–13 and obstructive sleep apnea.14 However, the exact pathogenesis of CSC remains obscure.2,15 As a result of multiple hypotheses for CSC pathogenesis, various treatments have been proposed.16 The therapeutic options may include psychotherapy,17 medical therapy such as a-adrenergic18 and b-adrenergic19 inhibitors and acetazolamide,20 retinal laser photocoagulation,21–23 photodynamic therapy (PDT),24–28 transpupillary thermotherapy,29 and re-
Methods Study design This study is an interventional, prospective uncontrolled clinical trial of 23 patients presenting with chronic
Retina Research Center, Khatam-Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
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symptomatic CSC and persistent SRF for longer than 3 months, consecutively between Feb 2013 and Feb 2014 at the Department of Ophthalmology in Khatam-Al-Anbia Eye Hospital, Mashhad, Iran. The study was approved by the Institutional Review Boards of Mashhad University of Medical Sciences (MUMS) and adhered to the tenets of the Declaration of Helsinki. The diagnosis was established with spectral domain optical coherence tomography (SD-OCT) and fundus fluorescein angiography (FFA) imagings. A detailed history of concomitant diseases, current or prior use of medications, and any interventions for CSC treatment before the referral to us were taken.
Eligibility criteria We included patients with visual symptoms lasting longer than 3 months and persistent SRF involving the fovea on SD-OCT as well as the presence of an active leakage at the level of the retinal pigment epithelium (RPE) on FFA. The patients were recommended PDT, and only those who refused PDT were offered a therapeutic trial of MTX. Exclusion criteria included the following: (1) previous treatment with laser photocoagulation, PDT, intravitreal bevacizumab (IVB), or any other therapeutic options within 3 months before the referral to us; (2) evidence of choroidal neovascularization (CNV), polypoidal choroidal vasculopathy, or any other cause of visual impairments; (3) systemic contraindication for MTX treatment such as pregnancy, which was ruled out by laboratory tests, liver or hematologic diseases, and abnormal results of blood analysis at baseline; (4) women who did not use a safe contraceptive method within 3 months before the onset of treatment; all included women were strongly recommended to use a safe contraceptive method within the trial period.
Baseline and follow-up examinations At baseline, we obtained the best corrected visual acuity (BCVA), SD-OCT, and FFA (Heidelberg Engineering, Heidelberg, Germany). BCVA was evaluated with the Snellen chart converted to logarithm of minimal angle resolution (Log MAR). On SD-OCT imagings, the macular thickness map was used to obtain total macular volume and central macular thickness (CMT). SRF was assessed by manually measuring the distance between the outer segment and the RPE. The maximum SRF on all OCT cross sections has been included in the statistical analysis. The potential risks and benefits of the treatment were completely discussed with the patients, and an informed consent was obtained before treatment. Volunteer patients were treated with a dose of 7.5 mg of oral MTX per week along with 1 mg of folic acid supplementation per day for 12 weeks and then monitored for 3 months without any medication. The MTX dose and duration of treatment were selected on the basis of data showing possible effects of MTX in CSC treatment with such dose and duration.36 BCVA and OCT testing were obtained at monthly followup visits for 6 months after starting the treatment with MTX. Treatment tolerance was assessed by blood analysis— differential complete blood count (CBC, diff), liver function tests (LFTs), and serum liver enzymes level—performed at baseline and monthly after the onset of MTX treatment.
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The treatment would be stopped in cases of significant rise of serum liver enzymes, abnormal LFTs, or any disorder in results of CBC.
Main outcome measures The primary outcomes were CMT, SRF, and total macular volume changes recorded by monthly OCT. The secondary outcomes were changes in BCVA—in Log MAR—within 6 months after starting MTX treatment and the percentage of eyes achieving complete resolution of CSC, which is defined as the absence of SRF on all OCT cross sections.
Analysis Variables before and after treatment were compared using the repeated measures test. If the result of the test was significant, we compared the data at baseline with data at third and sixth month, using the LSD method with Bonferroni adjustment. A P value < 0.05 was considered statistically significant.
Results Patient characteristics Forty-four patients were referred to our center with chronic symptomatic CSC. After an extensive discussion on current therapeutic options as well as the potential risks and benefits of MTX treatment with each patient, 25 patients preferred to be treated with MTX. Two patients were excluded because of evidences of other cause of visual impairments. Finally, 23 eyes of 23 patients were included in the study. Two patients lost the follow-up after 3 months, and 21 patients completed the follow-up visits.
Table 1.
Characteristics of the Included Cases
Demographics Mean age Age range Sex Mean duration of CSC Bilateral symptomatic CSC Outcomes Mean baseline BCVA (Log MAR) Mean BCVA at 3 months (Log MAR) Mean BCVA at 6 months (Log MAR) Mean baseline CMT (mm) Mean CMT at 3 months (mm) Mean CMT at 6 months (mm) Mean baseline SRF (mm) Mean SRF at 3 months (mm) Mean SRF at 6 months (mm) Mean baseline total macular volume (mm3) Mean total macular volume at 3 months (mm3) Mean total macular volume at 6 months (mm3)
42 years 30 to 58 years 70% male 13 months 0.09% cases 0.308 (0–0.699) 0.183 (0–0.699) 0.159 (0–0.398) 375 278 265 165 85 64 9.33
(201–754) (181–490) (176–451) (82–337) (0–194) (0–256) (7.96–12.17)
8.48 (7.65–9.56) 8.31 (6.58–9.80)
BCVA, best corrected visual acuity; CMT, central macular thickness; CSC, central serous chorioretinopathy; Log MAR, logarithm of minimal angle resolution; SRF, subretinal fluid.
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FIG. 1. Mean BCVA before and after treatment with methotrexate (mean – SEM). Mean BCVA improved from 20/ 40 at baseline to 20/30 at third month and 20/28 at sixth month (P = 0.002 and 0.003, respectively). BCVA, best corrected visual acuity; SEM, standard error of the mean.
The mean age of the patients was 42 years (ranged from 30 to 58 years). Sixteen cases (70%) were men. The mean duration of CSC was 13 months (ranged from 3 to 36 months). The left eye was involved in 14 (61%) cases. Two patients (9%) had bilateral symptomatic CSC, with 1 eye having acute CSC and the other with chronic CSC; therefore, the chronic eye was included in our analysis. No patient had a history of systemic or topical corticosteroid use. Four patients had been frequently treated with IVB. Two eyes were pseudophakic. Two patients had a history of hypothyroidism, and had been using levothyroxine. The characteristics of our series are summarized in Table 1.
Effect of MTX on visual acuity Mean BCVA was 20/40 (0.308 Log MAR, ranged from 0 to 0.699) at baseline, 20/30 (0.183 Log MAR, ranged from 0 to 0.699) at third month, and 20/28 (0.159 Log MAR, ranged from 0 to 0.398) at sixth month. BCVA at third and sixth month improved significantly compared to the baseline BCVA (P = 0.002 and 0.003, respectively) (Fig. 1).
Effect of MTX on total macular volume Mean total macular volume decreased significantly from 9.33 mm3 (ranged from 7.96 to 12.17 mm3) at baseline to 8.48 mm3 (ranged from 7.65 to 9.56 mm3) and 8.31 mm3 (ranged from 6.58 to 9.80 mm3) at the third and sixth month (P = 0.001 and 0.001, respectively) (Fig. 2).
Effect of MTX on CMT Mean CMT measured on OCT testing decreased significantly from 375 mm (ranged from 201 to 754 mm) at baseline to 278 mm (ranged from 181 to 490 mm) and 265 mm (ranged from 176 to 451 mm) at the third and sixth month (P = 0.002 and 0.007, respectively) (Fig. 3).
Effect of MTX on SRF Mean SRF decreased from 165 mm (ranged from 82 to 337 mm) at baseline to 85 mm (ranged from 0 to 194 mm) and 64 mm (ranged from 0 to 256 mm) at the third and sixth month, respectively (Fig. 4). Sixty-two percent of the eyes
FIG. 2. Mean total macular volume before and after treatment with methotrexate (mean – SEM). Mean total macular volume decreased from 9.33 mm3 at baseline to 8.48 mm3 at third month and 8.31 mm3 at sixth month (P = 0.001 and 0.001, respectively).
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FIG. 3. Mean CMT before and after treatment with methotrexate (mean – SEM). Mean CMT decreased from 375 mm at baseline to 278 mm at third month and 265 mm at sixth month (P = 0.002 and 0.007, respectively). CMT, central macular thickness.
(13 eyes) achieved complete resolution of SRF, on average, 4 months after the start of MTX treatment. SRF recurred in 2 eyes (9%) 8–12 weeks after stopping MTX use.
Probable prognostic factor(s) of visual outcome BCVA in 58% of patients who had a complete resolution of SRF improved to 20/20 (Fig. 5a, b). Mean BCVA in the remaining 42% of patients was 20/52, ranged from 2/20 to 20/28. We hypothesized that, in our series, the disruption of foveal photoreceptor inner segment/outer segment (IS/OS) junction and/or external limiting membrane (ELM) lines may affect the visual outcome despite complete resolution of SRF. We defined the disruption of IS/OS and ELM lines as the loss of hyper-reflective lines at the appropriate anatomical location and manually measured the length of the disruption of IS/ OS and ELM lines (Fig. 5c, d). The mean disruption lengths of IS/OS and ELM lines in those whose final BCVA did not improve to 20/20 despite a complete resolution of SRF were 2716 mm and 747 mm, respectively. The range of IS/OS disruption length was from 1818 mm to 3900 mm, while that of ELM disruption length was from 0 to 1289 mm. Pearson correlation coefficients showed that the length of IS/OS and
FIG. 4. Mean SRF before and after treatment with methotrexate (mean – SEM). Mean SRF decreased from 165 mm at baseline to 85 mm at third month and 64 mm at sixth month. SRF, subretinal fluid.
ELM disruptions is correlated with poor final visual acuity (P = 0.001 and 0.031, respectively). However, linear regression analysis with the stepwise method showed that only the IS/OS line disruption is associated with poor visual outcome (P = 0.001) and the ELM line disruption did not significantly affect the visual outcome (P = 0.649).
Treatment tolerance Tolerance to the treatment was evaluated monthly at every follow-up visit. None of the patients has shown any severe MTX side effects. CBC remained in the normal range for all patients at the follow-up period. One patient reported mild nausea at the day of MTX use, and 1 patient showed a 2-fold increase in serum liver enzymes level 2 months after starting MTX treatment, which returned spontaneously to the baseline 1 month later. He remained asymptomatic during the follow-up period.
Discussion Many therapeutic options have been suggested for the treatment of CSC. Previous medical treatments had no proven
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FIG. 5. Changes of OCT and fundus fluorescein angiography (FFA) imagings before and after treatment with methotrexate. (a, b) A 39-year-old man with chronic CSC in the right eye as well as persistent SRF for 24 months. Baseline OCT shows a maximum 101 mm SRF (a). BCVA improved from 9/10 at baseline to 10/10 at 6 months with a complete resolution of SRF and intact IS/OS junction and ELM lines (b). (c, d) A 56-year-old woman with chronic CSC in the right eye and persistent SRF for 12 months. Baseline OCT shows a maximum 124 mm SRF (c). Baseline BCVA was 4/10, which remained unchanged up to 6 months despite complete resolution of SRF (d). The disrupted IS/OS junction line was 2912 mm in length (arrows) while the ELM was intact. (e, f) FFA of a 30-year-old man shows a typical smokestack pattern of leakage at baseline (e), while angiography at 6 months shows no site of leakage (f). CSC, central serous chorioretinopathy; ELM, external limiting membrane; IS/OS, inner segment/outer segment; OCT, optical coherence tomography.
influence on the disease, and the results of studies on the effects of different laser modalities in treatment of CSC are controversial and not conclusive.39 In addition, focal laser photocoagulation increases the risk of macular scar formation and secondary CNV.40,41 PDT still carries the risk of RPE atrophy, choriocapillary hypoperfusion, and the development of CNV, especially with standard-dose PDT.16,42 Half-dose PDT seems to be effective and safe, but its long-term efficacy is unknown.43,44 Nevertheless, PDT still remains expensive and it is not covered for CSC by most insurance institutions and may not be financially available to a majority of patients. Subthreshold diode laser micropulse photocoagulation has been attempted showing some promise with early results but requires further studies.45 The use of IVB for CSC treatment is still under debate as long as there are contradictory reports in the literature.46–48 There is still little evidence to support the use of acetazolamide20 or mifepristone,33 and the promise of ketoconazole and eplerenone is short-lived.34,35 Another therapeutic option that may be helpful in the treatment of chronic CSC might be MTX.36 In our chronic
CSC cases, treatment with low-dose oral MTX was accompanied by concomitant improvement in BCVA and decrease in CMT, SRF, and total macular volume (Figs. 1–4). SRF was completely resolved in 62% of our cases, on average, 4 months after the start of treatment with MTX. BCVA in 58% of patients who had a complete resolution of SRF improved to 20/20 (Fig. 5a, b). Mean BCVA in the remaining 42% of patients was 20/52, ranged from 2/20 to 20/28. We hypothesized that, in our series, the disruption of foveal photoreceptor IS/OS junction and/or ELM lines may affect the visual outcome despite complete resolution of SRF. It was reported that the loss of IS/OS junction line and ELM line integrity affects the visual outcome in eyes with CSC.49 Our results showed that, in our series, the integrity of IS/OS junction line may be a prognostic factor that affects the visual outcome significantly (Fig. 5c, d). The success rate of our series may be comparable with that of other studies evaluating the effect of PDT. The visual acuity of eyes treated with PDT improved 1–4 lines on the vision testing chart, and OCT imagings demonstrated complete resolution of SRF in 60%–75% of eyes.26,27
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However, the duration of CSC in these studies is longer than that in our study, and the mean baseline visual acuity of the eyes is lower than that of our patients.26,27 Although the benefits of MTX treatment may be comparable with that of PDT, MTX may not induce the long-term anatomical alterations in the RPE or choriocapillaries associated with the application of PDT. However, possible direct effects of MTX on the RPE and choroid should not be ignored. The mechanism of action of MTX is complex. It may include immune suppression, raising of extracellular cyclic adenosine monophosphate levels,50 and antiangiogenesis.51 Moreover, animal models showed that MTX induces a reduction of steroid receptor expression.37 Although the exact pathogenesis of CSC has not been clearly understood, many studies reported that the accumulation of SRF in cases with CSC is associated with high levels of glucocorticoids.38,52 We hypothesized previously that high levels of glucocorticoids in cases with CSC may cause persistence of the focal leakage into the subretinal space (Norouzpour, A. and Abrishami, M., 2015). Therefore, on the basis of this hypothesis, MTX might decrease the focal leakage into the subretinal space, as shown in Fig. 5e and f, through counteracting the glucocorticoid effects. In addition, our results showed that most complete resolutions of SRF have occurred on an average of 4 months after the onset of treatment. Delayed maximal effects of MTX and a little tendency to CSC recurrence at the second and third months after stopping MTX might be explained by a reversible MTX-induced reduction in steroid receptor gene expression in chorioretinal tissues. Other studies investigating the effects of MTX on the steroid receptor expression might support this insight.37
Limitation Our study was limited by the small sample size and the lack of a control group. As the natural course of CSC remains unpredictable,53 it is not clear whether the improvement in visual acuity and OCT findings is related to MTX treatment or the natural course of the disease. However, the rapid improvement in visual acuity and OCT findings at the time of MTX administration may imply the efficacy of MTX treatment. A randomized controlled clinical trial is needed to increase the validity of the results. The MTX dose and duration of the treatment were constant in our study. MTX may take up to 6 months to produce its full anti-inflammatory effects.54 However, its effects in CSC treatment have not been well recognized yet. Increases in the dose and/or the duration of MTX treatment might increase its effects and reduce the recurrence rate of CSC. In addition, the follow-up period may not be long enough to show the long-term recurrence rate of CSC after MTX treatment. Further studies are needed to determine the optimal dosage and duration of treatment, as well as the longterm recurrence rate of CSC.
Conclusion Low-dose oral MTX may be an alternative therapeutic option for the treatment of chronic CSC. Further clinical investigations are needed to confirm the beneficial effects of MTX in the treatment of CSC and to compare costs and benefits of MTX treatment with other therapeutic options
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such as PDT. The data of this study pave the way for a randomized clinical trial comparing the effects of MTX treatment with PDT or observation, which would be the next step to further investigate the efficacy of MTX in CSC.
Acknowledgments The authors would like to acknowledge Drs. Touka Banaee, Nasser Shoeibi, MohammadReza Ansari, Naghmeh Tehranian, Ali Saadat for the referral of patients to them. This study was funded by the Mashhad University of Medical Sciences.
Author Disclosure Statement No competing financial interests exist.
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Received: January 11, 2015 Accepted: June 5, 2015 Address correspondence to: Dr. Seyedeh-Maryam Hosseini Retina Research Center Khatam-Al-Anbia Eye Hospital Mashhad University of Medical Sciences Ghareni Boulevard Mashhad 91959-61151 Iran E mail: [email protected]; [email protected]
