CHRONIC CENTRAL SEROUS CHORIORETINOPATHY RESPONSIVE TO RIFAMPIN Zac B. Ravage, MD,* Kirk H. Packo, MD,* Catherine M. Creticos, MD,† Pauline T. Merrill, MD*
Purpose: The purpose of this was to describe the clinical improvement of chronic central serous chorioretinopathy in a patient treated with rifampin for tuberculosis. Methods: A 54-year-old Hispanic man with a distant history of pulmonary tuberculosis presented with reduced vision in the right greater than left eye for over 1 year. He had diffuse chorioretinopathy in both eyes and a serous retinal detachment in his right eye. The findings were most consistent with chronic central serous chorioretinopathy, although tuberculosis -related choroiditis could not be excluded. Treatment with multidrug antituberculosis medications, including rifampin, resulted in the reduction in leakage and resolution of subretinal fluid. Fluid recurred on cessation of all medications and resolved again with retreatment. Monotherapy with rifampin maintained the absence of fluid. Discussion: This case represents the first report of chronic central serous chorioretinopathy responding to systemic therapy with rifampin. We hypothesize that the clinical response observed is secondary to induction of cytochrome P450 with increased hepatic metabolism of endogenous corticosteroids and a reduction in systemic cortisol levels. RETINAL CASES & BRIEF REPORTS 6:129–132, 2012
compounds, including corticosteroids.4,5 We present a case of chronic CSC responsive to rifampin. To our knowledge, this is the first report to describe the efficacy of such treatment.
From the *Department of Ophthalmology, Rush University Medical Center, Chicago, IL; and †Department of Infectious Diseases, Advocate Illinois Masonic Medical Center, Chicago, IL.
A
lthough the pathogenesis of central serous chorioretinopathy (CSC) is not fully understood, corticosteroids have been implicated in development of the disease.1 Pharmacotherapy with antiglucocorticoid medications, including mifepristone and ketoconazole, has been shown to be beneficial in some patients.2,3 Rifampin is active against Mycobacterium and is most commonly used for treatment active tuberculosis (TB). It is also a potent inducer of cytochrome P450, increasing hepatic metabolism of numerous
Case Report A 54-year-old Hispanic man presented with blurred vision primarily in the right eye for 1 year. His ocular history was significant for myopia and presbyopia, with no mention of retinal pathology on his last eye examination 3 years previously. The patient’s medical history was significant for TB infection in 1990 in Venezuela. At that time, he was treated with an oral 3-medication regimen for 6 months. He had been asymptomatic and without further treatment since. On examination, best-corrected visual acuity was 20/70 in the right eye and 20/25 in the left eye. Pupils were equal and reactive with no afferent papillary defect. Anterior segment and vitreous were normal. Intraocular pressure was 16 mmHg bilaterally. Ophthalmoscopy revealed diffuse pigmentary changes throughout the maculas and midperiphery in both eyes (Figure 1). On fluorescein angiography, these areas were hyperfluorescent in the early and late phases of the angiogram, including few localized points of leakage (Figure 2). Optical coherence tomography revealed central subretinal fluid (SRF) in the right eye and foveal attenuation in the left eye (Figure 3, A and B).
Presented at the Annual Meeting of the American Society of Retina Specialists, Vancouver, British Columbia, Canada, August 28, 2010. The authors have no proprietary interests pertaining to the case discussed herein. Reprint requests: Zac B. Ravage, MD, Department of Ophthalmology, Rush University Medical Center, 1725 West Harrison St., Suite 915, Chicago, IL 60612; e-mail: Zac_Ravage@ Rush.edu
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Fig. 2. Fluorescein angiography of the right and left eyes with broad areas of hyperfluorescence in the early and late phases of the angiogram, including few localized points of leakage. Fig. 1. Color photographs of the right and left eyes showing diffuse pigmentary changes throughout the maculas and midperiphery of both eyes.
The appearance of both eyes was most consistent with chronic CSC. The fundus findings lacked the typical progressive leading edge and associated vitritis present in serpiginouslike choroiditis seen in some patients with TB.6 However, given the medical history, latent TB with secondary choroiditis could not be completely excluded. Infectious disease evaluation showed the patient to be asymptomatic with a normal physical examination. Positive purified protein derivative and quantiferon gold testing were positive. Chest x-ray showed left apical scarring and pleural thickening, consistent with previous granulomatous disease. Testing for human immunodeficiency virus and syphilis were negative. The results confirmed distant pulmonary TB infection. The possibility, however remote, that the patient’s current ocular disease might be related to TB activity was of sufficient concern to prompt initiation of multidrug TB therapy. Treatment consisted of ethambutol 800 mg/day, isoniazid 300 mg/day (with vitamin B6 50 mg/day), pyrazinamide 1000 mg/day, and rifampin 600 mg/day. He was seen in follow-up in our office after 1 month of therapy. Visual acuity was 20/80 in the right eye and 20/30 in the left eye. Anterior segment and vitreous were normal. Ophthalmoscopy
showed diffuse pigmentary changes in both eyes, similar to the previous examination. Optical coherence tomography, however, revealed resolution of the SRF in the right eye (Figure 4A). The patient was maintained on multidrug anti-TB therapy for a standard period of 9 months. During this time, visual acuity remained stable with no leakage or recurrent SRF. His therapy was then discontinued. The patient was seen in follow-up after 1 month off all medications. Visual acuity was 20/80 in the right eye and 20/25 in the left eye. The areas of pigmentary degeneration were similar in size and distribution to previous examinations. On optical coherence tomography, recurrent SRF was evident in the right eye (Figure 4B). With evidence of recurrent activity, resumption of multidrug anti-TB therapy was recommended. After 1 month of retreatment, visual acuity was 20/60 in the right eye and 20/25 in the left eye. The optical coherence tomography demonstrated resolution of the serous fluid once again (Figure 4C). The improvement on rechallenge with anti-TB medications suggested that one of the antibiotics might be responsible. Rifampin, aside from its antibacterial properties, is a potent inducer of cytochrome P450 and has been shown to reduce circulating levels of endogenous and exogenous steroids.4,5 After follow-up with his infectious disease physician, including a gallium scan to ensure no evidence of active TB, the patient was
CSC RESPONSIVE TO RIFAMPIN RAVAGE ET AL
Fig. 3. A, B, Optical coherence tomography with central SRF in the right eye and foveal attenuation in the left eye.
switched to monotherapy with rifampin. One month later, visual acuity was 20/70+ in the right eye and 20/30+ in the left eye. The retinal examination was similar, and the optical coherence tomography still showed no SRF in the right eye (Figure 4D). He has been maintained on 600 mg/day of rifampin only since that time with stable vision and without recurrence of fluid.
Discussion The natural course of CSC is generally that of spontaneous resolution over 3 months to 4 months with recovery of good vision. In certain cases, SRF may persist or recur over time with permanent damage to the retina and retinal pigment epithelium and associated visual loss.7
Fig. 4. A–D, Optical coherence tomography of the right eye: (A) after the first month of multidrug anti-TB therapy showing resolution of SRF; (B) 1 month after discontinuation of multidrug anti-TB therapy with recurrent SRF; (C) 1 month after retreatment with multidrug anti-TB therapy and resolution of the serous fluid, again (D) on rifampin monotherapy that maintained the absence of fluid.
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This case describes a patient with previously undiagnosed chronic CSC characterized by diffuse retinal pigment epithelial damage bilaterally. There was active leakage with a central serous detachment and decreased vision in the right eye. Because of possible latent TB, multidrug antibiotic therapy was initiated that resulted in resolution of the SRF. Discontinuation caused the leakage to recur, with improvement again on retreatment with all medications. The effect was maintained on monotherapy with rifampin, verifying it as the responsible agent. Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic produced by Streptomyces mediterranei. It inhibits bacterial RNA synthesis by preventing attachment of RNA polymerase to bacterial DNA. Rifampin is active against microorganisms of the genus Mycobacterium, including M ycobacterium tuberculosis, and is used most commonly for the treatment of active TB. It is readily absorbed after oral administration and is widely distributed throughout the body. Rifampin and its metabolite are excreted principally by the liver. The association between corticosteroids, either endogenous or exogenous, and development of CSC is well established.1 Serum and urine cortisol levels have been shown to be significantly elevated in patients with CSC.8,9 We did not obtain cortisol levels in this patient, as our analysis of the case was largely retrospective. There was no evidence of Cushing syndrome. Antiglucocorticoid therapy, with mifepristone or ketoconazole, has previously been used successfully in limited trials for the treatment of chronic CSC.2,3 Furthermore, treatment of CSC with ketoconazole was shown to cause a reduction in 24-hour urine cortisol levels that preceded anatomical improvement.3
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Rifampin is a potent inducer of cytochrome P450. Doses of rifampin as low as 300 mg daily are known to induce hepatic metabolism of endogenous and exogenous glucocorticoids within several days of treatment, a generally more rapid effect than typical hepatic enzyme induction.4,5,10 We hypothesize that through this mechanism, administration of rifampin produced clinical improvement in our patient. This finding suggests a novel method for the treatment of chronic CSC and warrants further study. Key words: central serous chorioretinopathy, corticosteroids, rifampin, tuberculosis. Acknowledgment The authors would like to thank Rob Beckett, PharmD, for his assistance. References 1. Jampol LM, Weinreb R, Yannuzzi L. Involvement of corticosteroids and catecholamines in the pathogenesis of central serous chorioretinopathy: a rationale for new treatment strategies. Ophthalmology 2002;109:1765–1766.
2. Nielsen JS, Weinreb RN, Yannuzzi L, et al. Mifepristone treatment of chronic central serous chorioretinopathy. Retina 2007;27:119–122. 3. Meyerle CB, Freund KB, Bhatnagar P, et al. Ketoconazole in the treatment of chronic idiopathic central serous chorioretinopathy. Retina 2007;27:943–946. 4. Edwards OM, Courtenay-Evans RJ, Galley JM, et al. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548–551. 5. McAllister WAC, Thompson PJ, Al-Habet SM, et al. Rifampicin reduces effectiveness and bioavailibity of prednisolone. BMJ 1983;286:923–925. 6. Vasconcelos-Santos DV, Rao PK, Davies JB, et al. Clinical features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol 2010;128: 853–858. 7. Yannuzzi LA, Shakin JL, Fisher YL, Altomonte MA. Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. Ophthalmology 1984;91:1554–1572. 8. Garg SP, Dada T, Talwar D, Biswas NR. Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol 1997;81:962–964. 9. Haimovici R, Rumelt S, Melby J. Endocrine abnormalities in patients with central serous chorioretinopathy. Ophthalmology 2003;110:698–703. 10. Tatro DS, ed. Drug Interaction Facts. 10th ed. St Louis, MO: Facts & Comparisons; 2010.
Purpose: The purpose of this was to describe the clinical improvement of chronic central serous chorioretinopathy in a patient treated with rifampin for tuberculosis. Methods: A 54-year-old Hispanic man with a distant history of pulmonary tuberculosis presented with reduced vision in the right greater than left eye for over 1 year. He had diffuse chorioretinopathy in both eyes and a serous retinal detachment in his right eye. The findings were most consistent with chronic central serous chorioretinopathy, although tuberculosis -related choroiditis could not be excluded. Treatment with multidrug antituberculosis medications, including rifampin, resulted in the reduction in leakage and resolution of subretinal fluid. Fluid recurred on cessation of all medications and resolved again with retreatment. Monotherapy with rifampin maintained the absence of fluid. Discussion: This case represents the first report of chronic central serous chorioretinopathy responding to systemic therapy with rifampin. We hypothesize that the clinical response observed is secondary to induction of cytochrome P450 with increased hepatic metabolism of endogenous corticosteroids and a reduction in systemic cortisol levels. RETINAL CASES & BRIEF REPORTS 6:129–132, 2012
compounds, including corticosteroids.4,5 We present a case of chronic CSC responsive to rifampin. To our knowledge, this is the first report to describe the efficacy of such treatment.
From the *Department of Ophthalmology, Rush University Medical Center, Chicago, IL; and †Department of Infectious Diseases, Advocate Illinois Masonic Medical Center, Chicago, IL.
A
lthough the pathogenesis of central serous chorioretinopathy (CSC) is not fully understood, corticosteroids have been implicated in development of the disease.1 Pharmacotherapy with antiglucocorticoid medications, including mifepristone and ketoconazole, has been shown to be beneficial in some patients.2,3 Rifampin is active against Mycobacterium and is most commonly used for treatment active tuberculosis (TB). It is also a potent inducer of cytochrome P450, increasing hepatic metabolism of numerous
Case Report A 54-year-old Hispanic man presented with blurred vision primarily in the right eye for 1 year. His ocular history was significant for myopia and presbyopia, with no mention of retinal pathology on his last eye examination 3 years previously. The patient’s medical history was significant for TB infection in 1990 in Venezuela. At that time, he was treated with an oral 3-medication regimen for 6 months. He had been asymptomatic and without further treatment since. On examination, best-corrected visual acuity was 20/70 in the right eye and 20/25 in the left eye. Pupils were equal and reactive with no afferent papillary defect. Anterior segment and vitreous were normal. Intraocular pressure was 16 mmHg bilaterally. Ophthalmoscopy revealed diffuse pigmentary changes throughout the maculas and midperiphery in both eyes (Figure 1). On fluorescein angiography, these areas were hyperfluorescent in the early and late phases of the angiogram, including few localized points of leakage (Figure 2). Optical coherence tomography revealed central subretinal fluid (SRF) in the right eye and foveal attenuation in the left eye (Figure 3, A and B).
Presented at the Annual Meeting of the American Society of Retina Specialists, Vancouver, British Columbia, Canada, August 28, 2010. The authors have no proprietary interests pertaining to the case discussed herein. Reprint requests: Zac B. Ravage, MD, Department of Ophthalmology, Rush University Medical Center, 1725 West Harrison St., Suite 915, Chicago, IL 60612; e-mail: Zac_Ravage@ Rush.edu
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Fig. 2. Fluorescein angiography of the right and left eyes with broad areas of hyperfluorescence in the early and late phases of the angiogram, including few localized points of leakage. Fig. 1. Color photographs of the right and left eyes showing diffuse pigmentary changes throughout the maculas and midperiphery of both eyes.
The appearance of both eyes was most consistent with chronic CSC. The fundus findings lacked the typical progressive leading edge and associated vitritis present in serpiginouslike choroiditis seen in some patients with TB.6 However, given the medical history, latent TB with secondary choroiditis could not be completely excluded. Infectious disease evaluation showed the patient to be asymptomatic with a normal physical examination. Positive purified protein derivative and quantiferon gold testing were positive. Chest x-ray showed left apical scarring and pleural thickening, consistent with previous granulomatous disease. Testing for human immunodeficiency virus and syphilis were negative. The results confirmed distant pulmonary TB infection. The possibility, however remote, that the patient’s current ocular disease might be related to TB activity was of sufficient concern to prompt initiation of multidrug TB therapy. Treatment consisted of ethambutol 800 mg/day, isoniazid 300 mg/day (with vitamin B6 50 mg/day), pyrazinamide 1000 mg/day, and rifampin 600 mg/day. He was seen in follow-up in our office after 1 month of therapy. Visual acuity was 20/80 in the right eye and 20/30 in the left eye. Anterior segment and vitreous were normal. Ophthalmoscopy
showed diffuse pigmentary changes in both eyes, similar to the previous examination. Optical coherence tomography, however, revealed resolution of the SRF in the right eye (Figure 4A). The patient was maintained on multidrug anti-TB therapy for a standard period of 9 months. During this time, visual acuity remained stable with no leakage or recurrent SRF. His therapy was then discontinued. The patient was seen in follow-up after 1 month off all medications. Visual acuity was 20/80 in the right eye and 20/25 in the left eye. The areas of pigmentary degeneration were similar in size and distribution to previous examinations. On optical coherence tomography, recurrent SRF was evident in the right eye (Figure 4B). With evidence of recurrent activity, resumption of multidrug anti-TB therapy was recommended. After 1 month of retreatment, visual acuity was 20/60 in the right eye and 20/25 in the left eye. The optical coherence tomography demonstrated resolution of the serous fluid once again (Figure 4C). The improvement on rechallenge with anti-TB medications suggested that one of the antibiotics might be responsible. Rifampin, aside from its antibacterial properties, is a potent inducer of cytochrome P450 and has been shown to reduce circulating levels of endogenous and exogenous steroids.4,5 After follow-up with his infectious disease physician, including a gallium scan to ensure no evidence of active TB, the patient was
CSC RESPONSIVE TO RIFAMPIN RAVAGE ET AL
Fig. 3. A, B, Optical coherence tomography with central SRF in the right eye and foveal attenuation in the left eye.
switched to monotherapy with rifampin. One month later, visual acuity was 20/70+ in the right eye and 20/30+ in the left eye. The retinal examination was similar, and the optical coherence tomography still showed no SRF in the right eye (Figure 4D). He has been maintained on 600 mg/day of rifampin only since that time with stable vision and without recurrence of fluid.
Discussion The natural course of CSC is generally that of spontaneous resolution over 3 months to 4 months with recovery of good vision. In certain cases, SRF may persist or recur over time with permanent damage to the retina and retinal pigment epithelium and associated visual loss.7
Fig. 4. A–D, Optical coherence tomography of the right eye: (A) after the first month of multidrug anti-TB therapy showing resolution of SRF; (B) 1 month after discontinuation of multidrug anti-TB therapy with recurrent SRF; (C) 1 month after retreatment with multidrug anti-TB therapy and resolution of the serous fluid, again (D) on rifampin monotherapy that maintained the absence of fluid.
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This case describes a patient with previously undiagnosed chronic CSC characterized by diffuse retinal pigment epithelial damage bilaterally. There was active leakage with a central serous detachment and decreased vision in the right eye. Because of possible latent TB, multidrug antibiotic therapy was initiated that resulted in resolution of the SRF. Discontinuation caused the leakage to recur, with improvement again on retreatment with all medications. The effect was maintained on monotherapy with rifampin, verifying it as the responsible agent. Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic produced by Streptomyces mediterranei. It inhibits bacterial RNA synthesis by preventing attachment of RNA polymerase to bacterial DNA. Rifampin is active against microorganisms of the genus Mycobacterium, including M ycobacterium tuberculosis, and is used most commonly for the treatment of active TB. It is readily absorbed after oral administration and is widely distributed throughout the body. Rifampin and its metabolite are excreted principally by the liver. The association between corticosteroids, either endogenous or exogenous, and development of CSC is well established.1 Serum and urine cortisol levels have been shown to be significantly elevated in patients with CSC.8,9 We did not obtain cortisol levels in this patient, as our analysis of the case was largely retrospective. There was no evidence of Cushing syndrome. Antiglucocorticoid therapy, with mifepristone or ketoconazole, has previously been used successfully in limited trials for the treatment of chronic CSC.2,3 Furthermore, treatment of CSC with ketoconazole was shown to cause a reduction in 24-hour urine cortisol levels that preceded anatomical improvement.3
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Rifampin is a potent inducer of cytochrome P450. Doses of rifampin as low as 300 mg daily are known to induce hepatic metabolism of endogenous and exogenous glucocorticoids within several days of treatment, a generally more rapid effect than typical hepatic enzyme induction.4,5,10 We hypothesize that through this mechanism, administration of rifampin produced clinical improvement in our patient. This finding suggests a novel method for the treatment of chronic CSC and warrants further study. Key words: central serous chorioretinopathy, corticosteroids, rifampin, tuberculosis. Acknowledgment The authors would like to thank Rob Beckett, PharmD, for his assistance. References 1. Jampol LM, Weinreb R, Yannuzzi L. Involvement of corticosteroids and catecholamines in the pathogenesis of central serous chorioretinopathy: a rationale for new treatment strategies. Ophthalmology 2002;109:1765–1766.
2. Nielsen JS, Weinreb RN, Yannuzzi L, et al. Mifepristone treatment of chronic central serous chorioretinopathy. Retina 2007;27:119–122. 3. Meyerle CB, Freund KB, Bhatnagar P, et al. Ketoconazole in the treatment of chronic idiopathic central serous chorioretinopathy. Retina 2007;27:943–946. 4. Edwards OM, Courtenay-Evans RJ, Galley JM, et al. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548–551. 5. McAllister WAC, Thompson PJ, Al-Habet SM, et al. Rifampicin reduces effectiveness and bioavailibity of prednisolone. BMJ 1983;286:923–925. 6. Vasconcelos-Santos DV, Rao PK, Davies JB, et al. Clinical features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol 2010;128: 853–858. 7. Yannuzzi LA, Shakin JL, Fisher YL, Altomonte MA. Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. Ophthalmology 1984;91:1554–1572. 8. Garg SP, Dada T, Talwar D, Biswas NR. Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol 1997;81:962–964. 9. Haimovici R, Rumelt S, Melby J. Endocrine abnormalities in patients with central serous chorioretinopathy. Ophthalmology 2003;110:698–703. 10. Tatro DS, ed. Drug Interaction Facts. 10th ed. St Louis, MO: Facts & Comparisons; 2010.
