FLECKED RETINA, CHOROIDOPATHY, AND RETINAL PIGMENT EPITHELIAL TEAR IN FAMILIAL PULMONARY ARTERIAL HYPERTENSION Sara Torfs, MD, Anita M. Leys, MD, PhD
Background: Thanks to advancement in treatment modalities, the medial survival rate of patients with familial pulmonary arterial hypertension (FPAH) has been improved. Unfortunately, ocular complications because of the chronically elevated systemic venous pressure become more frequent. Methods: The authors report new FPAH-associated fundus changes in a 50-year-old male patient treated with sildenafil. The anomalies were studied with autofluorescence, fluorescein and indocyanine green angiography, and spectral optical coherence tomography including enhanced depth imaging. Results: Loss of vision and cystoid macular edema were associated with a flecked retina, a thick choroid, central serous choroidopathy-like changes in both eyes and with retinal pigment epithelium detachments and a retinal pigment epithelium tear in the right eye. Conclusion: Treatment of ocular findings associated with FPAH mainly involves optimal control of pulmonary arterial hypertension and ophthalmic supportive treatment toward preventing acute ocular complications. The ocular complications occur as a result of enhanced pressure in the superior vena cava and in the ophthalmic veins, resulting in dilation of the ocular veins and congestion of the choroid. Sildenafil treatment in FPAH may enhance the congestion of the choroid and can induce central serous choroidopathy-like changes. A flecked retina, central serous choroidopathy-like changes, and retinal pigment epithelium tear are rare complications of FPAH. RETINAL CASES & BRIEF REPORTS 7:278–284, 2013
From the Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
exudative retinal detachment, macular edema, venous stasis retinopathy, central retinal vein occlusion, choroidal detachment, and delayed choroidal perfusion on fluorescein angiography (FA).1–7 We observed a flecked retina, a thick choroid, central serous choroidopathy (CSC)-like changes, and retinal pigment epithelium (RPE) tear in a sildenafil-treated patient with FPAH.
F
amilial pulmonary arterial hypertension (FPAH) segregates as an autosomal trait with markedly reduced penetrance. The increased pulmonary arterial resistance causes right ventricular failure, which leads to increased pressure in the superior vena cava and ophthalmic veins. Ocular associations that have been reported with FPAH include the following: chemosis, dilated episcleral and conjunctival veins, myopisation, exophthalmia, elevated intraocular pressure, uveal effusion syndrome with intermittent angle closure,
Case Report A 50-year-old man first noticed blurred vision in the right eye (RE) in March 2007 and consulted an ophthalmologist 9 months later because of deterioration. A flecked retina was observed in the RE, and the patient was referred for investigation. Familial pulmonary arterial hypertension with autosomal dominant inheritance of BMPRII mutation had been diagnosed in his family, including his mother, the sister of his mother and her daughter, the patient himself, and his daughter. The patient was heterozygous for
Neither author has any financial/conflicting interests to disclose. Reprint requests: Anita M. Leys, MD, PhD, Department of Ophthalmology, University Hospitals Leuven, Sint Rafaelsziekenhuis 33, 3000 Leuven, Belgium; e-mail: [email protected]
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Fig. 1. The red-free photograph of the posterior pole of the RE at first presentation shows an abnormal fovea and scattered flecks, nasal of the disk, inferior to the papillomacular area, and temporal to the macula.
the C.631C.T or p.ARG211x mutation in exon 6 of the BMPRII gene. His daughter was diagnosed with primary pulmonary hypertension (PPH) in 2003. At that time, her father had no complaints, and screening tests for PPH were normal, including clinical examination, chest radiography, echocardiography, and pulmonary function test. However, in 2006, he had first symptoms of PPH with increasing dyspnea during exercise. The pulmonary function test and echocardiography were abnormal and right heart catheterization
279 confirmed severe PPH, which was not reversible with nitric oxide. Ventilation/perfusion lung scintigraphy showed no evidence of thromboembolic primary hypertension. At presentation for ocular examination, in January 2008, his medical therapy for PPH included sildenafil 3 · 80 mg/day, bosentan 2 · 125 mg/day, bumetanide 1 · 1 mg/day, and fenprocoumon 4.5 to 6 mg/day. The best-corrected visual acuity was 20/25 in the RE (mean refractive error (MRE) −0.75 diopters (D) and 20/20 in the left eye (LE) (MRE −0:25D). Amsler grid testing of the RE showed metamorphopsia. Biomicroscopy of the anterior segment was normal and ocular pressure was 14 mmHg in both eyes. In both eyes, mild retinal venous dilation was noticed without hemorrhages. A flecked retina was observed in the RE with subtle yellow subretinal flecks temporal of the macula, subfoveal, in the papillomacular region, and nasal of the optic disk (Figure 1). Spectral domain optical coherence tomography (SDOCT) with the Cirrus HD-OCT instrument (Carl Zeiss Meditec, Dublin, CA) showed no macular edema but confirmed in the RE a foveal abnormality with deep hyperreflectivity and suspicion of subfoveal fluid (Figure 2). In the papillomacular region, a small serous pigment epithelium detachment (PED) was noted. This PED was also noted on the FA, and temporal of the macula subtle focal subretinal leakage was observed (Figure 3, A–D). The fovea was normal on FA, and at this time, there was no cystoid macular edema. Moreover, delayed retinal perfusion and late patchy choroidal perfusion were noted in the RE. Based on these findings, we made the tentative diagnosis of venous stasis retinopathy and choroidopathy with CSC-like abnormalities as a result of PPH and triggered by sildenafil.8–10 Close follow-up of the PPH and of ocular complications was advised. Despite intense treatment of the PPH, dyspnea increased, and treprostinil 50 ng/kg subcutaneously was added to the existing treatment in July 2008, and with increasing dosage, the PPH stabilized for 2 years. In September
Fig. 2. A small serous PED is observed on spectral OCT, and the fovea is abnormal with deep hyperreflectivity and suspicion of subretinal fluid.
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Fig. 3. The FA shows at 16$ (A) and 22$(B) delayed perfusion and slow flow in retinal and choroidal vessels. At 39 (C) and 109 (D), the small serous PED is noted inferior to the disk margin, as well as scattered mild RPE window defects of RPE, and a focal subretinal leakage point temporal of the macula.
2010, the patient had more complaints of dyspnea, and loss of vision in the RE was noticed. Pulmonary pressure measured with right heart catheterization showed high pulmonary pressure, and for this reason, the patient underwent an atrial septostomy with subsequent improvement of the general condition but not of vision. In December 2010, best-corrected visual acuity was 20/63 in the RE and 20/20 in the LE. Prominent dilated episcleral and conjunctival vessels were noted in the RE without signs of rubeosis
iris or iridocorneal angle (Figure 4). The intraocular pressure was 18 mmHg in the RE and 12 mmHg in the LE. Fundus examination revealed in the RE more flecks than previously (Figure 5A), and autofluorescence showed marked autohyperfluorescence of these flecks (Figure 5B). Moreover, marked cystoid macular edema (central macular thickness [CMT], 500 mm) and a large subfoveal PED (thickness, 170 mm) were noted clinically and on OCT (Figure 5E), and a choroidal detachment and PED were observed in
281
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gressive loss of vision occurred. Bevacizumab was injected in October 2012, but this treatment could not prevent further deterioration. In January 2013 the patient complained of visual loss of the LE. Visual acuity was 20/125 in the RE and 20/20 in the LE. We noted in the left eye a subfoveal yellow spot and papillomacular flecks and OCT showed small serous detachments of RPE, similar to the findings observed in the right eye in 2008. The fluorescein angiography showed delayed and slow perfusion of the retinal and choroidal vessels in the LE and mild leakage in the areas with flecks, also similar to the changes observed in the RE in 2008. In the RE we noted pronounced macular edema, several small serous PED and a large PED in the upper temporal periphery. Central choroidal thickness was 500 micron OU. In March 2013 the patient received a pulmonary transplant with the aim to correct the primary dysfunction and to reduce the complications. Fig. 4. Three years later, prominent dilated episcleral and conjunctival vessels are noted in the RE without signs of rubeosis iridis
the temporal midperiphery. Ultrasound examination confirmed the choroidal detachment and PED in the RE. The axial length of both eyes was 25 mm. Fluorescein and indocyanine green angiography showed unilateral deep lesions according to the flecks. These flecks were hyperfluorescent on FA and were more prominent on FA than on indocyanine green angiography, with window defects and staining of fluorescein, and FA also showed macular leakage with pronounced cystoid macular edema (Figure 5C), deep masking in the area of the choroidal detachment, and pooling of dye under the PED (Figure 5D). Indocyanine green angiography showed dilated choroidal veins in both eyes, and yellow flecks are hypofluorescent on indocyanine green angiography. Eyedrops with dorzolamide 2% were administered 3 times a day in the RE. One month later, vision was improved, the subfoveal PED and cystoid macular edema were reduced (CMT, 380 mm), and the choroidal detachment was resolved. Another 2 months later, a RPE tear was detected at the site of the flattened choroidal detachment and confirmed with FA (Figure 6A). The choroidal detachment and RPE tear did not involve the macula and did not cause additional visual loss. Central macular thickness was 403 mm in the RE and 134 mm in the LE, and enhanced depth imaging of the choroid showed a thick choroid especially in the RE with subfoveal choroidal thickness (SCT) of 522 mm and 435 mm in the LE (Figure 6, B and C). Another 2 months later, SCT was unchanged (522 mm), and the maculopathy and PED were more pronounced in the RE (CMT, 432 mm; PED, 300 mm) and had increased despite continued treatment with dorzolamide eyedrops 3 times a day. At that time, 0.5 mg of ranibizumab was injected in the vitreous of the RE with the aim to reduce macular edema. On the next control examination, 2 months later, macular edema, PED and central choroidal thickness were less prominent (CMT, 382 mm; PED elevation, 190 mm; SCT, 480 mm). At the end of the consult, 1.25 mg of bevacizumab was injected in the vitreous of the RE. The next ocular examination was performed 3 months later, and there were no visual and no major macular changes in the RE (CMT, 377 mm; PED, 274 mm; SCT, 413 mm). A trial of acetazolamide was considered hoping to reduce the macular edema, and in agreement with the pulmonary hypertension treating team, peroral acetazolamide 250 mg was instituted, in addition to the already extensive medication including the diuretic bumetanide. Ten days later, OCT showed a normal macula in the RE, symmetric to the left macula, with total regression of the macular edema. Vision of the RE improved from 20/100 to 20/67, and the macula remained normal for another 8 months (Figure 7). At no time steroids were administered, acetazolamide was continued as well as sildenafil and all other medications used since 2008. In August 2012 macular edema recurred in the RE despite extensive medication and pro-
Discussion Familial pulmonary arterial hypertension is a rare disease. Thanks to advancement in treatment modalities, the medial survival rate of these patients is improving. They are surviving despite increased pulmonary arterial resistance, and right ventricular failure and elevated systemic venous pressure. However, they are at risk of complications including ocular complications caused by increased pressure in the superior vena cava and in the ophthalmic veins. Familial pulmonary arterial hypertension–associated ocular complications include chemosis, dilated episcleral and conjunctival veins, myopisation, exophthalmia, elevated intraocular pressure, uveal effusion syndrome with intermittent angle closure, exudative retinal detachment, macular edema, venous stasis retinopathy, central retinal vein occlusion, choroidal detachment, and delayed choroidal perfusion on FA.1–7 Increased hydrostatic pressure in choroid and choriocapillaris can result in choroidal detachment and CSC-like changes with inability of the RPE to pump out excessive fluid. Our patient had unilateral FPAH-associated ocular complications since March 2007 with visual loss, choroidopathy with thick choroid, choroidal detachment, and CSC-like changes with flecked retina and cystoid edema. Mild retinal venous dilation and slow flow in retina vessels was bilateral and did not change during the nearly 5-year follow-up. Although the posterior pole changes remained subtle in the LE, when last examined, conjunctival and scleral dilation of vessels had become prominent in the LE, as a first sign of progressive PHTassociated ocular involvement. Asymmetry of the ocular lesions as observed in our patient has been reported in patients with PHT.1,3,7 Factors that can contribute to the asymmetric ocular manifestations of PAHT are asymmetric arterial perfusion of the eyes, asymmetric intraocular pressure, and different axial length. The retinal yellow flecks, observed in our patient, were subtle at first examination and they corresponded to small RPE
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Fig. 5. Fundus examination reveals numerous flecks (A), and autofluorescence shows autohyperfluorescence of these flecks (B). Fluorescein angiography shows marked cystoid macular edema, leakage and staining of the flecks (C), and masking of the choroidal detachment and pooling under the PED (D). Optical coherence tomography HRA Spectralis shows cystoid macular edema with large cysts and a submacular PED (E).
detachments and irregularities identified on OCT images and FA. Over time the yellow flecks became prominent and numerous with well-defined window defects and staining on FA, and hypofluorescence of these lesions on ICGA. The flecks resolved completely and without scar formation after the administration of acetazolamide. As the flecks resolved, we believe that they corresponded to deposits probably of proteins derived from leaking choroidal vessels. As we did not perform a follow-up
fluorescein angiogram, we cannot exclude mild permanent damage of RPE. The treatment of PAHT-associated ocular complications mainly involves optimal control of pulmonary arterial hypertension and includes calcium channel blockers, oxygen, diuretics, digoxin, vasodilators, and anticoagulation. Sildenafil, a selective inhibitor of phosphodiesterase type-5 (PDE-5), is a frequently used drug to control FPAH when there is no response to an acute
FAMILIAL PULMONARY ARTERIAL HYPERTENSION
283
Fig. 6. Three months later, a RPE tear is detected and confirmed with FA (A). Central macular thickness was 403 mm in the RE and 134 mm in the LE, and enhanced depth imaging of the choroid showed a thick choroid especially in the RE with SCT of 522 mm and 435 mm in the LE (B and C).
vasodilator. PDE-5 is an isoenzyme found in higher concentrations in specific tissues, including the corpus cavernosus and the lungs. Sildenafil use results in an augmentation of the NO-cGMP pathway that mediates smooth muscle relaxation in the lung and corpus cavernosum. There is also evidence of sildenafil-increased choroidal blood flow and choroidal thickness.9 Increased choroidal thickness is a risk factor for CSC. Central serous choroidopathy associated with sildenafil has been reported, and resolution of the serous macular detachment has been observed in several patients after discontinuation of sildenafil.8,10 In our patient, enhancement of the PAHT-associated choroidopathy and CSC-like changes
may have occurred as a result of sildenafil, but there is no proof as the drug was administered without interruption. Ophthalmic supportive treatment toward preventing ocular complications includes dorzolamide eyedrops, anti–vascular endothelial growth factor intravitreal injections,6 and acetazolamide1,2,6 and was used in our patient. We first used topical dorzolamide in the RE with the aim to reduce macular edema and to flatten the choroidal detachment. Apparently, there was an initial response, but follow-up was indicative of chronic macular edema. A ranibizumab and a bevacizumab injection appeared helpful to some extent to reduce the macular edema. The edema resolved
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References
Fig. 7. After administration of acetazolamide, vision improved and stabilized, macular edema resolved completely, and flecks faded.
completely after administration of acetazolamide, with stabilization of vision. Optical coherence tomography and enhanced depth imaging OCT appear most useful in the follow-up of macular edema and choroidopathy. Key words: central serous choroidopathy-like changes, choroidal detachment, enhanced depth imaging OCT, familial pulmonary arterial hypertension, flecked retina, macular edema, retinal pigment epithelial tear, sildenafil, acetazolamide, thick choroid, venous stasis retinopathy.
1. Gíslason I, Jónasson F, Stefánsson E. Exudative retinal detachment in familial pulmonary hypertension. Acta Ophthalmol (Copenh) 1991;69:805–809. 2. Hammond CJ, Chauhan DS, Stanford MS. Pulmonary hypertension and diffuse macular edema responsive to acetazolamide. Arch Ophthalmol 1998;116:1535–1536. 3. Saran BR, Brucker AJ, Bandello F, Verougstraete C. Familial primary pulmonary hypertension and associated ocular findings. Retina 2001;21:34–39. 4. Krohn J, Bjune C. Uveal effusion and angle-closure glaucoma in primary pulmonary hypertension. Am J Ophthalmol 2003; 135:705–706. 5. Paire V, Weber M, Salama B. Hypertension artérielle pulmonaire primitive familiale révélée par l’association bilatérale chémosis, myopisation et exophtalmie. J Fr Ophtalmol 2006;29:10.e27. 6. Senthil S, Kaur B, Jalali S, Garudadri C. Secondary open-angle glaucoma and central retinal vein occlusion in a patient with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2009;40:50–53. 7. Yang S, Jeong J, Kim JG, Yoon YH. Progressive venous stasis retinopathy and open-angle glaucoma associated with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2006;37:230–233. 8. Fraunfelder FW, Fraunfeldzer FT. Central serous choroidopathy associated with sildenafil. Retina 2008;28:606–609. 9. Vance SK, Imamura Y, Freund KB. The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. Retina 2011; 31:332–335. Comments and author reply. Retina 2011; 1742–1743. 10. Quiram P, Dumars S, Parwar B, Sarraf D. Viagra-associated serous macular detachment. Graefes Arch Clin Exp Ophthalmol 2005;243:339–344.
Background: Thanks to advancement in treatment modalities, the medial survival rate of patients with familial pulmonary arterial hypertension (FPAH) has been improved. Unfortunately, ocular complications because of the chronically elevated systemic venous pressure become more frequent. Methods: The authors report new FPAH-associated fundus changes in a 50-year-old male patient treated with sildenafil. The anomalies were studied with autofluorescence, fluorescein and indocyanine green angiography, and spectral optical coherence tomography including enhanced depth imaging. Results: Loss of vision and cystoid macular edema were associated with a flecked retina, a thick choroid, central serous choroidopathy-like changes in both eyes and with retinal pigment epithelium detachments and a retinal pigment epithelium tear in the right eye. Conclusion: Treatment of ocular findings associated with FPAH mainly involves optimal control of pulmonary arterial hypertension and ophthalmic supportive treatment toward preventing acute ocular complications. The ocular complications occur as a result of enhanced pressure in the superior vena cava and in the ophthalmic veins, resulting in dilation of the ocular veins and congestion of the choroid. Sildenafil treatment in FPAH may enhance the congestion of the choroid and can induce central serous choroidopathy-like changes. A flecked retina, central serous choroidopathy-like changes, and retinal pigment epithelium tear are rare complications of FPAH. RETINAL CASES & BRIEF REPORTS 7:278–284, 2013
From the Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
exudative retinal detachment, macular edema, venous stasis retinopathy, central retinal vein occlusion, choroidal detachment, and delayed choroidal perfusion on fluorescein angiography (FA).1–7 We observed a flecked retina, a thick choroid, central serous choroidopathy (CSC)-like changes, and retinal pigment epithelium (RPE) tear in a sildenafil-treated patient with FPAH.
F
amilial pulmonary arterial hypertension (FPAH) segregates as an autosomal trait with markedly reduced penetrance. The increased pulmonary arterial resistance causes right ventricular failure, which leads to increased pressure in the superior vena cava and ophthalmic veins. Ocular associations that have been reported with FPAH include the following: chemosis, dilated episcleral and conjunctival veins, myopisation, exophthalmia, elevated intraocular pressure, uveal effusion syndrome with intermittent angle closure,
Case Report A 50-year-old man first noticed blurred vision in the right eye (RE) in March 2007 and consulted an ophthalmologist 9 months later because of deterioration. A flecked retina was observed in the RE, and the patient was referred for investigation. Familial pulmonary arterial hypertension with autosomal dominant inheritance of BMPRII mutation had been diagnosed in his family, including his mother, the sister of his mother and her daughter, the patient himself, and his daughter. The patient was heterozygous for
Neither author has any financial/conflicting interests to disclose. Reprint requests: Anita M. Leys, MD, PhD, Department of Ophthalmology, University Hospitals Leuven, Sint Rafaelsziekenhuis 33, 3000 Leuven, Belgium; e-mail: [email protected]
278
FAMILIAL PULMONARY ARTERIAL HYPERTENSION
Fig. 1. The red-free photograph of the posterior pole of the RE at first presentation shows an abnormal fovea and scattered flecks, nasal of the disk, inferior to the papillomacular area, and temporal to the macula.
the C.631C.T or p.ARG211x mutation in exon 6 of the BMPRII gene. His daughter was diagnosed with primary pulmonary hypertension (PPH) in 2003. At that time, her father had no complaints, and screening tests for PPH were normal, including clinical examination, chest radiography, echocardiography, and pulmonary function test. However, in 2006, he had first symptoms of PPH with increasing dyspnea during exercise. The pulmonary function test and echocardiography were abnormal and right heart catheterization
279 confirmed severe PPH, which was not reversible with nitric oxide. Ventilation/perfusion lung scintigraphy showed no evidence of thromboembolic primary hypertension. At presentation for ocular examination, in January 2008, his medical therapy for PPH included sildenafil 3 · 80 mg/day, bosentan 2 · 125 mg/day, bumetanide 1 · 1 mg/day, and fenprocoumon 4.5 to 6 mg/day. The best-corrected visual acuity was 20/25 in the RE (mean refractive error (MRE) −0.75 diopters (D) and 20/20 in the left eye (LE) (MRE −0:25D). Amsler grid testing of the RE showed metamorphopsia. Biomicroscopy of the anterior segment was normal and ocular pressure was 14 mmHg in both eyes. In both eyes, mild retinal venous dilation was noticed without hemorrhages. A flecked retina was observed in the RE with subtle yellow subretinal flecks temporal of the macula, subfoveal, in the papillomacular region, and nasal of the optic disk (Figure 1). Spectral domain optical coherence tomography (SDOCT) with the Cirrus HD-OCT instrument (Carl Zeiss Meditec, Dublin, CA) showed no macular edema but confirmed in the RE a foveal abnormality with deep hyperreflectivity and suspicion of subfoveal fluid (Figure 2). In the papillomacular region, a small serous pigment epithelium detachment (PED) was noted. This PED was also noted on the FA, and temporal of the macula subtle focal subretinal leakage was observed (Figure 3, A–D). The fovea was normal on FA, and at this time, there was no cystoid macular edema. Moreover, delayed retinal perfusion and late patchy choroidal perfusion were noted in the RE. Based on these findings, we made the tentative diagnosis of venous stasis retinopathy and choroidopathy with CSC-like abnormalities as a result of PPH and triggered by sildenafil.8–10 Close follow-up of the PPH and of ocular complications was advised. Despite intense treatment of the PPH, dyspnea increased, and treprostinil 50 ng/kg subcutaneously was added to the existing treatment in July 2008, and with increasing dosage, the PPH stabilized for 2 years. In September
Fig. 2. A small serous PED is observed on spectral OCT, and the fovea is abnormal with deep hyperreflectivity and suspicion of subretinal fluid.
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Fig. 3. The FA shows at 16$ (A) and 22$(B) delayed perfusion and slow flow in retinal and choroidal vessels. At 39 (C) and 109 (D), the small serous PED is noted inferior to the disk margin, as well as scattered mild RPE window defects of RPE, and a focal subretinal leakage point temporal of the macula.
2010, the patient had more complaints of dyspnea, and loss of vision in the RE was noticed. Pulmonary pressure measured with right heart catheterization showed high pulmonary pressure, and for this reason, the patient underwent an atrial septostomy with subsequent improvement of the general condition but not of vision. In December 2010, best-corrected visual acuity was 20/63 in the RE and 20/20 in the LE. Prominent dilated episcleral and conjunctival vessels were noted in the RE without signs of rubeosis
iris or iridocorneal angle (Figure 4). The intraocular pressure was 18 mmHg in the RE and 12 mmHg in the LE. Fundus examination revealed in the RE more flecks than previously (Figure 5A), and autofluorescence showed marked autohyperfluorescence of these flecks (Figure 5B). Moreover, marked cystoid macular edema (central macular thickness [CMT], 500 mm) and a large subfoveal PED (thickness, 170 mm) were noted clinically and on OCT (Figure 5E), and a choroidal detachment and PED were observed in
281
FAMILIAL PULMONARY ARTERIAL HYPERTENSION
gressive loss of vision occurred. Bevacizumab was injected in October 2012, but this treatment could not prevent further deterioration. In January 2013 the patient complained of visual loss of the LE. Visual acuity was 20/125 in the RE and 20/20 in the LE. We noted in the left eye a subfoveal yellow spot and papillomacular flecks and OCT showed small serous detachments of RPE, similar to the findings observed in the right eye in 2008. The fluorescein angiography showed delayed and slow perfusion of the retinal and choroidal vessels in the LE and mild leakage in the areas with flecks, also similar to the changes observed in the RE in 2008. In the RE we noted pronounced macular edema, several small serous PED and a large PED in the upper temporal periphery. Central choroidal thickness was 500 micron OU. In March 2013 the patient received a pulmonary transplant with the aim to correct the primary dysfunction and to reduce the complications. Fig. 4. Three years later, prominent dilated episcleral and conjunctival vessels are noted in the RE without signs of rubeosis iridis
the temporal midperiphery. Ultrasound examination confirmed the choroidal detachment and PED in the RE. The axial length of both eyes was 25 mm. Fluorescein and indocyanine green angiography showed unilateral deep lesions according to the flecks. These flecks were hyperfluorescent on FA and were more prominent on FA than on indocyanine green angiography, with window defects and staining of fluorescein, and FA also showed macular leakage with pronounced cystoid macular edema (Figure 5C), deep masking in the area of the choroidal detachment, and pooling of dye under the PED (Figure 5D). Indocyanine green angiography showed dilated choroidal veins in both eyes, and yellow flecks are hypofluorescent on indocyanine green angiography. Eyedrops with dorzolamide 2% were administered 3 times a day in the RE. One month later, vision was improved, the subfoveal PED and cystoid macular edema were reduced (CMT, 380 mm), and the choroidal detachment was resolved. Another 2 months later, a RPE tear was detected at the site of the flattened choroidal detachment and confirmed with FA (Figure 6A). The choroidal detachment and RPE tear did not involve the macula and did not cause additional visual loss. Central macular thickness was 403 mm in the RE and 134 mm in the LE, and enhanced depth imaging of the choroid showed a thick choroid especially in the RE with subfoveal choroidal thickness (SCT) of 522 mm and 435 mm in the LE (Figure 6, B and C). Another 2 months later, SCT was unchanged (522 mm), and the maculopathy and PED were more pronounced in the RE (CMT, 432 mm; PED, 300 mm) and had increased despite continued treatment with dorzolamide eyedrops 3 times a day. At that time, 0.5 mg of ranibizumab was injected in the vitreous of the RE with the aim to reduce macular edema. On the next control examination, 2 months later, macular edema, PED and central choroidal thickness were less prominent (CMT, 382 mm; PED elevation, 190 mm; SCT, 480 mm). At the end of the consult, 1.25 mg of bevacizumab was injected in the vitreous of the RE. The next ocular examination was performed 3 months later, and there were no visual and no major macular changes in the RE (CMT, 377 mm; PED, 274 mm; SCT, 413 mm). A trial of acetazolamide was considered hoping to reduce the macular edema, and in agreement with the pulmonary hypertension treating team, peroral acetazolamide 250 mg was instituted, in addition to the already extensive medication including the diuretic bumetanide. Ten days later, OCT showed a normal macula in the RE, symmetric to the left macula, with total regression of the macular edema. Vision of the RE improved from 20/100 to 20/67, and the macula remained normal for another 8 months (Figure 7). At no time steroids were administered, acetazolamide was continued as well as sildenafil and all other medications used since 2008. In August 2012 macular edema recurred in the RE despite extensive medication and pro-
Discussion Familial pulmonary arterial hypertension is a rare disease. Thanks to advancement in treatment modalities, the medial survival rate of these patients is improving. They are surviving despite increased pulmonary arterial resistance, and right ventricular failure and elevated systemic venous pressure. However, they are at risk of complications including ocular complications caused by increased pressure in the superior vena cava and in the ophthalmic veins. Familial pulmonary arterial hypertension–associated ocular complications include chemosis, dilated episcleral and conjunctival veins, myopisation, exophthalmia, elevated intraocular pressure, uveal effusion syndrome with intermittent angle closure, exudative retinal detachment, macular edema, venous stasis retinopathy, central retinal vein occlusion, choroidal detachment, and delayed choroidal perfusion on FA.1–7 Increased hydrostatic pressure in choroid and choriocapillaris can result in choroidal detachment and CSC-like changes with inability of the RPE to pump out excessive fluid. Our patient had unilateral FPAH-associated ocular complications since March 2007 with visual loss, choroidopathy with thick choroid, choroidal detachment, and CSC-like changes with flecked retina and cystoid edema. Mild retinal venous dilation and slow flow in retina vessels was bilateral and did not change during the nearly 5-year follow-up. Although the posterior pole changes remained subtle in the LE, when last examined, conjunctival and scleral dilation of vessels had become prominent in the LE, as a first sign of progressive PHTassociated ocular involvement. Asymmetry of the ocular lesions as observed in our patient has been reported in patients with PHT.1,3,7 Factors that can contribute to the asymmetric ocular manifestations of PAHT are asymmetric arterial perfusion of the eyes, asymmetric intraocular pressure, and different axial length. The retinal yellow flecks, observed in our patient, were subtle at first examination and they corresponded to small RPE
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Fig. 5. Fundus examination reveals numerous flecks (A), and autofluorescence shows autohyperfluorescence of these flecks (B). Fluorescein angiography shows marked cystoid macular edema, leakage and staining of the flecks (C), and masking of the choroidal detachment and pooling under the PED (D). Optical coherence tomography HRA Spectralis shows cystoid macular edema with large cysts and a submacular PED (E).
detachments and irregularities identified on OCT images and FA. Over time the yellow flecks became prominent and numerous with well-defined window defects and staining on FA, and hypofluorescence of these lesions on ICGA. The flecks resolved completely and without scar formation after the administration of acetazolamide. As the flecks resolved, we believe that they corresponded to deposits probably of proteins derived from leaking choroidal vessels. As we did not perform a follow-up
fluorescein angiogram, we cannot exclude mild permanent damage of RPE. The treatment of PAHT-associated ocular complications mainly involves optimal control of pulmonary arterial hypertension and includes calcium channel blockers, oxygen, diuretics, digoxin, vasodilators, and anticoagulation. Sildenafil, a selective inhibitor of phosphodiesterase type-5 (PDE-5), is a frequently used drug to control FPAH when there is no response to an acute
FAMILIAL PULMONARY ARTERIAL HYPERTENSION
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Fig. 6. Three months later, a RPE tear is detected and confirmed with FA (A). Central macular thickness was 403 mm in the RE and 134 mm in the LE, and enhanced depth imaging of the choroid showed a thick choroid especially in the RE with SCT of 522 mm and 435 mm in the LE (B and C).
vasodilator. PDE-5 is an isoenzyme found in higher concentrations in specific tissues, including the corpus cavernosus and the lungs. Sildenafil use results in an augmentation of the NO-cGMP pathway that mediates smooth muscle relaxation in the lung and corpus cavernosum. There is also evidence of sildenafil-increased choroidal blood flow and choroidal thickness.9 Increased choroidal thickness is a risk factor for CSC. Central serous choroidopathy associated with sildenafil has been reported, and resolution of the serous macular detachment has been observed in several patients after discontinuation of sildenafil.8,10 In our patient, enhancement of the PAHT-associated choroidopathy and CSC-like changes
may have occurred as a result of sildenafil, but there is no proof as the drug was administered without interruption. Ophthalmic supportive treatment toward preventing ocular complications includes dorzolamide eyedrops, anti–vascular endothelial growth factor intravitreal injections,6 and acetazolamide1,2,6 and was used in our patient. We first used topical dorzolamide in the RE with the aim to reduce macular edema and to flatten the choroidal detachment. Apparently, there was an initial response, but follow-up was indicative of chronic macular edema. A ranibizumab and a bevacizumab injection appeared helpful to some extent to reduce the macular edema. The edema resolved
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References
Fig. 7. After administration of acetazolamide, vision improved and stabilized, macular edema resolved completely, and flecks faded.
completely after administration of acetazolamide, with stabilization of vision. Optical coherence tomography and enhanced depth imaging OCT appear most useful in the follow-up of macular edema and choroidopathy. Key words: central serous choroidopathy-like changes, choroidal detachment, enhanced depth imaging OCT, familial pulmonary arterial hypertension, flecked retina, macular edema, retinal pigment epithelial tear, sildenafil, acetazolamide, thick choroid, venous stasis retinopathy.
1. Gíslason I, Jónasson F, Stefánsson E. Exudative retinal detachment in familial pulmonary hypertension. Acta Ophthalmol (Copenh) 1991;69:805–809. 2. Hammond CJ, Chauhan DS, Stanford MS. Pulmonary hypertension and diffuse macular edema responsive to acetazolamide. Arch Ophthalmol 1998;116:1535–1536. 3. Saran BR, Brucker AJ, Bandello F, Verougstraete C. Familial primary pulmonary hypertension and associated ocular findings. Retina 2001;21:34–39. 4. Krohn J, Bjune C. Uveal effusion and angle-closure glaucoma in primary pulmonary hypertension. Am J Ophthalmol 2003; 135:705–706. 5. Paire V, Weber M, Salama B. Hypertension artérielle pulmonaire primitive familiale révélée par l’association bilatérale chémosis, myopisation et exophtalmie. J Fr Ophtalmol 2006;29:10.e27. 6. Senthil S, Kaur B, Jalali S, Garudadri C. Secondary open-angle glaucoma and central retinal vein occlusion in a patient with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2009;40:50–53. 7. Yang S, Jeong J, Kim JG, Yoon YH. Progressive venous stasis retinopathy and open-angle glaucoma associated with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2006;37:230–233. 8. Fraunfelder FW, Fraunfeldzer FT. Central serous choroidopathy associated with sildenafil. Retina 2008;28:606–609. 9. Vance SK, Imamura Y, Freund KB. The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. Retina 2011; 31:332–335. Comments and author reply. Retina 2011; 1742–1743. 10. Quiram P, Dumars S, Parwar B, Sarraf D. Viagra-associated serous macular detachment. Graefes Arch Clin Exp Ophthalmol 2005;243:339–344.
