Int Ophthalmol (2014) 34:1271–1274 DOI 10.1007/s10792-014-9921-0
CASE REPORT
Significant reduction of diabetic macular edema following intravitreal ranibizumab injection in the fellow eye Tryfon Rotsos • Chrysanthos Symeonidis • Ioanna Triantafillopoulou • Spyridon Kanellopoulos Anastasios Kouris
•
Received: 14 March 2013 / Accepted: 4 February 2014 / Published online: 6 September 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract A significant therapeutic effect in the fellow eye after intravitreal ranibizumab injections was observed in a 39-year-old diabetic male. The patient was followed-up with fluorescein angiography (FA) and Optical Coherence Tomography (OCT). On referral, best-corrected visual acuity (BCVA) was 6/60 in the right eye and Counting Fingers in the left eye. FA revealed foveal leakage in both eyes. OCT revealed diabetic and cystoid macular edema (DMECME) in both eyes. The patient was treated with two intravitreal ranibizumab injections in the left eye. BCVA was 6/15 and 6/30 one month after the last injection. OCT revealed significant improvement (DME elimination and significant CME improvement) in both eyes, despite the fact that only the left eye was treated. It is conceivable that, in this eye, chronic vascular damage was limited and a minimal quantity of ranibizumab had a positive effect on vascular permeability, resulting in DME resolution.
Introduction Diabetic macular edema (DME) is a complex multifactorial condition. The disruption of the blood-retinal barrier leads to abnormal fluid accumulation into the neurosensory retina that can exceed fluid outflow. These pathologic changes may cause residual fluid accumulation in the macular intraretinal layers [1]. Anti-vascular endothelial growth factor (antiVEGF) agents have been shown to be effective in a variety of retinal diseases. Among them, ranibizumab has been licensed for use in DME management. After intravitreal delivery, a proportion of the injected quantity enters the systemic circulation and an even smaller proportion reaches the fellow eye. We report a significant therapeutic effect in the fellow eye of a patient suffering from DME following intravitreal ranibizumab injections.
Case report
T. Rotsos I. Triantafillopoulou S. Kanellopoulos A. Kouris Department of Ophthalmology, General Hospital of Athens, Athens, Greece C. Symeonidis (&) 2nd Department of Ophthalmology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Macedonia, Greece e-mail: [email protected]
A 39 year-old male with blurred vision in both eyes was referred to our department. The patient was diagnosed with type 1 diabetes 12 years ago but was not on antidiabetic treatment on a regular basis. Additionally, he was diagnosed with systemic hypertension and had a significant smoking habit. Twelve months prior to referral, he was diagnosed with diabetic maculopathy in both eyes and argon laser photocoagulation was performed.
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remained unaltered despite physician recommendations. He reported significant visual improvement in both eyes 6 months after the second injection. BCVA and OCT findings remained unaltered and no further intravitreal anti-VEGF treatment was administered.
Discussion
Fig. 1 a Right eye FA at baseline visit, b right eye FA following two intravitreal ranibizumab injections
Baseline best-corrected visual acuity (BCVA) was 6/60 in the right eye and Counting Fingers in the left eye. Fundus examination revealed clinically significant macular edema (CSME) in both eyes. Fluorescein angiography (FA) revealed foveal leakage in both eyes (Fig. 1a). Spectral-domain optical coherence tomography (SD-OCT) confirmed the aforementioned findings and revealed DME and cystoid macular edema (CME) in both eyes (Fig. 2a, b). One intravitreal injection of 0.5 mg ranibizumab was administered in the left eye followed by one additional injection 1 month later. BCVA was 6/15 and 6/30 1 month after the last injection. SD-OCT scans revealed significant improvement (DME elimination and significant CME improvement) in both eyes, despite the fact that only the left eye was treated (Fig. 2c, d). FA revealed significant foveal leakage reduction in both eyes (Fig. 1b). The metabolic status of the patient (glucose levels, weight, hypertension, smoking habit)
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Relevant literature on the potential therapeutic effect of intravitreal ranibizumab in the fellow eye is limited and focusing mainly on exudative age-related macular degeneration (AMD). According to initial reports, ranibizumab was not detected in the serum or the untreated fellow eye in a rabbit model [2]. In transgenic mice, bevacizumab appeared to cause significant suppression of subretinal neovascularization in the fellow eye (an indication of a systemic effect), while there was no similar observation following the use of ranibizumab [3]. In humans, intravitreal bevacizumab injection may result in a significant VEGF level decrease in not only in the vitreous but in the aqueous of the fellow eye as well [4]. Moreover, intravitreally administered IgG antibodies were detected in the systemic circulation more rapidly in mouse eyes that had undergone laser photocoagulation compared to non-treated eyes [5]. Regarding ranibizumab pharmacodynamics in AMD patients, vitreous elimination half-life was determined to be 9 days and systemic elimination half-life was determined to be *2 h. After intravitreal administration, the observed serum half-life was *9 days while systemic-to-vitreous exposure ratio was estimated to be 1:90,000 [6]. In patients with exudative AMD, mean central retinal thickness in the untreated eye was reported to be increased after intravitreal ranibizumab treatment [7]. Consequently, a therapeutic effect of ranibizumab in the untreated fellow eye could not be demonstrated. Moreover, recent evidence suggests that monthly ranibizumab injections do not significantly reduce choroidal neovascularization development rate in untreated fellow eyes [8]. In addition to a therapeutic effect, a pathologic effect may also be observed in the fellow eye following an anti-VEGF injection. In a relevant case, moderate vitritis was observed in an eye treated with intravitreal bevacizumab for choroidal neovascularization secondary to anisometropic high myopia. This
Int Ophthalmol (2014) 34:1271–1274
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Fig. 2 a Right eye SD-OCT scan at baseline visit, depicting DME and CME, b left eye SD-OCT scan at baseline visit, depicting DME and CME. c Right eye SD-OCT scan 1 month following the second ranibizumab injection in the left eye,
depicting significant anatomic improvement, d left eye SD-OCT scan 1 month following the second ranibizumab injection in the left eye, depicting significant anatomic improvement
complication was treated successfully with a 40 mg sub-Tenon’s triamcinolone injection [9]. In this case, significant anatomic and visual improvement was observed in the fellow eye following ranibizumab injections in a patient with DME. This finding is open to interpretation. DME pathogenesis includes chronic hyperglycemia, along with the accumulation of free radicals, protein kinase C (PKC) formation, and consequently, the activation of vascular endothelial growth factors (especially VEGF-A) in addition to an increase in vascular permeability. Furthermore, ischemia in addition to the release and activation of inflammatory factors (e.g. interleukin-6) also increase VEGF-A synthesis. All the aforementioned factors contribute to DME pathogenesis. Moreover, previous laser photocoagulation in the treated eye may have further facilitated ranibizumab elimination in the systemic circulation thus increasing the possibility of a therapeutic effect in the untreated
fellow eye. It is conceivable that, in this eye, limited chronic vascular damage and a minimal ranibizumab quantity had a positive effect on vascular permeability resulting in DME resolution.
References 1. Romero-Aroca P (2010) Targeting the pathophysiology of diabetic macular edema. Diabetes Care 33:2484–2485 2. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ (2007) Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 114:2179–2182 3. Miki K, Miki A, Matsuoka M, Muramatsu D, Hackett SF, Campochiaro PA (2009) Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor. Ophthalmology 116:1748– 1754 4. Matsuyama K, Ogata N, Matsuoka M, Wada M, Nishimura T, Takahashi K (2011) Effects of intravitreally injected bevacizumab on vascular endothelial growth factor in fellow eyes. J Ocul Pharmacol Ther 27:379–383
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1274 5. Kim H, Robinson SB, Csaky KG (2009) FcRn receptormediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis 15:2803–2812 6. Xu L, Lu T, Tuomi L, Jumbe N, Lu J, Eppler S, Kuebler P, Damico-Beyer LA, Joshi A (2013) Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. Invest Ophthalmol Vis Sci 54:1616–1624 7. Gamulescu MA, Helbig H (2010) Lack of therapeutic effect of ranibizumab in fellow eyes after intravitreal administration. J Ocul Pharmacol Ther 26:213–216
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Int Ophthalmol (2014) 34:1271–1274 8. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB (2010) Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol 149:939–946 9. Neri P, Mariotti C, Mercanti L, Salvolini S, Giovannini A (2008) Vitritis in the contralateral uninjected eye following intravitreal bevacizumab (Avastin). Int Ophthalmol 28:425–427
CASE REPORT
Significant reduction of diabetic macular edema following intravitreal ranibizumab injection in the fellow eye Tryfon Rotsos • Chrysanthos Symeonidis • Ioanna Triantafillopoulou • Spyridon Kanellopoulos Anastasios Kouris
•
Received: 14 March 2013 / Accepted: 4 February 2014 / Published online: 6 September 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract A significant therapeutic effect in the fellow eye after intravitreal ranibizumab injections was observed in a 39-year-old diabetic male. The patient was followed-up with fluorescein angiography (FA) and Optical Coherence Tomography (OCT). On referral, best-corrected visual acuity (BCVA) was 6/60 in the right eye and Counting Fingers in the left eye. FA revealed foveal leakage in both eyes. OCT revealed diabetic and cystoid macular edema (DMECME) in both eyes. The patient was treated with two intravitreal ranibizumab injections in the left eye. BCVA was 6/15 and 6/30 one month after the last injection. OCT revealed significant improvement (DME elimination and significant CME improvement) in both eyes, despite the fact that only the left eye was treated. It is conceivable that, in this eye, chronic vascular damage was limited and a minimal quantity of ranibizumab had a positive effect on vascular permeability, resulting in DME resolution.
Introduction Diabetic macular edema (DME) is a complex multifactorial condition. The disruption of the blood-retinal barrier leads to abnormal fluid accumulation into the neurosensory retina that can exceed fluid outflow. These pathologic changes may cause residual fluid accumulation in the macular intraretinal layers [1]. Anti-vascular endothelial growth factor (antiVEGF) agents have been shown to be effective in a variety of retinal diseases. Among them, ranibizumab has been licensed for use in DME management. After intravitreal delivery, a proportion of the injected quantity enters the systemic circulation and an even smaller proportion reaches the fellow eye. We report a significant therapeutic effect in the fellow eye of a patient suffering from DME following intravitreal ranibizumab injections.
Case report
T. Rotsos I. Triantafillopoulou S. Kanellopoulos A. Kouris Department of Ophthalmology, General Hospital of Athens, Athens, Greece C. Symeonidis (&) 2nd Department of Ophthalmology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Macedonia, Greece e-mail: [email protected]
A 39 year-old male with blurred vision in both eyes was referred to our department. The patient was diagnosed with type 1 diabetes 12 years ago but was not on antidiabetic treatment on a regular basis. Additionally, he was diagnosed with systemic hypertension and had a significant smoking habit. Twelve months prior to referral, he was diagnosed with diabetic maculopathy in both eyes and argon laser photocoagulation was performed.
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Int Ophthalmol (2014) 34:1271–1274
remained unaltered despite physician recommendations. He reported significant visual improvement in both eyes 6 months after the second injection. BCVA and OCT findings remained unaltered and no further intravitreal anti-VEGF treatment was administered.
Discussion
Fig. 1 a Right eye FA at baseline visit, b right eye FA following two intravitreal ranibizumab injections
Baseline best-corrected visual acuity (BCVA) was 6/60 in the right eye and Counting Fingers in the left eye. Fundus examination revealed clinically significant macular edema (CSME) in both eyes. Fluorescein angiography (FA) revealed foveal leakage in both eyes (Fig. 1a). Spectral-domain optical coherence tomography (SD-OCT) confirmed the aforementioned findings and revealed DME and cystoid macular edema (CME) in both eyes (Fig. 2a, b). One intravitreal injection of 0.5 mg ranibizumab was administered in the left eye followed by one additional injection 1 month later. BCVA was 6/15 and 6/30 1 month after the last injection. SD-OCT scans revealed significant improvement (DME elimination and significant CME improvement) in both eyes, despite the fact that only the left eye was treated (Fig. 2c, d). FA revealed significant foveal leakage reduction in both eyes (Fig. 1b). The metabolic status of the patient (glucose levels, weight, hypertension, smoking habit)
123
Relevant literature on the potential therapeutic effect of intravitreal ranibizumab in the fellow eye is limited and focusing mainly on exudative age-related macular degeneration (AMD). According to initial reports, ranibizumab was not detected in the serum or the untreated fellow eye in a rabbit model [2]. In transgenic mice, bevacizumab appeared to cause significant suppression of subretinal neovascularization in the fellow eye (an indication of a systemic effect), while there was no similar observation following the use of ranibizumab [3]. In humans, intravitreal bevacizumab injection may result in a significant VEGF level decrease in not only in the vitreous but in the aqueous of the fellow eye as well [4]. Moreover, intravitreally administered IgG antibodies were detected in the systemic circulation more rapidly in mouse eyes that had undergone laser photocoagulation compared to non-treated eyes [5]. Regarding ranibizumab pharmacodynamics in AMD patients, vitreous elimination half-life was determined to be 9 days and systemic elimination half-life was determined to be *2 h. After intravitreal administration, the observed serum half-life was *9 days while systemic-to-vitreous exposure ratio was estimated to be 1:90,000 [6]. In patients with exudative AMD, mean central retinal thickness in the untreated eye was reported to be increased after intravitreal ranibizumab treatment [7]. Consequently, a therapeutic effect of ranibizumab in the untreated fellow eye could not be demonstrated. Moreover, recent evidence suggests that monthly ranibizumab injections do not significantly reduce choroidal neovascularization development rate in untreated fellow eyes [8]. In addition to a therapeutic effect, a pathologic effect may also be observed in the fellow eye following an anti-VEGF injection. In a relevant case, moderate vitritis was observed in an eye treated with intravitreal bevacizumab for choroidal neovascularization secondary to anisometropic high myopia. This
Int Ophthalmol (2014) 34:1271–1274
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Fig. 2 a Right eye SD-OCT scan at baseline visit, depicting DME and CME, b left eye SD-OCT scan at baseline visit, depicting DME and CME. c Right eye SD-OCT scan 1 month following the second ranibizumab injection in the left eye,
depicting significant anatomic improvement, d left eye SD-OCT scan 1 month following the second ranibizumab injection in the left eye, depicting significant anatomic improvement
complication was treated successfully with a 40 mg sub-Tenon’s triamcinolone injection [9]. In this case, significant anatomic and visual improvement was observed in the fellow eye following ranibizumab injections in a patient with DME. This finding is open to interpretation. DME pathogenesis includes chronic hyperglycemia, along with the accumulation of free radicals, protein kinase C (PKC) formation, and consequently, the activation of vascular endothelial growth factors (especially VEGF-A) in addition to an increase in vascular permeability. Furthermore, ischemia in addition to the release and activation of inflammatory factors (e.g. interleukin-6) also increase VEGF-A synthesis. All the aforementioned factors contribute to DME pathogenesis. Moreover, previous laser photocoagulation in the treated eye may have further facilitated ranibizumab elimination in the systemic circulation thus increasing the possibility of a therapeutic effect in the untreated
fellow eye. It is conceivable that, in this eye, limited chronic vascular damage and a minimal ranibizumab quantity had a positive effect on vascular permeability resulting in DME resolution.
References 1. Romero-Aroca P (2010) Targeting the pathophysiology of diabetic macular edema. Diabetes Care 33:2484–2485 2. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ (2007) Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 114:2179–2182 3. Miki K, Miki A, Matsuoka M, Muramatsu D, Hackett SF, Campochiaro PA (2009) Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor. Ophthalmology 116:1748– 1754 4. Matsuyama K, Ogata N, Matsuoka M, Wada M, Nishimura T, Takahashi K (2011) Effects of intravitreally injected bevacizumab on vascular endothelial growth factor in fellow eyes. J Ocul Pharmacol Ther 27:379–383
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1274 5. Kim H, Robinson SB, Csaky KG (2009) FcRn receptormediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis 15:2803–2812 6. Xu L, Lu T, Tuomi L, Jumbe N, Lu J, Eppler S, Kuebler P, Damico-Beyer LA, Joshi A (2013) Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. Invest Ophthalmol Vis Sci 54:1616–1624 7. Gamulescu MA, Helbig H (2010) Lack of therapeutic effect of ranibizumab in fellow eyes after intravitreal administration. J Ocul Pharmacol Ther 26:213–216
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Int Ophthalmol (2014) 34:1271–1274 8. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB (2010) Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol 149:939–946 9. Neri P, Mariotti C, Mercanti L, Salvolini S, Giovannini A (2008) Vitritis in the contralateral uninjected eye following intravitreal bevacizumab (Avastin). Int Ophthalmol 28:425–427
