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Blue Toe Syndrome as a Complication of Intra-arterial Chemotherapy for Retinoblastoma

Blue Toe Syndrome as a Complication of Intra-arterial Chemotherapy for Retinoblastoma Intra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has become popular recently. Several studies demonstrated its effectiveness in the treatment of advanced intraocular Rb.1-4 However, it is not free of complications, and severe ocular vascular adverse effects including ophthalmic artery stenosis and retinal arteriolar embolizations were reported.1,2 The only reported systemic vascular complication, femoral artery occlusion, was transient (1 week) and resolved with aspirin treatment.4 Herein, we report another extraocular vascular complication, blue toe syndrome,5 following IAC for Rb with melphalan. Report of a Case A 7-month-old boy was referred for leukokoria in his left eye. Anterior segment examination findings were unremarkable. Funduscopy revealed a 12 × 10 × 6-mm macular retinoblastoma, which was diagnosed as unilateral sporadic group C Rb according to international classification of Rb. After discussion of all possible treatment options with the patient's parents, we decided to apply IAC. Institutional board review approval was obtained. The patient underwent 3 cycles of uneventful IAC with 3 mg of melphalan each time. The IAC was performed in the same manner by the same experienced interventional radiologist. After the parents gave written consent, the IAC catheterization procedures were performed under general anesthesia. We used catheterization techniques as described previously.3 In brief, Doppler ultrasonography was used to detect the femoral artery localization. Systemic anticoagulation with heparin sodium (75 IU/kg) was carried out intravenously. A 4F 45-cm introducer sheath was introduced into the left femoral artery and guided into the ipsilateral internal carotid artery using fluoroscopic guidance. A coaxial flow-guided Prowler 10 microcatheter was advanced toward the trunk of the ophthalmic artery and positioned at its ostium. After fluoroscopic confirmation of accurate positioning of the microcatheter, 3 mg of melphalan diluted in 30 mL of saline was delivered over 30 minutes with a flow-control injector pump. Once the infusion was complete, a final carotid angiogram was obtained to confirm the absence of any ocular or cerebral complications before removing the catheters. Hemostasis was achieved by initial manual compression of the femoral artery for 15 minutes, followed by use of a compression bandage for 1 day. The child was awakened and observed for 4 hours, then discharged the same day with no medication. The day after the third IAC, the patient returned with a blue, painful, tender left toe (Figure 1). Color Doppler ultrasonography findings of the lower limb were unremarkable, distal arteries up to the ankle were patent, and no major arterial occlusion was observed. There were no ocular vascular complications, and the tumor height decreased to 2.5 mm with type 3 regression. After consultations with the pediatric hematology and cardiovascular surgery departments, the patient was diagnosed as having blue toe syndrome and therapy with a parenteral anticoagulant (low-molecular-weight heparin sodium, 1000 IU/d) was initiated with concomitant oral aspirin, 40 mg/d. After 10 days, the blue appearance of the toe had totally disappeared (Figure 2). View LargeDownload Figure 1. Blue toe syndrome. The picture was taken the day after the third cycle of intra-arterial chemotherapy. The left toe was cyanotic and there was tenderness, which was consistent with blue toe syndrome. View LargeDownload Figure 2. Resolution of blue toe syndrome. There was no cyanosis or tenderness 10 days after beginning treatment with oral aspirin, 40 mg/d, and parenteral low-molecular-weight heparin sodium, 1000 IU/d, for 1 week. There was no color difference between toes. Discussion Intra-arterial chemotherapy is an endovascular approach that begins with femoral artery catheterization. Complications related to femoral artery catheterization include nonischemic and ischemic events. Although these complications are rare, most patients with them need to undergo surgery again to repair the vascular damage.6 The term blue toe syndrome is defined as the sudden onset of acute pain and cyanosis in 1 or more toes with evidence of a proximal source of emboli in the vascular tree, primarily in the femoral or popliteal arteries.5 In our case, we think there was formation of a thrombus due to intimal injury resulting from needle, guide wire, or catheter manipulation. Arterial spasm due to intimal injury might also contribute to thrombus formation. Eventually, distal thromboembolism occurred in the left toe and caused blue toe syndrome. Our patient was given both oral aspirin and parenteral low-molecular-weight heparin for 1 week. After 1 week, the blue color totally disappeared and the pain and tenderness were gone. To our knowledge, this is the first report to describe a distal peripheral vascular complication secondary to IAC for Rb. Both our patient and the patient described by Gobin et al4 did not need to have further surgery. However, severe limb ischemias, which were treated with bypass grafting, were reported following femoral artery catheterization in children. The risk factors were described as the patient being younger than 3 years, therapeutic intervention, number of catheterizations (≥3), and treatment features of most of the patients with Rb who were scheduled for IAC.6 Although IAC provides dramatic response in patients with Rb, it may cause vascular complications and should be used cautiously. Back to top Article Information Correspondence: Dr Sarici, Department of Ophthalmology, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa Street, Istanbul 34098, Turkey (ahmetsarici@gmail.com). Conflict of Interest Disclosures: None reported. References 1. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol. 2011;129(11):1407-141521670326PubMedGoogle ScholarCrossref 2. Munier FL, Beck-Popovic M, Balmer A, Gaillard MC, Bovey E, Binaghi S. Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina. 2011;31(3):566-57321273941PubMedGoogle ScholarCrossref 3. Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117(8):1623-162920381868PubMedGoogle ScholarCrossref 4. Gobin P, Marr B, Dunkel I, Brodie S, Abramson D. Intra-arterial chemotherapy (chemosurgery) in the ophthalmic artery for the treatment of retinoblastoma in children: 3 year experience. J Neurointerv Surg. 2009;1(1):77-78Google ScholarCrossref 5. Hirschmann JV, Raugi GJ. Blue (or purple) toe syndrome. J Am Acad Dermatol. 2009;60(1):1-2219103358PubMedGoogle ScholarCrossref 6. Lin PH, Dodson TF, Bush RL, et al. Surgical intervention for complications caused by femoral artery catheterization in pediatric patients. J Vasc Surg. 2001;34(6):1071-107811743563PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

Blue Toe Syndrome as a Complication of Intra-arterial Chemotherapy for Retinoblastoma

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Publisher
American Medical Association
Copyright
Copyright © 2013 American Medical Association. All Rights Reserved.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/jamaophthalmol.2013.1458
Publisher site
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Abstract

Intra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has become popular recently. Several studies demonstrated its effectiveness in the treatment of advanced intraocular Rb.1-4 However, it is not free of complications, and severe ocular vascular adverse effects including ophthalmic artery stenosis and retinal arteriolar embolizations were reported.1,2 The only reported systemic vascular complication, femoral artery occlusion, was transient (1 week) and resolved with aspirin treatment.4 Herein, we report another extraocular vascular complication, blue toe syndrome,5 following IAC for Rb with melphalan. Report of a Case A 7-month-old boy was referred for leukokoria in his left eye. Anterior segment examination findings were unremarkable. Funduscopy revealed a 12 × 10 × 6-mm macular retinoblastoma, which was diagnosed as unilateral sporadic group C Rb according to international classification of Rb. After discussion of all possible treatment options with the patient's parents, we decided to apply IAC. Institutional board review approval was obtained. The patient underwent 3 cycles of uneventful IAC with 3 mg of melphalan each time. The IAC was performed in the same manner by the same experienced interventional radiologist. After the parents gave written consent, the IAC catheterization procedures were performed under general anesthesia. We used catheterization techniques as described previously.3 In brief, Doppler ultrasonography was used to detect the femoral artery localization. Systemic anticoagulation with heparin sodium (75 IU/kg) was carried out intravenously. A 4F 45-cm introducer sheath was introduced into the left femoral artery and guided into the ipsilateral internal carotid artery using fluoroscopic guidance. A coaxial flow-guided Prowler 10 microcatheter was advanced toward the trunk of the ophthalmic artery and positioned at its ostium. After fluoroscopic confirmation of accurate positioning of the microcatheter, 3 mg of melphalan diluted in 30 mL of saline was delivered over 30 minutes with a flow-control injector pump. Once the infusion was complete, a final carotid angiogram was obtained to confirm the absence of any ocular or cerebral complications before removing the catheters. Hemostasis was achieved by initial manual compression of the femoral artery for 15 minutes, followed by use of a compression bandage for 1 day. The child was awakened and observed for 4 hours, then discharged the same day with no medication. The day after the third IAC, the patient returned with a blue, painful, tender left toe (Figure 1). Color Doppler ultrasonography findings of the lower limb were unremarkable, distal arteries up to the ankle were patent, and no major arterial occlusion was observed. There were no ocular vascular complications, and the tumor height decreased to 2.5 mm with type 3 regression. After consultations with the pediatric hematology and cardiovascular surgery departments, the patient was diagnosed as having blue toe syndrome and therapy with a parenteral anticoagulant (low-molecular-weight heparin sodium, 1000 IU/d) was initiated with concomitant oral aspirin, 40 mg/d. After 10 days, the blue appearance of the toe had totally disappeared (Figure 2). View LargeDownload Figure 1. Blue toe syndrome. The picture was taken the day after the third cycle of intra-arterial chemotherapy. The left toe was cyanotic and there was tenderness, which was consistent with blue toe syndrome. View LargeDownload Figure 2. Resolution of blue toe syndrome. There was no cyanosis or tenderness 10 days after beginning treatment with oral aspirin, 40 mg/d, and parenteral low-molecular-weight heparin sodium, 1000 IU/d, for 1 week. There was no color difference between toes. Discussion Intra-arterial chemotherapy is an endovascular approach that begins with femoral artery catheterization. Complications related to femoral artery catheterization include nonischemic and ischemic events. Although these complications are rare, most patients with them need to undergo surgery again to repair the vascular damage.6 The term blue toe syndrome is defined as the sudden onset of acute pain and cyanosis in 1 or more toes with evidence of a proximal source of emboli in the vascular tree, primarily in the femoral or popliteal arteries.5 In our case, we think there was formation of a thrombus due to intimal injury resulting from needle, guide wire, or catheter manipulation. Arterial spasm due to intimal injury might also contribute to thrombus formation. Eventually, distal thromboembolism occurred in the left toe and caused blue toe syndrome. Our patient was given both oral aspirin and parenteral low-molecular-weight heparin for 1 week. After 1 week, the blue color totally disappeared and the pain and tenderness were gone. To our knowledge, this is the first report to describe a distal peripheral vascular complication secondary to IAC for Rb. Both our patient and the patient described by Gobin et al4 did not need to have further surgery. However, severe limb ischemias, which were treated with bypass grafting, were reported following femoral artery catheterization in children. The risk factors were described as the patient being younger than 3 years, therapeutic intervention, number of catheterizations (≥3), and treatment features of most of the patients with Rb who were scheduled for IAC.6 Although IAC provides dramatic response in patients with Rb, it may cause vascular complications and should be used cautiously. Back to top Article Information Correspondence: Dr Sarici, Department of Ophthalmology, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa Street, Istanbul 34098, Turkey (ahmetsarici@gmail.com). Conflict of Interest Disclosures: None reported. References 1. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol. 2011;129(11):1407-141521670326PubMedGoogle ScholarCrossref 2. Munier FL, Beck-Popovic M, Balmer A, Gaillard MC, Bovey E, Binaghi S. Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina. 2011;31(3):566-57321273941PubMedGoogle ScholarCrossref 3. Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117(8):1623-162920381868PubMedGoogle ScholarCrossref 4. Gobin P, Marr B, Dunkel I, Brodie S, Abramson D. Intra-arterial chemotherapy (chemosurgery) in the ophthalmic artery for the treatment of retinoblastoma in children: 3 year experience. J Neurointerv Surg. 2009;1(1):77-78Google ScholarCrossref 5. Hirschmann JV, Raugi GJ. Blue (or purple) toe syndrome. J Am Acad Dermatol. 2009;60(1):1-2219103358PubMedGoogle ScholarCrossref 6. Lin PH, Dodson TF, Bush RL, et al. Surgical intervention for complications caused by femoral artery catheterization in pediatric patients. J Vasc Surg. 2001;34(6):1071-107811743563PubMedGoogle ScholarCrossref

Journal

JAMA OphthalmologyAmerican Medical Association

Published: Jun 1, 2013

References

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